[Federal Register Volume 69, Number 226 (Wednesday, November 24, 2004)]
[Rules and Regulations]
[Pages 68611-68688]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-25798]



[[Page 68611]]

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Part IV





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Parts 16, 1270, and 1271



Current Good Tissue Practice for Human Cell, Tissue, and Cellular and 
Tissue-Based Product Establishments; Inspection and Enforcement; Final 
Rule

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / 
Rules and Regulations

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16, 1270, and 1271

[Docket No. 1997N-484P]


Current Good Tissue Practice for Human Cell, Tissue, and Cellular 
and Tissue-Based Product Establishments; Inspection and Enforcement

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

DATES: This rule is effective May 25, 2005.

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:

Table of Contents

I. Introduction
    A. Background
    B. Legal Authority
II. Revisions to the Proposed Rule
    A. Plain Language
    B. HCT/P Definition
    C. Function and Integrity
    D. Core CGTP Requirements
    E. Other Revisions
III. Comments on the Proposed Rule and FDA's Responses
    A. General
    B. Definitions (Sec.  1271.3)
    C. Part 1271, Subpart D--Current Good Tissue Practice
    D. Part 1271, Subpart E--Additional Requirements for Establishments 
Described in Sec.  1271.10
    E. Part 1271, Subpart F--Inspection and Enforcement of 
Establishments Described in Sec.  1271.10
    F. Economic Impacts
IV. Effective Date of 21 CFR Part 1271 and Applicability of 21 CFR Part 
1270
    A. Effective Date for Part 1271
    B. Applicability of Part 1270
V. Analysis of Economic Impacts
    A. Risks Associated with HCT/Ps
    B. Estimated Cost Impact
VI. Environmental Impact
VII. Federalism Assessment
VIII. The Paperwork Reduction Act of 1995
IX. References

I. Introduction

    This rule represents the culmination of FDA's efforts to establish 
a comprehensive new system for regulating HCT/Ps. The regulations now 
being issued require certain HCT/Ps to be manufactured in compliance 
with CGTP. The rule also contains provisions relating to establishment 
inspection and enforcement, as well as certain labeling and reporting 
requirements, which are applicable to those HCT/Ps regulated solely 
under the authority of section 361 of the PHS Act (42 U.S.C. 264) and 
the regulations in part 1271 (21 CFR part 1271), and not as drugs, 
devices, and/or biological products under the Federal Food, Drug, and 
Cosmetic Act (the act).
    At this time we (FDA) are not responding to comments submitted on 
subparts D and E of the proposed rule relating to reproductive HCT/Ps. 
With two minor exceptions, the regulations in subparts D and E are not 
being finalized with respect to reproductive HCT/Ps described in Sec.  
1271.10 and regulated solely under section 361 of the PHS Act and the 
regulations in part 1271. The docket will remain open, and we ask that 
interested parties submit comments on communicable disease risks 
associated with reproductive HCT/Ps and appropriate regulation to 
minimize those risks (other than that stipulated in part 1271 subparts 
A, B, C, and F, and Sec. Sec.  1271.150(c) and 1271.155 in subpart D).

A. Background

    In February 1997, FDA proposed a new, comprehensive approach to the 
regulation of human cellular and tissue-based products (now called 
human cells, tissues, and cellular and tissue-based products or HCT/
Ps). The agency announced its plans in two documents entitled 
``Reinventing the Regulation of Human Tissue'' and ``A Proposed 
Approach to the Regulation of Cellular and Tissue-based Products'' 
(hereinafter ``proposed approach document''). 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 final rules and one 
interim final rule to implement aspects of the proposed approach. On 
January 19, 2001, we issued regulations to create a new, unified system 
for registering HCT/P establishments and for listing their HCT/Ps 
(registration final rule, 66 FR 5447). Part of the definition of 
``human cells, tissues, or cellular or tissue-based products'' became 
effective on January 21, 2004. On January 27, 2004 (69 FR 3823), we 
issued an interim final rule to except human dura mater and human heart 
valve allografts from the scope of that definition until all of the 
tissue rules became final. On May 25, 2004, we issued regulations 
requiring most cell and tissue donors to be tested and screened for 
relevant communicable diseases (donor-eligibility final rule, 69 FR 
29786).
    This rulemaking was initiated with a proposed rule on January 8, 
2001 (Current Good Tissue Practice for Manufacturers of Human Cellular 
and Tissue-Based Products; Inspection and Enforcement (66 FR 1508) 
(hereinafter ``proposed rule'')). 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. The proposed rule would 
require establishments that manufacture HCT/Ps to 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 and other regulations would be contained in part 
1271, along with provisions relating to establishment registration and 
donor eligibility that have previously been issued. We are now making 
those proposed regulations final for HCT/Ps collected on or after the 
effective date of this rule. We are also amending part 1270 (21 CFR 
part 1270), which now applies to certain HCT/Ps collected before the 
effective date of this rule, by modifying the definition of human 
tissue intended for transplantation (21 CFR 1270.3(j)) to limit its 
applicability to tissue collected before the effective date. We are not 
revoking part 1270 as previously proposed (66 FR 1508 at

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1509). See section IV.B. of this document for further discussion.
    Part 1271 contains six subparts. Subpart A of part 1271 sets forth 
scope and purpose as well as definitions. Subpart B of part 1271 
contains registration procedures. Subpart C of part 1271 sets forth 
provisions for the screening and testing of donors to determine their 
eligibility. This rule puts in place three additional subparts. Subpart 
D of part 1271 contains the provisions on CGTP. Subpart E of part 1271 
contains certain labeling and reporting requirements, and subpart F of 
part 1271 contains the inspection and enforcement provisions. The 
subparts apply as follows:
     Subparts A through D apply to all HCT/Ps, i.e., to those 
HCT/Ps described in Sec.  1271.10 and regulated solely under section 
361 of the PHS Act, and to those regulated as drugs, devices, and/or 
biological products; and
     Subparts E and F, which pertain to labeling, reporting, 
inspection, and enforcement, apply only to those HCT/Ps described in 
Sec.  1271.10 and regulated solely under section 361 of the PHS Act.
However, as previously noted in section I of this document, with the 
exception of two provisions (Sec. Sec.  1271.150(c) and 1271.155) 
subparts D and E are not being implemented for reproductive HCT/Ps 
described in Sec.  1271.10 and regulated solely under section 361 of 
the PHS Act.
    The publication of this final rule completes the set of regulations 
that implements FDA's proposed approach to regulating HCT/Ps. We 
recognize that over the course of this rulemaking, inadvertent errors 
or inconsistencies may have been introduced into the regulations. 
Accordingly, we anticipate that we may need to issue technical 
corrections in the future.

B. Legal Authority

    FDA is issuing these new regulations under the authority of section 
361 of the PHS Act. Under that section, by delegation from the Surgeon 
General and the Secretary of Health and Human Services, 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. It is important to recognize 
that HCT/P manufacturing inevitably has interstate effects. HCT/Ps 
recovered in one State may be sent to another for processing, then 
shipped for use throughout the United States, or beyond. FDA has been 
involved in many recalls where HCT/Ps processed in a single 
establishment have been distributed in many States. In any event, 
intrastate transactions affecting interstate communicable disease 
transmission may also be regulated under section 361 of the PHS Act. 
(See Louisiana v. Mathews, 427 F. Supp. 174, 176 (E.D. La. 1977).)
    Section 361 of the PHS Act authorizes FDA to issue regulations 
necessary to prevent the introduction, transmission, or spread of 
communicable diseases. Certain diseases, such as those caused by the 
human immunodeficiency virus (HIV) and the hepatitis B and C viruses 
(HBV and HCV respectively), may be transmitted through the 
implantation, transplantation, infusion, or transfer of HCT/Ps derived 
from infected donors. The agency required, in another rule, that most 
cell and tissue donors be screened and tested for these and other 
relevant communicable diseases (donor-eligibility final rule, 69 FR 
29786 at 29830). However, donor screening and testing, although 
crucial, are not sufficient to prevent the transmission of disease by 
HCT/Ps. Rather, each step in the manufacturing process needs to be 
appropriately controlled. Errors in labeling, mixups of testing 
records, failure to adequately clean work areas, and faulty packaging 
are examples of improper practices that could produce a product capable 
of transmitting disease to its recipient. Similarly, as noted in the 
proposed approach document, improper handling of an HCT/P can lead to 
bacterial or other pathogenic contamination of the HCT/P, or to cross-
contamination between HCT/Ps, which in turn can endanger recipients. 
The agency has determined that the procedural provisions of this rule 
are necessary to ensure that the important protections created by these 
regulations are actually effected and are not simply empty promises. 
Only manufacturing conducted in accordance with established procedures 
can assure that HCT/Ps meet the standards in these rules. When 
processes are made up as the manufacturer goes along, mistakes 
inevitably are made. Moreover, review of procedures can be critical to 
determining the cause of a disease transmission. Without that analysis, 
it would be impossible to prevent a future occurrence, with possibly 
fatal consequences.
    The record requirements of this rule are similarly necessary. A 
single donor may be the source of a large number of HCT/Ps. It may be 
discovered, long after the donation and transplantations have been 
completed, that, due to an error in processing, the donor tissue was 
infected and capable of spreading communicable disease. Although it 
might be too late to prevent infections in the recipients, it would not 
be too late for the recipient to obtain treatment and take steps to 
avoid infecting others, such as close family members. Unless adequate 
records were maintained, and maintained for the period of time 
throughout which infections may be identified, it would be impossible 
to identify the recipients potentially infected by the donor's HCT/Ps. 
This would be a critical breakdown in the prevention of disease 
transmission.
    Moreover, a single processing error, such as an improper practice 
that permitted bacterial contamination of all tissue processed at a 
location during a limited period of time, may also have wide ranging 
effects. Without reporting and study of adverse events involving the 
transmission of communicable disease, or involving the release of HCT/
Ps presenting an increased risk of such transmission, common causes of 
seemingly isolated incidents would never come to light. Affected HCT/Ps 
would continue to place patients at risk of communicable disease. 
Accordingly, FDA has also determined that HCT/P tracking, maintenance 
and retention of records, and reporting of adverse reactions and HCT/P 
deviations are necessary to prevent the transmission of communicable 
disease through HCT/Ps.
    The CGTP regulations govern the methods used in, and the facilities 
and controls used for, the manufacture of HCT/Ps. CGTP requirements are 
a fundamental component of FDA's risk-based approach to regulating HCT/
Ps. HCT/Ps regulated solely under section 361 of the PHS Act and the 
regulations in part 1271 are not regulated under the act or section 351 
of the PHS Act (42 U.S.C. 262). By requiring that HCT/Ps meeting the 
criteria listed in Sec.  1271.10 (361 HCT/Ps) be manufactured in 
compliance with CGTP, in combination with the other requirements in 
part 1271, the agency can ensure that 361 HCT/Ps are subject to 
sufficient regulatory controls to protect the public health.
    HCT/Ps regulated as drugs, devices, and/or biological products, and 
not as 361 HCT/Ps, must be manufactured in accordance with CGTP, in 
addition to existing requirements. The CGTP regulations supplement the 
current good manufacturing practice (CGMP) and quality system (QS) 
regulations applicable to drugs, devices, and biological products in 
parts 210, 211, and 820 (21 CFR parts 210, 211, and 820). Thus, in 
keeping with the plan outlined in the proposed approach document, those 
HCT/Ps regulated as drugs, devices, and/or biological products are 
subject to CGMP regulations as well as to CGTP regulations. In the 
donor-eligibility final

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rule, the agency amended the existing CGMP regulations for drugs and 
the QS requirements for devices to reference the testing and screening 
provisions of part 1271, subpart C, as well as the CGTP procedures of 
part 1271, subpart D.
    FDA is also relying on its authority under section 361 of the PHS 
Act for several reporting, labeling, inspection, and enforcement 
provisions. Because products regulated as drugs, devices, or biological 
products are already subject to similar requirements, these provisions 
in subparts E and F would apply only to 361 HCT/Ps. Subpart E of part 
1271 contains regulations on reporting and labeling pertaining to 361 
HCT/Ps and is discussed in section III.D. of this document. Subpart F 
of part 1271 contains inspection and enforcement provisions also 
applicable only to 361 HCT/Ps; the relevant discussion appears in 
section III.E of this document.
    In addition, under section 368(a) of the PHS Act (42 U.S.C. 271), 
any person who violates a regulation prescribed under section 361 of 
the PHS Act may be punished by imprisonment for up to 1 year. 
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. For organizational defendants, 
fines range up to $200,000 and $500,000. Individuals and organizations 
also face possible alternative fines based on the amount of gain or 
loss. (18 U.S.C. 3559 and 3571(b) to (d)). Federal District Courts also 
have jurisdiction to enjoin individuals and organizations from 
violating regulations implementing section 361 of the PHS Act. (See 
Califano v. Yamasaki, 442 U.S. 682, 704-05 (1979); United States v. 
Beatrice Foods Co., 493 U.S. 961 (1975).)

II. Revisions to the Proposed Rule

A. Plain Language

    On June 1, 1998, the Presidential Memorandum on Plain Language in 
Government Writing was issued in the Federal Register (63 FR 31885). 
The purpose of the plain language initiative is to create government 
documents that are easier to understand.
    In response to this initiative, we have written the CGTP 
regulations in plain language. We have:
     Reorganized some regulatory sections for greater clarity, 
and
     Followed other plain-language conventions, such as using 
``must'' instead of ``shall.''
    The resulting codified language is easier to read and understand 
than the proposed regulation. These editorial changes are for clarity 
only and do not change the substance of the requirements.

B. HCT/P Definition

    In the registration final rule, we discussed our decision to 
replace the term ``human cellular and tissue-based products'' with 
``human cells, tissues, and cellular and tissue-based products'' 
(abbreviated ``HCT/Ps'') (66 FR 5447 at 5455). For consistency, we have 
made the same change in this final rule.
    Also in the registration final rule, we put into place a two-part 
definition of HCT/P to stagger the effective dates of the registration 
and listing regulations for different types of HCT/Ps. We stated in the 
registration final rule that, when all the regulations that make up 
part 1271 are issued, we would revoke Sec.  1271.3(d)(1) and renumber 
paragraph (d)(2) as a conforming amendment. At that time the new 
regulatory framework contained in part 1271 would be instituted as a 
whole (66 FR 5447 at 5450). We recognized that unanticipated delays in 
completing the rulemaking for the remainder of part 1271 could occur, 
and we noted that, should the rulemaking proceedings be delayed past 
the anticipated 2-year timeframe, we would consider whether to maintain 
the 2-year effective date for the HCT/Ps described in Sec.  
1271.3(d)(2) or whether to extend that date (66 FR 5447 at 5449). Since 
the rulemaking proceedings were delayed past the original 2-year 
effective date of January 21, 2003, we delayed the effective date of 
Sec.  1271.3(d)(2) until January 21, 2004(68 FR 2690, January 21, 
2003), on which date Sec.  1271.3(d)(2) became effective.
    On January 27, 2004, we issued an interim final rule excepting 
human dura mater and human heart valve allografts from the definition 
of HCT/P in Sec.  1271.3(d) (69 FR 3823). We stated that, when the 
comprehensive framework is in place, FDA intends that human dura mater 
and human heart valves will be subject to it, and that FDA intends to 
revoke the interim rule at that time (69 FR 3823 and 3824). With the 
effective date of this final rule, we are revoking the interim rule and 
revising the language in Sec.  1271.3(d).

C. Function and Integrity

    The proposed rule contained provisions addressing our concerns 
about the spread of communicable disease through the use of products 
whose function or integrity have been impaired (66 FR 1508 at 1510). As 
discussed in Comment 9, we have removed from the regulations all 
references to function or integrity.

D. Core CGTP Requirements

    In drafting this rule, we have re-evaluated each requirement of the 
proposed rule to ensure that it either directly prevents the 
introduction, transmission, or spread of communicable diseases (e.g., 
the requirement to store HCT/Ps at an appropriate temperature), or that 
it supports such a requirement (e.g., the requirement to periodically 
review recorded temperatures to ensure that the temperatures have been 
within acceptable limits). We have removed requirements where the 
connection to the prevention of the introduction, transmission, or 
spread of communicable diseases may be more attenuated.
    As a result of this analysis, these final regulations are organized 
differently from the proposed regulations and contain fewer 
requirements. ``Core CGTP requirements'' are listed in Sec.  
1271.150(b); these requirements are directly related to preventing the 
introduction, transmission, or spread of communicable diseases. Certain 
requirements in subparts D and E are now limited in their applicability 
to these core CGTP requirements (e.g., the required records management 
system in Sec.  1271.270(b) relates solely to core CGTP requirements). 
We have also reorganized sections within these subparts so that the 
core CGTP requirements appear first within a section, with supporting 
requirements following (e.g., Sec.  1271.190 on facilities has been 
reorganized so that requirements for procedures and records, which are 
not core requirements, occur in paragraph (d)).
    Due to the more limited nature of these final regulations, we have 
removed certain proposed requirements, despite their potential 
importance to an establishment's operations. We stress that their 
absence from these final regulations should not be seen as a 
determination that they are without value. Rather, at this time, we are 
issuing a more limited set of requirements than proposed. These 
requirements represent minimum expectations, but an establishment may 
decide to do more than this minimum.

E. Other Revisions

    We are amending, rather than revoking, the regulations in part 
1270. See section IV of this document for further discussion.
    We have made changes from the proposal throughout the regulations 
to be more clear; to link the regulations more closely to preventing 
the transmission of communicable diseases,

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as discussed in section II.D of this document; and in response to 
comments discussed in section III of this document. These revisions 
include:
     Adding Sec.  1271.145, which requires establishments to 
manufacture HCT/Ps in a way that prevents the introduction, 
transmission, or spread of communicable diseases;
     Revising the definitions for ``adverse reaction,'' 
``available for distribution,'' ``complaint,'' ``distribution,'' 
``product deviation,'' ``processing,'' ``quality audit,'' and ``quality 
program'';
     Adding Sec.  1271.215, which requires establishments to 
recover HCT/Ps in a way that does not cause contamination or cross-
contamination during recovery, or otherwise increase the risk of the 
introduction, transmission, or spread of communicable disease through 
the use of the HCT/P;
     Deleting proposed Sec.  1271.220(b) Processing material 
and the definition of that term in proposed Sec.  1271.3(hh);
     Adding paragraph (b) to Sec.  1271.265;
     Adding language in Sec.  1271.420 to facilitate rapid 
admissibility decisions for imported HCT/Ps that meet requirements, and 
to except cells and tissues from a sexually intimate partner, and 
peripheral blood stem/progenitor cells from the requirement for an 
admissibility decision; and
     Adding pertinent references to ``preventing the 
introduction, transmission, or spread of communicable diseases,'' where 
it is useful to explain the purposes or scope of a requirement.
    We have also made technical amendments to Sec. Sec.  1271.10(a)(3) 
and 1271.22(b) and (c). Section 1271.10(a)(3) is revised by adding 
``water'' and ``crystalloids'' to the exceptions because, as with 
sterilizing, preserving and storage agents, these substances generally 
do not raise safety concerns. Water or crystalloids (e.g., saline 
solution, Ringer's lactate solution, or 5% dextrose in water) are 
typically added to lyophilized HCT/Ps by the user to reconstitute the 
HCT/P. We have also revised Sec.  1271.10(a)(3) by replacing ``the 
combination of the cell or tissue component with a drug or device'' 
with ``the combination of cells or tissues with an article.'' We found 
that establishments were confused by the reference to drugs and devices 
in this context, and did not understand how to evaluate the drug or 
device function of the additive in the context of the product. By 
substituting the term ``article,'' we eliminate this ambiguity, we 
focus more directly on the risks presented by such additives, and we 
therefore make this provision more consistent with the risk-based 
approach supporting the balance of the rule.
    Section 1271.22 is revised by updating the mailcodes in paragraphs 
(b)(i) and (c)(i), by removing paragraph (b)(iv) since the Fax 
Information System is no longer in service, and by providing 
information for the electronic submission of Form FDA 3356.
    Section 1271.45(a) is amended by adding that other CGTP 
requirements are set out in subpart D of part 1271. This statement 
clarifies that subparts C and D together constitute CGTP requirements.

III. Comments on the Proposed Rule and FDA's Responses

    We received 47 comments on the proposed rule. Several comments 
raised issues that were addressed in the registration final rule (e.g., 
determining the regulatory categorization of HCT/Ps). Responses to 
these comments may be found in the registration final rule at Comment 7 
(66 FR 5447 at 5451), Comment 8 (66 FR 5447 at 5452), and Comment 30 
(66 FR 5447 at 5459). Other comments on this rule raised issues 
relating to the donor-eligibility rule; we addressed these comments in 
the donor-eligibility final rule at Comment 25 (69 FR 29786 at 29796), 
Comment 32 (69 FR 29786 at 29799), Comment 48 (69 FR 29786 at 29806), 
Comment 59 (69 FR 29786 at 29809), and in section III.D.3 (69 FR 29786 
at 29797).

A. General

1. General Comments
    (Comment 1) Numerous comments supported the proposed rule. These 
comments called the rule well written and organized, easy to 
understand, comprehensive, and reasonable. One comment appreciated the 
philosophy we adopted in defining objectives rather than specific 
methodologies. Another comment stated that the formulation of the 
proposed rule and the development of the entire regulatory framework 
were an enormous undertaking of great importance and timeliness.
    (Response) We appreciate these supportive comments. We agree with 
those comments recognizing both the importance of this rule and the 
fact that it represents the culmination of our efforts to develop a 
comprehensive new system of regulation for HCT/Ps.
    We also note that most of the comments we received on this rule 
were helpful and well organized. For example, many comments were 
arranged by section number of the proposed regulation and contained 
specific suggestions on how to revise each section, often including new 
language. We appreciate the care with which these comments were 
prepared.
    (Comment 2) Some comments stated general opposition to the proposed 
rule. One comment stated that tissue banks are self-regulating and that 
the rules are unnecessary. This comment further asserted that smaller 
tissue banks have not been informed and have been ignored, while we 
worked only with large organizations.
    (Response) We recognize that some comments oppose the proposed rule 
as a general matter and do not consider the new regulations necessary 
or beneficial. We disagree with those comments. We also disagree with 
the statement that, in developing these rules, we have consulted only 
large professional organizations and have ignored the concerns of small 
banks or failed to inform them of our rulemaking. Even before this 
rulemaking began, we took pains to make our intentions clear to all 
interested parties by issuing notices and rulemakings in the Federal 
Register, which is accessible to both large and small organizations. We 
have held several public meetings on issues affecting the rulemaking 
that were open to all interested parties. We also prepared an analysis 
of the impact of the rulemaking on small entities in the proposed rule 
(66 FR 1508 at 1545). Moreover, this final rule incorporates many 
changes made in response to comments from a range of interested 
parties, including many small entities. We also will be issuing a small 
entity compliance guide, which will assist small entities in complying 
with part 1271.
    (Comment 3) Several comments compared the proposed rule to industry 
standards. Three comments complimented us for the proposed rule's 
consistency with current good industry practice. In contrast, one 
comment argued that the proposed rule offered little additional benefit 
over industry standards currently in place. One comment asserted that 
the rule is reasonable to the extent it mirrors good manufacturing 
practice (GMP)/QS regulations for in vitro diagnostics and current 
bloodborne pathogen guidelines, but that many provisions are 
duplicative of the regulations and guidelines in place and create 
another layer of unnecessary recordkeeping. This comment stated that 
the rule goes beyond its original intent and places an undue regulatory 
burden, which would bring a halt to innovative activities.
    (Response) The proposed requirements were based on current good 
industry practice and were intended to address what we consider to

[[Page 68616]]

be important minimum criteria for the manufacture of HCT/Ps in a manner 
that effectively reduces the risk of communicable disease transmission. 
In developing the proposed CGTP regulations, we reviewed several sets 
of industry standards (66 FR 1508 at 1511). These comments indicate 
that we were successful in reflecting current good practices. We note 
that, to the extent that industry standards are consistent with and at 
least as stringent as CGTP requirements and are appropriate for the 
operations conducted, an establishment may adopt industry's standard 
procedures as a way of complying with these regulations (Sec.  
1271.180(d)). However, we decline to mandate compliance with the 
standards of a particular professional organization. Industry 
associations are welcome to submit their standards to the agency for 
potential adoption as guidance subject to public comment. (See 21 CFR 
10.115.)
    We disagree that these regulations require unnecessary 
recordkeeping or create an undue regulatory burden. In this final rule, 
we have made numerous changes to the regulatory provisions in response 
to comments; many of these changes will have the effect of reducing the 
regulatory burden from that originally proposed while still addressing 
communicable disease risks.
    With respect to the comment on duplicative requirements applicable 
to HCT/Ps regulated as devices, drugs, and/or biological products, we 
note that Sec.  1271.150(d) states that CGTP and CGMP regulations in 
parts 210 and 211 and the QS regulations in part 820 supplement each 
other unless the regulations explicitly provide otherwise. In the event 
of a conflict between applicable requirements, the regulations more 
specifically applicable to the product will supersede the more general 
requirements. FDA believes that, in the event of such a conflict, the 
more specifically applicable regulation would be found in part 1271. It 
is unnecessary to maintain two sets of records to indicate compliance 
with both CGTP and CGMP or QS requirements; a single set of records is 
adequate.
    (Comment 4) Several comments requested that these regulations be 
phased in over time. Two comments requested a grace period of 1 to 2 
years; one comment requested a 2-year implementation period; and 
another comment requested an extension of the compliance deadline to 1 
year after publication.
    (Response) We understand the request for a long implementation 
period. However, recent reports of bacterial infections in patients who 
received HCT/Ps support the implementation of the CGTP requirements as 
soon as possible. (Ref. 1) The effective date of the CGTP final rule 
will coincide with the effective date of the previously issued donor 
eligibility requirements. We believe that this will provide an adequate 
amount of time to comply with the requirements in part 1271.
    (Comment 5) Two comments opposed the retrospective application of 
any regulation or guidance to tissue recovered before its issuance, 
because tissue may have a shelf life of up to 5 years. The comments 
suggested that the final rule should apply to HCT/Ps recovered after 
the effective date, and that for tissues recovered before the effective 
date of the final rule, the regulations in part 1270 would continue to 
apply.
    (Response) We agree that the final rule will apply to HCT/Ps 
recovered on or after the rule's effective date. Cells and tissue 
recovered before that date are subject to the regulations in effect at 
the time of recovery. The regulations in part 1270 are being amended in 
this rulemaking so that those regulations will continue to apply only 
to human tissue for transplantation recovered before the effective date 
of this rule. See section IV.B of this document for further discussion.
    (Comment 6) One comment asserted that the regulations should cover 
the procurement and storage of human organs for transplant, 
reproductive cells (sperm and ova), and the storage of human milk.
    (Response) Part 1271 does not apply to human organs or to human 
milk. Subparts D and E are not being implemented with respect to 
reproductive HCT/Ps, except for Sec. Sec.  1271.150(c) and 1271.155.
    (Comment 7) Several comments objected to the terms ``manufacture'' 
and ``product'' as inappropriate for use with respect to donated human 
tissue. One comment asserted that corneas are recovered and evaluated, 
not manufactured. Some comments suggested substitute terminology: e.g., 
``donor program'' or ``tissue service organization'' instead of 
``manufacturer''; ``handle'' instead of ``manufacture''; and ``human 
cellular and tissue-based material'' instead of ``product.'' One 
comment asserted that, because the terminology used in the rule does 
not correlate with eye bank practices, it was difficult to determine 
which sections apply to eye banking; this comment cited the additional 
terms ``process,'' ``processing,'' ``processing material,'' 
``validation,'' and ``verification.''
    (Response) In the registration final rule, we changed the term 
``human cellular or tissue-based product'' to ``human cells, tissues, 
and cellular and tissue-based products,'' or ``HCT/Ps.'' We made this 
change in response to comments that opposed calling donated tissue a 
``product.'' In that final rule, we noted that we needed a term broad 
enough to cover both cells and tissues, and one that would include 
within its scope such diverse articles as unprocessed tissue, highly 
processed cells, and tissues that are combined with certain drugs or 
devices (66 FR 5447 at 5455). We believe the term ``HCT/P'' addresses 
the concerns expressed in the comments, and we will use that term in 
these regulations.
    In the registration final rule, we also considered substituting a 
different term for ``manufacture,'' in response to similar comments, 
but were unable to find a satisfactory replacement. Among other terms, 
we considered ``handling,'' but rejected it as too limited in scope. 
Thus, we have continued to use the word ``manufacture'' as an umbrella 
term to capture the many different actions that HCT/P establishments 
might take in preparing HCT/Ps for use (66 FR 5447 at 5455).
    Many different types of establishments are involved in the 
recovery, screening, testing, processing, storage, labeling, packaging, 
and distribution related to HCT/Ps. Some of these may accurately be 
called tissue service organizations, donor programs, or tissue 
procurement organizations, and may certainly continue to call 
themselves by these names. However, these terms are too limited to 
cover those establishments that perform other manufacturing functions, 
and for that reason we decline to adopt any of these suggested terms in 
this regulation. We note that, although these rules at times refer to 
``manufacturers,'' the more frequently used term is ``establishment.''
    With respect to the comment on the applicability of these 
regulations to eye banks, we discuss the applicability of specific 
sections throughout this final rule. We note that each establishment is 
required to comply only with those requirements that apply to the 
activities in which it engages. We are working, with input from 
industry and others, to develop guidances specific to different types 
of HCT/Ps; this effort is intended to help establishments comply with 
these CGTP requirements to control the risk of communicable disease 
transmission.
    (Comment 8) Comments from eye banking organizations stated that eye 
and cornea banking differ from other tissue banking.

[[Page 68617]]

    (Response) We acknowledge that, in some ways, eye banking differs 
from other tissue banking. However, since 1993, ocular tissue has been 
regulated under the regulatory model for all human tissues for 
transplantation. Eye banks are similar to tissue banks in that they 
recover, process (although minimally), store, label, package, or 
distribute human tissue, screen and test the tissue donor, report 
adverse reactions, and track tissue. We have intentionally crafted 
broad CGTP regulations for flexibility with the expectation that each 
bank will specify its own operating procedures. In addition, we have 
stated that an establishment need only comply with those requirements 
that are applicable to the operations in which it engages.
2. Function and Integrity
    The proposed CGTP requirements were intended, in part, to prevent 
the introduction, transmission, or spread of communicable disease by 
helping to ensure that the function and integrity of HCT/Ps are not 
impaired through improper manufacturing (proposed Sec.  1271.150(a); 
see 66 FR 1508 at 1510). Many of the provisions of the proposed rule 
contained requirements intended to help ensure HCT/P function and 
integrity. For example, proposed Sec.  1271.260 would require an 
establishment to control its storage areas to prevent conditions that 
may adversely affect function or integrity.
    (Comment 9) Approximately nine comments objected to the proposed 
rule's provisions on function and integrity. Some of these comments 
criticized our justification for these provisions as weak or 
theoretical; these comments questioned whether the impairment of an 
HCT/P's function and integrity actually increases the risk of disease 
transmission. Other comments argued that section 361 of the PHS Act 
cannot be interpreted to cover an HCT/P's function and integrity. 
Several comments requested that the phrase be defined or deleted.
    Several comments expressed concern that the provisions on function 
and integrity could be interpreted to mean that an establishment assess 
each HCT/P's function and integrity. These comments agreed generally 
with the concept of ensuring function and integrity, which they 
described as ensuring that an HCT/P is ``fit for use,'' but asked the 
agency to clarify the relationship between the concept and a risk-based 
system.
    Most comments on the general issue of function and integrity also 
objected to specific sections of the proposed rule where that term 
appears. These comments requested the deletion of, or a substitution 
for, the phrase ``function and integrity,'' as well as related terms.
    (Response) To increase clarity, and because of the confusion 
expressed by comments about the term ``function and integrity,'' we 
have removed from the regulations all references to function or 
integrity. For the same reason, we have also removed references to the 
related terms, ``deterioration'' and ``adverse effect.''
    To avoid repetition throughout this document, comment summaries do 
not contain references to function and integrity (or related terms), 
where we received comments on that issue. Moreover, references to 
function and integrity, deterioration, and adverse effect, have been 
removed from summaries of the provisions proposed in the proposed rule. 
References to function and integrity have been removed from discussions 
of the following proposed provisions: Sec. Sec.  1271.3(bb) and (kk), 
1271.160, 1271.200, 1271.210, 1271.220, 1271.260, 1271.265, 1271.350, 
and 1271.420.

B. Definitions (Sec.  1271.3)

    We have grouped all definitions pertinent to part 1271 in a single 
definitions section (Sec.  1271.3), among the general provisions of 
subpart A. The proposed rule contained proposed definitions from Sec.  
1271.3(ff) through (tt); these have been renumbered from Sec.  
1271.3(y) through (ll). We have also reordered the definitions to 
maintain some alphabetical order, and they are discussed according to 
their new order.
    We have revised Sec.  1271.3(d) by deleting paragraph (d)(1), as it 
is no longer applicable with the effective date of this rulemaking. We 
have added the terms ``repair'' and ``reconstruction'' to the 
definition of ``homologous use'' at Sec.  1271.3(c) (the registration 
final rule, 66 FR 5447 at 5467), to provide a more complete and 
accurate description of the definition.
1. Adverse Reaction (Sec.  1271.3(y))
    The proposed rule would define ``adverse reaction'' as a noxious 
and unintended response to any HCT/P 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) (66 FR 1508 at 1520). 
Adverse reaction reporting requirements are set out in proposed Sec.  
1271.350(a).
    (Comment 10) Several comments argued that the proposed definition 
of ``adverse reaction'' is too broad. One comment asserted that a 
transplant recipient could experience a reaction to a substance in a 
tissue even though the manufacturer followed CGTP requirements. One 
comment suggested changing ``reasonable possibility'' to ``reasonable 
probability.''
    (Response) The definition of ``adverse reaction'' is intended to 
capture those situations that may indicate a problem with an HCT/P and 
that a manufacturer should therefore investigate. A noxious and 
unintended response to a substance in an HCT/P would meet the 
definition of ``adverse reaction,'' and an establishment should 
evaluate the situation.
    The receipt of adverse reaction reports enables us to evaluate 
potential relationships between reports. For example, if several 
separate establishments reported that a recipient of tissue that the 
establishments made available for distribution developed a wound 
infection with Clostridium sp., FDA might determine that a single 
establishment recovered or processed all of those tissues. An FDA 
investigation would be initiated.
    It is important to note that not all adverse reactions are required 
to be investigated and reported. Section 1271.350(a) sets out those 
situations in which an establishment must make an adverse reaction 
report to us. An investigation is required when an adverse reaction 
involves a communicable disease. A report is required when such an 
adverse reaction is fatal or life-threatening; results in permanent 
impairment or damage; or necessitates medical or surgical intervention. 
The criteria set out in Sec.  1271.350(a) limit the scope of the 
adverse reaction reporting requirement. As discussed in the preamble to 
the proposed rule (66 FR 1508 at 1520), this approach, and the 
definition of adverse reaction, are consistent with other rules we are 
developing and with international standards (See, e.g., ``International 
Conference on Harmonisation; Guideline on Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting; 
Availability'' (ICH guideline), 60 FR 11284, March 1, 1995).
    We decline to replace the word ``possibility'' with the suggested 
term, ``probability.'' We interpret ``reasonable possibility'' to mean 
that there is a possible causal relationship between an adverse 
experience and an HCT/P; ``there are facts (evidence) or arguments to 
suggest a causal relationship.'' (ICH guidance, 60 FR 11284 at 11286).
    (Comment 11) One comment questioned the phrase ``the relationship 
cannot be ruled out.'' This comment noted that there may be multiple 
possible causes of a patient's problems,

[[Page 68618]]

and that in some instances it may be unlikely that the HCT/P is 
responsible.
    (Response) We have removed the phrase ``the relationship cannot be 
ruled out'' from the definition of ``adverse reaction.'' On further 
examination, we believe it is not helpful in explaining what is meant 
by ``reasonable possibility.'' We recognize that there may be 
situations in which there are multiple possible causes of a patient's 
problem. Nevertheless, if one of the reasonable possibilities is that 
the HCT/P caused the problem, then this would meet the definition of 
``adverse reaction.'' This would include situations in which the 
relationship between the response and the HCT/P is ``unlikely'' but 
nevertheless possible.
2. Available for Distribution (Sec.  1271.3(z))
    The proposed regulations in Sec.  1271.3(ff) would define 
``available for distribution'' to mean that an HCT/P has been 
determined to meet all release specifications and to be suitable for 
distribution.
    (Comment 12) One comment suggested this definition should be 
harmonized with the final rule on biologic product deviations (65 FR 
66621 at 66634, November 7, 2000; 21 CFR 600.14) to clarify that 
reporting product deviations is only necessary after an HCT/P has left 
control of the establishment (i.e., has been distributed).
    (Response) We agree that, under Sec.  1271.350(b), you are required 
to report an HCT/P deviation only when the HCT/P has been distributed. 
However, we disagree that there is any need to modify the definition of 
``available for distribution'' as requested by the comment. The phrase 
``available for distribution'' does not appear in Sec.  1271.350(b). We 
have, however, removed the words ``and to be suitable for 
distribution'' from the definition of ``available for distribution.'' 
As defined in the final rule, an HCT/P is ``available for 
distribution'' if it has been determined to meet all release criteria.
    We discuss the definition of ``distribution'' in Comment 16.
3. Complaint (Sec.  1271.3(aa))
    Proposed Sec.  1271.3(ii) would define ``complaint'' as any 
written, oral, or electronic communication that alleges that an HCT/P 
has transmitted or may have transmitted a communicable disease; or any 
other problem with an HCT/P that could result from the failure to 
comply with CGTP (66 FR 1508 at 1520).
    (Comment 13) One comment stated that the definition is vague and 
would leave eye banks open to baseless accusations by recipients, 
family members, or physicians for graft failure that may have been due 
to other causes. According to this comment, eye banks should be given 
an opportunity to filter out unfounded complaints.
    (Response) We have revised the definition to specify that 
information must relate to the potential for transmission of 
communicable disease, such as the failure to comply with current good 
tissue practice (which would include the donor eligibility 
regulations). However, we note that a complaint may come from any 
source and may be a written, oral, or electronic communication. Section 
1271.320 requires each establishment to have procedures in place to 
evaluate complaints that relate to core CGTP requirements and to 
determine whether investigation is necessary.
    (Comment 14) Several comments noted their belief that the proposed 
requirements on complaints would apply only to HCT/Ps that have been 
released to distribution.
    (Response) We agree with these comments and revised the definition 
to apply to distributed HCT/Ps only.
    (Comment 15) Two comments requested the deletion of proposed Sec.  
1271.3(ii)(3), which covered any other problem with an HCT/P that could 
result from the failure to comply with CGTP. Two other comments 
suggested that we revise proposed Sec.  1271.3(ii)(3) to refer to 
deficiencies related to the identity, quality, durability, reliability, 
safety, or performance of a product after it is released for 
distribution. A third comment recommended that paragraph (ii)(3) be 
deleted or clarified to indicate its application to tissues released to 
distribution.
    (Response) We decline to delete proposed Sec.  1271.3(ii)(3), which 
has been renumbered as Sec.  1271.3(aa)(2). As previously noted, we 
intend the requirements with respect to complaints to apply to HCT/Ps 
that have been distributed. It is necessary for all establishments to 
have in place a system to handle communications about problems with its 
distributed HCT/Ps. Some problems may be traced to a failure to comply 
with CGTP, which could lead to additional problems that increase the 
risk of communicable disease transmission if not corrected. Deleting 
proposed Sec.  1271.3(ii)(3) would unduly narrow the scope of the 
definition, allowing establishments to ignore important communications 
about their products. (However, we note that, as discussed in Comment 
13, we have specified that information under this paragraph must relate 
to the potential for transmission of communicable disease.)
4. Distribution (Sec.  1271.3(bb))
    We proposed to define ``distribution'' in Sec.  1271.3(jj) as any 
conveyance or shipment of HCT/Ps (including importation and 
exportation), whether or not such conveyance or shipment is entirely 
intrastate and whether or not possession of the product is taken. We 
originally described our intended definition of ``distribution'' in the 
preamble to the registration proposed rule (63 FR 26744 at 26750), and 
we responded to several comments on ``distribution'' in the 
registration final rule (66 FR 5447 at 5456).
    (Comment 16) One comment asserted that the definition of 
distribution in the proposed rule is inconsistent with the definition 
in the registration final rule. The comment pointed out that, in the 
preamble to the registration final rule, we agreed that an entity that 
does not take possession of HCT/Ps is not distributing them for the 
purposes of this rule.
    (Response) The proposed rule, which contained the proposed codified 
definition of ``distribution,'' preceded the registration final rule, 
in which we indicated we would make changes to the proposed definition. 
We are now making the change to the definition that we discussed in the 
registration final rule; i.e., we have removed the phrase ``whether or 
not possession is taken'' from the definition and replaced it with ``If 
an entity does not take physical possession of an HCT/P that entity is 
not considered a distributor.''
    (Comment 17) One comment requested that we clarify that 
intracompany transfers of HCT/Ps are not included within the definition 
of ``distribution,'' consistent with FDA's policy with respect to other 
medical products.
    (Response) In response to this comment, we have modified the 
definition of ``distribution'' to mean any conveyance or shipment of an 
HCT/P ``that has been determined to meet all release criteria.'' This 
change is intended to make clear that the shipment of an HCT/P before 
it is ready for release would not be considered distribution (e.g., the 
movement of an HCT/P from a recovering establishment to a processing 
establishment). This sort of predistribution shipment might also take 
place between establishments that are part of the same company. On the 
other hand, not all intracompany shipments are appropriately excepted 
from the definition of ``distribution.'' For example, releasing an HCT/
P from a collection/processing facility to an

[[Page 68619]]

operating room in the same facility would be considered distribution.
5. Establish and Maintain (Sec.  1271.3(cc))
    Proposed Sec.  1271.3(ll) would define ``establish and maintain'' 
as define, document (in writing or electronically), and implement, then 
follow, review, and, as needed, revise on an ongoing basis.
    We received no comments on the proposed definition of ``establish 
and maintain.''
6. HCT/P Deviation (Sec.  1271.3(dd))
    Proposed Sec.  1271.3(kk) would define ``product deviation'' as an 
event that represents a deviation from CGTP, 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 an HCT/P to a recipient, or 
may lead to product contamination.
    In response to comments on the term ``product,'' we have changed 
the defined term from ``product deviation'' to ``HCT/P deviation'' (see 
66 FR 5447 at 5455). We have also narrowed the definition of HCT/P 
deviation by revising the phrase ``a deviation from current good tissue 
practice, applicable standards, or established specifications'' to read 
``a deviation from applicable regulations in this part or from 
applicable standards or established specifications that may relate to 
the prevention of communicable disease transmission or to the 
prevention of HCT/P contamination.''
    Proposed Sec.  1271.350(b) would require you to report those HCT/P 
deviations that could reasonably be expected to lead to a reportable 
adverse reaction.
    (Comment 18) One comment suggested that we use the term ``process 
deviation'' instead of ``product deviation,'' because the definition 
refers to an event rather than to a deviation in the HCT/P.
    (Response) We decline to make the suggested change because to do so 
could exclude problems that occur in areas of manufacture other than 
``processing,'' such as recovery and storage, and would therefore be 
narrower than ``HCT/P deviation.'' Moreover, the term ``process 
deviation'' might introduce inconsistency with our reporting 
requirements in Sec.  600.14 (21 CFR 600.14) for biological products 
other than blood and blood components. Establishments that manufacture 
HCT/Ps regulated under section 351 of the PHS Act will report under 
Sec.  600.14. Establishments that manufacture HCT/Ps regulated as drugs 
or devices under the act will make any reports under drug and device 
reporting provisions.
    (Comment 19) One comment noted that there are no established 
specifications for corneas, although there are proxy indicators (e.g., 
cell counts and cell morphology) that can be taken into account when 
evaluating tissue, and that outcomes may be dependent upon factors 
beyond an eye bank's control.
    (Response) We understand that an eye bank might not set 
specifications for corneas. However, we expect that an establishment 
will generally set out acceptable criteria for its HCT/Ps in its 
standard operating procedures. These criteria may relate to such 
factors as storage temperature, and although not considered 
specifications by the establishment, they serve much the same role. 
Since storage temperature may relate to the prevention of communicable 
disease transmission or HCT/P contamination, a deviation from these 
criteria would be considered an HCT/P deviation You must review the 
deviation to determine if it must be reported under Sec.  1271.350(b).
7. Importer of Record (Sec.  1271.3(ee))
    Proposed Sec.  1271.3(tt) would define ``importer of record'' as 
``the person, establishment, or its representative responsible for 
making entry of imported goods in accordance with all laws affecting 
such importation.'' (66 FR 1508 at 1552).
    We received no comments on the proposed definition of ``importer of 
record.''
8. Processing (Sec.  1271.3(ff))
    Processing is one of the activities listed in the definition of 
``manufacture'' in Sec.  1271.3(e). The proposed rule would define 
``processing'' in Sec.  1271.3(mm) as any activity performed on an HCT/
P other than recovery, donor screening, donor testing, storage, 
labeling, packaging, or distribution. Processing would include, but not 
be limited to, preparation, sterilization, steps to inactivate and 
remove adventitious agents, preservation for storage, and removal from 
storage. We have added to the definition ``testing for microorganisms'' 
because this activity may occur at this stage of manufacturing.
    (Comment 20) One comment requested clarification of the terms 
``process'' and ``processing'' as those terms are used in proposed 
Sec. Sec.  1271.220 (process controls) and 1271.225 (process changes).
    (Response) We believe that ``process'' is a generally understood 
term; one accepted definition of ``process'' is a ``set of interrelated 
or interacting activities which transfers inputs into outputs'' 
(International Standards Organization (ISO) 9000:2000, 3.4.1). In the 
context of this final rule, the set of processing activities that an 
establishment performs on an HCT/P would be considered a ``process.'' 
We consider the proposed definition of ``processing'' to be 
sufficiently clear and have made no substantive changes to it.
    (Comment 21) One comment from an eye bank requested clarification 
of ``preparation,'' ``preservation for storage,'' and ``removal from 
storage.'' The comment noted that corneas are stored in media to 
maintain viability but are not preserved for long-term storage.
    (Response) We believe that these terms are generally understood; 
however, not all of them may be applicable to eye banks. We agree that 
corneas are usually not preserved for long-term storage, but 
nevertheless, they are preserved in a corneal storage media, even for 
short-term storage.
    Examples of corneal processing may include gross and microscopic 
examination of the cornea, microbiological culture of the rim, 
preservation in a corneal storage media, and placement into and removal 
from the refrigerator.
9. Processing Material
    The proposed rule would define ``processing material'' in 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 HCT/P when it is made available for distribution.
    We have deleted the relevant provision on processing material, in 
proposed Sec.  1271.220(b), and as a result are also deleting this 
definition.
10. Quality Audit (Sec.  1271.3(gg))
    We proposed to define ``quality audit'' in 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.
    We have revised the definition of quality audit to mean a 
documented, independent inspection and review of an establishment's 
activities related to core CGTP requirements. The definition further 
states that the purpose of a quality audit is to verify, by examination 
and evaluation of objective evidence, the degree of compliance with 
those aspects of the quality program under review.

[[Page 68620]]

    (Comment 22) One comment recommended that we define ``independent'' 
or insert a reference to proposed Sec.  1271.160(d)(2), which would 
require that a quality audit be performed by an individual who does not 
have direct responsibility for the processes being audited. Another 
comment asked us to clarify ``independent inspection'' and asked 
whether an employee could perform the independent inspection. A third 
comment asked whether an outside accreditation process could constitute 
an independent review.
    (Response) We do not believe it is necessary to define 
``independent.'' We consider an inspection and review by an individual 
who does not have direct responsibility for the processes being audited 
to be ``independent.'' This individual could be someone outside the 
firm, or could be an individual within the firm who does not have 
direct responsibility for the matters being audited. If an 
accreditation process is equivalent to an internal quality audit, it 
would be acceptable. We decline to add a reference to the quality audit 
provision of Sec.  1271.160, which has been revised.
11. Quality Program (Sec.  1271.3(hh))
    We proposed to define ``quality program'' in Sec.  1271.3(oo) as an 
organization's comprehensive system for manufacturing and tracking HCT/
Ps. As defined, the program would include preventing, detecting, and 
correcting deficiencies that may lead to circumstances that increase 
the risk of introduction, transmission, or spread of communicable 
diseases.
    We have revised the definition of ``quality program'' for clarity. 
The definition now states, in part, that a quality program is designed 
to prevent, detect, and correct deficiencies that may lead to 
circumstances that increase the risk of introduction, transmission, or 
spread of communicable diseases.
    (Comment 23) One comment endorsed the concept of a quality program 
but noted that the preamble referred to an organization's ``method,'' 
while the proposed definition used the term ``system for 
manufacturing.'' The comment suggested that we change the codified 
definition to reflect the preamble.
    (Response) We decline to make the suggested change; rather, we note 
that it would have been clearer if we had referred in the preamble to a 
``system'' rather than to a ``method.'' As stated in the preamble to 
the proposed rule (66 FR 1508 at 1513), we use the term ``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. Whether this set of activities is regarded 
as a part of manufacture or as a separate system for overseeing 
manufacture, as preferred by the comment, is not material.
12. Recovery (Sec.  1271.3(ii))
    Proposed Sec.  1271.3(pp) would define ``recovery'' as the 
``process of obtaining from a donor cells or tissues that are intended 
for use in human implantation, transplantation, infusion, or 
transfer.'' (66 FR 1508 at 1551 and 1552).
    (Comment 24) One comment suggested rewording the definition of 
``recovery'' to avoid referring to recovery as a process.
    (Response) We agree with this comment. The word ``process'' in the 
definition of ``recovery'' could be confused with the definition of 
``processing'' in proposed Sec.  1271.3(mm), which does not include 
recovery. The definition now reads: Recovery means obtaining from a 
donor cells or tissues that are intended for use in human implantation, 
transplantation, infusion, or transfer.
13. Storage (Sec.  1271.3(jj))
    Storage is one of the activities listed in the definition of 
manufacture in Sec.  1271.3(e). We proposed to define ``storage'' in 
Sec.  1271.3(qq) as holding HCT/Ps for future processing and/or 
distribution.
    (Comment 25) One comment recommended that we clarify that the 
definition does not refer only to finished HCT/Ps ready for shipment 
and suggested that the definition refer also to ``materials.''
    (Response) Although we agree that the term ``storage'' does not 
apply only to finished HCT/Ps, but to HCT/Ps at any stage of 
processing, we do not consider a revision of the definition to be 
necessary. The term HCT/P encompasses HCT/Ps at any stage of 
manufacture, from recovery to distribution (66 FR 5447 at 5448). 
Moreover, the definition of ``storage'' refers to ``future 
processing,'' which indicates that the definition applies not only to 
finished products but also to cells or tissues that may be subject to 
future processing.
14. Validation (Sec.  1271.3(kk))
    Proposed Sec.  1271.3(rr) would define ``validation'' as 
confirmation by examination and provision of objective evidence that 
particular requirements can consistently be fulfilled. The definition 
went on to define validation of a process, or ``process validation,'' 
as establishing by objective evidence that a process consistently 
produces a result or product meeting its predetermined specifications.
    (Comment 26) One comment requested that we harmonize the proposed 
definition with that of the International Conference on Harmonisation 
(ICH). The comment suggested that the new definition read:
    A documented program that provides a high degree of assurance 
that a specific process, method, or system will consistently produce 
a result meeting predetermined acceptance criteria.
    (Response) We decline to make this change. Harmonization of the two 
definitions is unnecessary, because the proposed definition is 
consistent with the language suggested by the comment. The proposed 
definition is preferable, however, because it explains in more specific 
terms what is expected (e.g., ``confirmation by examination''; 
``provision of objective evidence''). In addition, the proposed 
definition is consistent with the ISO 9000:2000 definition of 
validation (Quality management system--Fundamentals and vocabulary).
    (Comment 27) Two comments questioned the use of the term 
``validation'' throughout the proposed rule. These comments cited 
industry standards that require a level of review tailored to the type 
of processing used for a particular tissue (e.g., validation of certain 
shipping containers versus verification of other aspects of 
processing). The comments requested clarification that compliance with 
these standards would be deemed compliance with the rule's validation 
requirements.
    (Response) Where the appropriate action depends on the type of 
tissue or processing, the rule provides establishments with the 
flexibility to determine whether verification or validation is 
appropriate (e.g., Sec. Sec.  1271.210(c) and 1271.225). Verification 
activities may be sufficient for certain processes if the results can 
be adequately determined through inspection and testing methods. When 
full and complete verification cannot be achieved, the process must be 
validated. The manufacturer should have the requisite knowledge of the 
processes and operations conducted at its facility to determine which 
actions are needed.
    FDA cannot make a determination that compliance with professional 
standards ensures compliance with the validation requirements of this 
rule. Each establishment will need to assess its operations to make 
sure the applicable requirements of the CGTP regulation are met. We 
encourage

[[Page 68621]]

professional organizations and others to submit drafts of proposed 
guidance in this area for FDA to consider for possible adoption.
15. Verification (Sec.  1271.3(nn))
    Proposed Sec.  1271.3(ss) would define ``verification'' as 
``confirmation by examination and provision of objective evidence that 
specified requirements have been fulfilled.'' (66 FR 1508 at 1552).
    We received no comments on the proposed definition of 
``verification, `` and it is unchanged.

C. Part 1271, Subpart D--Current Good Tissue Practice

    Part 1271, subpart D, sets forth CGTP requirements. We have added, 
in Sec.  1271.145, an explicit statement of the basic requirement that 
underpins all of the provisions of this subpart. Section 1271.145 
states that you must recover, process, store, label, package, and 
distribute HCT/Ps, and screen and test cell and tissue donors, in a way 
that prevents the introduction, transmission, or spread of communicable 
diseases.
1. Current Good Tissue Practice Requirements (Sec.  1271.150)
    General (Sec.  1271.150(a))
    Proposed Sec.  1271.150(a) states in part that the CGTP 
requirements are intended to prevent the introduction, transmission, or 
spread of communicable disease through the use of HCT/Ps by helping to 
ensure that they do not contain communicable disease agents and that 
they do not become contaminated during manufacturing. We have revised 
this sentence for clarity, have added the phrase ``that they are not 
contaminated,'' and have included the statement that ``you must follow 
CGTP requirements.''
    We have also added to Sec.  1271.150(a) the statement that 
communicable diseases include, but are not limited to, those 
transmitted by viruses, bacteria, fungi, parasites, and transmissible 
spongiform encephalopathy (TSE) agents. Although the proposed CGTP 
requirements were intended to prevent contamination of HCT/Ps with 
these agents (e.g., see 66 FR 1508 at 1509, 1510, 1514, and 1515), we 
believe that these examples of communicable disease make this provision 
more clear.
    A 2002 Morbidity and Mortality Weekly Report (MMWR) discusses 26 
cases of bacterial infection associated with musculoskeletal allografts 
and reinforces the importance of following CGTP to prevent the 
contamination of HCT/Ps with such communicable disease agents. In the 
MMWR, the Centers for Disease Control and Prevention (CDC) make several 
significant recommendations on preventing bacterial contamination. 
Among other things, the CDC states that ``[s]terilization of tissue 
that does not adversely affect the functioning of tissue when 
transplanted into patients is the best way to reduce the risk for 
allograft-associated infections.'' Throughout this final rule, we 
discuss the CDC's recommendations and note the applicability of 
specific provisions of the final rule to the prevention of bacterial 
contamination (Ref. 1).
    Core CGTP Requirements (Sec.  1271.150(b))
    Paragraph (b) lists the core CGTP requirements, discussed in 
section II.D of this document. We have identified the following as core 
CGTP requirements: Sec.  1271.190(a) and (b) (relating to facilities); 
Sec.  1271.195(a) (environmental controls); Sec.  1271.200(a) 
(equipment); Sec.  1271.210(a) and (b) (supplies and reagents); Sec.  
1271.215 (recovery); Sec.  1271.220 (processing and process controls); 
Sec.  1271.250(a) and (b) (labeling controls); Sec.  1271.260(a) 
through (d) (storage); Sec.  1271.265(a) through (d) (receipt, 
predistribution shipment, and distribution); and Sec. Sec.  1271.50, 
1271.75, 1271.80, and 1271.85 (donor eligibility determinations, donor 
screening, and donor testing).
    Compliance With Applicable Requirements (Sec.  1271.150(c)(1))
    Proposed Sec.  1271.150(b)(1) states that an establishment that 
engages in only some operations subject to the regulations in this 
subpart and subpart C of this part need only comply with those 
requirements applicable to the operations in which it engages. It 
further states that when an establishment engages a second 
establishment to perform any step in manufacturing, the second 
establishment would be required to comply with the requirements 
applicable to that manufacturing step. In addition, the first 
establishment would be responsible for ensuring that the work at the 
other establishment is performed in compliance with subparts C and D. 
Proposed paragraph (b) of Sec.  1271.150 has been redesignated as 
paragraph (c).
    The following table summarizes the responsibilities that are 
assigned in the final rule to each manufacturer when multiple 
establishments are involved in manufacturing an HCT/P:

                                                    Table 1a
----------------------------------------------------------------------------------------------------------------
                If you:                                                 You must:
----------------------------------------------------------------------------------------------------------------
Perform any step in the manufacture of   Follow CGTP (subparts C and D) (Sec.   1271.150(a)) as it relates to
 an HCT/P                                 that step.
----------------------------------------------------------------------------------------------------------------
Perform only some and not all            1. Follow only those requirements applicable to the operations you
 operations of manufacturing, and do      perform (Sec.   1271.150(c)(1).
 not make the HCT/P available for        2. When you receive the HCT/P, determine whether the HCT/P meets all
 distribution                             pre-established criteria, designed to prevent communicable disease
                                          transmission, for acceptance or rejection, and place the HCT/P in
                                          quarantine as appropriate (Sec.   1271.265(a)).
                                         3. When you prepare to ship an HCT/P, ship the HCT/P only in quarantine
                                          and after determining criteria designed to prevent communicable
                                          disease are met (Sec.   1271.265(b)).
                                         4. Investigate all HCT/P deviations related to a distributed HCT/P for
                                          which you performed a manufacturing step and report any deviation
                                          related to core CGTP requirements that occurred in your facility or in
                                          a facility that performs a manufacturing step for you under contract,
                                          agreement, or other arrangement (Sec.   1271.350(b)(1) and (b)(2)).
----------------------------------------------------------------------------------------------------------------
Engage another establishment to perform  1. Enter into and maintain such an arrangement only with a reliable
 any step in manufacturing for you        establishment that complies with applicable CGTP requirements. (Sec.
 under contract, agreement, or other      1271.150(c)(1)).
 arrangement                             2. Investigate all HCT/P deviations related to a distributed HCT/P for
                                          which you performed a manufacturing step and report any deviation
                                          related to core CGTP requirements that occurred in your facility or in
                                          a facility that performs a manufacturing step for you under contract,
                                          agreement, or other arrangement (Sec.   1271.350(b)(1) and (b)(2)).
----------------------------------------------------------------------------------------------------------------

[[Page 68622]]

 
Make the HCT/P available for             1. Review manufacturing and tracking records to determine that the HCT/
 distribution                             P meets all the release criteria (Sec.  Sec.   1271.150(c)(2) and
                                          1271.265(c)) and maintain records relevant to the release
                                          determination (Sec.   1271.270(a)).
                                         2. Ensure that manufacturing and tracking records demonstrate that the
                                          HCT/P has been manufactured and tracked from recovery to the consignee
                                          following CGTP (Sec.  Sec.   1271.150(c)(2) and 1271.290).
                                         3. Investigate and report any adverse reaction involving a communicable
                                          disease (Sec.   1271.350(a)).
                                         4. Investigate all HCT/P deviations related to any step in the
                                          manufacture of a distributed HCT/P that you performed, and report any
                                          HCT/P deviation relating to core CGTP requirements if the deviation
                                          occurred in your facility or in a facility that performed a
                                          manufacturing step for you under contract, agreement, or other
                                          arrangement (Sec.   1271.350(b)(1) and (b)(2)).
----------------------------------------------------------------------------------------------------------------

    (Comment 28) Several comments objected to the statement in proposed 
Sec.  1271.150(b)(1) that 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 CGTP and 
donor-eligibility requirements. One comment asserted that the language 
is too broad and open to interpretation, and could make eye banks 
responsible for ensuring that entities such as couriers, medical 
examiner's offices, and laboratories meet regulatory requirements 
applicable to the subcontracted function. Another comment asked whether 
an establishment must inspect Federal Express, UPS, or the Postal 
Service to ensure that they comply with the regulations when shipping 
corneas.
    (Response) We have revised the language of the proposed rule. Under 
Sec.  1271.150(c)(1), if an establishment (e.g., an eye bank) engages 
another establishment to perform a manufacturing step, under a 
contract, agreement, or other arrangement, it must enter into and 
maintain such an arrangement only with a reliable establishment that 
complies with applicable CGTP requirements. Under this provision, an 
establishment should choose its partners with care. This requirement 
extends to relationships with establishments such as medical examiner 
offices and laboratories, but it does not apply with respect to 
carriers, such as Federal Express, UPS, or the Postal Service, who are 
exempt from the regulations in this part as noted in Sec.  1271.15(c).
    (Comment 29) One comment stated that it is unrealistic to require 
validation of a subcontractor's work on each tissue, and that it is 
expensive and nearly impossible to find staff with specific expertise 
to review each type of subcontractor. Another comment stated that eye 
banks are not qualified to be responsible for ensuring compliance by 
subcontractors and recommended that compliance by subcontractors be 
deemed met by a letter of intent from the subcontractor. This comment 
also asserted that eye banks do not have the expertise to inspect or 
validate a blood testing laboratory or Bausch & Lomb.
    One comment suggested that an initial audit of the contractor 
should be sufficient. Another comment suggested that each establishment 
have a system in place designed to ensure that the contractor's work is 
performed in compliance with the regulatory requirements.
    (Response) Section 1271.150(c)(1) is intended to clarify the 
relationship between you and another establishment that performs one or 
more steps in manufacture for you (e.g., a procurer engages an outside 
testing laboratory to perform communicable disease tests for it; a 
processor engages an outside firm to perform terminal sterilization, 
such as irradiation, on the final HCT/P). (We have added these examples 
to the regulation.) You do not have to validate the processes of these 
outside firms (who are themselves subject to the regulations in part 
1271), and we appreciate the fact that you may lack the expertise to do 
so. However, you are required to enter into and maintain such 
arrangements only with establishments that comply with applicable CGTP 
requirements.
    We note that there are many ways of performing the due diligence 
necessary when entering into a manufacturing arrangement with another 
establishment. The example of an initial audit provided by the comment 
is one method. Other ways of learning about another establishment 
before you enter into an arrangement with it might include reviewing 
test kit package inserts and a testing laboratory's standard operating 
procedures (SOPs); and reviewing an establishment's compliance history. 
If you intend to enter into an arrangement with an establishment that 
does not have a compliance history, review of that establishment's SOPs 
might assist in ascertaining that entity's compliance status.
    Although we recognize the usefulness of an initial audit before 
entering into an arrangement with another establishment, we note that 
an initial audit would not satisfy this requirement throughout the term 
of a continuing relationship. Under Sec.  1271.150(c)(1), you may not 
ignore information that indicates that a company that performs work for 
you is not in compliance with applicable CGTP requirements. For 
example, if you have reason to suspect that an establishment performing 
work for you is not in compliance with those requirements, you would 
need to take appropriate action and determine whether the establishment 
is still in compliance with CGTP. Other regulations in part 1271 may 
also apply with regard to products manufactured, in part, by an 
establishment that does not comply with applicable requirements. For 
example, Sec.  1271.145 provides, ``You must * * * store * * * and 
distribute HCT/Ps * * * in a way that prevents the introduction, 
transmission, or spread of communicable diseases.'' You may also have 
obligations under Sec. Sec.  1271.160, 1271.265, 1271.320, and 
1271.350. If you determine that the establishment is not in compliance 
with applicable CGTP requirements, you must terminate your contract, 
agreement, or other arrangement with that establishment. If you 
determine that an exemption or alternative from this requirement would 
be consistent with the goals of protecting the public health and/or 
preventing the introduction, transmission, or spread of communicable 
diseases, and you either have information that would justify an 
exemption, or have a proposed alternative that would satisfy the

[[Page 68623]]

purpose of this requirement, you may seek an exemption or alternative 
under Sec.  1271.155.
    We intend to issue guidance, which will further elaborate on your 
responsibilities for ensuring that another establishment that performs 
one or more steps in manufacture for you is in compliance with part 
1271. Our economic impact analysis also indicates that the methods 
described in this response are not overly costly or burdensome.
    (Comment 30) One comment suggested limiting an establishment's 
responsibility toward contractors to ensuring that the contractor is a 
registered tissue bank establishment.
    (Response) We agree that establishments under contract must 
register with FDA. However, we note that some individuals who recover 
cells or tissue under contract, agreement, or other arrangement are 
excepted from registration under Sec.  1271.15(f); this is one reason 
that it would not be sufficient to limit an establishment's 
responsibility to ensuring that a contractor is registered. Moreover, 
although registration is an important component of the regulation of 
HCT/P establishments, such a requirement would not go far enough toward 
safeguarding the public against the communicable disease risks 
associated with HCT/Ps. Therefore, if you engage another establishment 
under a contract, agreement, or other arrangement to perform any step 
in manufacture for you, you must first determine that the establishment 
complies with applicable CGTP requirements, and you must investigate 
further if you receive information suggesting that the establishment 
may no longer be in compliance with those requirements.
    Compliance With Applicable Requirements (Sec.  1271.150(c)(2))
    Proposed Sec.  1271.150(b)(2) explained how we would assign 
ultimate responsibility for an HCT/P. That paragraph states that the 
establishment that determines that an HCT/P meets release criteria and 
makes it available for distribution, whether or not it is the actual 
distributor, is responsible for ensuring that the HCT/P has been 
manufactured in compliance with the requirement of subparts C and D and 
any other applicable requirements. In Sec.  1271.150(c)(2), we have 
added the responsibility for tracking (consistent with Sec.  1271.290).
    (Comment 31) Under proposed Sec.  1271.150(b)(2), the establishment 
that determines that an HCT/P meets release criteria and makes it 
available for distribution would be responsible for ensuring that the 
HCT/P has been manufactured in compliance with the requirements in 
subparts C and D and any other applicable requirements. Several 
comments agreed with this allocation of responsibility or with the 
``cascading'' set of responsibilities discussed in the preamble to the 
proposed rule, under which
    * * * 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 (66 FR 1508 at 
1512).
    One comment asserted that, although the proposed allocation of 
responsibility was the most reasonable of those considered, it was 
unclear what sort of documentation would be sufficient to ensure that 
establishments that handled the HCT/P before receipt were in compliance 
(in particular, international donor centers), and another comment 
asserted that proposed Sec.  1271.150(b) would require every company to 
collect and store documents for all other companies participating in 
the manufacturing process.
    One comment stated that the more prudent approach would be to hold 
each establishment specifically responsible for the activities that 
went before. Another proposed that, since more than one establishment 
may actually make an HCT/P available for distribution, the last 
establishment that releases the product should be responsible. Another 
comment recommended that overall responsibility for compliance be 
assigned only to establishments within the United States.
    (Response) We have revised proposed Sec.  1271.150(b)(2) (and 
renumbered it Sec.  1271.150(c)(2)) to state that if you are the 
establishment that determines that an HCT/P meets all release criteria 
and makes the HCT/P available for distribution, whether or not you are 
the actual distributor, you are responsible for reviewing manufacturing 
and tracking records to determine that the HCT/P has been manufactured 
and tracked in compliance with the requirements of this subpart and 
subpart C of this part and any other applicable requirements. This 
record review would include, for example, reviewing documentation of 
donor test results for relevant communicable disease agents to 
determine that results are negative or nonreactive and that appropriate 
testing was performed (Sec. Sec.  1271.80 and 1271.85); matching the 
distinct identification code on the HCT/P container with the code in 
the summary of records (Sec.  1271.290)c); reviewing records pertaining 
to donor screening for risk factors for and clinical evidence of 
relevant communicable disease agents (Sec.  1271.75); reviewing records 
pertaining to storage temperature (Sec.  1271.260), processing (Sec.  
1271.220), and other manufacturing steps. The requirement applies to 
any establishment that makes an HCT/P available for distribution, 
whether it is foreign or domestic, and whether or not another 
establishment may later make it again available for distribution. An 
establishment that makes the HCT/P available for distribution must 
maintain the records in question.
    Section 1271.150(c)(2) ties in closely with Sec.  1271.265, which 
covers receipt, predistribution shipment, and distribution of an HCT/P. 
Section 1271.265(c) sets out requirements for making an HCT/P available 
for distribution, including reviewing records pertaining to the HCT/P, 
and, on the basis of that record review, verifying and documenting that 
the release criteria have been met.
    (Comment 32) One comment discussed the following scenario. If the 
first establishment releases the HCT/P to a consignee under its own 
label, releases it to another distributor, or releases it back to the 
contracting firm (which may in turn serve as a distributor), then the 
first establishment is responsible for ensuring that the HCT/P has been 
manufactured in compliance with CGTP. This comment stated that, if its 
interpretation of the proposal was correct, then it endorsed the 
proposal.
    (Response) The examples provided by the comment illustrate three 
different ways in which an establishment might make an HCT/P available 
for distribution. Under Sec.  1271.150(c)(2), the establishment has the 
same responsibility in each case: To review manufacturing and tracking 
records to determine that the HCT/P has been manufactured and tracked 
in compliance with regulatory requirements.
    (Comment 33) One comment asked for further clarification, stating 
that it is not clear whether the responsibility pertains to the 
manufacturing facility or just the distributor. If the distributor were 
an institutional laboratory that receives an HCT/P that was processed 
at a commercial laboratory, then the requirement would be unduly 
burdensome, according to the comment.
    (Response) In the situation described, the institutional laboratory 
is not the establishment that makes the HCT/P available for 
distribution, and would not be ultimately responsible. In fact, an 
institutional laboratory (e.g., hospital bone bank) that does no 
further manufacturing of the HCT/P, but only

[[Page 68624]]

receives the finished HCT/P from a commercial tissue processor, and 
``distributes'' the HCT/P in the same facility, is excepted from these 
regulations (Sec.  1271.15(d)). However, if the institutional 
laboratory performs additional manufacturing steps on the HCT/P, this 
laboratory is then considered a ``processor'' and is subject to the 
CGTP requirements.
    (Comment 34) One comment asserted that responsibility should be 
apportioned appropriately among the entities involved. This comment 
recommended avoiding a situation where screening by various entities 
would lead to numerous re-contacts of donor families.
    (Response) It is not our intention to have various establishments 
re-contact the donor's family to reconfirm the medical history, for 
example. The initial establishment that performed the donor medical 
history interview would document the findings. The establishment that 
made the HCT/P available for distribution would review the records of 
the findings to make sure that all release criteria (including donor 
eligibility) were met, and would retain the documented findings.
    (Comment 35) When there are multiple establishments involved in the 
manufacture of an HCT/P, one comment suggested that we limit the 
penalties only to the noncompliant establishment.
    (Response) Generally, we will not take enforcement action against 
all parties involved in the manufacturing of HCT/Ps. We will evaluate 
all available information related to the violative activities and the 
circumstances concerning the event. If circumstances indicate that 
multiple parties have not complied with the applicable regulations, we 
may take enforcement action as appropriate.
    Compliance With Applicable Requirements (Sec.  1271.150(c)(3))
    Paragraph (c)(3) of Sec.  1271.150 states that with the exception 
of Sec. Sec.  1271.150(c) and 1271.155 of this subpart, the regulations 
in this subpart are not being implemented for reproductive HCT/Ps 
described in Sec.  1271.10 and regulated solely under section 361 of 
the PHS Act and the regulations in this part, or for the establishments 
that manufacture them.
    Compliance With Parts 210, 211, and 820 of this Chapter (Sec.  
1271.150(d))
    Proposed 1271.150(c) explains, in part, that for HCT/Ps regulated 
as biological drugs or devices, the procedures contained in this 
subpart and in subpart C, and the procedures contained in parts 210, 
211, and 820, supplement rather than supersede each other.
    (Comment 36) We received one comment on proposed Sec.  1271.150(c). 
This comment asserted that the last sentence in that paragraph provides 
no useful guidance and should be deleted. The last sentence in proposed 
Sec.  1271.150(c) stated
    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. (66 FR 1508 at 1552.)
    (Response) In the preamble of the proposed rule, we explained why 
an HCT/P regulated as a biological drug or device must comply with part 
1271 (CGTP) as well as parts 210 and 211 (CGMP) or 820 (QS). CGMP and 
QS do not contain requirements written explicitly to prevent the spread 
of communicable disease. CGTP is focused on preventing circumstances 
that increase the risk of the introduction, transmission, or spread of 
communicable disease, which makes CGTP regulations less extensive than 
CGMP and QS regulations. Therefore, CGTP and CGMP or QS are intended to 
supplement each other. In the event that a regulation in part 1271 is 
in conflict with a requirement in parts 210, 211, or 820 of this 
chapter, the regulations more specifically applicable to the product in 
question will supersede the more general. FDA believes that, in the 
event of such a conflict, the more specifically applicable regulation 
would be found in part 1271.
    Where Appropriate (Sec.  1271.150(e))
    ``Where appropriate'' in proposed Sec.  1271.150(d) would mean that 
a practice is required unless the establishment can document 
justification otherwise. A requirement would be considered 
``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.
    We received no comments on this section.
2. Exemptions and Alternatives(Sec.  1271.155)
    Proposed Sec.  1271.155 sets out the procedures that an 
establishment must follow to request an exemption from, or an 
alternative to, a CGTP requirement, as well as the criteria that the 
Center Director will follow in considering such a request. In the final 
rule, we have modified Sec.  1271.155(b) to allow requests for 
exemptions or alternatives to be submitted to the appropriate Center 
Director (e.g., the Center for Biologics Evaluation and Research (CBER) 
or the Center for Devices and Radiological Health), rather than only 
the CBER Director. We have revised Sec.  1271.155(d) for clarity; 
instead of referring to ``limited circumstances,'' the final regulation 
states that, if circumstances make it difficult (e.g., there is 
inadequate time) to submit your request in writing, you may make the 
request orally.
    We have also added Sec.  1271.155(g), which in a public health 
emergency permits the Director to issue an exemption or alternative to 
any requirement in part 1271 of title 21 of the Code of Federal 
Regulations. An exemption or alternative under this section may be 
necessary to help ensure that certain HCT/Ps will be available in a 
specified location to respond to an unanticipated immediate need for 
such HCT/Ps.
    (Comment 37) One comment recommended that Sec.  1271.155 should be 
implemented first, and that the remaining provisions of the rule should 
be implemented 2 years later.
    (Response) We do not agree with this comment. It is not clear why 
implementation of the exemption provisions should precede 
implementation of the rest of the final rule. If the requirements are 
not in effect, then an exemption request is not necessary.
    (Comment 38) One comment noted that international establishments 
that produce peripheral blood stem cells and umbilical cord blood units 
are subject to their own national and regional regulatory requirements. 
The comment stated its assumption that these establishments would 
submit their foreign government's regulations to FDA under Sec.  
1271.155.
    (Response) The comment's assumption is incorrect. A foreign 
establishment that distributes HCT/Ps in this country must comply with 
FDA regulations. It is a foreign establishment's responsibility to 
determine whether complying with the foreign government's requirements 
would also satisfy FDA requirements. If a foreign establishment 
identifies a discrepancy (e.g., an area where FDA regulations are more 
stringent or in conflict), the establishment may request an exemption 
or alternative under Sec.  1271.155, and FDA will consider whether the 
request is justified by the evidence submitted.
    (Comment 39) One comment recommended that the rule establish a 
maximum time period of 30 working

[[Page 68625]]

days for an agency decision on a request for an exemption or 
alternative.
    (Response) Although we agree that timely decisions are important, 
we disagree that this regulation should contain a specific timeframe. 
Depending on the nature of the request, more or less time may be needed 
to give the request adequate consideration. We note that other FDA 
regulations dealing with exemptions do not specify a deadline for a 
reply (see, e.g., Sec.  640.120 (21 CFR 640.120) and 21 CFR 803.19). 
The time for our review of requests under Sec.  640.120 for variances 
related to the blood regulations has varied from two weeks to four 
months, depending on the complexity and urgency of the request. We 
intend to respond to variance requests under Sec.  1271.155 within 
similar timeframes, with our time to respond tied to the complexity and 
urgency of the request.
    (Comment 40) One comment asserted that the criteria in proposed 
Sec.  1271.155(c) for granting an exemption or alternative are too 
narrow, in that they do not afford an establishment an exemption or 
alternative to a particular requirement not relevant to the tissue in 
question. The comment suggested adding the phrase: ``and that such 
goals are not impaired by an exemption or alternative.''
    (Response) We disagree with this comment. The suggested language is 
unnecessary and would narrow the criteria for granting an exemption or 
alternative. We note that if a requirement is not relevant to a 
particular establishment's operations, it is not necessary to request 
an exemption (Sec.  1271.150(c)(1)).
    We have, however, modified the criteria for granting an exemption 
or alternative in Sec.  1271.155(c) to permit the Center Director 
greater flexibility in responding to critical medical needs. That 
paragraph now reads, in part
    The Director may grant an exemption or alternative if he or she 
finds that such action is consistent with the goals of protecting 
the public health and/or preventing the introduction, transmission, 
or spread of communicable disease.
    (Comment 41) One comment noted that proposed Sec.  1271.155(d) and 
(e) are internally inconsistent, because paragraph (d) would allow for 
an oral request and reply, but paragraph (e) states that an 
establishment must not begin operating under the terms of a requested 
exemption or alternative until it had been granted in writing. The 
comment asked us to clarify that orally granted exemptions and 
alternatives would have immediate effect, and that an establishment 
would not be required to wait for a written statement from the agency.
    (Response) We agree with this comment and have deleted the words 
``in writing'' from Sec.  1271.155(e).
    (Comment 42) Another comment stated that FDA should evaluate how a 
small entity may qualify for reasonable exemptions and alternatives.
    (Response) We have written Sec.  1271.155(b) to apply to both large 
and small entities. Supporting documentation that either justifies a 
requested exemption, or describes a proposed alternative, must 
accompany a request. To assist all establishments, large and small, in 
pursuing appropriate exemptions and alternatives, we intend to make 
available to the public on the CBER Web site information concerning 
exemptions and alternatives that have been granted, while following 
statutory requirements prohibiting public disclosure of confidential 
information.
3. Quality Program (Sec.  1271.160)
    Proposed Sec.  1271.160 would require an establishment that 
performs any step in the manufacture of an HCT/P to establish and 
maintain a quality program that is appropriate for the specific HCT/Ps 
manufactured and the manufacturing steps performed, and that meets the 
requirements of subpart D of part 1271.
    Section 1271.160 of this final regulation requires instead that the 
quality program address all core CGTP requirements. We have also 
removed two items from the list in Sec.  1271.160(b) of a quality 
program's functions: Proposed paragraph (b)(5) (on monitoring systems) 
and proposed paragraph (b)(6) (on record maintenance systems).
    (Comment 43) One comment strongly supported the requirement for a 
quality program. Another comment appreciated the differentiation 
between the quality program and the quality system requirement for 
devices and blood products. This comment stated that giving tissue 
banks flexibility in how defined functions are accomplished, and not 
requiring the employment of staff free of other responsibilities, 
recognizes the undue burden that it would create. In contrast, two 
other comments asserted that eye banks would have to hire separate 
quality control employees, which would be time consuming and expensive.
    (Response) We appreciate the comments supporting the requirement. 
We note that the regulation does not require an establishment to hire a 
separate quality control employee; moreover, we have removed the 
requirement for the designation of an individual with authority over 
the program (proposed Sec.  1271.160(c)).
    (Comment 44) Two comments supported the idea that a quality program 
should be commensurate with the manufacturing steps performed and the 
types of tissues involved. These comments requested that FDA 
distinguish between ``quality programs'' and other quality 
requirements, to ensure that establishments are not held to unsuitable 
quality requirements.
    (Response) The quality program required under Sec.  1271.160 is a 
system that each establishment sets up to ensure its compliance with 
core CGTP requirements. These regulations do not contain generalized 
quality requirements.
    (Comment 45) We received three comments on proposed Sec.  
1271.160(b)(2), which would require procedures for sharing with other 
establishments that are known to have recovered cells or tissue from 
the same donor any information pertaining to the possible contamination 
of the HCT/P or the potential transmission of communicable disease by 
the HCT/P. One comment asserted that it would not be appropriate to 
share information about an autologous donor's baseline viral status 
with another establishment. This comment also expressed concern that 
the required procedure would be inconsistent with the requirement in 
proposed Sec.  1271.270 pertaining to donor confidentiality. The other 
two comments suggested narrowing the provision so that establishments 
would not be required to disclose proprietary information to 
competitors.
    (Response) We decline to modify the requirement as requested. The 
purpose of this requirement is to ensure that, if an establishment 
learns that a donor is ineligible or that an HCT/P is contaminated, the 
establishment has a procedure in place for informing consignees and 
other establishments that are known to have recovered cells or tissues 
from the same donor. Recognizing that other establishments may have 
received HCT/Ps from the same donor, even if they did not recover them, 
we have added to this list, ``other establishments that are known to 
have performed manufacturing steps with respect to the same HCT/P.''
    There is no requirement that an establishment disclose customer 
lists, manufacturing processes, or other proprietary information to 
competitors. Moreover, these procedures can be designed so that patient 
confidentiality is not compromised.
    With respect to the comment on sharing information about an 
autologous donor, we are unable to envision a

[[Page 68626]]

situation where this requirement would necessitate such a disclosure. 
Since HCT/Ps for other recipients would not be recovered from the 
autologous donor, there would be no need to share information regarding 
the donor's baseline viral status.
    (Comment 46) Proposed Sec.  1271.160(b)(7) would require 
establishments to investigate and document all product deviations in 
manufacturing. (These are now referred to as ``HCT/P deviations.'') One 
comment asserted that product deviation review and analyses should be 
treated in the same manner as internal audits (i.e., not available for 
review on inspection). Two comments asserted that the periodic audit of 
product deviations and collation of complaint files are tools of 
quality management and that FDA should guarantee the confidentiality of 
these quality management activities.
    (Response) We have renumbered proposed paragraph (b)(7) as (b)(6) 
and removed the requirement for a periodic review and analysis of HCT/P 
deviations. Under the final regulation, you are required to investigate 
and document HCT/P deviations and trends of HCT/P deviations relating 
to core CGTP requirements and to make reports if required to do so 
under Sec.  1271.350(b) or other applicable regulations.
    (Comment 47) One comment requested that we limit the requirement 
for reporting product deviations to those identified post-release.
    (Response) The reporting requirement in Sec.  1271.350(b)(1) 
applies only to distributed HCT/Ps, regardless of the time at which the 
deviation is identified.
    (Comment 48) Two comments asked us to clarify that Sec.  
1271.160(b)(7) includes only product deviations in manufacturing that 
would increase the risk of disease transmission.
    (Response) The term ``HCT/P deviation'' is defined in Sec.  
1271.3(dd) of this final rule to include events that may increase the 
risk of communicable disease transmission, because they: (1) Represent 
a deviation from applicable regulations in this part or from applicable 
standards or established specifications relating to the prevention of 
communicable disease transmission or HCT/P contamination, or (2) 
constitute an unexpected or unforeseeable event that may relate to the 
transmission or potential transmission of a communicable disease or may 
lead to HCT/P contamination.
    (Comment 49) Under proposed Sec.  1271.160(c), one or more 
designated persons would have authority over the quality program, and 
these persons would report to management at least once a year on the 
performance of the quality program, unless more frequent reports are 
necessary. If these persons also perform other tasks in the 
establishment, they must not have final oversight over their own work.
    Two comments on this provision asserted that the requirement for 
independent oversight is too stringent. One comment stated that, in 
small laboratories with only a single technician, it may not be 
possible for an independent person to have oversight. The other comment 
recommended that the oversight requirement be dropped as costly and 
impracticable.
    (Response) We have removed this requirement from the final rule.
    Audits
    (Comment 50) One comment requested more flexible language to 
replace the requirement for a comprehensive quality audit no less than 
once in 12 months. Another comment asserted that the requirement for an 
annual comprehensive audit is more stringent than the requirements 
applicable to blood component processing.
    (Response) In response to these comments, we have revised proposed 
Sec.  1271.160(d). Section 1271.160(c) now requires only that a quality 
audit of core CGTP activities be performed periodically for management 
review. The new language provides establishments with a greater degree 
of flexibility in determining how and when to audit their quality 
programs. We also may issue future guidance making recommendations on 
what we would consider to be a periodic audit.
    (Comment 51) Two comments asserted that internal audit findings 
should not be available to FDA representatives.
    (Response) With respect to quality audits, while some firms choose 
to provide quality audits to FDA, FDA's current practice is generally 
not to review or copy the actual quality audit reports during routine 
inspections and investigations except in certain limited circumstances 
(FDA Compliance Policy Guide 130.300). However, the firm should have a 
mechanism to demonstrate to the FDA representative that quality audits 
are being performed and that corrective actions are being implemented 
when problems are identified.
    Computers
    Proposed Sec.  1271.160(e) would require establishments to validate 
computer software used as part of manufacturing or tracking or for 
maintaining data relating to those activities.
    (Comment 52) One comment asserted that it is reasonable to require 
that computer systems used in manufacturing and data maintenance be 
tested to confirm that they perform as intended, and that the testing 
and results be documented. This comment asked us to confirm that we are 
distinguishing between this limited requirement and the term 
``validation'' as it has been applied to computer systems identified as 
medical devices.
    (Response) We agree with this comment. Therefore, we revised the 
requirement in Sec.  1271.160(d) to permit verification or validation 
of the computer software for its intended use.
    (Comment 53) Several comments opposed the proposed requirement on 
computer software validation. One comment asserted that software 
validation can be a financial burden and stated that the requirement 
should be implemented to the extent validation will minimize the risk 
of disease transmission during the manufacturing process. The comment 
further noted that there was no exemption in this provision for 
general-purpose software (e.g., spreadsheet, database, and word 
processing software) intended for broad general use, which are 
currently exempt from most of the general controls under the act. Two 
comments suggested limiting the scope of the requirement to the most 
necessary areas, to encourage the use of software programs in lieu of 
manual recordkeeping. Another comment asked that we amend the provision 
to reflect that software must be validated only if it is relied upon as 
the sole data source for the decisionmaking processes of the quality 
system.
    (Response) We do not intend that the requirements for computer 
validation be unduly burdensome. As a result of these comments, we are 
modifying the requirements in Sec.  1271.160(d). This section now 
applies only to software that you rely upon to comply with core CGTP 
requirements. You must validate the performance of software for its 
intended use only if the software is custom software or commercially 
available software that has been customized or programmed (including 
software programmed to perform a user-defined calculation or table) to 
perform a function related to core CGTP requirements. If you rely on 
commercially distributed, noncustom, software to perform a function 
related to core CGTP requirements, then you are only required to verify 
the performance of that software for its intended use. With these 
changes, we have limited the scope of this provision so that it applies 
to computer software that directly

[[Page 68627]]

affects communicable disease transmission risks. If such software is 
inappropriately designed, implemented, or used, the software may 
increase the risk of communicable disease transmission, perhaps by 
authorizing the release of HCT/Ps from an infectious donor, or by 
recording screening test results inaccurately. However, we recognize 
that commercially distributed general use software has undergone more 
rigorous testing before it is distributed. When such general use 
software is used without modification to comply with core GTP 
requirements, it is adequate for the establishment only to verify the 
performance of the software for its intended use, rather than 
undertaking more onerous validation.
    For example, an eye bank that uses commercially distributed 
software (e.g., spreadsheet, database, word processing) to comply with 
a core CGTP requirement such as control of storage areas (Sec.  
1271.260(a)), but not for making decisions or determinations, must 
verify that this general purpose software can be used reliably in such 
a way, but would not have to validate the software. Verification in a 
situation such as this is not intended to be onerous. However, if the 
eye bank decided to modify and use commercially available computer 
software for determining donor eligibility, the modifications would 
increase the risk of problems and the eye bank would then be required 
to validate the software for this intended use.
    (Comment 54) One comment noted that eye banks do not use computers 
as decisionmaking instruments, but only for information storage and 
retrieval, word processing, and form printing. This comment asserted 
that appropriate validation in this instance should entail: (1) Routine 
backup of computer system, (2) physical check of computer printout 
against paper chart, and (3) signoff by final supervisor before tissue 
release.
    (Response) The examples provided are not core CGTP requirements and 
so the requirements of Sec.  1271.160(d) would not apply.
4. Organization and Personnel (Sec.  1271.170)
    Proposed Sec.  1271.170 would require establishments to maintain an 
adequate organizational structure and sufficient personnel with the 
necessary education, experience, training and retraining to ensure 
competent performance of their assigned functions. Personnel records 
documenting these requirements would be required.
    (Comment 55) Two comments supported Sec.  1271.170 as proposed. One 
comment agreed that tissue bank personnel should be educated concerning 
the possible consequences of improperly performing their duties, and 
noted that unacceptable tissue practices could have monumental 
implications in disease transmission. This comment further asserted 
that recordkeeping on personnel training is appropriate.
    (Response) We appreciate the supportive comments. However, we have 
removed both of these proposed requirements from Sec.  1271.170. 
Section 1271.170 also does not require an establishment to maintain an 
adequate organization structure.
    (Comment 56) One comment asserted that FDA should set guidelines 
for the credentials of tissue bank directors.
    (Response) We have not included in the regulations requirements for 
specific credentials. Instead, we require that personnel have the 
necessary education, experience, and training to ensure competent 
performance of their assigned functions. Professional organizations, 
accrediting bodies, and States may decide to develop guidelines for 
certain personnel credentials.
    (Comment 57) One comment from a professional organization suggested 
replacing the phrase ``education and experience'' in proposed Sec.  
1271.170(b) with ``training and documentation of competency.''
    (Response) We agree with the comment that ``training'' should be 
added to the requirements in Sec.  1271.170(b), and we have made this 
change; however, we disagree with the proposal to remove ``education 
and experience.'' As revised, Sec.  1271.170(b) requires you to have 
personnel with the necessary education, experience, and training to 
ensure competent performance of their assigned functions.
    (Comment 58) One comment on proposed Sec.  1271.170(c) asserted 
that it is unclear what criteria a company should use to determine the 
qualifications of laboratory personnel.
    (Response) There are a variety of ways to comply with the 
requirement in Sec.  1271.170(c) that an establishment train all 
personnel to perform their assigned responsibilities adequately. Each 
establishment should establish its own criteria. Some examples of 
criteria an establishment might use to determine the qualifications of 
laboratory personnel include: Achievement of a minimum score on a 
written test, direct observation and evaluation by a supervisor, 
successful completion of continuing education courses (e.g., passing an 
examination), accreditation or proficiency testing by an outside 
organization.
5. Procedures (Sec.  1271.180)
    Proposed Sec.  1271.180 would require establishments to establish 
and maintain procedures for all significant steps that it performs in 
the manufacture of HCT/Ps.
    We have reorganized Sec.  1271.180 by dividing it into paragraphs 
for greater clarity and ease of reading. In addition, Sec.  1271.180 
now requires you to establish and maintain procedures appropriate to 
meet core CGTP requirements for all steps that you perform in the 
manufacture of HCT/Ps and further requires that these procedures be 
designed to prevent circumstances that increase the risk of the 
introduction, transmission, or spread of communicable diseases through 
the use of HCT/Ps.
    We note that, depending on the activities that you perform, your 
procedures may need to cover such issues as the length of time a 
cadaver may be stored, or the conditions of storage (e.g., 
temperature). Moreover, to prevent the recovery of contaminated cells 
or tissues, you need to establish and maintain procedures to prevent 
the recovery of cells or tissue from a septic donor or from an area of 
the body where there is a localized infection. The MMWR report cited in 
section III.C.1 of this document (Ref. 1) discussed a case in which 
tissue probably became hematogenously seeded by bowel flora before 
harvesting. The report noted that factors that may contribute to such 
contamination include the time interval between death and tissue 
retrieval, delays in refrigeration, and mode of death (e.g., trauma). 
The procedures of an establishment that recovers cells and tissue 
should appropriately address these possible causes of HCT/P 
contamination to comply with Sec.  1271.180(a).
    (Comment 59) One comment supported the section as proposed. Another 
comment asked for examples of what does or does not constitute a 
``significant step'' and asked how it differs from ``any step'' in the 
quality program requirements.
    (Response) A ``significant step'' is a step in manufacturing listed 
in the definition of ``manufacture'' in current Sec.  1271.3(e), i.e., 
all steps in the recovery, processing, storage, labeling, packaging, or 
distribution, and the screening and testing of the donor, and is not 
considered different from ``any step in the manufacture of human 
cellular and tissue-based products.'' Therefore, we have removed the 
term ``significant'' from Sec.  1271.180(a).
    (Comment 60) Proposed Sec.  1271.180 would require establishments 
to review

[[Page 68628]]

and, if necessary, revise all procedures at least once in a 12-month 
period. One comment objected to the specificity of this requirement, 
citing the more flexible requirements in the CGMP and QS regulations.
    (Response) We agree with this comment and note that the comparable 
requirements in the CGMP and QS regulations (Sec. Sec.  211.100 and 
820.40) do not require an annual review of procedures. For this reason, 
we are deleting the proposed requirement in Sec.  1271.180 that all 
procedures be reviewed on an annual basis. However, we note that the 
periodic quality audit required under Sec.  1271.160(c) should include 
a review of an establishment's SOPs.
    (Comment 61) Several comments objected to the proposed requirement 
that deviations from procedures be authorized in advance, because 
deviations are not foreseeable and cannot be authorized before they 
occur. One comment suggested requiring a justification for the 
deviation to be recorded at the time of the occurrence, and requiring 
approval of the deviation by a responsible person before release of the 
tissue.
    (Response) We agree with these comments and have modified the 
requirement in accordance with the suggestion; the requirement, which 
is now located in Sec.  1271.265, requires an establishment to record 
and justify any departure from a procedure at the time of its 
occurrence, rather than before. (We replaced the word ``deviation'' 
with the word ``departure'' to avoid confusion with the defined term 
``HCT/P deviation.) The provision further states that you must not make 
available for distribution any HCT/P manufactured under a departure 
from a procedure designed to protect against risks of communicable 
disease transmission, unless a responsible person has determined that 
the departure does not increase the risk of communicable disease 
transmission through the use of the HCT/P. For example, if the 
technician at the recovery site uses a different brand of sterile gauze 
because the brand stated in the standard operating procedures is not 
available, the establishment may make the HCT/P available for 
distribution provided that the departure was recorded and justified at 
the time, and the responsible person determines that the substitution 
did not increase the risks of communicable disease transmission.
    (Comment 62) Proposed Sec.  1271.180 would require obsolete 
procedures to be archived for at least 10 years. One comment suggested 
that a longer retention period of 10 years after transplantation would 
be more appropriate and consistent with record retention requirements 
in Sec.  1271.270.
    (Response) We have removed this requirement from the final 
regulation. However, although we do not require you to retain obsolete 
procedures, under Sec.  1271.270(d) you are required to retain records 
for 10 years unless otherwise stated.
6. Facilities (Sec.  1271.190)
    Proposed Sec.  1271.190 would require that any facility used in the 
manufacture of products be of suitable size, construction, and location 
to facilitate cleaning, relevant maintenance, and proper operations; be 
maintained in a good state of repair; and have adequate lighting, 
ventilation, plumbing, drainage, and washing and toilet facilities. 
Proposed Sec.  1271.190 also contained requirements relating to the 
division of a facility into operational areas, and relating to facility 
cleaning and sanitation.
    Section 1271.190 has been reorganized.
    (Comment 63) Three comments objected that proposed Sec.  1271.190 
is too broad and asserted that it should be limited to requirements for 
preventing the transmission of disease. Two comments suggested new 
language.
    (Response) In response to these comments, we have revised the 
language of Sec.  1271.190, reflecting the suggested language. The 
first sentence of Sec.  1271.190(a) now states that any facility used 
in the manufacture of HCT/Ps ``must be of suitable size, construction, 
and location to prevent contamination of HCT/Ps with communicable 
disease agents and to ensure orderly handling of HCT/Ps without 
mixups.''
    (Comment 64) One comment on proposed Sec.  1271.190(a) questioned 
the interpretation of ``suitable size, construction, and location.'' 
Another comment asked us to clarify the meaning of ``location.''
    (Response) As discussed in the previous comment, we have changed 
the wording of Sec.  1271.190(a) to make it clear that the suitability 
of a facility's size, construction, and location relates to preventing 
the contamination of HCT/Ps with communicable disease agents and 
ensuring orderly handling of HCT/Ps. We do not believe any other change 
is necessary. We decline to dictate specific requirements for an HCT/P 
establishment's size, construction, and location; it is more 
appropriate for establishments to make these determinations for 
themselves, based on the objectives set out in this regulation.
    By location, the regulation refers to the facility's site. Some 
examples of unsuitable locations for an HCT/P establishment, because of 
the risk of transmission of communicable disease, might include a site 
on a loading dock or in the same building as a slaughterhouse.
    (Comment 65) One comment asserted that, if an establishment is a 
tenant in a building, then bringing a problem to the attention of the 
building management, with the understanding that a response would occur 
in a reasonable time period, should be an acceptable way of complying 
with this section.
    (Response) An establishment that is a tenant should ensure that, 
under its rental agreement, the landlord will undertake the activities 
required in this section on a routine basis and within a reasonable 
amount of time. In this situation, a responsible establishment would 
communicate regularly with the landlord to bring problems to the 
landlord's attention in a timely manner. However, if a facility's 
conditions are such that the establishment is unable to manufacture 
HCT/Ps in an acceptable manner, then manufacturing activities should 
stop immediately; in this situation, where immediate repairs are 
required, simply notifying the landlord is not sufficient.
    (Comment 66) One comment requested a modification to proposed Sec.  
1271.190(a) to delete the requirement for toilet facilities.
    (Response) We decline to delete the requirement for toilet 
facilities. However, we have modified the requirement so that it now 
refers to ``access to sinks and toilets.'' As modified, the regulation 
requires toilets to be accessible, but not necessarily within the 
establishment. We have further revised the last sentence of paragraph 
(a) to state that you must provide lighting, ventilation, plumbing, 
drainage, and access to sinks and toilets to prevent the introduction, 
transmission, or spread of communicable disease.
    (Comment 67) One comment on proposed Sec.  1271.190(c) asserted 
that developing and maintaining procedures for routine cleaning and 
maintenance, such as trash removal, cleaning toilets, and sweeping 
floors, would be a waste of time and resources.
    (Response) We disagree. Maintaining a clean facility is fundamental 
to an establishment's ability to prevent the contamination of HCT/Ps. 
Without procedures in place, this important responsibility may be left 
to chance. An establishment's procedures might state, for example, how 
often a particular floor

[[Page 68629]]

is to be mopped and which disinfectant must be used. Such procedures 
are basic elements of communicable disease prevention and are not 
trivial matters.
    We recognize, however, that not all cleaning and sanitation that 
you may perform will relate to these requirements (e.g., vacuuming the 
lobby); thus, we have modified paragraph (d)(1) to limit its scope to 
procedures for facility cleaning and sanitation for the purpose of 
preventing transmission of communicable disease. We have made a similar 
change to paragraph (b)(1), which now requires you to maintain 
facilities in a clean, sanitary, and orderly manner, to prevent the 
transmission of communicable disease.
    The requirements for facility cleaning in proposed paragraphs 
(c)(1) and (c)(2) are now in paragraph (b); the requirement for 
procedures in proposed Sec.  1271.190(c)(3) is contained in Sec.  
1271.190(d)(1); and the requirement for record retention in proposed 
Sec.  1271.190(c)(4) is contained in Sec.  1271.190(d)(2).
    (Comment 68) Another comment asked for clarification of the phrase 
``significant cleaning and sanitation activities'' in proposed Sec.  
1271.190(c)(4). This comment opposed a requirement to keep mopping 
records for 10 years, but supported keeping records of changing the air 
handling filters.
    (Response) For clarity, we have removed the word ``significant'' 
from Sec.  1271.190(c)(4), now renumbered as paragraph (d)(2). This 
paragraph now requires you to document and maintain records of ``all 
cleaning and sanitation activities performed to prevent contamination 
of HCT/Ps.'' Generally, cleaning and sanitation activities performed in 
the manufacturing area would be performed to prevent contamination of 
HCT/Ps, while these activities performed elsewhere in the establishment 
(e.g., business offices, lobby) would not be performed for that 
purpose. Thus, all sanitation activities in certain areas would need to 
be documented. Although it is not necessary to maintain actual mopping 
records, you do need to document that cleaning in accordance with 
procedures took place (e.g., by having the person performing this task 
initial a log).
    We also agree with the comment regarding record retention and we 
have revised the requirement for retaining records of facility cleaning 
and sanitation activities from 10 years to 3 years, which allows the 
records to be available for an inspection cycle.
7. Environmental Control and Monitoring (Sec.  1271.195)
    Proposed Sec.  1271.195 would require establishments to establish 
and maintain procedures to adequately control and monitor environmental 
conditions and to provide proper conditions for operations. It would 
also require inspections and recordkeeping.
    We have reorganized Sec.  1271.195. The requirement for 
environmental monitoring in proposed paragraph (a) is now contained in 
paragraph (c). Moreover, paragraph (a) no longer requires the 
establishment and maintenance of procedures for the control and 
monitoring of environmental conditions. That paragraph now states, in 
part, that ``you must adequately control environmental conditions.''
    (Comment 69) Three comments discussed the applicability of this 
section to eye banking. One comment asserted that because corneas 
remain in closed, sealed vials once final placement in media occurs, 
the requirement for control and monitoring of ventilation and air 
filtration systems would not apply. Two other comments cited the use of 
laminar flow hoods in work on eye tissue and argued that the 
installation of a major environmental control system would be cost 
prohibitive and unnecessary.
    (Response) Rather than require environmental control and monitoring 
by all establishments in all situations, we have adopted a flexible 
approach that allows each establishment to assess its particular needs. 
Thus, Sec.  1271.195(a) requires environmental control and monitoring 
``where environmental conditions could reasonably be expected to cause 
contamination or cross-contamination of HCT/Ps or equipment, or 
accidental exposure of HCT/Ps to communicable disease agents.'' In 
those situations, you must adequately control environmental conditions 
and provide proper conditions for operations. The regulation lists 
control activities or systems that must be employed, where appropriate. 
(``Where appropriate'' is explained in Sec.  1271.150(e).) It may not 
be necessary to institute a facility-wide control system in situations 
where work on HCT/Ps is performed in a controlled environment (e.g., 
use of a laminar hood that is subject to control).
    (Comment 70) Proposed Sec.  1271.195(a)(3) would require cleaning 
and disinfecting of rooms and equipment to ensure aseptic processing 
operations, where appropriate. Two comments asserted that, where other 
control systems to prevent contamination are in place, cleaning and 
disinfection of rooms and equipment are not necessary.
    (Response) The regulation allows establishments to develop 
environmental control systems that are appropriate to their activities. 
If control systems are in place to prevent contamination, then an 
establishment should institute measures to ensure that these controls 
are performing as intended. It appears unlikely, however, that cleaning 
and disinfection would not be a necessary component of controls.
    (Comment 71) Proposed Sec.  1271.195(a)(5) would require 
environmental monitoring for organisms, where appropriate. One comment 
asserted that there is no expert consensus on which organisms to 
monitor and that the regulation should be more specific.
    (Response) We agree that there is no expert consensus on a single 
list of organisms for which all facilities should monitor; however, we 
disagree that it is necessary for us to provide a list in this 
regulation. Conditions may differ from facility to facility (and even 
from room to room within a facility), with common microorganisms found 
in one area but not another. Each establishment should determine the 
microorganisms that may exist in its facilities and design its 
monitoring program accordingly.
    FDA has issued a draft guidance document entitled ``Guidance for 
Industry: Sterile Drug Products Produced by Aseptic Processing, Current 
Good Manufacturing Practice,'' dated August 2003, (http://www.fda.gov/cber/gdlns/steraseptic.htm) that may provide useful information to an 
HCT/P establishment that is developing procedures on environmental 
control and monitoring. Information on environmental monitoring may 
also be found in the U.S. Pharmacopoeia.
    The requirement for monitoring for microorganisms in proposed Sec.  
1271.195(a)(5) has been moved to Sec.  1271.195(c).
8. Equipment (Sec.  1271.200)
    Proposed Sec.  1271.200 would require that equipment used in the 
manufacture of HCT/Ps be appropriately designed for its use, and be 
suitably located and installed to facilitate operations, including 
cleaning and maintenance. It also contained requirements for procedures 
and schedules, calibration of equipment, inspections, and records.
    (Comment 72) One comment asserted that the proposed requirement is 
overly broad and that the regulation should allow establishments to 
write and

[[Page 68630]]

maintain procedures for use of equipment, cleaning, and calibration 
that prevent circumstances that increase the risk of introduction, 
transmission, or spread of communicable disease. Another comment asked 
whether the requirements in Sec.  1271.200 should be limited to 
concerns of communicable disease transmission.
    (Response) We agree with the comments that Sec.  1271.200 should be 
limited to concerns of communicable disease transmission. Therefore, 
the first sentence of Sec.  1271.200(a) now reads
    To prevent the introduction, transmission, or spread of 
communicable diseases, equipment used in the manufacture of HCT/Ps 
must be of appropriate design for its use and must be suitably 
located and installed to facilitate operations, including cleaning 
and maintenance.
    Under Sec.  1271.200(b), an establishment must establish and 
maintain procedures for cleaning, sanitizing, and maintaining equipment 
to prevent malfunctions, contamination or cross-contamination, 
accidental exposure of HCT/Ps to communicable disease agents, and other 
events that could reasonably be expected to result in the introduction, 
transmission, or spread of communicable diseases.
    (Comment 73) Several comments asked that vendor validation and 
maintenance records be acceptable for compliance with Sec.  1271.200.
    (Response) You may use vendor validation and maintenance records to 
demonstrate compliance with Sec.  1271.200; however, you are still 
responsible for having a system in place designed to ensure that the 
services provided by the contractor are adequate and in compliance with 
applicable requirements. Section 1271.150 addresses the question of 
work performed by other establishments or contractors.
    (Comment 74) Proposed Sec.  1271.200(a) would require, in part, 
that any automated, mechanical, electronic, computer, or other 
equipment used for inspection, measuring, and testing be capable of 
producing valid results. One comment asked us to clarify the meaning of 
``valid results'' in proposed Sec.  1271.200(a). The comment stated 
that valid results may be obtained through appropriate validation and/
or calibration of equipment.
    (Response) We agree that ``capable of producing valid results'' 
does not mean validation of equipment. The requirement is for the 
equipment to work properly, thereby providing ``valid results.'' This 
may be accomplished by calibrating, inspecting, and maintaining 
equipment. (See e.g., ``Medical Devices; Current Good Manufacturing 
Practice (CGMP) Final Rule; Quality System Regulation,'' 61 FR 52602, 
October 7, 1996.)
    (Comment 75) Proposed Sec.  1271.200(c) would require calibration 
of all automated, mechanical, electronic, computer, or other equipment 
used for inspection, measuring, and testing. One comment objected to 
the requirement for calibration of computers because computers do not 
make measurements, and asserted that validation should be sufficient. 
Another comment stated that the calibration of slit lamps is not 
practical.
    (Response) We have revised paragraph (c) in response to these 
comments. First, we have removed computers from the listed types of 
equipment in this paragraph and in paragraph (a). Second, we have added 
``where appropriate'' to the first sentence of the paragraph. We have 
made these changes because we recognize that there are certain pieces 
of equipment that cannot be calibrated (e.g., computers, slit lamps). 
We have also removed the second and third sentences of proposed 
paragraph (c), which related to direction for calibration; accuracy and 
precision limits; and corrective actions.
    (Comment 76) Approximately eight comments objected to the 
requirement in proposed Sec.  1271.200(e) that records of recent 
maintenance, cleaning, sanitizing, calibration, and other activities be 
kept ``at each piece of equipment.'' One comment recommended that 
facilities be allowed the flexibility to maintain the records in a 
location that is easily accessible to the equipment but not directly at 
the equipment site. Another comment agreed that these records must be 
maintained but noted that it is important to keep the amount of paper 
to a minimum in a clean room environment and suggested that the 
documents need only be readily retrievable. One comment noted that 
records cannot physically be kept on small instruments such as pipettes 
and suggested the use of a central repository.
    (Response) We agree with these comments and have revised the 
regulation. Section 1271.200(e) now states, in part, that you must 
display records of recent maintenance, cleaning, sanitizing, 
calibration, and other activities on or near each piece of equipment, 
or make the records readily available to the individuals responsible 
for performing these activities and to the personnel using the 
equipment. This new language, which is based on Sec.  820.72, provides 
establishments with more flexibility than the proposed provision would 
have given.
    (Comment 77) One comment asserted that the records requirement in 
proposed Sec.  1271.200(e) should be limited to major equipment and 
should not include simple instruments that are regularly washed and 
disinfected or disposable equipment that has a validated procedure for 
cleaning and disinfecting.
    (Response) We disagree with the suggestion to exempt simple 
instruments from the requirements of this rule. Records for cleaning 
and maintenance of instruments, tools, and other equipment used or 
reused in the manufacturing of HCT/Ps must be kept to document that the 
items were adequately cleaned and maintained to prevent their 
contamination or cross-contamination by communicable disease agents. 
Single-use instruments, tools, or other equipment would not be subject 
to the requirement if they are used only one time and are disposed of 
after use.
9. Supplies and Reagents (Sec.  1271.210)
    Proposed Sec.  1271.210 would require the establishment to 
establish and maintain procedures for receiving supplies and reagents 
used in the manufacture of HCT/Ps. These items would be verified to 
meet specifications designed to prevent circumstances that increase the 
risk of introduction, transmission, or spread of communicable disease 
through HCT/P contamination. Supplies and reagents are materials that 
might be used during manufacture, but do not include any material that 
might become a component of an HCT/P (66 FR 1508 at 1515).
    We have reorganized Sec.  1271.210. The requirement for validation 
or verification of the production of in-house reagents is now in 
paragraph (c) and refers to processes instead of procedures; records 
requirements are now in paragraph (d).
    (Comment 78) One comment supported the regulation as proposed, 
noting however that compliance would be costly.
    (Response) We address concerns about compliance costs separately, 
in section V of this document.
    (Comment 79) One comment on proposed Sec.  1271.210(a) questioned 
whether the receipt requirements pertained to supplies used solely in 
the recovery of human tissues.
    (Response) Section 1271.210 applies to all steps in the manufacture 
of HCT/Ps, including recovery. Use of a contaminated or otherwise 
defective supply or reagent in the manufacture of an HCT/P could lead 
to such problems as the introduction of a disease agent or

[[Page 68631]]

the failure to properly preserve the HCT/P. It is important for 
establishments to establish and maintain procedures for receiving 
supplies and reagents, including verification, at each step of 
manufacture, beginning with recovery. We note that Sec.  1271.210(a) no 
longer contains a requirement for procedures. However, Sec.  
1271.210(a) and (b) are core CGTP requirements listed in Sec.  
1271.150(b); therefore, the requirement for establishing procedures 
under Sec.  1271.180 applies to these two paragraphs.
    (Comment 80) One comment asked whether vendor verification is 
required for all supplies or only for those that come in contact with 
the donor or the recovered tissue.
    (Response) Verification by you or the supply vendor is required for 
all supplies and reagents that may be used in the course of 
manufacture, not simply those that may come in contact with a donor or 
an HCT/P. For example, a reagent used in donor testing must be 
verified, even if it does not come into contact with the donor or the 
donated tissue.
    (Comment 81) One comment asserted that the requirement is overly 
broad and requested that we allow establishments to write and maintain 
procedures for use of supplies and reagents that prevent circumstances 
that increase the risk of introduction, transmission, or spread of 
communicable disease.
    (Response) We have narrowed Sec.  1271.210 to apply more 
specifically to preventing the introduction, transmission, or spread of 
communicable diseases.
    (Comment 82) Proposed Sec.  1271.210(c) contains records 
requirements, and paragraph (c)(3) would require records of the use of 
each supply or reagent, including the identification of each HCT/P 
manufactured with the supply or reagent. One comment noted that, for 
many HCT/Ps, lots are small, and a requirement for separate records 
would present an enormous burden. Another comment questioned the 
utility of listing each product processed by each pipette or bottle of 
medium. A third comment asserted that, although the processing records 
for each hematopoietic stem/progenitor cell preparation should identify 
supplies and reagents used for processing, it would be prohibitively 
time-consuming to maintain separate records of each transplant prepared 
with each reagent.
    (Response) You should establish a system under which particular 
lots of supplies and reagents can be linked to individual HCT/Ps. This 
does not require an individual record for each HCT/P prepared with each 
reagent, as the comment suggested. Therefore, we have added ``lot'' to 
renumbered paragraph (d)(3) to make clear the lesser burden. We have 
also added ``quantity'' so that the establishment may find all supplies 
and reagents received in the event of a recall by the manufacturer. 
Maintaining the records required in paragraph (d)(3) will enable you to 
do a cross-check to determine which lots of supplies and reagents were 
used at a particular time and which HCT/Ps were processed during that 
same time period (e.g., if there is a recall of a particular lot of 
reagent or supplies).
10. Recovery (Sec.  1271.215)
    This final rule includes a new section specific to the recovery of 
cells and tissues, Sec.  1271.215. This section states that, if you are 
an establishment that recovers HCT/Ps, you must recover each HCT/P in a 
way that does not cause contamination or cross-contamination during 
recovery, or otherwise increase the risk of the introduction, 
transmission, or spread of communicable disease through the use of the 
HCT/P. This requirement was implicit in the proposed rule (e.g., Sec.  
1271.180); however, in reorganizing the rule we have determined that it 
is necessary to make this requirement explicit. Section 1271.215 is 
listed as a core CGTP requirement in Sec.  1271.150(b). As discussed in 
section III.C.5 of this document, you must establish and maintain 
procedures for cell and tissue recovery.
11. Processing and Process Controls (Sec.  1271.220)
    Proposed Sec.  1271.220 would require an establishment engaged in 
processing to develop, conduct, control, and monitor its manufacturing 
processes to ensure that each HCT/P conforms to specifications, is not 
contaminated, and is manufactured so as to prevent transmission of 
communicable disease by the HCT/P. Proposed Sec.  1271.220 also 
contains requirements with respect to processing materials, pooling, 
and in-process monitoring.
    We have moved the provision on dura mater from proposed Sec.  
1271.230(c) to Sec.  1271.220(d); we address comments on the proposed 
provision with other comments on proposed Sec.  1271.230.
    (Comment 83) One comment requested an exemption for eye banks from 
this section, because corneas are not processed in accordance with 
FDA's definition. Another comment asserted that the section is 
inapplicable to eye banks.
    (Response) We disagree. Eye banks that perform even minimal 
processing must control their processes. At Comment 21, we explain the 
applicability of the term ``processing'' to eye banking.
    (Comment 84) Proposed Sec.  1271.220(a) would require, in part, 
that each establishment develop, conduct, control, and monitor its 
manufacturing processes to ensure that each HCT/P conforms to 
specifications. One comment required that we define ``specifications.'' 
Another comment noted that there are no specifications set for corneas, 
but that criteria are determined by local medical directors in 
conjunction with professional standards.
    (Response) Requirements with respect to in-process control and 
testing are now contained in Sec.  1271.220(c). We have also removed 
references to specifications from Sec.  1271.220(a). That paragraph now 
requires that, if you are an establishment that processes HCT/Ps, you 
must process each HCT/P in a way that does not cause contamination or 
cross-contamination during processing, and that prevents the 
introduction, transmission, or spread of communicable disease through 
the use of the HCT/P.
    We recognize, however, that the term ``specifications'' appears 
elsewhere in this regulation (e.g., Sec.  1271.3(dd), definition of 
``HCT/P deviation''). We noted in the preamble to the proposed rule 
that, by ``specifications,'' we meant those criteria established by a 
manufacturer for an HCT/P that must be met at defined stages in the 
manufacturing process and before the product is made available for 
distribution (66 FR 1508 at 1516). Ordinarily, an establishment will 
set specifications for various operations within its facility, not just 
processing. Because we believe the term is generally well understood, 
we do not consider it necessary to define the term in this rule.
    As noted in our response to Comment 19, we understand that an eye 
bank might not set specifications for corneas. However, we expect that 
an establishment will generally set out acceptability criteria for its 
HCT/Ps in its standard operating procedures.
    (Comment 85) One comment requested clarification of the requirement 
for monitoring and control of validated processes. This comment asked 
if the quality review is sufficient to ensure that specific processes 
continue to be met.
    (Response) We have removed from Sec.  1271.220(a) the specific 
requirement for monitoring and control of processes. However, we 
believe that, to ensure that you are processing HCT/Ps in a way that 
does not cause contamination or cross-

[[Page 68632]]

contamination during processing, and that prevents the introduction, 
transmission, or spread of communicable disease through the use of the 
HCT/P, a firm should establish appropriate, objective mechanisms to 
control and monitor each validated process. This may include a variety 
of activities, e.g., statistical process-control methods, review of 
product acceptance criteria and results, as well as a meaningful 
quality audit.
    (Comment 86) One comment asserted that we seem to be requiring that 
tissue be sterile and that decontamination processes be validated to 
produce tissue that is not contaminated or is sterile. The comment 
asserted that viable tissue cannot be made sterile and that reducing 
bioburden is not the same as eradicating contamination.
    (Response) FDA is not requiring at this time that tissue be 
sterile, but we do expect aseptic techniques to be used during 
manufacturing to prevent contamination and cross-contamination. Indeed, 
it is the current industry practice to use aseptic techniques during 
recovery and processing. Whenever an activity is used in the processing 
of HCT/Ps, that activity must be controlled to limit the introduction 
of disease agents. When technology progresses to the extent that viral 
clearance or sterilization is feasible, FDA may revise these CGTPs to 
require that HCT/Ps be sterile. FDA welcomes submissions as to when 
technology will have progressed to this point.
    (Comment 87) One comment on proposed Sec.  1271.220(a) requested 
clarification of the term ``manufacturing process.''
    (Response) We have re-examined our use of the phrase 
``manufacturing process'' in Sec.  1271.220(a) and have concluded that 
it is confusing. Processing is one of the steps in manufacture, as 
defined in Sec.  1271.3(e). Because Sec. Sec.  1271.220, 1271.225, and 
1271.230 pertain only to processing, rather than to the other steps in 
manufacture, we have replaced ``manufacturing process'' with 
``process.''
    (Comment 88) We received five comments on proposed Sec.  
1271.220(b), which addressed processing materials. Two comments noted 
that it is not always possible to document that a processing material 
has been removed from an HCT/P, and that validated procedures should be 
sufficient. One comment proposed the use of published data and industry 
practice to determine whether a processing material or its residues may 
elicit an adverse reaction. This comment also recognized that product 
labeling may be used to warn potential users with respect to the 
possible presence of residues.
    (Response) We have removed proposed paragraph (b) in its entirety 
from Sec.  1271.220 and renumbered the paragraphs accordingly.
    Pooling.
    Proposed Sec.  1271.220(c) states that human cells or tissues from 
two or more donors shall not be pooled (placed in physical contact or 
mixed in a single receptacle) during manufacturing. We noted that 
commingling of cells or tissues from a single infected donor with cells 
or tissues from other donors could contaminate the entire pooled 
quantity, greatly increasing the risk of exposure to infectious agents 
to recipients of the pooled materials (66 FR 1508 at 1516). Proposed 
paragraph (c) has been renumbered as (b).
    (Comment 89) Approximately six comments agreed with the proposed 
prohibition on pooling. Several comments pointed to an increased risk 
of infectious disease transmission associated with pooling, and 
asserted that pooling could increase the threat of previously unknown 
transmissible diseases. One comment asserted that there is a 
particularly high risk for Rh-negative women of childbearing age who 
receive tissue from Rh-positive donors. Two comments argued that 
pooling would impair the effectiveness of tissue recalls, because 
tracing to the source of a problem would be impossible. Comments also 
questioned the efficacy of processes used to manufacture pooled HCT/Ps 
and noted that no process entirely eliminates the risk of infectious 
disease transmission. Two comments asserted that pooling would be 
distasteful to donors and their families.
    (Response) These comments raise valid concerns. We agree in 
particular with the concerns expressed about the increased risk of 
communicable disease transmission and the difficulty of tracking pooled 
HCT/Ps.
    (Comment 90) Approximately 10 comments opposed our proposal to 
prohibit the pooling of cells or tissues. Several comments argued that 
the proposed regulation is too restrictive and could stifle new 
technologies.
    (Response) Although we are aware of promising new technologies that 
involve the pooling of cells from two or more donors, we remain 
concerned about the infectious disease risks inherent in pooling. On 
June 26, 2002, FDA consulted the Transmissible Spongiform 
Encephalopathies Advisory Committee (TSEAC) about the validation of 
procedures to prevent contamination and cross-contamination of HCT/Ps 
by TSE agents. At this meeting, speakers presented information on the 
three approaches that could be taken to reduce the risk of TSE 
transmission:
     Careful screening of the donor for TSE and risk factors 
for TSE;
     Control of the recovery and processing of cells and 
tissues to prevent contamination and cross-contamination; and
     Use of steps during processing to remove or inactivate any 
TSE agents that may be present.
    One of the processing controls discussed was the use of single 
donor aseptic recovery and processing, rather than a process that would 
involve pooling of cells or tissues from two or more donors. When asked 
about specific measures and controls appropriate to prevent TSE agent 
transmission (e.g., single donor aseptic processing), the committee 
voted unanimously that single donor processing should be considered the 
gold standard, but that a pooled process may be appropriate under 
certain circumstances with adequate controls. The committee members did 
not discuss which circumstances and what controls would be adequate.
    Under Sec.  1271.155, an establishment may submit a request for an 
alternative or exemption from the prohibition from pooling provided 
that it has data showing that the processing method adequately 
addresses the risks associated with pooling.
    (Comment 91) Two comments opposed our assertion that commingling 
cells or tissues from different donors, who have been screened and 
tested, would increase the risk to recipients of exposure to infectious 
agents.
    (Response) We disagree with these comments. Screening and testing 
of donors, although crucial, does not completely eliminate infectious 
disease risk, for several reasons. The donor may be in the ``window 
period'' during which he or she may be infectious (i.e., have viral 
marker levels that are below detection by current tests). Chronic 
carriers of a disease may be immuno-silent; i.e., they do not mount an 
antibody response. In addition, laboratory errors may be made, or an 
HCT/P may be released improperly. Moreover, current tests may not 
detect all genetic variants of a particular virus, or a donor may be 
infected with an ``emerging infectious disease,'' for which screening 
measures or tests have not been developed. Finally, there may be 
questions about the accuracy of current tests that are not approved by 
FDA for use with cadaveric specimens and about the reliability of donor 
histories obtained from another person

[[Page 68633]]

(not the donor). Each of these risks is small, and presents a small 
chance of leading to communicable disease transmission to a single HCT/
P recipient. However, the risk is magnified when HCT/Ps from different 
donors are pooled during manufacture. Information provided at the TSEAC 
meeting described previously showed that the risk of exposing a 
recipient to an infectious disease agent contained in a pool, where one 
or more units in the pool were recovered from an infected donor, is 
directly proportional to the prevalence of the agent in the donor 
population and the size of the pool.
    (Comment 92) Several comments pointed out benefits of pooling. Two 
comments pointed to the need for pooling to obtain a sufficient dose of 
an HCT/P, especially in adults (e.g., from cord blood). One comment 
stated that pooling contributes to product consistency and uniformity.
    (Response) We are retaining the prohibition on pooling during 
manufacturing in Sec.  1271.220(b). We continue to believe that, in 
general, the risks of pooling HCT/Ps (increased risk of communicable 
disease transmission) outweigh the benefits of pooling. For some 
biological products, e.g., plasma derivatives, the benefits of pooling 
outweigh the risks. In the case of plasma derivatives, pooling 
contributes to product consistency. In fact, 21 CFR 640.102(d) requires 
that material from not less than 1,000 donors be pooled to make immune 
globulin. For plasma derivatives, it is necessary to pool plasma from 
many donors to obtain an adequate amount of product to treat one 
recipient (i.e., a sufficient dose). In addition, pooling plasma may 
dilute the viral burden or provide neutralizing antibodies that may 
inactivate any virus present in the pool. However, these benefits of 
pooling do not apply, in general, to the pooling of HCT/Ps from many 
donors. For instance, tendons from different donors would not need to 
be pooled to provide consistency or to obtain a sufficient dose. 
Neither would bones pooled from different donors provide neutralizing 
antibodies to inactivate any virus present in the pool, since 
neutralizing antibodies are present in plasma. In the case of cord 
blood, most of the plasma is removed during processing, so that pooling 
of cord blood from different donors would not provide sufficient 
neutralizing antibodies to neutralize any virus present in the pool. 
Furthermore, when cord blood units from more than one donor are 
administered to an adult recipient to obtain a sufficient dose, the 
units are generally given sequentially and are not pooled.
    In order for us to determine whether any benefits to pooling HCT/Ps 
from different donors outweigh the risks in a particular case, we would 
need additional data. Such data may be submitted and evaluated under a 
request for an alternative or exemption in Sec.  1271.155.
    (Comment 93) Several comments asserted that the risks of pooling 
could be mitigated through validated procedures for clearing pathogens 
or sterilizing the pooled HCT/Ps. One of these comments suggested 
additional regulatory language that would permit pooling where it is 
necessary and does not create an unreasonable risk of communicable 
disease transmission. Another comment proposed that the final rule 
should allow the pooling of stem cell products from two or more donors, 
as long as the resulting pooled product is transplanted into only one 
recipient.
    (Response) We agree that, in some instances, it may be appropriate 
to assess the risks and benefits of pooling. Such assessment could be 
submitted under Sec.  1271.155 in a request for an exemption or 
alternative to the prohibition on pooling in Sec.  1271.220(b). 
However, we decline to modify the proposed regulation as suggested and, 
for the reasons explained in Comments 89 through 92, we have retained 
the general prohibition on pooling.
    (Comment 94) One comment that supported proposed Sec.  1271.220(c) 
asserted that no waivers or exceptions should be allowed that would 
permit pooling.
    (Response) We disagree with this comment. Although we remain very 
concerned about the communicable disease risks associated with pooling, 
we do not rule out the possibility that pooling may be appropriate in 
some specific situations. We will consider requests for exemptions from 
or alternatives to Sec.  1271.220(b) under the provisions of Sec.  
1271.155. At the June 2002 TSEAC meeting described previously, the 
committee members supported the possibility that exemptions from the 
proposed pooling prohibition might be appropriate, but did not discuss 
criteria upon which to grant such an exemption.
    In-process control and testing.
    Proposed Sec.  1271.220(d) would require procedures to ensure that 
specified requirements for in-process HCT/Ps are met. These procedures 
must ensure that an in-process HCT/P is controlled until the required 
inspection and tests or other verification activities have been 
completed or necessary approvals are received and documented. In 
addition, sampling of in-process HCT/Ps must be representative of the 
material to be evaluated.
    There were no comments on this provision, which has been renumbered 
paragraph (c). We have revised this paragraph to cover in-process 
control and testing. Paragraph (c) requires you to ensure that 
specified requirements, consistent with paragraph (a) of this section, 
for in-process controls are met, and that each in-process HCT/P 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 HCT/Ps must be 
representative of the material to be evaluated.
    We note that paragraph (c) includes the prevention of bacterial and 
other contamination. Compliance with this paragraph requires checking 
the results of testing at various steps in processing (for example, by 
sampling in-process HCT/Ps). The sample selected for testing (e.g., 
culture) must be representative of the entire HCT/P. This may not be 
the case if a small snip of the HCT/P or companion tissue (i.e., tissue 
adjacent to the HCT/P that is processed along with the HCT/P) is 
cultured. The MMWR cited in section III.C.1 of this document 
recommended that performing both destructive (i.e., performed on tissue 
that had been ground up) and swab cultures (of the tissue surface) 
should be considered (Ref. 1).
    Dura mater.
    Proposed Sec.  1271.230(c) would require dura mater to be processed 
using a validated procedure that reduces TSE while preserving the 
clinical utility of the product. We have moved proposed Sec.  
1271.230(c) to Sec.  1271.220(d) because it relates more closely to 
processing and process controls than to process validation.
    (Comment 95) Three comments objected to proposed Sec.  1271.230(c). 
One comment urged us to eliminate the provision, because FDA should not 
endorse the concept of an acceptable level of TSE risk, and another 
comment asserted that there is no acceptable level of TSE 
contamination. Another comment opined that the proposed rule is 
arbitrary because FDA has not validated methods for decontaminating 
tissue contaminated with prions.
    (Response) We disagree that FDA is endorsing the concept of an 
acceptable level of TSE risk. The donor-eligibility rule requires 
screening of all HCT/P donors for TSE risk factors and testing of dura 
mater donors (see Sec. Sec.  1271.75(a) and 1271.85(e)). In this rule, 
we are requiring additional processing safeguards to reduce the level 
of the TSE agent that may be present in dura mater,

[[Page 68634]]

even after a donor has been determined to be eligible based on 
screening and testing. Taken together, these requirements are intended 
to help prevent the transmission of TSE by dura mater and should by no 
means be considered to endorse an acceptable level of risk. Eliminating 
proposed Sec.  1271.230(c) would decrease the safeguards in place and 
elevate the risk; we decline to take this step.
    We disagree that the requirement to use a validated procedure is 
arbitrary or that it is necessary for FDA to validate procedures for 
the removal of the TSE agent in human tissue. TSEAC has recommended 
treating human dura mater with sodium hydroxide (June 26, 2002), and in 
the preamble to the proposed rule we cited a sodium hydroxide (NaOH) 
protocol as an example of a validated procedure (66 FR 1508 at 1517). 
The TSEAC recommendation was based on a study in an animal model, in 
which 1.0N NaOH treatment reduced Creutzfeld Jakob Disease (CJD) 
infectivity (Refs. 2, 3, and 4). However, we realize that this method 
is not being used for reducing TSE infectivity in human dura mater 
distributed at this time, and that there are no other validated methods 
currently available. Although 1.0N NaOH treatment reduces infectivity, 
this process can also decrease the clinical utility of the dura mater. 
Therefore, Sec.  1271.220(d) requires use of a published validated 
process when one becomes available.
    As new validated processes become available, they will be published 
in the literature. You do not have to validate the published procedure; 
rather you must verify that the previously validated process has been 
fully and properly implemented in your establishment. We recognize that 
processing methods may be developed that reduce the risk of TSE but 
that render the HCT/P no longer useful for its purpose. Accordingly, 
you are not required to implement a process if it adversely affects the 
clinical utility of the dura mater. Alternatively, you may validate an 
equivalent procedure for use in your establishment that is at least as 
effective as the published procedure, without adversely affecting the 
clinical utility of the dura mater.
    We recognize that, due to a variety of circumstances, you may not 
be aware when there is a published, validated process that reduces the 
risk of TSE. We intend to follow the good guidance practices set out in 
21 CFR 10.115 to advise you when we have identified the existence of a 
published, validated process that reduces the risk of TSE, and we would 
ordinarily solicit public comment before issuing a final guidance.
12. Process Changes (Sec.  1271.225)
    Proposed Sec.  1271.225 would require the establishment to 
establish and maintain procedures for making changes to a process. Such 
changes would be verified or validated, and approved by a responsible 
person before implementation. We have removed from Sec.  1271.225 the 
requirement that establishments have procedures for making process 
changes.
    (Comment 96) One comment asserted that this section does not apply 
to eye banks and that they should not be required to comply. Another 
comment from an eye bank stated that the section is too broad and 
should be narrowed.
    (Response) Section 1271.225 applies to establishments engaged in 
the processing of HCT/Ps, including eye banks that perform processing 
activities. For example, a switch from one brand of storage solution to 
another would be a process change. In this situation, the eye bank must 
verify that the new process performs as intended in a manner that does 
not introduce, transmit, or spread communicable disease agents.
    Under Sec.  1271.150(b), an establishment need only comply with 
those requirements applicable to the operations in which it engages 
(Sec.  1271.150(b)). Thus, if you are an establishment that does not 
engage in the processing of HCT/Ps, you do not need to comply with 
Sec.  1271.225. We have discussed the meaning of ``processing'' at 
Comment 20. We disagree that it is necessary to narrow the provision, 
which is intended to apply to the full range of HCT/P establishments 
engaged in processing.
    (Comment 97) One comment on proposed Sec.  1271.225(a) asserted 
that most, but not all, changes will need to be verified or validated. 
As examples of simple changes that should not require verification or 
validation, the comment cited requirements for additional training or 
changes in location or storage of records. The comment suggested that 
we add the phrase ``if appropriate as determined by a risk 
assessment.''
    (Response) Under Sec.  1271.225, if you are an establishment 
engaged in the processing of HCT/Ps, you are required to verify or 
validate any change to a process, to ensure that the change does not 
create an adverse impact elsewhere in the operation. The examples cited 
by the comment are not examples of process changes.
    (Comment 98) Proposed Sec.  1271.225(b) contained requirements for 
maintaining change records. One comment agreed that records of the 
rationale for each change should be maintained, calling this 
requirement a real time saver. Another comment asserted that Sec.  
1271.225(b) is more stringent than the comparable requirement for 
blood.
    (Response) We have removed the requirement for documenting all 
changes to an established process and the rationale for such a change. 
We have maintained the proposed requirement for communicating approved 
changes to appropriate personnel in a timely manner; however, it no 
longer appears in paragraph (b), which has been deleted.
13. Process Validation (Sec.  1271.230)
    Where the results of a process cannot be fully verified by 
subsequent inspection and tests, proposed Sec.  1271.230 would require 
the process to be validated and approved according to established 
procedures. The validation activities, results, and the date and 
signature of the individual approving the validation would be 
documented. Re-validation would be required where appropriate in the 
case of changes to a validated procedure.
    We have revised Sec.  1271.230. Paragraph (a) now refers to 
processing described in Sec.  1271.220. Paragraph (b) now refers to 
written representations, rather than claims, and is more limited than 
proposed. Paragraph (c) on dura mater is now Sec.  1271.220(d). 
Paragraph (d) requiring procedures for the monitoring and control of 
validated processes has been deleted. For clarity, we have deleted the 
word ``deviations'' from proposed Sec.  1271.230(e), now Sec.  
1271.230(c); that paragraph now refers only to changes to a validated 
process.
    (Comment 99) Several comments asserted that the requirement for 
process validation in proposed Sec.  1271.230 does not apply to eye 
banking. One comment cited the use of annually validated mechanical 
devices used in processing eye tissue and the evaluation of tissue by 
trained personnel.
    Another comment asserted that the rule is vague as to which 
processes a company should validate and approve and how the validation 
and approval should be conducted. This comment further asserted that 
the rule fails to take into account the unique biological 
characteristics of the various human cell and tissue types (e.g., 
musculoskeletal tissue).
    (Response) We have carefully worded Sec.  1271.230 to take into 
account the uniqueness of various HCT/Ps. Thus, Sec.  1271.230(a) 
requires validation of a process where the results of processing 
described in Sec.  1271.220 cannot be fully

[[Page 68635]]

verified by subsequent inspection and tests. Rather than being vague, 
this language recognizes that an establishment has specific knowledge 
of the HCT/Ps it manufactures, including when verification activities 
will suffice and when process validation is required because results 
cannot be fully verified. We agree that the control and results of the 
processes performed at eye banks may be able to be achieved through 
verification activities; in this case, validation would not be 
required.
    (Comment 100) One comment asserted that the documentation of eye 
and tissue banking successes in medical literature should constitute 
sufficient objective evidence for procedures that have been in use for 
years and that documentation of meeting predetermined specifications 
should only be required for new procedures that are not consistent with 
pre-existing standards and practices.
    (Response) We disagree. Medical literature alone is insufficient to 
verify or validate the processes performed at a specific establishment. 
Each establishment that performs steps in the processing of HCT/Ps must 
demonstrate that it has validated or verified a given process at that 
particular establishment and that it is capable of controlling that 
process. These steps must be taken for all processes conducted by an 
establishment, regardless of when the process was initiated or how long 
the process has been in place.
    (Comment 101) Proposed Sec.  1271.230(a) states, in part, that 
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. Two comments recommended deleting 
the word ``fully'' from this provision, arguing that it is too broad 
and could be subject to inconsistent application. These comments 
asserted that, once a process has been validated, if changes are 
required that do not increase the risk of communicable disease 
transmission to the recipient, a written justification for not 
revalidating should be sufficient.
    (Response) We disagree with the comments' suggestion to delete 
``fully.'' The term ``fully verified'' has been used with respect to 
process validation in ISO standards for years. Moreover, the term is 
used in the QS regulation on process validation applicable to medical 
devices (Sec.  820.75(a)).
    The MMWR discussed at III.C.1 of this document cited CDC concerns 
with bacteriostasis (i.e., the arrestment or inhibition of bacterial 
growth and reproduction) (Ref. 1). The report surmised that because 
tissues later implicated in patient deaths were cultured only after 
suspension in an antibiotic/antifungal solution, residual antibiotics 
on the tissues might have caused a false-negative culture result 
because of bacteriostasis. Undetected organisms in stasis can later 
multiply (e.g., once an HCT/P has been transplanted into a patient and 
the residual antibiotic is metabolized so that it no longer inhibits 
growth of the bacteria). Therefore, we recommend that a validated 
microbiological culturing process include bacteriostatic and 
fungistatic testing.
    In accordance with Sec.  1271.150(e) (``where appropriate''), we 
agree that an assessment with written justification for not 
revalidating a change to a validated process would be sufficient under 
Sec.  1271.230(c) if the establishment can show that the change does 
not increase the risk of communicable disease transmission to the 
recipient.
    (Comment 102) Proposed Sec.  1271.230(b) states, in part, that any 
process-related claim in labeling or promotional materials, e.g., a 
claim for sterility or viral inactivation, must be based on a validated 
process. One comment asked why, if verification is performed on each 
and every finished product, this could not be claimed in labeling. 
Three comments asked us to allow sterility claims based on verification 
rather than validation when technology limitations exist and when 
established manufacturing approaches have not led to clinical problems.
    (Response) We agree with these comments and have modified Sec.  
1271.230(b) to include verification as well as validation. That 
paragraph now requires that any written representation that your 
processing methods reduce the risk of transmission of communicable 
disease by an HCT/P, including but not limited to a representation of 
sterility or pathogen inactivation of an HCT/P, be based ``on a fully 
verified or validated process.''
    (Comment 103) One comment suggested deleting claims for sterility 
or viral inactivation from proposed Sec.  1271.230(b) and creating a 
new paragraph that specifically addresses the validation of processes 
intended to achieve sterility or viral clearance.
    (Response) We decline to make this change. Providing specific 
methods for validation or verification of processes is not within the 
scope of this rulemaking. However, we have narrowed paragraph (b) so 
that it no longer covers ``any process-related claim,'' but now is 
limited to any written representation that your processing methods 
reduce the risk of transmission of communicable disease by an HCT/P, 
including but not limited to, a representation of sterility or pathogen 
inactivation of an HCT/P.
14. Labeling Controls (Sec.  1271.250)
    Proposed Sec.  1271.250 would require procedures to control the 
labeling of HCT/Ps, designed to ensure proper product identification 
and prevent mixups. These procedures would include verification of 
label accuracy, legibility, and integrity; they would further ensure 
that each HCT/P be labeled in accordance with all applicable 
requirements.
    We have reorganized this section into three paragraphs for clarity 
and have corrected the cross-references to labeling requirements in 
part 1271.
    Two comments supported this section as consistent with industry 
standards applicable to eye banking.
    (Comment 104) One comment criticized as burdensome the proposed 
requirement for procedures to ensure that each product made available 
for distribution is accompanied by documentation of the donor 
eligibility determination as required under Sec.  1271.55. This comment 
asserted that, if the product is going from the laboratory to the 
clinical unit of the same program, detailed documentation of donor 
testing does not need to accompany the HCT/P, as it can be found in the 
laboratory. According to the comment, such documentation of testing 
only makes sense if distribution means distribution outside of the 
institution.
    (Response) We disagree with this comment. As discussed at Comment 
17, distribution includes the intracompany shipment of a finished HCT/
P; e.g., the release of an HCT/P from a collection/processing facility 
to an operating room in the same facility. Similarly, the release of an 
HCT/P from a laboratory to the clinical unit of the same program is 
distribution, and the HCT/P must be accompanied by the documentation 
required by Sec.  1271.55. We have modified Sec.  1271.55 in the donor-
eligibility final rule (69 FR 29786 at 29831) to remove the requirement 
that an HCT/P be accompanied either by the relevant medical records or 
a summary of those records; that section now requires HCT/Ps to be 
accompanied by a distinct identification code, a statement of whether 
or not the donor has been determined eligible, and a summary of the 
records used to determine donor eligibility. This requirement is not 
burdensome. Moreover, it is very important that the administering 
physician have in hand specific and accurate information about the HCT/
P; availability of the

[[Page 68636]]

documentation in another part of a facility is insufficient.
    (Comment 105) One comment asserted that the type of information 
called for is exorbitant for the identification of individual 
transplant products. This comment requested that the rules be 
streamlined along the lines of industry standards that provide for 
coded identification of donor, identification of intended recipient, 
and critical information regarding donor eligibility and type of 
processing used.
    (Response) We disagree that the labeling information required by 
these rules is excessive. A review of the industry standards cited by 
the comment indicates that they specify the same information as 
required by these regulations, as well as additional information not 
required under these regulations; e.g., the identification of intended 
recipient, the type of processing used (Foundation for the 
Accreditation of Cellular Therapy (FACT) 2002; American Association of 
Blood Banks (AABB) 2002).
15. Storage (Sec.  1271.260)
    Proposed Sec.  1271.260 would require each establishment to control 
its storage areas and stock rooms to prevent mixups, commingling, 
deterioration, contamination, and cross-contamination of HCT/Ps and 
supplies, and to prevent improper release for distribution. The 
establishment would also be required to store the HCT/Ps at an 
appropriate temperature, assign an expiration date for the HCT/P where 
appropriate, and take and document corrective action when indicated.
    One comment supported this section as proposed.
    (Comment 106) We received several comments on the storage 
temperature and period requirements in proposed Sec.  1271.260(b). Some 
comments asked whether establishments must validate storage 
temperatures and periods, and noted that many of these have been 
established by the tissue industry based on experience. Another comment 
cited specific industry standards for eye banks. One comment asserted 
that the proposed parameters for setting storage temperature may not be 
optimal at the same temperature.
    (Response) Voluntary standards issued by professional organizations 
exist for many aspects of these regulations, and we agree that 
establishments may follow these established industry standards where 
the standards meet the requirements set forth in this section. However, 
these standards may only apply to specific HCT/P types (e.g., corneas) 
and, moreover, are not always sufficiently comprehensive to include all 
of the requirements in this rule. Alternatively, establishments may 
establish and validate their own criteria for storage temperature and 
storage period, as determined for specific HCT/Ps stored in their 
facilities.
    The regulation (Sec.  1271.260(b)) now requires storage at an 
appropriate temperature. Section 1271.260(e)) requires you to establish 
acceptable temperature limits to inhibit the growth of infectious 
agents.
    (Comment 107) Proposed Sec.  1271.260(c) would require 
establishments to assign expiration dates to their HCT/Ps, where 
appropriate. Two comments stated that the safe duration of 
cryopreservation for hematopoietic stem/progenitor cells is unknown and 
will take years to validate.
    (Response) The requirement for establishing an expiration date is 
qualified by the term, ``where appropriate.'' Section 1271.150(e) 
explains that a requirement is ``appropriate'' unless an establishment 
can justify otherwise, and maintains documentation of that 
justification. We consider it appropriate to assign expiration dates 
for ``fresh'' (i.e., noncryopreserved) HCT/Ps, and for those HCT/Ps 
that are thawed after cryopreservation and storage. If such applicable 
expiration dates have been established by industry or medical practice 
and meet the requirements of this section, you may use those dates for 
your HCT/Ps, whether ``fresh'' or cryopreserved. If scientific data do 
not exist for establishing expiration dates, then no expiration date is 
required at this time. We encourage the industry to perform studies to 
establish expiration dates for those HCT/Ps that currently do not have 
expiration dates.
    We have modified Sec.  1271.260(c)(2) to refer to ``processing,'' 
rather than ``processing procedures,'' to avoid redundancy.
16. Receipt, Predistribution Shipment, and Distribution of an HCT/P 
(Sec.  1271.265)
    Proposed Sec.  1271.265 would require establishments to establish 
and maintain procedures for receipt, acceptance or rejection, 
distribution, and destruction or other disposition of HCT/Ps; and 
document these activities.
    Several comments supported proposed Sec.  1271.265. One comment 
indicated that the provisions are worthwhile, and another comment 
supported documenting the identity of the consignee.
    We have reorganized Sec.  1271.265. Paragraphs (a) through (d) now 
contain substantive requirements with respect to receipt, 
predistribution shipment, distribution, packaging and shipping. Each of 
these is a core CGTP requirement. Paragraph (e) requires you to 
establish and maintain procedures for activities under paragraphs (a) 
through (d) and to document these activities. (This documentation must 
include, for example, the identification of the HCT/P; in this rule we 
have specified that you must also document the establishment that 
supplied the HCT/P (e.g., by maintaining receipt records).) Paragraph 
(f) relates to returns to inventory, as proposed.
    (Comment 108) One comment asked for clarification to ensure that 
all donated materials are subject to Sec.  1271.265, regardless of 
their processing status.
    (Response) We agree that all donated materials are subject to this 
section. The definition of HCT/P covers cells and tissues at all stages 
of manufacture, from recovery through distribution (66 FR 5447 at 
5448).
    Although we do not believe it is necessary to modify Sec.  1271.265 
as suggested by the comment, we have made a related change, by adding a 
new provision on ``pre-distribution shipment'' (Sec.  1271.265(b)). 
This change is necessitated by our revision of the definition of 
``distribution,'' discussed at Comment 17, to refer to the conveyance 
or shipment of an HCT/P that has been determined to meet all release 
criteria. Predistribution shipment includes, for example, shipment of 
an HCT/P within your establishment or to another establishment, or 
shipment from an establishment that recovers cells or tissue to an 
establishment that packages them.
    Section 1271.265(b) states that if you ship an HCT/P within your 
establishment or between establishments (e.g., procurer to processor) 
and the HCT/P is not available for distribution as described in 
paragraph (c) of this section, you must ship the HCT/P in quarantine.
    (Comment 109) Proposed Sec.  1271.265(b) would require each 
incoming HCT/P to be inspected according to established procedures. Two 
comments on proposed Sec.  1271.265(b) asked if it is sufficient to 
inspect a shipping container for physical damage, or if the containers 
must be opened.
    (Response) You should tailor your acceptance procedures to the 
specific HCT/P and circumstances. As the comments point out, in some 
instances opening a sealed shipping container could potentially damage 
an HCT/P. In

[[Page 68637]]

designing your acceptance procedures, you should take into account this 
possibility, as well as alternate ways of inspecting the HCT/P (e.g., 
inspection of container, ensuring proper temperature has been 
maintained during transit). If, after receiving the HCT/P, you hold it 
in storage, your storage conditions must comply with Sec.  1271.260.
    The MMWR cited at section III.C.1 of this document recommended 
that, to minimize the potential of bacterial contamination, tissue 
should be cultured before suspension in antimicrobial solutions, and if 
bacteria are isolated, all tissue from the same donor should be 
discarded if it cannot be sterilized (Ref.1). Where appropriate, your 
acceptance procedures should include tests and should spell out 
criteria for rejecting incoming HCT/Ps. Preprocessing cultures may be 
appropriate in some situations.
    (Comment 110) One comment on proposed Sec.  1271.265(c) 
(availability for distribution) asserted that ``deterioration'' is 
vague and open to interpretation.
    (Response) By ``deterioration,'' we mean decay or decomposition. 
However, in response to Comment 9 we have removed references to 
``deterioration'' from the CGTPs, including Sec.  1271.265.
    (Comment 111) One comment on proposed Sec.  1271.265(c) asserted 
that the requirements for making an HCT/P available for distribution 
should not apply to distributors themselves.
    (Response) The requirements in Sec.  1271.265(c) are intended to 
apply to the establishment that first makes an HCT/P available for 
distribution (defined in Sec.  1271.3(z)). This establishment, which 
may or may not be the actual distributor, needs to have procedures in 
place under Sec.  1271.265(e) for determining that an HCT/P may be made 
available for distribution, including release criteria designed to 
prevent communicable disease transmission. The regulation specifies 
that you must not make available for distribution any HCT/P that is in 
quarantine, is contaminated, is recovered from a donor who has been 
determined to be ineligible or for whom a donor-eligibility 
determination has not been completed (except as provided under 
Sec. Sec.  1271.60, 1271.65, and 1271.90), or that otherwise does not 
meet release criteria designed to prevent communicable disease 
transmission. Release criteria include criteria for releasing a product 
under Sec.  1271.60, Sec.  1271.65, or Sec.  1271.90 that ensure, among 
other things, that the conditions for such release are met and that the 
HCT/P is labeled with the warnings required by the regulations.
    (Comment 112) Proposed Sec.  1271.265(d) would require packaging 
and shipping containers to be designed, validated, and constructed to 
protect the HCT/P from contamination during customary conditions of 
processing, storage, handling, and distribution. The final rule 
requires that packaging and shipping containers protect HCT/Ps from 
contamination.
    Three comments on proposed Sec.  1271.265(d) suggested that 
verification of packaging containers is more appropriate than 
validation.
    (Response) We agree that either validation or verification may be 
appropriate ways of ensuring the adequacy of packaging and shipping 
containers. Please note, however, that the final rule has been revised 
so that it does not require either verification or validation of 
packaging and shipping containers.
    (Comment 113) Proposed Sec.  1271.265(e) would require that 
appropriate shipping conditions be defined for each type of product to 
be maintained during transit. One comment questioned whether shipping 
conditions must be defined for each type of graft (e.g., femur ring, 
bone powder) or for each type of tissue (freeze-dried bone).
    (Response) The final rule renumbers this provision as Sec.  
1271.265(d), combines it with the provision on packaging, and provides 
each establishment with the flexibility to determine whether to 
establish shipping conditions for each type of graft or for each type 
of tissue. Either approach may be appropriate.
    (Comment 114) One comment on proposed Sec.  1271.265(f) stated that 
the requirement to establish procedures for returning HCT/Ps to 
inventory is not applicable to all HCT/Ps.
    (Response) We agree that some establishments may not engage in all 
activities covered by the CGTPs. Under Sec.  1271.150(c), 
establishments need only comply with the requirements that are 
applicable to the operations in which they engage. Thus, an 
establishment that does not return HCT/Ps to inventory is not required 
to establish procedures for that activity.
17. Records (Sec.  1271.270)
    Proposed Sec.  1271.270 would require establishments to maintain 
records concurrently with the performance of each significant step 
required in subparts C and D. A records management system would be 
established and maintained. Records would be maintained: 
Electronically, as original paper records, or as true copies; 10 years 
after their creation; and for contracts, agreements, and other 
arrangements with another establishment to perform a step in 
manufacturing. One comment from a professional organization supported 
the goal of this provision, which it identified as chain of custody.
    (Comment 115) One comment on Sec.  1271.270(b) asserted that 
maintaining records organized by product type is not practical and that 
it is more useful to organize records by donor. Another comment 
asserted that detailing how to organize records is an unnecessary 
intrusion and that the example given was unduly complicated.
    (Response) In response to the first comment, we have deleted the 
words ``of each type'' from the third sentence of Sec.  1271.270(b), so 
that it now reads: ``Records pertinent to the manufacture of HCT/Ps * * 
* must also be maintained and organized under the records management 
system.'' In response to the second comment, we note that, although 
paragraph (b) requires you to establish and maintain a records 
management system, it does not specify the details of such a system. It 
is the responsibility of the establishment to organize its records in a 
useful manner. The example given in the preamble to the proposed rule 
was intended simply to explain, to those unfamiliar with the term, what 
is meant by a ``records management system'' (66 FR 1508 at 1518). We 
have revised paragraph (b) so that the requirement for a records 
management system applies only to core CGTP requirements.
    (Comment 116) We received two comments on the requirement in 
proposed Sec.  1271.270(c) that information on the identity and 
relevant medical records of a donor must be in English or, if in 
another language, must be translated to English and accompanied by a 
statement of authenticity by the translator that specifically 
identifies the translated document.
    (Response) Proposed paragraph (c) of Sec.  1271.270 would relate to 
the donor-eligibility requirements in subpart C of part 1271. In the 
donor-eligibility final rule (69 FR 29786 at 29831), we incorporated 
the contents of proposed Sec.  1271.270(c) into the records 
requirements in Sec.  1271.55 and responded to these comments. We are 
now removing proposed paragraph (c) from Sec.  1271.270.
    (Comment 117) Proposed Sec.  1271.270(e) would require records to 
be kept for 10 years. We specifically requested comments on whether 
there are specific types of record for which retention period shorter 
than 10 years

[[Page 68638]]

would be appropriate (66 FR 1508 at 1518).
    Two comments responded that a 10-year record retention is 
appropriate, and one of these comments cited an industry standard 
requiring records to be maintained 10 years.
    (Response) We have maintained the 10-year record retention 
requirement for all records. Proposed Sec.  1271.270(e) has been 
renumbered Sec.  1271.270(d).
    (Comment 118) Three comments pointed out that the record retention 
requirement in proposed Sec.  1271.270(e) is confusing, and each of 
these comments suggested new language. One suggestion would require 
that the establishment retain records for 10 years after 
transplantation, or after expiration if transplant date is unknown. Two 
comments suggested that we require the retention of records for a 
minimum of 10 years after creation, 10 years after the expiration of a 
HCT/P, or 10 years after the appropriate disposition of dura mater.
    (Response) We have revised proposed paragraph (e) by replacing the 
words ``implantation, transplantation, infusion, or transfer'' with 
``administration.'' The second sentence of Sec.  1271.270(d) now reads
    However, you must retain the records pertaining to a particular 
HCT/P at least 10 years after the date of its administration, or if 
the date of administration is not known, then at least 10 years 
after the date of the HCT/P's distribution, disposition, or 
expiration, whichever is latest.
    (Comment 119) Proposed paragraph (e) would require an establishment 
to make provisions for all records to be maintained for the required 
period in the event that the establishment ceases operation. One 
comment asserted that it is not practical for an establishment to 
retain records if it has gone out of business.
    (Response) We encourage you to make provisions for keeping records 
in the event that your establishment goes out of business, because some 
communicable disease have very long incubation periods before symptoms 
appear (e.g., CJD). However, because of difficulties in enforcing the 
proposed requirement, we have removed it from the final regulation.
18. Tracking (Sec.  1271.290)
    Proposed Sec.  1271.290 would require each establishment that 
performs any step in manufacturing to set up a system for tracking each 
HCT/P so that the HCT/P may be tracked from donor to recipient and 
recipient to donor.
    We have clarified that tracking requirements apply to those 
facilities that handle the HCT/P. If you do not handle the HCT/P (e.g., 
you are the testing laboratory that receives a blood specimen, but you 
do not actually handle the HCT/P), you do not have to participate in 
the tracking requirements.
    We have also added language to clarify that the purpose of a 
tracking system is to facilitate the investigation of actual or 
suspected transmission of communicable disease and any appropriate and 
timely corrective action.
    Finally, we have revised the tracking provisions to require a 
system that enables tracking to and from the consignee, rather than to 
and from the recipient, and have added that labeling includes 
information designed to facilitate effective tracking, using the 
distinct identification code, from the donor to the recipient and from 
the recipient to the donor.
    (Comment 120) We received several comments in support of the 
proposed requirements. One comment responded to our request for 
comments from establishments that have already developed and 
implemented tracking systems about the success or failure of those 
systems (66 FR 1508 at 1519). This comment described its successful 
tracking system and noted that tracking fulfills its ongoing 
responsibility to the patients who have received its tissues. The 
establishment provides hospitals with peeloff labels that identify each 
unique product and the bank that provided it, and also with tracking 
logs for the hospitals to use to control inventory. Information on the 
use of the HCT/P is returned to the tissue bank by the hospital in a 
self-addressed envelope and then entered into the establishment's 
database. The establishment sends regular reminders to hospitals 
notifying them of tissue for which it has not received transplant 
records. The comment noted that hospitals willingly participate, and it 
cited a high (85 to 100 percent) return of transplant records.
    (Response) We appreciate this detailed information and believe it 
demonstrates both the feasibility and the importance of developing a 
functioning tracking system.
    (Comment 121) Two comments argued that the proposed requirements 
could not be justified based on risk and were inconsistent with 
industry standards. The comments also asserted that the proposed 
tracking requirement would require collection of confidential patient 
information in conflict with privacy regulations issued under the 
Health Insurance Portability and Accountability Act (45 CFR parts 160 
and 164). Those regulations were finalized on December 28, 2000 (65 FR 
82462), and amended on August 14, 2002 (67 FR 53182).
    (Response) We disagree. Not only are these requirements justified 
by the communicable disease risks posed by HCT/Ps, but they are 
consistent with industry standards. AATB standards require traceability 
and dispensing records by the tissue dispensing service (medical, 
dental, hospital facility, physician's office) (See the American 
Association of Tissue Banks (AATB) Standards 2002, L4.000). The Eye 
Bank Association of America (EBAA) medical standards require that 
recipient identification readily traceable to each unique graft number 
be retained in the eye banks' records (See EBAA Medical Standards 2002, 
M1.400).
    The proposed tracking requirements are not inconsistent with the 
HIPAA privacy regulation, which sets up protections for individually 
identifiable health information. The privacy rule applies only to 
``covered entities'': e.g., health plans, health care clearinghouses, 
and health care providers conducting certain transactions in electronic 
form (45 CFR 164.104). HCT/P establishments subject to the tracking 
requirements are unlikely to meet the definition of a covered entity. 
Thus, the privacy regulation would not apply to their activities, and 
the use in product tracking of a distinct identification code by an 
entity that is not covered by that rule would not be subject to the 
privacy rule.
    In the unusual event that an establishment met the definition of 
covered entity, the establishment's disclosure of individually 
identifiable health information would be subject to the privacy rule. 
However, the privacy rule allows covered entities to share de-
identified health information for any purpose and includes requirements 
for determining whether information is de-identified. (45 CFR 
164.502(d), 164.514(a)-(c)). Further, a covered entity may assign a 
code to otherwise de-identified data, if the code is not derived from 
or related to information about the individual and is not otherwise 
capable of being translated so as to identify the individual, and if 
the covered entity does not use or disclose the code or other means of 
record identification for any other purpose, and does not disclose the 
mechanism for reidentification (45 CFR 164.514(c). Thus, an 
establishment that is a covered entity is not in violation of the 
privacy rule if it discloses information de-identified in accordance 
with 45 CFR 164.514(a)-(c), including a distinct identification code 
that meets the requirements of 45 CFR 164.514(c).

[[Page 68639]]

    Consignees are likely to meet the definition of a covered entity, 
and would therefore be covered by the privacy rule. However, the 
tracking provision does not require consignees to provide individually 
identifiable health information; it requires only that establishments 
be able to track HCT/Ps to consignees.
    We note that a consignee may on occasion wish to disclose protected 
health information to an establishment. For example, a consignee may 
wish to report to the establishment that a recipient of an HCT/P 
developed an infection at the site of the transplant. Under the public 
health activities provisions of the privacy rule, the rule permits, but 
does not require, entities that meet the definition of a covered entity 
to disclose protected health information to persons subject to the 
jurisdiction of FDA with respect to an FDA-regulated product or 
activity for which that person has responsibility, for the purpose of 
activities related to the quality, safety or effectiveness of such FDA-
regulated product or activity (45 CFR 164.512(b)(1)(iii)). The rule 
specifically identifies tracking FDA-regulated products as a purpose 
permitting such disclosures, along with collecting and reporting 
adverse events and enabling product recalls, repairs, replacement, or 
lookback (45 CFR 164.512(b)(1)(iii)(A), (b)(1)(iii)(B), and 
(b)(1)(iii)(C)). Finally, in the event that one of the previously 
mentioned provisions is not applicable, covered entities may disclose 
protected health information pursuant to an authorization from the 
individual or the individual's personal representative (45 CFR 
164.502(g)(1) and 164.508). We further discuss the applicability of the 
privacy rules in the context of donor eligibility in Comment 4 to the 
donor eligibility rule (69 FR 29786 at 29790).
    (Comment 122) One comment suggested that the regulations should 
refer to ``tracing'' instead of ``tracking,'' to avoid confusion with 
device tracking.
    (Response) We disagree. The term ``tracking'' adequately defines 
the operations being performed with respect to the HCT/P and is a term 
that is recognizable by industry.
    (Comment 123) Several comments from eye banks asked for an 
exception for corneas that are distributed internationally, noting the 
difficulty of obtaining information on recipients. One of these 
comments asked that the consignee's signature and intended disposition 
be acceptable.
    (Response) We decline to grant an exception for corneas that are 
distributed internationally. However, we note that the tracking 
requirements in Sec.  1271.290 do not require tracking to the recipient 
level, but rather to the consignee. In the case of international 
distribution, obtaining the consignee's signature and intended 
disposition is acceptable.
    (Comment 124) Two comments asserted that it would be impossible to 
comply with proposed Sec.  1271.290 unless all establishments adopt a 
uniform tracking method, and further opined that many vendors may elect 
not to participate in tracking due to the potential disclosure of 
proprietary information.
    (Response) We disagree with these comments. We prefer to provide 
establishments with flexibility in complying with Sec.  1271.290, and 
for that reason we decline to mandate a uniform tracking method. It is 
unclear why it would be impossible to comply with the requirement in 
the absence of uniformity. It is also unclear what proprietary 
information would be disclosed via a tracking system. However, we note 
that each establishment has the choice of maintaining its own tracking 
method or participating in the system developed by another 
establishment; a vendor who shares the concerns expressed by these 
comments may choose not to participate in another establishment's 
tracking system. We have revised Sec.  1271.290 to clarify that a 
``system'' involves the tracking of an HCT/P from the donor to the 
consignee or from the consignee to the donor; and that a ``method'' is 
an action that enables tracking.
    (Comment 125) One comment on proposed Sec.  1271.290(b) asserted 
that a single designated establishment should collect tracking 
information and maintain the entire history of collection, processing, 
and release. Another comment argued that tracking responsibilities 
should be placed on the entity that makes the product available for 
distribution, and that subsequent entities (i.e., distributors) should 
be allowed to follow that entity's existing tracking procedures.
    (Response) Section 1271.290(b) provides establishments with the 
flexibility to participate in the tracking system set up by another 
establishment, provided that the system complies with all requirements 
in this section. However, the responsibility lies with each 
establishment involved in the manufacture of an HCT/P. For example, if 
only the establishment that made the HCT/P available for distribution 
were responsible for tracking, establishments ``upstream'' would not 
necessarily participate. This would not enable tracking from donor to 
consignee because the distributor would not have the information for 
linking the consignee to the donor, since the establishment performing 
recovery would be the only entity that would know the identity of the 
donor.
    (Comment 126) Proposed Sec.  1271.290(c) would require 
establishments to ensure that each HCT/P that it manufactures is 
assigned and labeled with a distinct identification code that relates 
the HCT/P to the donor and to all records pertaining to the HCT/P. One 
comment on this provision asked us to clarify that a single 
identification code may be used for an entire lot of morselized 
structural tissue of the same type from the same donor, even if the lot 
is distributed in more than one immediate container.
    (Response) We agree with this comment's interpretation of the 
regulation.
    We have added to paragraph (c) the requirement that labeling 
include information designed to facilitate effective tracking, using 
the distinct identification code, from the donor to the recipient and 
from the recipient to the donor. Although Sec.  1271.290 does not 
require establishments to establish a tracking system from the 
recipient to the donor and from the donor to the recipient, this 
labeling requirement will enable such tracking to be performed. An 
example of a labeling statement that would comply with this requirement 
is: ``IMPORTANT NOTICE TO END-USER: Please record this distinct 
identification code in your records and in the patient's file.''
    (Comment 127) One comment asked us to permit tracking from 
production lot rather than from donor. This method would apply to lot-
processed or batch-processed products manufactured using a validated 
sterilization method.
    (Response) We decline to modify the regulation to make the 
requested change. However, we would consider a request for an 
alternative submitted under Sec.  1271.155. The requestor should show 
that the proposed alternative tracking method satisfies the purposes of 
the requirement in Sec.  1271.290(e).
    (Comment 128) Proposed Sec.  1271.290(d) would require an 
establishment to ensure that the identifier and type of HCT/P that is 
implanted 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.
    One comment asserted that the manufacturer has no authority over 
the content of the medical record and suggested that the manufacturer 
provide paper documentation appropriate for the medical record and 
notice of the Federal regulations requiring that the

[[Page 68640]]

information be placed in the medical record. Another comment asserted 
that, because of tissue establishment's inability to mandate hospital 
compliance, FDA should revise proposed Sec.  1271.290(d) to allow 
tracking to the production lot, or eliminate the provision altogether.
    (Response) We have revised paragraph (d) to remove the requirement 
for ensuring that information on an HCT/P is recorded in a recipient's 
medical records or other pertinent records. That paragraph now requires 
an establishment to establish and maintain a method for recording the 
distinct identification code and type of each HCT/P distributed to a 
consignee to enable tracking from the consignee to the donor.
    In response to Comment 126, we discuss the new requirement in 
paragraph (c) for label information designed to facilitate tracking 
between recipient and donor.
    (Comment 129) Proposed Sec.  1271.290(e) would require 
establishments to document, and maintain records of, the disposition of 
each HCT/P, to enable tracking from the donor to the recipient or final 
disposition. This information must permit the prompt identification of 
the recipient of the HCT/P, if any.
    One comment asked us to specify an acceptable timeframe for the 
identification of the recipient. Another comment asked whether, with 
regard to ``prompt'' identification, the name and hospital or social 
security number are sufficient information to allow identification. A 
third comment suggested requiring tracking, not to the recipient, but 
to the distributor, transplant facility, or transplanting surgeon, as 
appropriate. This comment asserted that neither tissue banks nor the 
agency has the authority to mandate hospital or physician compliance 
with the tissue banks request for recipient information.
    (Response) FDA agrees that it cannot mandate hospital or physician 
compliance, and we have revised paragraph (e) to require tracking to 
the consignee, rather than to the recipient. However, as described in 
Comment 119, we note that successful tracking systems have been 
implemented, in which hospitals readily participate. In addition, 
hospitals accredited by the Joint Commission on Accreditation of 
Healthcare Organizations (JCAHO) are required to keep records that 
permit tracking of any tissue from the donor or source facility to all 
recipients or other final disposition. (Joint Committee, 2000-2001, 
``Comprehensive Accreditation Manual for Pathology and Clinical 
Laboratory Services,'' pp. QC 36-37.)
    We decline to specify a timeframe for the identification of the 
consignee, because the timeframe may vary with the circumstances.
    (Comment 130) One comment asked for a clarification of the term 
``consignee.'' This comment asked whether a hospital that receives an 
HCT/P is considered the consignee, or if the surgeon who uses the HCT/P 
is the consignee.
    (Response) Either or both parties may be the consignee, depending 
on the particular situation. Generally, the person and/or entity to 
which an HCT/P is distributed would be considered the consignee.
    (Comment 131) Proposed Sec.  1271.290(f) would require 
establishments, at or before the time of distribution of an HCT/P, to 
inform the consignee in writing of the regulatory requirements and of 
the tracking method that the establishment has put into place. The 
establishment would also 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.
    Several comments questioned how proposed Sec.  1271.290(f) would 
work. One comment asked whether a signed agreement would have to be 
obtained before sending the tissue, and noted that this would be 
difficult. This comment also asked who should be authorized to sign the 
agreement. Another comment noted that it sends a ``tissue usage form'' 
with its tissues, but that many facilities do not return the form; this 
comment further noted that a contract does not always exist between a 
tissue bank and the end user. Several comments asserted that tissue 
banks lack the authority or means to ensure compliance with the 
regulation and should not be held responsible for gathering tracking 
information, and one comment asked how far an eye bank must go to 
demonstrate that it has attempted to obtain an agreement from the 
consignee. One comment stated that a tissue facility cannot and should 
not withhold tissue for a prior failure of a facility to provide 
required documentation, and that if it did so, another source of 
tissues would be sought.
    One comment expressed concern that: (1) Establishments may develop 
agreements that are least burdensome rather than most effective; (2) an 
establishment would not be able to provide an HCT/P to a consignee in 
an emergency until the consignee developed a tracking system; (3) the 
tracking requirements conflict with the new privacy rules, because a 
tissue establishment must review recipient records to ascertain whether 
a consignee maintained an adequate system; (4) patients change 
practitioners or localities without providing their new addresses; and 
(5) it would be unwieldy and unrealistic for an establishment with 
thousands of consignees to take all necessary steps to ensure their 
compliance.
    (Response) We have removed the requirement in proposed paragraph 
(f) to obtain agreement from a consignee to participate in an 
establishment's tracking system.
19. Complaint Files (Sec.  1271.320)
    Proposed Sec.  1271.320 would require each establishment to 
establish and maintain procedures for the prompt review, evaluation, 
and documentation of all complaints, and the investigation of 
complaints as appropriate. We defined ``complaint'' in proposed Sec.  
1271.3(ii) and have made several changes to that definition, now 
renumbered Sec.  1271.3(aa), which are discussed at Comment 13.
    We have revised Sec.  1271.320 so that its requirements relate to 
the core CGTP requirements.
    (Comment 132) One comment asked us to clarify the meaning of 
``promptly.''
    (Response) We expect complaints to be investigated quickly enough 
to meet the reporting requirements, in case the complaint necessitates 
reporting. However, because the interpretation of the term ``promptly'' 
is somewhat vague, we have replaced ``promptly'' in paragraph (c) with 
``as soon as practical.''
    (Comment 133) Two comments raised concerns about the requirement in 
proposed Sec.  1271.320(b) that confidential complaint files be made 
available for review and copying upon request from an authorized FDA 
employee.
    (Response) We recognize the comments' concerns about maintaining 
donor and patient confidentiality. When copying complaint files, the 
agency will take steps to protect the identity of the donor or patient 
in conformance with 21 CFR parts 20 and 21.

D. Part 1271, Subpart E--Additional Requirements for Establishments 
Described in Sec.  1271.10

1. Applicability (Sec.  1271.330)
    Proposed Sec.  1271.330 explained that the regulations in subpart E 
would be applicable only to HCT/Ps described in Sec.  1271.10, i.e., 
regulated solely under section 361 of the PHS Act and the regulations 
in part 1271.
    We received no comments on this section. We have, however, modified

[[Page 68641]]

Sec.  1271.330 to state that the provisions in subpart E (on reporting 
and labeling) are currently being implemented only for nonreproductive 
HCT/Ps described in Sec.  1271.10 and regulated solely under 361 of the 
PHS Act and the regulations in this part, and the establishments that 
manufacture them.
2. Reporting Requirements (Sec.  1271.350)
    Proposed Sec.  1271.350(a) sets out requirements for reporting 
adverse reactions, and Sec.  1271.350(b) deals with reports of product 
deviations (now called ``HCT/P deviations'').
    (Comment 134) One comment on proposed Sec.  1271.350 stated that 
the section is unnecessarily burdensome because a professional 
organization already requires reporting, and requested ``deemed 
status'' for that organization.
    (Response) We disagree that these reporting requirements are 
duplicative. Reporting to professional organizations is not required 
under these regulations. More importantly, we do not receive reports of 
adverse reactions and HCT/P deviations from professional organizations.
    Adverse Reaction Reporting (Sec.  1271.350(a))
    (Comment 135) Several comments asserted that our authority to 
require adverse reaction reports is limited to those that involve the 
transmission of communicable disease or product contamination. Three 
comments requested that reportable adverse reactions be defined, for 
corneas, as any communicable or other disease transmitted by and 
attributable to transplantation of donor eye tissue, including 
infection and biologic dysfunction, and any systemic infectious disease 
that develops in a recipient. One comment requested that the rule be 
revised to take into account that transplants can be rejected or cause 
reactions such as graft-versus-host disease.
    (Response) You are now required to investigate any adverse reaction 
involving a communicable disease. You must make a report if the adverse 
reaction meets one of the criteria set out in Sec.  1271.350(a)(1). We 
decline to set out specific requirements for corneas but note that the 
situations described in the comments would meet the requirements in 
Sec.  1271.350(a) for reporting adverse reactions. Problems not 
connected with communicable disease transmission are not required to be 
reported e.g., primary graft failure.
    (Comment 136) One comment suggested limiting reporting requirements 
to adverse reactions ``directly related to the product'' to reflect 
that an HCT/P establishment is not responsible for reporting 
communicable disease transmission from other sources (e.g., blood 
products administered during surgery).
    (Response) We decline to make the suggested change. It may take 
longer than 15 days for an establishment to determine whether or not an 
adverse reaction is directly related to an HCT/P. For the protection of 
the public health, it is more important for information about the 
transmission of a communicable disease or HCT/P contamination to be 
reported to us within 15 days, even if further followup indicates that 
communicable disease transmission came from a source other than the 
HCT/P.
    However, we note that in cases where there is no reasonable 
possibility of a relationship between an unintended and noxious 
response and the HCT/P, then the event would not be considered an 
adverse reaction under Sec.  1271.3(y), and reporting would not be 
required under Sec.  1271.350(a).
    (Comment 137) One comment asked whether, if the investigation of a 
complaint points to a cause other than a failure of an eye bank's good 
tissue practice, the eye bank is required to report these results.
    (Response) If immediate investigation indicates that there is not a 
reasonable possibility of a relationship between an unintended and 
noxious response and the HCT/P, then the event is not considered an 
adverse reaction and you are not required to report it. If, however, 
there exists a reasonable possibility that the HCT/P caused the event, 
then the event is an adverse reaction and it may be reportable under 
Sec.  1271.350(a). If, after you have made a required report, you 
discover additional information, you must report this information to 
the agency under Sec.  1271.350(a)(3) within 15 calendar days of 
receipt of the new information. If your investigation determines that 
the HCT/P did not cause the unintended and noxious response, then you 
must submit this information to FDA.
    (Comment 138) Proposed Sec.  1271.350(a) would require you to make 
reports of adverse reactions to us within 15 calendar days of the 
initial receipt of the information. Several comments suggested 
extending this timeframe to 30 days to allow for more thorough follow-
up; one comment suggested 30 to 60 days; and another comment suggested 
30 days, in the absence of death or disease transmission.
    (Response) We disagree with these comments. The timeframe set out 
in Sec.  CFR 1271.350(a) is consistent with adverse reaction reporting 
requirements for other regulated products (see 21 CFR 314.80 and 
600.80; Medical Device Reporting is required within 10 days (21 CFR 
803.10)). The adverse reactions that must be reported to the agency 
under Sec.  1271.350(a) warrant action in less than 1 or 2 months. It 
is reasonable for us to require reporting without delay of an adverse 
reaction that is fatal or life-threatening, results in permanent 
impairment of a body function or permanent damage to body structure, or 
necessitates medical or surgical intervention, including 
hospitalization. We recognize that followup may be appropriate, and 
Sec.  1271.350(a)(3) sets out procedures for submitting new information 
to the agency or responding to an agency request for additional 
information.
    (Comment 139) Several comments objected to the breadth of the 
proposed requirement for reporting cases where medical or surgical 
intervention is required. Two comments suggested adding the phrase ``to 
preclude permanent impairment of a body function or permanent damage to 
a body structure'' for consistency with medical device reporting 
regulations (see Sec.  803.3(bb)).
    (Response) We decline to make the suggested change because the 
communicable disease risks with HCT/Ps are different from the types of 
risks associated with most medical devices. It is important for FDA to 
know of infections that may have been caused by HCT/Ps even if 
permanent impairment of a body function or permanent damage to a body 
structure is not likely, because such infections may alert us to 
broader issues (e.g., a positive donor who was the source of additional 
HCT/Ps; CGTP failures in the establishment). For this reason, we would 
generally consider that an infection at the site of a transplant would 
be reportable under Sec.  1271.350(a).
    (Comment 140) One comment stated that it is unclear which 
establishment must report adverse reactions to FDA.
    (Response) Any establishment that receives information (e.g., 
through a complaint) about an adverse reaction related to an HCT/P that 
it made available for distribution must comply with Sec.  1271.350(a). 
We have inserted this language into Sec.  1271.350(a) for clarity.
    (Comment 141) One comment noted that it may be important to specify 
the need to facilitate, encourage, and even solicit adverse reaction 
information by establishments themselves. The comment further noted 
that the probability of receiving this information may be determined in 
part by the

[[Page 68642]]

presence or absence of a well-defined active followup program 
implemented by the establishment.
    (Response) We agree with this comment and encourage establishments 
to develop programs to help them comply with the reporting requirements 
in Sec.  1271.350.
    HCT/P Deviation Reporting (Sec.  1271.350(b))
    (Comment 142) One comment on proposed Sec.  1271.350(b) asserted 
that the regulation should not require reporting of minor or 
unimportant deviations. Two comments criticized the proposed reporting 
requirement as burdensome and questioned the agency's capacity to 
review submitted reports. These comments suggested limiting reports to 
instances involving issues of disease transmission.
    (Response) We have modified the proposed definition of HCT/P 
deviation. An HCT/P deviation as defined in Sec.  1271.3(dd) is limited 
to an event that represents a deviation from applicable regulations or 
established specifications that may relate to the prevention of 
communicable disease transmission or HCT/P contamination; or that is an 
unexpected or unforeseeable event that may relate to the transmission 
or potential transmission of a communicable disease or may lead to HCT/
P contamination.
    (Comment 143) Two comments asked for clarification of whether 
deviations must be reported if the HCT/P is not distributed.
    (Response) As in the proposed rule, reporting of HCT/P deviations 
is required only when the involved HCT/P has been distributed.
    We have also clarified that the establishment must investigate all 
HCT/P deviations related to a distributed HCT/P for which the 
establishment performed a manufacturing step.
    (Comment 144) One comment suggested changing the requirement to 
report ``as soon as possible'' to a maximum reporting period of 45 
days.
    (Response) We agree with this comment and have made the suggested 
change. In this regard, we wish to emphasize that HCT/P establishments 
should not wait to report deviations until after completing their 
corrective actions. Rather, HCT/P establishments should submit 
deviation reports as soon as possible but no later than 45 days after 
the date that the establishment first discovers information reasonably 
suggesting a reportable event has occurred. The reports should include 
information on the intended followup to be taken if followup is not 
completed prior to submission of the report.
    (Comment 145) One comment pointed out discrepancies between 
proposed Sec.  1271.350(b) and the biologic product deviations final 
rule, and suggested that reporting requirements be harmonized.
    (Response) We have largely harmonized Sec.  1271.350(b) with Sec.  
600.14(b), as suggested by the comment. In addition, we have clarified 
in Sec.  1271.350(b)(2) your obligation to report an HCT/P deviation 
relating to the core CGTP requirements, if the HCT/P deviation occurs 
in your facility or in a facility that performs a manufacturing step 
for you under contract, agreement, or other arrangement. The 
establishment responsible for reporting HCT/P deviations relating to 
the core CGTP requirements would receive the necessary information from 
a contract establishment in accordance with Sec.  1271.160(b)(2).
3. Labeling (Sec.  1271.370)
    Proposed Sec.  1271.370 would have required clear and accurate 
labels for each HCT/P.
    Proposed Sec.  1271.370 would apply only to 361 HCT/Ps; HCT/Ps 
regulated as drugs, devices, and/or biological products are subject to 
labeling requirements currently in place. The regulations under 21 CFR 
parts 201 and 610 will apply to HCT/Ps regulated as drugs and/or 
biological products, as will relevant statutory provisions and any 
conditions of product licensure or approval. HCT/Ps regulated as 
devices are subject to the labeling requirements in 21 CFR part 801, in 
addition to the provisions of the act and any applicable conditions of 
approval or clearance. In the proposed rule, we proposed to interpret 
several current regulations as encompassing the information set out in 
proposed Sec.  1271.370(a), and stated that we would expect the 
information listed in that section to appear on the label or package 
insert of those products regulated as biological drugs or devices (66 
FR 1508 at 1522). We received no comments on this proposal.
    To coordinate with the requirement in Sec.  1271.290(c) that you 
label each HCT/P with a distinct identification code, we have added to 
Sec.  1271.370 the requirement that this code be affixed to the HCT/P 
container.
    (Comment 146) One comment stated that the required label 
information would not fit on vials and requested that this information 
be permitted on labeling. Another comment asserted that putting the 
name and address of the establishment that determined donor eligibility 
on the label would breach donor/recipient confidentiality and suggested 
that this information appear instead in the package insert.
    (Response) The establishment name and address information is 
important to enable traceability if needed. However, we recognize the 
difficulty in fitting this information on the HCT/P label, and we have 
changed the regulation in Sec.  1271.370(c) to require that this 
information must either appear on the HCT/P label or accompany the HCT/
P. We also note that when we use the term ``label'' in this subpart, we 
mean either: (1) Affix to the HCT/P container, or (2) attach a tie-tag 
with the appropriate information to the container.
    (Comment 147) Proposed Sec.  1271.370(a)(3)(ii) would require 
warnings on the label or package insert, where appropriate. One comment 
stated that guidance is needed on ``warnings.''
    (Response) In Sec. Sec.  1271.60, 1271.65, and 1271.90 of the 
donor-eligibility final rule, we now require warning statements related 
to informing the recipient about certain unusual circumstances, e.g., 
``WARNING: Advise patient of communicable disease risk'' when an HCT/P 
is distributed before completion of the donor eligibility 
determination. These warning statements must appear on the HCT/P label. 
In addition, the establishment should determine what other information 
the user needs to know before using an HCT/P; this information would be 
considered ``other warnings'' (we have revised Sec.  1271.370(c)(3)). 
Other warnings would include information about risks resulting from 
procedures to reduce communicable disease risks during the manufacture 
of an HCT/P. An example would be a warning that the product was 
processed aseptically and is not sterile (e.g., may harbor 
microorganisms).
    Because certain warnings are required to appear on the label 
itself, we have added Sec.  1271.370(b)(4), which lists, as information 
that must appear on the label, warnings required under Sec.  1271.60, 
Sec.  1271,65, or Sec.  1271.90, if applicable.
    (Comment 148) One comment stated that some of the labeling 
provisions exceed the statutory authority because the relationship to 
communicable disease transmission is too attenuated.
    (Response) We have revised Sec.  1271.370 to strengthen the 
connection between the labeling requirements and the prevention of 
communicable disease. For example, Sec.  1271.370(c)(4) now requires 
instructions for use when related to the prevention of the 
introduction, transmission, or spread of communicable diseases. Other 
information we have required to be included in the labeling is intended 
to facilitate proper use and tracking of the HCT/P; both are essential 
to prevent the

[[Page 68643]]

spread of communicable disease. We have removed proposed paragraph (b); 
Sec.  1271.370 no longer covers claims.
    (Comment 149) One comment on proposed Sec.  1271.370(b) asserted 
that HCT/Ps with claims for reconstruction or repair should be 
regulated under section 351 of the PHS Act because it cannot be 
assumed, in the absence of substantial clinical evidence, that these 
products perform as intended. The comment provided as an example 
autologous expanded cartilage.
    (Response) As previously noted, we have removed the proposed 
provision on claims from Sec.  1271.370. However, the comment's scope 
extends beyond the proposed language, and for that reason we note our 
disagreement. HCT/Ps with claims for ``reconstruction or repair'' can 
be appropriately regulated solely under section 361 of the PHS Act if 
such HCT/Ps meet all of the criteria in Sec.  1271.10, including 
minimal manipulation and homologous use. To further clarify this point, 
we have added the terms ``repair'' and ``reconstruction'' to the 
definition of ``homologous use'' under Sec.  1271.3(c).
    The example provided by the comment is not appropriate. Autologous 
expanded cartilage cells are not regulated solely under section 361 
because they are more than minimally manipulated when they are cultured 
and, thus, do not meet the criteria in Sec.  1271.10.
    (Comment 150) Two comments asserted that proposed Sec.  
1271.370(b)(2) is unnecessary and could create confusion regarding the 
definition of homologous use. These comments suggested removing the 
paragraph in question and allowing the existing definition of 
``homologous use'' to stand as the sole definition.
    (Response) We agree with this comment and have removed the proposed 
paragraph on claims from Sec.  1271.370. ``Homologous use'' is defined 
in Sec.  1271.3(c)(the registration final rule) as ``the replacement or 
supplementation of a recipient's cells or tissues with an HCT/P that 
performs the same basic function or functions in the recipient as in 
the donor.'' As previously noted, we have added reconstruction and 
repair to the definition of ``homologous use'' under Sec.  1271.3(c).
    (Comment 151) One comment asserted that we should clarify this rule 
to identify examples of homologous use claims.
    (Response) This rule no longer contains language relating to 
homologous use claims. However, we take this opportunity to note that 
the examples of homologous and nonhomologous claims given in the 
registration final rule are still valid, with one exception (see 66 FR 
5447 at 5458). After reviewing additional data from one manufacturer, 
we now consider the use of that manufacturer's minimally manipulated 
amniotic membrane alone for ocular repair as homologous. However, when 
amniotic membrane is combined with limbal stem cells, such an HCT/P is 
regulated under section 351 of the PHS Act.

E. Part 1271, Subpart F--Inspection and Enforcement of Establishments 
Described in Sec.  1271.10

1. Applicability (Sec.  1271.390)
    Proposed subpart F of part 1271 contains provisions on inspections; 
HCT/Ps offered for import; and orders of retention, recall, 
destruction, and cessation of manufacturing. Subpart F would apply only 
to those establishments described in Sec.  1271.10 (i.e., those 
establishments that manufacture HCT/Ps regulated solely under the 
authority of section 361 of the PHS Act and the regulations in part 
1271, and not as drugs, devices, and/or biological products). We 
received no comments on this section.
2. Inspections (Sec.  1271.400)
    Proposed Sec.  1271.400 would require an establishment to permit an 
authorized representative of FDA at any reasonable time and in a 
reasonable manner to inspect the establishment.
    (Comment 152) In the proposed rule, we invited comments on possible 
alternative inspection and enforcement provisions that would leverage 
our resources, be cost-effective, and achieve the public health goals 
of the proposed rule (66 FR 1508 at 1523). We received four comments in 
response to this request. These comments suggested third-party 
inspections, training of FDA representatives by professional 
organizations, and special recognition for accreditation.
    (Response) We appreciate these helpful comments. Instituting a 
third-party inspectional process would require additional resources 
(for startup) and would also require that establishments have an 
inspectional history. Because many HCT/P establishments do not have an 
inspectional history, and because of resource limitations, we decline 
to adopt this approach at present. However, we intend to reconsider the 
idea in the future.
    The suggestion that the agency and industry organizations partner 
to train FDA representatives is also a good idea, and would represent 
the continuation of existing FDA practice. To date, both EBAA and AATB 
have participated in regional training courses for FDA representatives, 
and we hope to continue this useful practice.
    The suggestion that special recognition be given to establishments 
that are accredited by a professional association has already been 
implemented, in that we give establishments that are not accredited a 
higher priority for inspection.
    (Comment 153) One comment suggested amending Sec.  1271.400 to 
require that FDA representatives be appropriately trained to examine 
establishments that manufacture HCT/Ps according to the type of tissue 
manufactured by the facility.
    (Response) We decline to modify Sec.  1271.400 as suggested. FDA 
representatives receive significant training on an ongoing basis, and 
they will continue to do so.
    (Comment 154) One comment expressed concern that inspections would 
disrupt the practice of reproductive medicine.
    (Response) FDA inspections involve document review; interviewing 
employees; and physical inspection of equipment, products, labeling, 
facilities, and operations. We conduct these activities in a manner 
that is as unobtrusive as possible, and our expectation is that an 
establishment will be able to conduct business as usual during the 
course of an inspection. FDA has extensive experience conducting 
inspections in a variety of clinical settings (e.g., hospital 
bloodbanks performing time-critical activities and confidential donor 
screening).
    We recognize and understand that responsible personnel at times may 
be involved in procedures that make them temporarily unavailable to the 
FDA representative. In this situation, the FDA representative will 
perform some other aspect of the inspection that does not require the 
responsible person's presence until that person is again available to 
be interviewed.
    Inspections will focus on assessing compliance with applicable 
requirements; to make this clear, we have added the word ``applicable'' 
to the first sentence of Sec.  1271.400(a). For example, the inspection 
of an establishment that engages solely in processing would address 
processing-related requirements, rather than donor testing and 
screening. With respect to establishments that manufacture reproductive 
HCT/Ps regulated solely under section 361 of the PHS Act and these 
regulations, an inspection would be limited to issues of compliance 
with the donor-eligibility requirements

[[Page 68644]]

contained in subpart C of this part, but would not consider compliance 
with the requirements in subparts D and E.
    (Comment 155) One comment stated that it is not appropriate for the 
interpretation of SOPs and the validation of tissue banks to be subject 
to the individual regulatory representative's judgment and that a more 
standard approach is needed.
    (Response) We agree with the concerns expressed by this comment, 
and note that for several years FDA has used a standard approach for 
tissue establishment inspections. Compliance Program 7341.002 
(Inspection of Tissue Establishments) provides standard inspectional, 
regulatory, and administrative guidance to all FDA representatives 
involved in conducting inspections of human tissue establishments and 
to management personnel who evaluate the results of those inspections. 
FDA representatives evaluate the adequacy of a firm's SOPs and process 
validation or verification on site. All observations they may record on 
a Form FDA-483 are subject to further review by FDA management, to 
ensure consistency with FDA regulations, before any regulatory action 
is taken. The firm can respond to items recorded on the Form FDA-483 
during the discussion with the FDA representative at the conclusion of 
the inspection or subsequently in writing, if the firm wishes to do so.
    (Comment 156) Two comments on proposed Sec.  1271.400(a) requested 
that we provide from 1 to 5 days notice before an inspection.
    (Response) FDA has tried a variety of announced and unannounced 
inspection procedures in the past. Our current practice is generally 
not to preannounce inspections because such a commitment affects the 
overall productivity of field staff. An establishment must be in 
compliance at all times, which should make it unnecessary to 
preannounce an inspection for the establishment to ``prepare'' for an 
inspection. For clarity, we have modified the language of the final 
regulation to state that an inspection may be made with or without 
``prior notification.''
    (Comment 157) Proposed Sec.  1271.400(c) states that FDA's 
representative will call upon the most responsible person available at 
the time of an inspection. Three comments requested that this 
representative be the executive director or a person functioning in 
that position at the time of the inspection. One comment pointed out 
that eye banks are usually small and that key staff may be out of the 
bank performing other duties.
    (Response) We decline to modify the regulation as requested. Firms 
should have a plan in place to instruct their staff exactly who would 
accompany an FDA representative in the absence of the most responsible 
person. The FDA representative will determine whether or not a 
meaningful inspection can be conducted, given the available personnel.
    (Comment 158) Proposed Sec.  1271.400(c) also states that the FDA 
representative conducting an inspection may question the personnel of 
the establishment, as the representative deems necessary. One comment 
objected to the exercise of our discretion, if unfettered, to question 
any employee and stated that, historically, FDA has allowed companies 
to designate spokespeople. Another comment asserted that FDA should 
question a senior official who is well acquainted with the SOPs of the 
facility (not just the most responsible person available).
    (Response) It is agency practice for the FDA representative 
conducting an inspection to observe and interview employees to 
determine if they are performing their various functions in accordance 
with the firm's current SOPs, to determine if activities are being 
documented concurrently with the performance of each significant step, 
and to evaluate if employees are properly trained and supervised. We 
agree that it is a good idea to make a spokesperson available to 
accompany the FDA representative and provide historical, statistical, 
and administrative information about the company. All employees at an 
establishment should be well acquainted with the SOPs related to their 
work in that establishment.
    (Comment 159) Under proposed Sec.  1271.400(d), FDA's 
representative may review and copy any records required to be kept 
under part 1271 and may take photographs or make videotapes. One 
comment questioned FDA's intentions with respect to records of quality 
assurance activities. Another comment asked that this section be 
revised to exempt from FDA review records of management review, quality 
audits, supplier evaluations, and other types of information (e.g., 
financial). One comment suggested new language limiting reproduction to 
data that would relate to possible communicable disease transmission 
and/or biologic dysfunction of tissue.
    (Response) The FDA representative may review and copy any records 
required to be kept under part 1271. Financial records and personnel 
records are not required records under part 1271. Given the scope of 
the requirements in part 1271 and their focus on preventing the 
introduction, transmission, or spread of communicable disease, it is 
unnecessary to limit Sec.  1271.400 as suggested. With respect to 
quality audits, while some firms choose to provide quality audits to 
FDA, FDA's current practice is generally not to request or copy the 
actual quality audit reports except in certain limited circumstances 
(FDA Compliance Policy Guide 130.300). However, the firm should have a 
mechanism to demonstrate to the FDA representative that quality audits 
are being performed and that corrective actions are being implemented 
when problems have been identified.
    (Comment 160) Several comments questioned the provisions of 
proposed Sec.  1271.400(d) on photography and videos. Two comments 
questioned the agency's authority to do so.
    (Response) FDA's practice is to record images (e.g., by way of 
photographs or videotapes) to accurately record the conditions in an 
establishment. These tools may be employed as long as the inspection is 
lawful. See United States v. Gel Spice Co., 601 F. Supp. 1214, 1220 
(E.D.N.Y. 1985); United States v. Acri Wholesale Grocery Co., 409 F. 
Supp. 529, 532-533 (S.D. Iowa 1976). Inspections conducted under 
regulations issued under section 361 of the PHS Act are lawful. 
However, we have modified the wording of Sec.  1271.400(d) to delete 
the specific references to photographs and videotapes, and to state 
instead that FDA's representatives may use other appropriate means to 
record evidence of observations during inspections conducted under this 
subpart.
    FDA also has the authority to take samples to support observational 
findings. To clarify this previously implied capability, we have added 
to Sec.  1271.400(d) that FDA also may take samples.
4. Imports (Sec.  1271.420)
    When an HCT/P is offered for entry, proposed Sec.  1271.420 would 
require the importer of record to notify the director of the district 
of the FDA having jurisdiction over the port of entry. The HCT/P would 
be held intact until it is released by FDA.
    We have made several revisions to Sec.  1271.420(a) and (b) for 
clarity and for consistency with agency import policy. We have replaced 
the phrase ``offered for entry'' with the more accurate phrase, 
``imported or offered for import.'' Consistent with other agency 
regulations, HCT/Ps ``imported or offered for import'' include, not 
only

[[Page 68645]]

those HCT/Ps imported or offered for import into the United States for 
use, storage, or distribution in the United States, but also those 
imported or offered for import for transshipment through the United 
States to another country, for future export, or for use in a United 
States Foreign Trade Zone. (See, e.g., ``Prior Notice of Imported Food 
Under the Public Health Security and Bioterrorism Preparedness and 
Response Act of 2002,'' interim final rule, 68 FR 58974 at 58990 and 
58991, October 10, 2003.)
    We have specified in paragraph (a) that notification of the 
director of the FDA district having jurisdiction over the port of entry 
may occur either before or at the time of importation. The term ``port 
of entry'' is defined in 19 CFR 101.1 as any place designated by 
Executive order of the President, by order of the Secretary of the 
Treasury, or by act of Congress, at which a Customs officer is 
authorized to accept entries of merchandise, to collect duties, and to 
enforce the various provisions of the Customs and navigation laws. To 
make certain that importers understand our expectations (e.g., 
accompanying records required under Sec.  1271.55, and entry 
information required by United States Bureau of Customs and Border 
Protection), we have added the requirement that the importer of record 
must provide sufficient information for FDA to make an admissibility 
decision.
    Finally, we have replaced the phrase in proposed paragraph (b), 
``until it is released by FDA,'' with ``until an admissibility decision 
is made,'' which more accurately reflects FDA's actions.
    (Comment 161) One comment suggested the addition of language to 
clarify that the regulation only applies to HCT/Ps ``intended for 
clinical use.''
    (Response) We agree that Sec.  1271.420 applies only to HCT/Ps 
intended for clinical use, but we do not consider it necessary to 
modify the regulation as suggested. The regulations in part 1271 do not 
apply to establishments that use HCT/Ps solely for nonclinical 
scientific or educational purposes (Sec.  1271.15(a)); moreover, Sec.  
1271.3(d) defines an HCT/P as intended for implantation, 
transplantation, infusion, or transfer into another human (i.e., 
clinical use).
    (Comment 162) One comment requested an exemption for reproductive 
HCT/Ps imported under the authority of the owner of the reproductive 
materials.
    (Response) We have modified Sec.  1271.420 to except from its 
provisions reproductive HCT/Ps regulated solely under section 361 of 
the PHS Act and the regulations in this part, and donated by a sexually 
intimate partner of the recipient for reproductive use. (See Sec.  
1271.420(c).)
    (Comment 163) One comment asked about the relationship between the 
proposed FDA inspection and inspections of hematopoietic stem/
progenitor cells currently performed by other agencies, such as the 
Department of Transportation (DOT).
    (Response) The inspection that FDA will conduct with respect to 
imported HCT/Ps is distinct from inspections conducted by other 
agencies. For example, DOT inspects for compliance with its labeling 
and packaging regulations, whereas FDA inspects for compliance with the 
regulations that require accompanying documentation and labeling 
information about donor screening and testing.
    (Comment 164) Proposed Sec.  1271.420(b) would require that an HCT/
P offered for import must be held intact until it is released by FDA. 
Four comments on this provision raised strong objections to this 
provision because of its potential adverse effect on imported 
hematopoietic stem/progenitor cells. These comments asserted that any 
delay is life-threatening and that these HCT/Ps should be immediately 
cleared through customs.
    (Response) Prior to infusion, recipients of peripheral blood stem/
progenitor cells undergo a myeloablative treatment regimen (i.e., high 
dose chemotherapy and total body irradiation), which may have begun 
before importation takes place. We agree with the comments' concerns 
about the risk of delay in this situation and have accordingly revised 
Sec.  1271.420. Section 1271.420(d) states that this section does not 
apply to peripheral blood stem/progenitor cells regulated solely under 
section 361 of the PHS Act and the regulations in this part, except 
that paragraphs (a) and (b) apply when circumstances occur under which 
such imported peripheral blood stem/progenitor cells may present an 
unreasonable risk of communicable disease transmission, which indicates 
the need to review the information referenced in paragraph (a). We 
believe this provision affords access to peripheral blood stem/
progenitor cells and appropriate public health protection. We also 
believe that situations in which information would be needed for review 
under paragraph (a) will be rare or unlikely to occur. Because the 
regulations in subpart F apply only to those HCT/Ps regulated solely 
under section 361 of the PHS Act and the regulations in part 1271, the 
exception in paragraph (d) affects only the subset of peripheral blood 
stem/progenitor cells that are regulated in this way (e.g., those for 
autologous use, or allogeneic use in a first-degree or second-degree 
blood relative). In the event that issues arise with respect to imports 
of peripheral blood stem/progenitor cells that are regulated as 
biological drugs, and so are subject to the import provisions in 
section 801 of the act (21 U.S.C 381), we would consider those issues 
and take appropriate actions.
    Consideration of these comments has led us to make a clarification 
to Sec.  1271.420(b) that will apply to HCT/Ps that are not excepted 
from these import provisions. Paragraph (b) states that an HCT/P 
offered for import must be held intact by the importer or the 
consignee, under conditions necessary to prevent transmission of 
communicable disease, until an admissibility decision is made by FDA. 
Under paragraph (b), the HCT/P may be transported under quarantine to 
the consignee, while FDA reviews the documentation accompanying the 
HCT/P. While the HCT/P is being held intact pending an admissibility 
determination, under conditions that prevent the transmission of 
communicable disease, the HCT/P cannot be manipulated in any way or 
administered. If the FDA district office determines that the entry is 
in compliance with the appropriate FDA regulations, the district office 
will notify the importer of record. Under paragraph (a), the importer 
can facilitate the entry process by notifying the FDA district office 
before the actual import occurs.
3. Orders of Retention, Recall, Destruction, and Cessation of 
Manufacturing (Sec.  1271.440)
    Proposed Sec.  1271.440 describes the procedures FDA would use to 
issue orders for the retention, recall, and destruction of HCT/Ps and 
for the cessation of manufacturing operations. Under the proposed rule, 
we would issue such orders upon an agency finding that an HCT/P or 
establishment is in violation of the regulations in subparts C and D.
    (Comment 165) Several comments asserted that these enforcement 
actions are too dramatic and far-reaching. One comment argued that the 
standard for taking these actions should be higher than mere CGTP 
deficiencies and should involve imminent danger to public health. One 
comment asserted that the regulation should define procedures to be 
followed to protect the rights of the manufacturer to due process.
    (Response) We disagree with the view that the proposed enforcement 
procedures for noncompliance with CGTP regulations are too dramatic and

[[Page 68646]]

far-reaching. However, to address the concerns raised in these 
comments, FDA has revised the proposed procedures for serving upon an 
establishment an order to cease manufacturing. We have clarified that 
an order to cease manufacturing will be effective immediately only when 
the agency finds that there are reasonable grounds to believe that 
there is a danger to health. In other circumstances, the order will be 
effective after one of the following events, whichever is later:
     Passage of 5 working days from the establishment's receipt 
of the order; or
     If the establishment requests a hearing in accordance with 
paragraph (e) and part 16 (21 CFR part 16), a decision in, and in 
accordance with, those proceedings.
    FDA reiterates that, as stated in Sec.  1271.440(e), part 16 
provides an opportunity to request a hearing concerning any matter 
related to orders of retention, recall, destruction, and cessation of 
manufacturing of HCT/Ps (Sec.  16.1(b)(2)). Part 16 permits FDA to
    * * * take such action pending a hearing * * * as the 
Commissioner concludes is necessary to protect the public health, 
except where expressly prohibited by statute or regulation. A 
hearing to consider action already taken, and not stayed by the 
Commissioner, will be conducted on an expedited basis. (Emphasis 
added). (Sec.  16.24(d))
    If FDA issues an order to cease one or more steps in the 
manufacture of an HCT/P, or issues an immediately effective order to 
retain, recall, and/or destroy the HCT/P, and the Commissioner of Food 
and Drugs (the Commissioner) does not stay the order upon receiving a 
hearing request, FDA will provide an opportunity for an expedited 
hearing. (See Sec.  1271.440(e).) As a technical amendment, we are 
revising Sec.  16.1(b)(2) by adding Sec.  1271.440(e).
    (Comment 166) One comment stated that these enforcement actions 
should relate to a violation that may result in communicable disease 
transmission.
    (Response) We agree. This final rule, issued under the authority of 
section 361 of the PHS Act, is intended to help prevent the 
introduction, transmission, or spread of communicable disease. In 
response to this comment, we have revised paragraph (a) to state that a 
violative HCT/P includes an HCT/P that is infected or contaminated so 
as to be a source of dangerous infection to humans. We have also 
revised that paragraph in two other ways. Rather than simply referring 
to an HCT/P or an establishment ``in violation of the regulations of 
this part,'' the regulation now refers to
    * * * reasonable grounds to believe that an HCT/P is a violative 
HCT/P because it was manufactured in violation of the regulations in 
this part and, therefore, the conditions of manufacture of the HCT/P 
do not provide adequate protections against risks of communicable 
disease transmission * * * or an establishment is in violation of 
the regulations in this part and, therefore, does not provide 
adequate protections against the risks of communicable disease 
transmission.
    (Comment 167) One comment asked for clarification of the term 
``recall'' and suggested that ``notification'' might be a more 
appropriate term in cases where the tissue has already been 
transplanted.
    (Response) Recall is an effective method of removing or correcting 
consumer products that are in violation of laws administered by FDA 
(Sec.  7.40(a)) (21 CFR 7.40(a)). Public notification is an important 
part of a recall strategy (see 21 CFR 7.50), especially where physical 
recall may be impossible or impractical. Guidelines on voluntary 
recalls, including public notification, are set out in Sec. Sec.  7.40 
through 7.59 (21 CFR 7.40 through 7.59). To the extent applicable, FDA 
follows the same policy regarding notifications for mandatory recalls. 
The term ``recall'' encompasses all elements of a recall strategy, 
including notification, and no change to the rule is necessary.
    (Comment 168) One comment noted that issuance of a recall or 
destruction order creates a potential for raising public alarm, and 
suggested the addition of a new paragraph requiring FDA to conduct a 
followup investigation to determine the reasonableness and necessity of 
its initial findings.
    (Response) Concerns about raising public alarm upon issuance of an 
order of recall or destruction are no greater than those associated 
with ordered recalls of other regulated products. FDA does not intend 
to pursue minor violations of part 1271, but would take regulatory 
action in urgent situations to protect public health.
    (Comment 169) One comment requested that FDA acknowledge the 
limitations on corrective actions arising from the ownership status of 
reproductive HCT/Ps.
    (Response) We acknowledge the difficulty of the issues raised by 
the comment, and we note that the provisions of Sec.  1271.440 provide 
the agency with a range of enforcement options. For example, in some 
instances a firm working with FDA could develop a recall strategy that 
involved notification of affected parties. We have added paragraph (f) 
to Sec.  1271.440, which states that FDA will neither issue an order 
for the destruction of reproductive tissue, nor will it carry out such 
destruction itself.
    (Comment 170) One comment asserted that the order to cease 
manufacturing under proposed Sec.  1271.440 violates the Due Process 
Clause of the Fifth Amendment of the United States Constitution. Citing 
Bell v. Burson, 402 U.S. 535, 542 (1971), the comment stated that, 
under the Due Process Clause, before a State seeks to terminate an 
entitlement (e.g., pursuit of a profession), it must provide notice and 
opportunity for hearing appropriate to the nature of the case before 
the termination becomes effective, ``except in emergency situations.'' 
The comment noted that although proposed Sec.  1271.440 permits a 
facility to request a hearing, it does not provide a date on which a 
hearing must be held or that a hearing must be held at all. This 
provision also does not specify when a decision regarding the validity 
of the order is to be made. The comment also observed that an order 
under proposed Sec.  1271.440 could be of potentially infinite 
duration, lasting as long as the agency believes that regulatory 
compliance has not been achieved. Another comment also asserted that, 
under American Bus Ass'n v. Slater, 231 F.3d 1 (D.C. Cir. 2000), this 
provision exceeds FDA's statutory authority under section 361 of the 
PHS Act and is invalid.
    (Response) We disagree that Sec.  1271.440 is either 
unconstitutional or outside the agency's statutory authority. Under 
section 361 of the PHS Act, FDA is expressly authorized to enforce the 
regulations it issues to prevent the introduction, transmission, or 
spread of communicable disease through such means as inspection, 
disinfection, sanitation, destruction, and ``other measures as in 
[FDA's] judgment may be necessary.'' Orders to retain, recall, destroy, 
or cease manufacturing are such other measures that we have concluded 
are necessary to prevent communicable disease transmission. An order to 
cease manufacturing does not terminate any interest or right related to 
the pursuit of a profession. Such an order is intended for use in 
situations when needed to prevent the spread of communicable disease 
and is lawful so long as we provide an opportunity for a hearing ``at a 
meaningful time and in a meaningful manner''; the hearing does not need 
to be provided before the order issues. Armstrong v. Manzo, 380 U.S. 
545, 552 (1965). To clarify this intent we have added language to Sec.  
1271.440(a)(3) stating that an order to cease manufacturing until 
compliance with the regulations in part 1271 has been achieved will 
have immediate effect

[[Page 68647]]

only when FDA determines that there are reasonable grounds to believe 
that there is a danger to health if the establishment continues to 
manufacture (see Comment 165 of this document).
    Under Sec.  1271.440 of this final rule, any person who receives an 
order to cease manufacture will have the opportunity to request an 
expedited hearing in accordance with part 16. We have also included a 
statement in Sec.  1271.440(e) that FDA will provide an opportunity for 
an expedited hearing on an order of cessation that is not stayed by the 
Commissioner, when a request for a hearing is made in accordance with 
part 16. We decline to provide a specific timeframe within which a 
hearing must be held or within which a final decision must be rendered. 
Each request for a hearing should be reviewed within the timeframe 
appropriate for its specific circumstances. Some cases may need 
resolution within a few days, while other, more complicated cases may 
need more time to prepare for a hearing or to resolve the issues.
    The comment's reliance on American Bus Ass'n v. Slater is 
misplaced. In American Bus, the United States Court of Appeals for the 
District of Columbia invalidated a Federal regulation that imposed 
money penalties (a fine), which was not expressly authorized under the 
Americans with Disabilities Act (ADA). The ADA explicitly provided for 
injunctive or similar preventive relief and permitted civil proceedings 
for money damages, but was silent about the imposition of money 
penalties. The Court held that ``Congress unambiguously intended to 
preclude [the Department of Transportation] from authorizing money 
damages.'' (231 F.3d at 4.) By contrast, section 361 of the PHS Act 
expressly authorizes FDA to enforce regulations using such means as
    * * * inspection, fumigation, disinfection, sanitation, pest 
extermination, destruction of animals or articles found to be so 
infected or contaminated as to be sources of dangerous infection to 
human beings, and other measures, as in [FDA's] judgment may be 
necessary.
    Like an order of fumigation, disinfection, and sanitation, an order 
to cease manufacturing is a remedial action taken to put important 
protections in place to prevent communicable disease transmission. 
Unlike the fine in American Bus, it is not a punitive action.
    As explained in the proposed rule and earlier in this response, it 
is FDA's judgment that an order to cease manufacture of an HCT/P may be 
necessary to prevent the introduction, transmission, or spread of 
communicable diseases. Such an order would be issued where violations 
created an urgent situation involving a communicable disease, because 
an establishment is in violation of the regulations in this part and, 
therefore, does not provide adequate protections against the risks of 
communicable disease transmission (e.g., an establishment fails to test 
donors in compliance with subpart C of part 1271). By contrast, we 
would not issue an order to cease manufacture to punish an 
establishment for past violations or violations that do not result in 
an urgent situation.
    (Comment 171) One comment asserted that the 5-day timeframe for 
recall or destruction in proposed Sec.  1271.440(c) is inadequate.
    (Response) FDA disagrees that 5 days is an insufficient timeframe. 
However, we recognize that circumstances may exist or occur that would 
require a time period other than the prescribed 5 working days for the 
implementation of corrective action or recall and/or destruction of 
HCT/Ps. Accordingly, we note that Sec.  1271.440(c)(1), which states 
that ``[a] written order issued under paragraph (a)(1) of this section 
will ordinarily provide that the HCT/P be recalled and/or destroyed 
within 5 working days from the date of receipt of the order'' (emphasis 
added), provides for circumstances where we determine that an alternate 
timeframe is appropriate. The response to comment 167 describes the 
recall guidelines. In the event that FDA issues an order of destruction 
for HCT/Ps, such destruction would occur in accordance with applicable 
local, State, and Federal laws (i.e., Environmental Protection Agency) 
and under FDA supervision.

F. Economic Impacts

    (Comment 172) Three comments suggested that the CGTP rule would 
impose significant cost burdens on affected entities and that FDA has 
significantly underestimated the compliance costs.
    (Response) We disagree. Our analysis of economic impacts suggests 
that the cost burden of the CGTP final rule will not be significant. 
Further, these comments did not provide any data that refute FDA's cost 
estimates or suggest alternative estimates of compliance costs.
    (Comment 173) Three comments provided alternative estimates of the 
financial impact/compliance costs of the CGTP rule for eye banks 
ranging from $41,533 to $180,000 per year. One of these comments 
suggested that the financial impact of the CGTP rule could force many 
eye banks out of business.
    (Response) FDA is unable to assess these comments as no information 
or data were provided to support the estimates of financial impact/
compliance costs. The agency does not anticipate a significant economic 
impact on the eye bank industry because nearly all eye banks are 
believed to be following the current EBAA standards, which meet or 
exceed most requirements of the CGTP rule. We therefore disagree that 
the impact of the rule could force many eye banks out of business.
    (Comment 174) One comment stated that most of the requirements of 
the CGTP rule are not difficult to meet but will require additional 
steps and documentation. The comment also suggested that all eye banks 
will have to increase quality control efforts and hire a separate 
quality control employee to track each provision of the program which 
will be time consuming and expensive.
    (Response) FDA realizes that the CGTP rule will impose some 
additional financial burden on affected entities. However, eye bank 
personnel who oversee the quality assurance program currently required 
under EBAA standards perform duties similar to those required under the 
CGTP final rule. Therefore, the agency does not believe that a separate 
quality control employee will be required. Further, FDA's analysis of 
economic impacts suggests that these requirements will not be overly 
time consuming or expensive.
    (Comment 175) One comment indicated that all eye banks would have 
to add or revise a procedure to handle complaints and that FDA's 
estimate of two complaints per year is too low, especially for large 
volume eye banks.
    (Response) The agency recognizes that some eye banks may experience 
a greater number of complaints. However, this estimate is designed to 
be representative of the number of complaints handled annually by a 
typical entity. The comment did not provide an alternative estimate of 
the number of complaints reported annually.
    (Comment 176) One comment suggested that FDA (implicitly) assumed 
that all primary graft failures will be prevented under the rule, and 
provided no evidence to support any reduction in re-transplants 
required. Two comments suggested that FDA misinterpreted the results of 
a study of eye banks by Wilhelmus, et al. (1995), and failed to 
acknowledge the author's conclusion that no clearly defined factor 
accounted for most cases of primary graft failure. Two comments 
suggested that FDA has

[[Page 68648]]

overstated both the risk of primary corneal graft failure and the 
benefits of the rule, and that it is unlikely that CGTPs will have a 
significant impact.
    (Response) The analysis of economic impacts has been revised to 
eliminate the implicit assumption that all cases of primary corneal 
graft failure will be prevented by the CGTP rule. The evidence on the 
risk, incidence and causes of primary graft failure is limited, and 
mostly mixed and inconclusive. While no clearly defined factor accounts 
for most cases of primary corneal graft failure, storage conditions 
(i.e. preservation media and duration) are identified in a number of 
studies as a possible explanatory factor, and are regulated under the 
CGTP final rule. The possibility that implementation of CGTPs may 
reduce the risk of primary corneal graft failure and generate public 
health benefits cannot be ruled out.
    (Comment 177) One comment noted that a study reported in the 
journal Cornea (1994), found that eye bank-related factors were not 
important in explaining primary corneal graft failure despite the 
author's initial suspicions and hypothesis. Thus, FDA's cost savings 
estimate is greatly exaggerated.
    (Response) FDA has revised its estimate of the benefits of 
implementing the CGTP final rule for eye banks in response to comments 
received, and based on additional and more recent information. However, 
the study cited in the comment also reports, ``interpretation of the 
results of this study is limited by the small sample size, which may 
preclude the detection of some associations,'' and, ``(m)issing data 
for relevant variables, most notably eye bank factors, make 
interpretation of related results difficult.'' (emphasis added). The 
comment does not provide any alternative estimates of benefits.
    (Comment 178) One comment indicated that, in 1999, primary corneal 
graft failure occurred in only 42 cases and intraocular infection in 
only 14 cases out of approximately 40,000 transplants. Another comment 
noted that the 1994 Agency for Health Care Policy Research data 
referenced by FDA suggests 7,443 corneal transplants were performed 
that year, while the actual number reported to EBAA was 35,022.
    (Response) FDA has revised the analysis of impacts of the CGTP 
final rule to address these comments and to incorporate the most 
current information available.
    (Comment 179) One comment objected to the use of 1996 labor 
statistics to derive tissue bank employee wages.
    (Response) The agency has updated the wage estimates used in the 
analysis of impacts of the CGTP final rule to reflect current labor 
costs.
    (Comment 180) One comment objected to FDA's identification of the 
laboratory director and medical director as the same individual.
    (Response) According to industry consultants, the medical director 
often serves as the laboratory director, particularly in small tissue 
facilities. Since all 134 eye banks, and a majority of facilities in 
the other HCT/P industry sectors, are believed to meet the criteria 
characterizing small entities in the relevant industry sector, FDA 
viewed this as an appropriate simplifying assumption.
    (Comment 181) One comment noted that FDA did not add clerical 
expense for the revision of minor policies and procedures.
    (Response) We agree that clerical expense may be incurred in the 
revision or preparation of a minor procedure. Therefore, FDA has added 
clerical expense for both the revision and preparation of a minor 
procedure to the cost impact estimates for the CGTP final rule.
    (Comment 182) One comment objected to FDA's bundling of the cost of 
preparing or revising procedures with training costs.
    (Response) As procedural changes generally necessitate the training 
or retraining of employees, the agency views such bundling as both 
logical and reasonable.
    (Comment 183) One comment suggested that several sections of the 
rule lack cost estimates because no basis for predicting such costs 
exists.
    (Response) Some requirements reviewed in the analysis of economic 
impacts show no costs because they are expected to impose no new 
financial burden on affected entities, not because there is no basis 
for predicting these costs. More specifically, no cost estimate is 
provided for a section or provision of the CGTP rule if analysis showed 
the requirement: (1) Does not apply, (2) has no new cost impact, or (3) 
is met by another subsection of the rule.
    (Comment 184) One comment argued that FDA has underestimated the 
compliance costs for stem cell facilities, and presents alternative 
compliance cost figures based on FDA's analysis of economic impacts.
    (Response) The compliance cost figures provided in the comment are 
not comparable to FDA's cost estimates for a number of reasons. First, 
the cost estimates provided in the comment fail to recognize and 
reflect an important difference between one-time costs and annual or 
recurring costs. Second, FDA's cost estimates are weighted based on the 
proportion of entities in each sector of the HCT/P industry estimated 
to be noncompliant with individual provisions of the CGTP rule. These 
noncompliance rates (weights) are based on information obtained from 
industry professional associations and communication with industry 
consultants. The cost estimates in the comment are not adjusted to 
reflect the estimated rates of industry noncompliance.
    (Comment 185) One comment noted that the Foundation for the 
Accreditation of Cellular Therapy (FACT) is already inspecting to 
standards that are very close to the proposed regulations.
    (Response) FDA does not dispute this, but following the FACT 
standards is voluntary, and evidence does not show that 100 percent of 
entities in the stem cell sector are currently following these 
standards. FDA believes that mandatory requirements are necessary to 
adequately protect public health and safety.
    (Comment 186) One comment suggested that the requirement for 
oversight and audits would impose costs that might significantly reduce 
the number of participants in the National Marrow Donor Program.
    (Response) We disagree. With respect to provisions governing 
oversight and audits, the agency notes the following. Section 
1271.160(c) is expected to impose no new financial burden on affected 
entities. Section 1271.160(d) is expected to impose an additional 
burden of $228 on entities currently following FACT standards, and 
$1,140 in additional costs on firms not following these standards. 
Thus, the maximum burden on any one firm of these provisions is $1,140 
per year. The agency does not view this as a significant cost burden, 
nor do we believe that these provisions will significantly reduce the 
number of donor centers participating in the National Marrow Donor 
Program.
    (Comment 187) One comment expressed serious concerns and 
reservations regarding the accuracy of FDA's estimates of the risks 
associated with hematopoietic stem/progenitor cell transplants, and the 
costs and benefits of the proposed rule. Two comments argued that the 
costs for a bone marrow transplant are much different in 2001 than they 
were in 1994, and that much of the cost is for supportive care and not 
due to contamination of the graft. Therefore, the benefits of the rule 
are overstated.
    (Response) FDA has revised the analysis of impacts for stem cell 
facilities to reflect the most recent

[[Page 68649]]

available risk and cost information. The agency points out that the 
cost for a bone marrow transplant was presented in the analysis of 
impacts of the proposed rule for illustrative purposes only, and was 
not used directly in generating an estimate of the benefits of the CGTP 
rule for stem cell facilities.
    (Comment 188) One comment suggested that the impact of the software 
validation requirements on small tissue facilities would be beyond the 
means of many and could force them out of business. The comment 
suggested that Sec.  1271.160(e) be amended to require software 
validation only if it is relied upon as the sole source of data for 
quality-related decisionmaking.
    (Response) With respect to computer software validation FDA 
assumed: (1) None of the affected entities currently validate custom 
software, (2) 10 percent of all facilities in each sector have 
developed custom software requiring validation, and (3) validation of 
custom software will require 60 hours of laboratory supervisor time 
($36 per hour, total cost = $2,160 per affected entity). We have 
modified Sec.  1271.160(e) to indicate that either validation or 
verification can be performed, whichever is appropriate. Verification 
is less burdensome.
    (Comment 189) One comment suggested that annual human heart valve 
allograft distribution is likely ten-fold lower (5,000-6,000) than the 
61,000 annually referenced in the preamble and, further, that fewer 
than 10 infections per year are caused by contaminated valves since 
direct reports by implanting surgeons suggests less than 1 per year.
    (Response) FDA has revised the analysis of impacts of the CGTP 
final rule to reflect both information provided in the comment and 
information on the risks associated with human heart valve allograft 
reported in the clinical literature.
    (Comment 190) One comment expressed concern that the CGTP rule will 
be particularly onerous on small business, and would like FDA to ensure 
that they are not creating artificial market barriers by implementing 
the rule.
    (Response) Nearly all facilities in the HCT/P industry are 
recognized as small entities and most would be similarly affected by 
the rule. Further, the requirements of the CGTP final rule are largely 
met, and in some cases exceeded, by the voluntary standards firms are 
required to meet to gain accreditation by professional associations in 
their respective HCT/P industry sectors. Finally, the agency's analysis 
suggests that the cost burden of the CGTP rule will not be significant 
(expressed as a percentage of average annual firm revenues) and, 
therefore, should not constitute a market barrier to small business.
    (Comment 191) One comment noted that FDA chose not to certify that 
the rule would not have a significant economic impact on a substantial 
number of small entities. The comment suggested that FDA should 
increase its outreach to small entities in an effort to obtain the 
information necessary to fully assess the rule's impacts before 
finalization.
    (Response) FDA's analysis of economic impacts is based on: 
Information obtained under the registration final rule; administrative 
data on the number of facilities within each industry sector; and the 
number of entities accredited by various industry associations. FDA 
also obtained information from individual experts identified through 
contact with the various industry professional associations. We 
explicitly recognized the uncertainty of our estimates with respect to 
the number of facilities in each sector, degree of compliance with 
current industry standards and impact of the rule on affected entities. 
In the proposed rule, FDA requested detailed industry comment regarding 
our analysis of impacts, and data sources and underlying assumptions. 
Finally, the agency made presentations at the annual conferences of 
several industry professional associations, and held individual 
meetings with many of these groups at their request. We believe this 
represents a significant level of outreach and information gathering 
effort.
    (Comment 192) One comment suggested that, upon publication of the 
final rule, FDA should address all comments received regarding small 
business impacts and provide an assessment of small business revenues 
that are likely to be affected.
    (Response) FDA has provided responses to all comments received in 
the preamble to the final rule. A comprehensive assessment of the 
rule's effects on small business entities is provided in the analysis 
of economic impacts as required under the Regulatory Flexibility Act.
    (Comment 193) One comment noted that if FDA significantly 
underestimated firm revenues, the rule's resultant costs to firms could 
be far greater than those estimated.
    (Response) FDA believes that if average firm revenues were 
significantly underestimated, then the rule's resultant costs would 
appear greater (as a percentage of revenues) than they really are, 
thereby overstating the impact of the rule. We believe the comment 
intended to address the effect of FDA having overestimated firm 
revenues. In this case, compliance costs (expressed as a percentage of 
revenues) would appear smaller than they really are, thereby 
understating the impact of the rule.
    Nevertheless, FDA's estimates of average annual revenues were 
obtained from a variety of sources including a published study of the 
tissue banking industry, information obtained from industry consultants 
and other published data sources. In the CGTP proposed rule, FDA 
requested detailed industry comment on the distribution of firm 
revenues in the HCT/P industry, and also on our estimates of average 
revenue per firm. We received no detailed information in response to 
our request, and no comments provided alternative estimates of annual 
firm revenues.
    (Comment 194) One comment suggested that Sec.  1271.155 of the rule 
seems to allow all businesses affected by the regulation to seek an 
exemption or alternative from the requirements of the rule.
    (Response) While an exemption from or an alternative to a 
particular provision of the rule may be requested by any business, the 
granting of such a request is by no means assured. The entity 
requesting an exemption or alternative must demonstrate that the 
exemption is justified based on scientific data and other evidence, and 
that the alternative satisfies the purpose of the requirement. Section 
1271.155 does not provide a mechanism by which all businesses may 
become generally exempt from compliance with the CGTP rule.
    (Comment 195) One comment assumes that Sec.  1271.155 is FDA's 
attempt to comply with section 603(c) of the Regulatory Flexibility 
Act, which requires agencies to identify any significant alternatives 
available to small entities in their initial regulatory flexibility 
analysis.
    (Response) This assumption is incorrect. The agency has written the 
CGTP rule broadly so as to allow comprehensive regulatory oversight of 
the diverse HCT/P industry. Section 1271.155 is designed to provide 
some flexibility, recognizing that an exemption from, or alternative 
to, a specific provision may be appropriate given the unique properties 
of a particular HCT/P.
    (Comment 196) One comment noted that the FDA estimates between 75 
percent and 100 percent of affected entities are already compliant with 
the provisions of the CGTP rule, and

[[Page 68650]]

questions whether the rule will create another layer of unnecessary 
recordkeeping and training requirements for the affected firms.
    (Response) Because compliance with current voluntary industry 
standards is less that 100%, FDA believes the CGTP rule is the best way 
to establish a consistent standard of safety for marginal firms not 
currently following voluntary industry standards and guidelines, and to 
protect public health and safety. We believe that the recordkeeping and 
training requirements are necessary to achieve the desired public 
health and safety goals.
    (Comment 197) One comment expressed concern that the ultimate 
responsibility is placed in the hands of the firm distributing the HCT/
P, while other firms will also be involved in manufacturing. Noting 
that the distributor is responsible for maintaining documentation from 
all other companies involved in manufacturing the HCT/P, the comment 
expressed concern that this will place an unacceptable burden on small 
entities, and suggests that, to minimize this burden, FDA should adopt 
an alternative approach, discussed in the proposed rule, using a 
cascading set of responsibilities.
    (Response) Before Comment 28, we set out a table to assist 
establishments in understanding their responsibilities when multiple 
establishment are involved in manufacturing an HCT/P. At Comments 28 
through 35 we discuss the allocation of responsibilities in Sec.  
1271.150(c) and 1271.265. FDA believes that this approach is largely 
consistent with the cascading set of responsibilities described in the 
comment and discussed at Comment 31. Both approaches place 
responsibility on each establishment that performs manufacturing 
functions, with the establishment that makes the product available for 
distribution ultimately responsible for ensuring that the manufacturing 
and tracking records for an HCT/P demonstrate that it has been 
manufactured and tracked in compliance with the requirements of this 
subpart and subpart D.

IV. Effective Date of 21 CFR Part 1271 and Applicability of 21 CFR Part 
1270

A. Effective Date for Part 1271

    This final rule is effective May 25, 2005. All HCT/Ps recovered on 
or after the effective date must be in compliance with applicable 
requirements in part 1271.
    As of the effective date, establishments that manufacture HCT/Ps 
defined in Sec.  1271.3(d) that are regulated solely under the 
authority of section 361 of the PHS Act (as described in Sec.  1271.10) 
must comply with all applicable requirements in part 1271, whether or 
not the HCT/P enters into interstate commerce.
    The regulations under 21 CFR 207.20(f) and 807.20(d) require 
establishments that manufacture HCT/Ps that are regulated as drugs, 
devices, and/or biological products under section 351 of the PHS Act 
and/or the act to register and list their HCT/Ps following the 
procedures in subpart B of part 1271. Section 1271.21 requires HCT/P 
establishments to register and list every HCT/P that the establishment 
manufactures within 5 days after beginning operations, or within 30 
days of the effective date of the registration regulation, whichever is 
later. HCT/P establishments that manufacture HCT/Ps subject to 
investigational new drug (IND) or investigational device exemption 
(IDE) provisions are not required to register and list their HCT/Ps 
until the investigational HCT/P is approved through a Biologics License 
Application (BLA), a New Drug Application (NDA), or a Premarket 
Approval Application (PMA); or cleared through a Premarket Notification 
Submission (510(k)).
    As required by Sec. Sec.  210.1(c), 211.1(b), and 820.1(a), 
establishments that manufacture HCT/Ps that are regulated as drugs, 
devices, and/or biological products under section 351 of the PHS Act 
also must comply with the requirements in subparts C and D of part 1271 
in addition to all other applicable regulations.

B. Applicability of Part 1270

    The retrospective application of part 1271 to human tissue, defined 
in Sec.  1270.3(j), recovered before the effective date of the final 
rule would be overly burdensome and impractical. Therefore, we are not 
concurrently revoking part 1270 with the effective date of part 1271 as 
stated in the proposed rule (66 FR 1508 at 1524). However, we intend to 
revoke part 1270 in the future when we are confident that there is no 
human tissue regulated under 1270 available for use.
    Part 1270 applies now only to human tissue defined in Sec.  
1270.3(j) and recovered before May 25, 2005. We have amended Sec.  
1270.3(j) to implement this provision. Products that meet the 
definition of HCT/P in Sec.  1271.3(d) that are recovered before May 
25, 2005, and that have been regulated as drugs, devices, and/or 
biological products under section 351 of the PHS Act and/or the act 
will continue to be subject to the applicable requirements for drugs, 
devices, and/or biological products.

V. Analysis of Economic Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (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 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 this final rule is a significant regulatory action as 
defined by the Executive order and so is subject to review.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The majority of establishments within the HCT/P 
industry that will be affected by this final rule can be classified as 
small business entities, and a number of these establishments will 
incur new costs. Because of the limited information with which to 
characterize the current good tissue practice at many of these 
establishments, and thus the increased effort required to meet the 
standards of the final rule, the cost impact on small business entities 
is uncertain. Therefore, the following analysis, along with other 
relevant sections of this preamble, represents FDA's final regulatory 
flexibility analysis.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing
    * * any rule that includes any Federal mandate that may result 
in the expenditure by State, local and tribal governments, in the 
aggregate, or by the private sector, of $100,000,000 or more 
(adjusted annually for inflation) in any one year.
    The current threshold after adjustment for inflation is $ 110 
million. FDA does not expect this final rule to result in any 1-year 
expenditure that would meet or exceed this amount.
    Based on the following economic analysis, FDA estimates that the 
total one-time costs to comply with this final rule will be 
approximately $6.91

[[Page 68651]]

million, and that the total annual or recurring costs will be about 
$7.13 million. These figures imply a total annualized cost estimate for 
the CGTP final rule of approximately $7.94 million to $8.11 million. 
The average annualized cost of CGTPs per affected small entity, 
expressed as a percentage of average annual revenue, ranges from 0.6 
percent to 3 percent. This range of small entity impacts reflects 
uncertainty with respect to the current practices of affected entities 
and differences in the impact of the CGTP final rule across the various 
sectors of the HCT/P industry.

A. Risks Associated with HCT/Ps

    FDA has conducted an extensive search for information with which to 
quantitatively assess and characterize the risks associated with HCT/
Ps, but has found very little information available. The primary reason 
for this lack of information is the absence of mandatory reporting 
requirements for adverse events, including the incidence of 
communicable disease transmission and graft failure, associated with 
HCT/Ps. The CGTP final rule will help to improve upon this situation by 
requiring entities that make HCT/Ps available for distribution to 
report to the agency any adverse reaction that meets the requirements 
of Sec.  1271.350(a), as well as reports of HCT/P deviations required 
in Sec.  1271.350(b). This information will be highly valuable to the 
agency in identifying and addressing areas of existing and emerging 
public health and safety risks associated with HCT/Ps. The available 
information regarding the risks associated with HCT/Ps known to the 
agency is summarized in the discussion that follows. Specific examples 
of risks associated with individual HCT/Ps are discussed in detail in 
section C of this analysis of economic impacts.
    The HCT/P industry is currently growing and evolving rapidly. Since 
the CGTP proposed rule was published in January 2001, there have been 
significant increases in both the number of tissue donors and 
manufacturing establishments, as well as the number of HCT/Ps 
processed, distributed, and transplanted. Estimates of the current 
number of establishments in each sector of the HCT/P industry are 
presented in table 1b, along with recent information reflecting the 
approximate numbers of tissue donors and tissue products produced 
annually.

    Table 1b.--Numbers of HCT/P Establishments, Tissue Donors and Products Produced By Major Industry Sector
----------------------------------------------------------------------------------------------------------------
                                                                                            Number of Products
          Type of HCT/P            Number of Establishments\1\      Number of Donors        Produced Annually
----------------------------------------------------------------------------------------------------------------
Eye Tissue\2\                                              134                   47,796                   94,186
----------------------------------------------------------------------------------------------------------------
Conventional Tissue\3\                                     166                   20,000                  750,000
----------------------------------------------------------------------------------------------------------------
Hematopoietic Stem/Progenitor                              425                    5,700                    6,031
 Cells\4\
----------------------------------------------------------------------------------------------------------------
Reproductive Tissue\5\                                     510                    4,640                  122,200
----------------------------------------------------------------------------------------------------------------
\1\ Information obtained under the registration and listing final rule or provided by HCT/P industry
  professional associations. See section B.1 and table 3 of this analysis of economic impacts for additional
  details.
\2\ EBAA, 1999.
\3\ AATB, 1999.
\4\ AABB/FACT, 1999.
\5\ The American Society of Reproductive Medicine (ASRM), 1999.

    One source of potential communicable disease transmission risk 
associated with HCT/Ps is a lack of standard quality assurance 
procedures and recordkeeping requirements intended to ensure compliance 
with such procedures. Currently, in every major sector of the HCT/P 
industry, professional organizations have in place standards specifying 
appropriate operating procedures that establishments should follow to 
ensure that the products produced are safe for use and of high quality. 
Individual establishments in the various sectors of the HCT/P industry 
may also apply for accreditation through these professional 
organizations, which periodically inspect member establishments to 
ensure that they are following the appropriate standards. However, as 
discussed in detail in V.B and C of this economic analysis, following 
industry standards and seeking accreditation through the professional 
organizations is voluntary, and the rates of compliance and 
accreditation within the various sectors of the HCT/P industry vary 
significantly. Furthermore, there are currently no comprehensive 
monitoring or enforcement mechanisms governing establishments that 
choose not to follow voluntary industry standards or seek 
accreditation, and that may produce and distribute for use HCT/Ps that 
may present a serious threat to public health and safety.
    The agency is aware of numerous reports of adverse health events 
and several patient deaths that have been linked to HCT/Ps. 
Transplantation of tissue has resulted in transmission of viral, 
bacterial, fungal, and other diseases, although such instances are 
rare. Some of these adverse events have been associated with HCT/Ps 
produced by large entities that do not follow voluntary industry 
standards and are not accredited by their respective professional 
associations. In March of 2002, the CDC published the results of their 
investigation of 26 reported cases of tissue allograft-associated 
infection, one of which resulted in the death of the patient (Ref.1). 
The CDC concluded that of the 26 reported cases, ``14 (were) associated 
with a single tissue processor,'' and further suggested that their
    * * * findings * * * have important implications for patient 
safety and indicate that current federal regulations and industry 
standards on processing and quality control methods need to be 
enhanced and implemented to prevent * * * allograft-associated 
infections.
    Problems due to inadequate product processing and quality controls, 
contributing to post-operative infection and/or graft failure, are one 
category of the many potential causes of the reported adverse health 
events associated with HCT/Ps. Implementation of the CGTP final rule, 
by establishing an enforceable set of product quality assurance 
procedures and standards, is expected to reduce the risk of 
communicable disease transmission as well as the incidence of other 
types of adverse health events associated with HCT/Ps.

[[Page 68652]]

    Recent information on the number of infections following surgery, 
incidence of communicable disease transmission, graft failures, and 
additional surgeries required as a result for various types of HCT/Ps 
is summarized in table 2 of this document. Although these numbers 
suggest that the risks associated with the various types of HCT/Ps are 
relatively low, it is important to consider the limitations of these 
data.
    It is highly unlikely that the available data provide an accurate 
accounting of the true risks associated with HCT/Ps because there is 
currently no mandatory reporting requirement for adverse health events, 
including communicable disease transmission and graft failure, 
associated with tissues. Thus, the case reports that are known to the 
agency are almost certainly not representative of the risks associated 
with HCT/Ps, because a significant number of these events may go 
unreported. In the eye banking industry, the EBAA requests that adverse 
event information be voluntarily reported, but acknowledges that not 
all members provide this information. The AATB does not request 
information on the number of adverse events reported to accredited 
conventional tissue banks. Further, the New York Department of Health 
indicated that they know of no entity that collects information on 
graft failures or repeat surgeries due to complications associated with 
musculoskeletal tissues. Thus, despite a significant effort on the part 
of the agency, very little information with which to identify and 
quantify the risks associated with various types of HCT/Ps was found. 
In summary, the limited information presented in this analysis of 
impacts is not likely representative of the true risks associated with 
HCT/Ps, because no mandatory adverse event reporting requirements 
exist, the information that is available is reported voluntarily and, 
in some sectors of the tissue industry, the necessary information is 
not available because it is not collected by any source.

                            Table 2.--Summary of Available HCT/P Risk Information\1\
----------------------------------------------------------------------------------------------------------------
                                                           Number of       Number of  Graft       Additional
        Type of HCT/P          Number of  Transplants      Infections          Failures      Surgeries  Required
----------------------------------------------------------------------------------------------------------------
Ocular (Eye)\2\               33,035                                   9                 37                   37
----------------------------------------------------------------------------------------------------------------
Musculoskeletal\4\            NDF\3\                                  52                NDF                    4
----------------------------------------------------------------------------------------------------------------
Heart Valve Allografts\5\     4,000                                   26                 41                   41
----------------------------------------------------------------------------------------------------------------
Hematopoeitic Stem/           18,123 (in 1997)                       NDF                NDF                  NDF
 Progenitor Cells;
 Peripheral Blood\6\
----------------------------------------------------------------------------------------------------------------
Hematopoeitic Stem/           2000 (from 1988 to                     NDF                NDF                  NDF
 Progenitor Cells; Cord        2002, inclusive)
 Blood\7\
----------------------------------------------------------------------------------------------------------------
\1\ Annual data except as noted otherwise.
\2\ EBAA, 2001 Statistical Report.
\3\ NDF: Denotes No Data Found or Available.
\4\ AATB, 2001.
\5\ FDA, CDRH, Office of Surveillance and Biometrics, 2001.
\6\ Transfusion, vol. 42, 2002.
\7\ Current Opinion in Oncology, vol. 14, No. 2, March 2002.

    The agency obtained additional information on the risks associated 
with HCT/Ps by reviewing establishment inspection reports (EIRs) filed 
by agency inspectors. The following information summarizes some of the 
inspector's observations made in the course of their inspections of 
establishments processing human tissues. This information was obtained 
from a manual search of approximately 150 EIR reports filed in 2000 and 
2001, and reflects observations from 15 of the 150 EIRs that were not 
citable under 21 CFR part 1271, but would be citable under 21 CFR part 
1271. As such, this discussion is not a comprehensive assessment of the 
results of FDA inspections of HCT/P processing establishments. Instead, 
it is intended to provide an illustration of the type of processing and 
quality assurance problems that currently exist in the tissue industry, 
and that would be addressed through implementation of the CGTP final 
rule.
    Failure to validate procedures for various stages of HCT/P 
processing was identified in 8 of the 15 reports. More specifically, 
observations included failure to validate procedures for the prevention 
of infectious disease contamination and cross-contamination during 
processing, and failure to prepare written procedures for designating 
and identifying quarantined tissue. Failure to document the destruction 
or disposition of human tissue, failure to designate and identify the 
person responsible for making the determination that an HCT/P was 
suitable for transplantation, and/or failure to accompany quarantined 
tissue with records indicating the tissue was not determined to be 
suitable for transplantation were identified in 5 of the 15 reports. 
Failure to maintain adequate records of each significant step in the 
processing of human tissues and/or performance of infectious disease 
screening, as well as failure to maintain accurate records thereof, 
were cited in 6 of the 15 inspection reports. Finally, failure to 
prepare and follow written procedures for all significant steps for 
obtaining, reviewing, and assessing the relevant medical records of 
tissue donors, or failure to provide along with dispensed tissue a 
summary of the records of the donor eligibility determination, were 
cited in 7 of the 15 inspection reports. Although this summary of 
examples of FDA inspector's observations related to provisions under 
part 1270 is not comprehensive, it does indicate the type of procedures 
and quality control problems observed in HCT/P processing 
establishments in 2000 and 2001. Each example could have an adverse 
impact on the HCT/P, and all are further addressed by various 
provisions of the CGTP final rule.
    To gain additional insights into the risks associated with HCT/Ps, 
FDA also reviewed reports of adverse events associated with human 
tissue products submitted through the MedWatch

[[Page 68653]]

system. Between 2000 and 2001, FDA received 21 voluntary MedWatch 
reports of problems associated with HCT/Ps. Because there is no 
mandatory requirement for reporting adverse reactions involving tissue 
products, the extent to which these reported events are representative 
of the risks associated with HCT/Ps during this period is unclear. It 
is likely, however, that a significant number of adverse events 
associated with HCT/Ps are unreported under the current voluntary 
MedWatch system. The 21 reported adverse events included: 4 patient 
deaths (3 of which were probably due to underlying disease and not 
directly attributable to HCT/Ps); 5 life-threatening situations; 5 
surgical or other medical interventions; 2 cases of permanent 
disability; 9 additional hospitalizations; and 7 cases of mold 
contamination of HCT/P packaging material. Many of the potential 
underlying causes of these voluntarily reported adverse events are 
addressed by various provisions of the CGTP final rule, implementation 
of which is expected to reduce communicable disease transmission risks 
and the number of adverse events associated with the various types of 
HCT/Ps.

B. Estimated Cost Impact

    With the CGTP final rule, FDA is furthering completion of the set 
of proposals that represent a comprehensive new system for regulating 
the rapidly evolving HCT/P industry. Manufacturers of HCT/Ps may need 
to make certain changes to their operations to comply with this rule, 
such as creating new procedures revising existing procedures, and 
providing additional documentation. This final rule, in its entirety, 
affects several types of entities involved in the manufacture of HCT/Ps 
including eye banks, conventional tissue banks and establishments 
processing hematopoietic stem/progenitor cells. As explained elsewhere 
in this preamble, Assisted Reproductive Technology (ART) establishments 
and semen banks are subject only to the inspection and enforcement 
provisions of the CGTP final rule as they apply to donor eligibility 
requirements under subpart C. As such, reproductive tissue 
establishments will be only minimally affected by this final rule.
    Information obtained under the registration final rule forms the 
basis for FDA's estimates of the number of affected eye banks and 
conventional tissue banks. The agency's estimates of the number of 
affected eye banks, hematopoietic stem/progenitor cell establishments, 
ART establishments, and semen banks rely heavily on information 
obtained from various professional organizations associated with the 
HCT/P industry. Where good statistical data are not available, FDA's 
cost impact estimates have incorporated the quantitative judgments of 
individual experts identified through contacts with HCT/P industry 
professional associations. Because of the lack of comprehensive data 
with which to characterize patterns of current practice within each 
affected industry sector, and the importance of this data for 
development of an accurate assessment of cost impact, FDA requested 
detailed industry comment on the number of establishments involved in 
the manufacture of HCT/Ps, and the net change in quality assurance 
efforts needed for those establishments to comply with the CGTP 
proposed rule. To the extent possible, this information has been 
incorporated into FDA's analysis of the economic impact of this final 
rule.
1. The Number and Type of Entities Affected
    The analysis of the economic impact of this final rule is organized 
around four major subgroups: Eye banks, conventional tissue banks, 
hematopoietic stem/progenitor cell establishments, and reproductive 
tissue establishments. The number of establishments and the percentage 
of establishments that follow current industry standards are summarized 
in table 3 of this document. In estimating net new costs for eye banks, 
conventional tissue banks and hematopoietic stem/progenitor cell 
establishments, it is critical to account for establishment compliance 
with existing industry standards. In a number of these HCT/P sectors, 
current industry standards for many manufacturing operations meet or 
exceed the specifications in this final rule. Establishments following 
those standards will experience very little impact in complying with 
the new FDA standards.
    As presented in table 3 of this document, FDA has a record of 134 
registered establishments listing eye tissue including 96 eye banks, 
approximately 93 of which are currently accredited by the EBAA. 
According to industry experts, virtually all operating eye banks 
currently comply with EBAA medical and procedural standards for quality 
control. For affected eye banks, the incremental costs associated with 
this final rule result from additional quality assurance steps and 
process documentation as specified under the CGTP final rule.
    FDA has a record of 166 registered tissue banks involved in the 
manufacture of other conventional HCT/Ps, e.g., skin allografts, bone 
allografts, fascia, tendons and ligaments (hereafter referred to as 
``conventional tissue banks''). The AATB lists approximately 75 
accredited tissue banks and projects another 40 to 60 members 
unaccredited. Industry sources report that approximately 75 to 80 
percent of these establishments currently follow the voluntary 
standards established by the AATB. For these establishments, there will 
be some additional cost associated with review of this final rule and 
with alignment of their current SOPs with FDA's new requirements. There 
may also be some additional recurring cost, where documentation and 
quality control required under the CGTP final rule extend beyond 
current practice. For the remaining 20 to 25 percent of establishments 
not following the AATB standards, the cost of compliance will be 
somewhat higher. These establishments may need to establish more formal 
procedures and quality control measures, and may need to devote 
additional staff hours to performing these procedures and processing 
controls.
    Establishments that produce hematopoietic stem/progenitor cells 
from peripheral blood or from umbilical cord blood will also be 
affected by this final rule. FDA finds that available data with which 
to estimate the number of peripheral blood stem/progenitor cell (PBSC) 
establishments and evaluate current practices are quite limited, and 
the actual number of PBSC establishments may range from 200 to 400. As 
of April 2002, CBER has a record of 178 voluntarily registered 
establishments listing ``stem cell'' as a type of product or 
establishment. The National Marrow Donor Program (NMDP), which includes 
establishments that recover PBSCs, lists approximately 92 donor centers 
and 113 collection centers. Approximately 150 establishments involved 
with PBSCs are currently accredited by the AABB and an estimated 107 
are accredited by the Foundation for the Accreditation of Cellular 
Therapy (FACT). Industry sources estimate that 80 of these 
establishments are seeking dual AABB/FACT accreditation, suggesting an 
unduplicated count of approximately 200 PBSC establishments assumed to 
be accredited by AABB and/or FACT. However, the number and 
manufacturing practices of nonaccredited establishments are unknown. 
The International Bone Marrow Transplant Registry/Autologous

[[Page 68654]]

Blood and Marrow Transplant Registry (IBMTR/ABMTR) estimates that the 
total number of peripheral blood or bone marrow establishments may be 
as high as 400 (e.g., 200 more than the number estimated to be 
accredited by AABB and/or FACT), but the number of IBMTR/ABMTR-
estimated establishments that actually process peripheral blood (as 
opposed to bone marrow) is uncertain. For the purposes of this 
analysis, FDA has assumed that 400 PBSC establishments will be affected 
by this final rule.
    Although there is no single national organization that keeps track 
of the number of establishments for umbilical cord blood banking, FDA 
estimates that there are approximately 25 cord blood banks currently 
operating in the United States. These establishments would also seek 
accreditation through FACT or AABB. Based on this information, the 
agency estimates that a total of 425 establishments involved in 
manufacturing hematopoietic stem/progenitor cells would be affected by 
this final rule.
    In addition, 67 establishments produce licensed biological products 
or approved medical devices that are currently regulated under the act 
and/or section 351 of the PHS Act, but would be subject to the 
provisions of this final rule. The impact of CGTPs on these firms is 
expected to be minimal because they are already subject to existing 
CGMP regulations for drugs or QS regulations for medical devices. Those 
requirements are largely consistent with the requirements of this final 
rule.
    Finally, the inspection and enforcement provisions of this final 
rule, as they apply to donor eligibility requirements under subpart C, 
will affect establishments involved with reproductive tissue, primarily 
ART establishments and semen banks. For purposes of this discussion, 
references to ART establishments include infertility clinics, as well 
as andrology and embryology laboratories. The ASRM has a membership of 
approximately 400 fertility centers, 370 of which have provided reports 
for the 1999 Society for Assisted Reproductive Technology registry 
(Ref. 29). The ASRM also has a 1996 list of approximately 110 semen 
banks operating in the United States. Based on conversations with 
consultants, most ART and commercial semen banking establishments 
currently adhere to industry standards similar to those in the CGTP 
final rule. There are currently 11 semen banks accredited by the AATB 
and, according to industry consultants, the remaining commercial semen 
banks are licensed by State health agencies, including the California 
Department of Health and the New York Department of Health.
    Semen banks and andrology laboratories at ART establishments are 
also regulated under the Clinical Laboratory Improvement Amendment 
(CLIA) of 1988.
    The Committee on Laboratory Accreditation and JCAHO also inspect 
embryo laboratories for accreditation. The requirements for 
accreditation by the College of American Pathologists (CAP), which 
accredits ART establishments, closely resemble those in the CGTP final 
rule, with a few exceptions. Consultants estimate that as many as 80 
percent of ART establishments may currently comply with the CAP 
requirements.

 Table 3.--Estimated Percentage of Establishments That Follow Voluntary
                           Industry Standards
------------------------------------------------------------------------
                                                         Percentage of
                                         Relevant       Firms Following
         Affected Industry              Voluntary          Voluntary
                                         Industry           Industry
                                        Standards          Standards
------------------------------------------------------------------------
Eye Tissue: 134 FDA Registered      EBAA               100 %
 Establishments
------------------------------------------------------------------------
Conventional Tissue: (e.g.,         AATB               75 to 80%
 pericardium, dura mater, heart
 valves, skin allograft, bone
 allograft, fascia, tendons,
 ligaments, other viable)
166 FDA Registered Establishments
------------------------------------------------------------------------
Stem/Progenitor Cells:              AABB or FACT       85 % of
Peripheral Blood (PB): 400          AABB or FACT        accredited PB
 establishments                                         establishments
Cord Blood (CB): 25 establishments                     100 % of all CB
                                                        establishments
------------------------------------------------------------------------
Reproductive Tissue:                AATB; CAP          20 largest
Semen Banks: 110 establishments      accreditation;St   establishments
                                     ate Licensed       (accounting for
                                     (e.g., NY, CA);    95% of total
                                     and/or CLIA-       production)
                                     certified
------------------------------------------------------------------------
Reproductive Tissue:                CAP                80 %
ART Establishments: 400              accreditation;
 establishments                      State Licensed
                                     (e.g., NY, CA);
                                     ASRM guidelines
------------------------------------------------------------------------

2. Estimated Impact on Eye Banks, Conventional Tissue Banks and 
Hematopoietic Stem/Progenitor Cell Establishments
    In the sections that follow, the agency considers each of the 
provisions of this final rule and estimates the impact on 
establishments in those sectors of the HCT/P industry subject to CGTPs 
in their entirety. The impact analysis distinguishes expected cost 
impacts based on both facility size and estimated rates of current 
adherence to voluntary industry standards. Based on size standards 
established by the U.S. Small Business Administration (SBA), a small 
establishment in this industry sector (the North American Industry 
Classification Scheme (NAICS) code 621991, Blood and Organ Banks) has 
annual receipts of less than $8.5 million (Refs. 21 and 22).

[[Page 68655]]



Table 4.--Estimated Cost Per Establishment and Estimated Percentage of Establishments Affected By the CGTP Final
                                                     Rule\1\
----------------------------------------------------------------------------------------------------------------
                                                                                                Stem/Progenitor
  21 CFR  Section                 Title                 Eye Tissue      Conventional Tissue           Cell
                                                      Establishments          Sm./Lrg.           Establishments
----------------------------------------------------------------------------------------------------------------
1271.150             Current Good Tissue Practice                 --                       --                 --
                      Requirements.
----------------------------------------------------------------------------------------------------------------
1271.155             Exemptions and Alternatives...               --                       --                 --
----------------------------------------------------------------------------------------------------------------
1271.160             Establishment and Maintenance   ...............  .......................  .................
                      of a Quality Program: General.
                       -Establishment with Minor          $511 (95%)        $511/$1,278 (23%)         $511 (80%)
                        Deficiencies.
                       -Establishment with Major         $2,498 (5%)       $2,498/$4,832 (5%)        $2,498 (5%)
                        Deficiencies.
                       -Cost for Additional Quality     $1,344 (95%)             $1,344 (23%)       $1,344 (80%)
                        Control Work.
  (b)(2)               Procedures for Sharing             $380 (95%)        $760/$2,172 (23%)         $760 (80%)
                        Information.
  (b)(3)               Corrective Actions..........       $456 (95%)               $912 (23%)         $912 (80%)
  (b)(6)               Investigations..............     $2,214 (95%)             $2,214 (23%)       $2,214 (80%)
  (c)                  Audits......................       $456 (95%)        $912/$1,824 (23%)         $912 (80%)
  (d)                  Validate Custom Computer         $2,160 (10%)             $2,160 (10%)       $2,160 (10%)
                        Software.
----------------------------------------------------------------------------------------------------------------
1271.170             Organization and Personnel:...  ...............  .......................  .................
  (b)                  Competent Personnel.........               --            $15,560 (23%)      $15,560 (95%)
  (c)                  Training....................               --      $2,476/$3,104 (23%)       $2,476 (95%)
----------------------------------------------------------------------------------------------------------------
1271.180             Procedures--General                 $9,120 (5%)             $9,120 (23%)       $9,120 (95%)
                      Requirements.
----------------------------------------------------------------------------------------------------------------
1271.190             Establishments:...............  ...............  .......................  .................
  (d)(1)               Cleaning and Sanitation             $348 (5%)          $348/$532 (23%)         $348 (95%)
                        Procedures.
  (d)(2)               Cleaning and Sanitation                    --                       --                 --
                        Records.
----------------------------------------------------------------------------------------------------------------
1271.195             Environmental Control and       ...............  .......................  .................
                      Monitoring:.
  (a)                  Environmental Control.......               --          $348/$532 (23%)         $348 (95%)
  (b)(c)               Inspections and Monitoring..      $1,000 (5%)                       --       $1,000 (95%)
  (d)                  Records.....................       $174 (95%)          $174/$348 (23%)         $174 (95%)
----------------------------------------------------------------------------------------------------------------
1271.200             Equipment:....................  ...............  .......................  .................
  (b)                  Procedures/Schedules--                     --      $1,460/$2,979 (23%)       $1,460 (95%)
                        Cleaning, Sanitizing and
                        Maintenance.
  (c)                  Calibration.................               --      $1,460/$2,979 (23%)       $1,460 (95%)
  (d)                  Inspections.................       $216 (95%)          $432/$684 (23%)         $216 (95%)
  (e)                  Records.....................  ...............  .......................  .................
                        -of Cleaning, Sanitizing          $174 (95%)          $348/$696 (23%)         $174 (95%)
                         and Calibration Activities.
                        -of the Use of Each Piece         $696 (95%)      $1,392/$2,784 (23%)       $1,392 (95%)
                         of Equipment.
----------------------------------------------------------------------------------------------------------------
1271.210             Supplies and Reagents:........  ...............  .......................  .................
  (a)                  Verification................       $131 (95%)          $348/$532 (23%)         $348 (95%)
  (c)                  In-house Reagents...........               --          $348/$532 (23%)         $348 (95%)
  (d)(1)                Records of Receipt,               $174 (95%)          $174/$348 (23%)         $174 (95%)
                        Verification, and Lot.
----------------------------------------------------------------------------------------------------------------
1271.220             Process Controls:.............  ...............  .......................  .................
                       In-Process Monitoring              $380 (95%)        $380/$1,086 (23%)         $760 (95%)
                        Procedures.
----------------------------------------------------------------------------------------------------------------
1271.225             Process Changes:..............  ...............  .......................  .................
                       Validation of Process              $760 (95%)        $760/$2,172 (23%)         $760 (95%)
                        Changes.
                       Records/Documentation.......       $456 (95%)          $456/$912 (95%)         $456 (95%)
----------------------------------------------------------------------------------------------------------------
1271.230             Process Validation:...........  ...............  .......................  .................
  (a)                  General.....................     $1,700 (95%)             $1,700 (95%)       $1,700 (95%)
                       Procedures..................     $1,520 (95%)        $760/$2,172 (95%)       $1,520 (95%)
  (c)                  Validation/Revalidation of         $850 (95%)             $1,700 (95%)       $1,140 (95%)
                        Process Changes.
----------------------------------------------------------------------------------------------------------------
1271.250             Labeling Controls:............  ...............  .......................  .................
  (a)(b)               Procedures..................        $380 (5%)         $380/$1,086 (5%)         $380 (95%)
----------------------------------------------------------------------------------------------------------------
1271.260             Storage.......................               --                       --                 --
----------------------------------------------------------------------------------------------------------------
1271.265             Receipt, Pre-Distribution       ...............  .......................  .................
                      Shipment and Distribution:.
                       Recordkeeping and                   $864 (5%)       $1,728/$3,456 (5%)        $3,456 (5%)
                        Documentation.
  (a)                  Procedures--Receiving                      --        $380/$1,086 (23%)         $760 (95%)
                        Activities.
  (c)                  Procedures--Availability for               --        $380/$1,086 (23%)         $760 (95%)
                        Distribution.
  (d)                  Packaging and Shipping......     $1,392 (95%)             $1,392 (95%)         $576 (95%)
  (f)                  Procedures--Return to                      --          $348/$532 (23%)         $348 (95%)
                        Inventory.
----------------------------------------------------------------------------------------------------------------
1271.270             Records:......................  ...............  .......................  .................
  (a)                  General.....................       $728 (95%)        $728/$1,618 (95%)         $728 (95%)
  (b)                  Records Management System...     $3,040 (95%)      $3,040/$6,080 (23%)       $3,040 (95%)

[[Page 68656]]

 
  (d)                  Length of Retention.........         $18 (5%)                $18 (23%)          $18 (95%)
----------------------------------------------------------------------------------------------------------------
1271.290             Tracking:.....................  ...............  .......................  .................
  (b)(c)               System of Product Tracking:         $760 (5%)        $380/$1,086 (23%)         $380 (95%)
                        General Requirements.
  (d)(e)               System of Product Tracking:       $1,728 (5%)      $3,456/$6,912 (23%)       $3,456 (95%)
                        Specific Requirements.
  (f)                  Consignees..................      $1,520 (5%)             $1,520 (23%)       $1,520 (95%)
----------------------------------------------------------------------------------------------------------------
1271.320             Complaint File:...............  ...............  .......................  .................
  (a)                  Procedures..................       $131 (95%)          $348/$532 (23%)         $348 (95%)
  (b)                  Complaint File..............               --                       --                 --
  (c)                  Review and Evaluation of           $608 (95%)        $608/$1,216 (23%)         $608 (95%)
                        Complaints.
----------------------------------------------------------------------------------------------------------------
1271.350             Reporting.....................      $592 (100%)              $592 (100%)        $592 (100%)
----------------------------------------------------------------------------------------------------------------
1271.370             Labeling......................               --                       --                 --
----------------------------------------------------------------------------------------------------------------
1271.400             Inspections...................  ...............  .......................  .................
  (a)                  General.....................      $768 (100%)              $768 (100%)        $768 (100%)
----------------------------------------------------------------------------------------------------------------
1271.420             HCT/Ps Offered for Import.....               --                       --                 --
----------------------------------------------------------------------------------------------------------------
1271.440             Orders of Retention, Recall,                 --                       --                 --
                      Destruction and Cessation of
                      Manufacturing.
----------------------------------------------------------------------------------------------------------------
\1\ Only subsections expected to impose new compliance costs for a particular industry sector are shown. No cost
  is estimated for a subsection if analysis revealed that the requirements: (1) do not apply, (2) have no new
  cost impact, or (3) are met by another subsection of the CGTP final rule. Estimated noncompliance rates are in
  parentheses.

    As indicated by the information in table 4 of this document, the 
impact of the CGTP final rule varies significantly, depending upon the 
sector of the HCT/P industry, size of the affected entity and the 
particular provision. For many of the CGTP provisions, the 
establishment level impact will entail development of new procedures, 
or revision of existing procedures. The scope and degree of complexity 
of these changes will vary. FDA expects that the staff typically 
involved in the development, revision, and finalization of 
establishment procedures will include technicians, clerical staff, lab 
supervisors, and the lab director. Although FDA did not specify 
personnel requirements for individual provisions of the CGTP final 
rule, for purposes of industry-wide estimation, the agency's cost 
analysis relies on standardized estimates of the type of personnel, 
level of effort, and hourly labor cost for revising or establishing 
each type of procedure. Table 5 of this document summarizes the 
agency's assumptions, which are based on published wage and benefits 
data and input from HCT/P industry consultants.\1\
---------------------------------------------------------------------------

    \1\ A detailed presentation of level of effort and cost 
assumptions for nonreproductive tissue establishments is provided in 
FDA's Cost Impacts of the Proposed Current Good Tissue Practice Rule 
on Eye Banks, Conventional Tissue Banks, and Stem Cell Facilities: 
Background Paper, April 1999, and for reproductive tissue facilities 
in Cost Impacts of the Proposed Current Good Tissue Practice Rule on 
Semen Banks and ART Facilities, February 1999, prepared by Eastern 
Research Group (ERG), Inc. These documents are available in docket 
97N-484P.

  Table 5.--Estimated Level of Effort and Cost Per Procedure Revised or Prepared to Comply With the CGTP Final
                                                      Rule
----------------------------------------------------------------------------------------------------------------
                                                         Minor Procedures                Major Procedures
                                                 ---------------------------------------------------------------
                    Category:                         Revise                          Revise
                                                     Existing       Prepare New      Existing       Prepare New
----------------------------------------------------------------------------------------------------------------
Small Establishment
----------------------------------------------------------------------------------------------------------------
  Total level of staff effort                             3 hrs.          7 hrs.          8 hrs.         16 hrs.
----------------------------------------------------------------------------------------------------------------
  Cost (rounded)                                            $131            $348            $380            $760
----------------------------------------------------------------------------------------------------------------
Large Establishment
----------------------------------------------------------------------------------------------------------------
  Total level of staff effort                             5 hrs.         13 hrs.         27 hrs.         54 hrs.
----------------------------------------------------------------------------------------------------------------
  Cost (rounded)                                            $192            $532          $1,086          $2,172
----------------------------------------------------------------------------------------------------------------


[[Page 68657]]

    The analysis of cost impacts for HCT/P industry sectors subject to 
CGTPs in their entirety is summarized in the following discussion of 
the rule's individual provisions, and the expected type and extent of 
industry impact. The pertinent section of the final rule is noted to 
facilitate reference to the related cost estimates presented in table 4 
of this document.
    a. Section 1271.150--current good tissue practice: general. The 
final rule requires manufacturers of HCT/Ps to follow CGTPs. Section 
1271.150(a) provides an overview of CGTPs but does not present specific 
compliance requirements. The specific requirements are addressed in 
subsequent sections. Section 1271.150(b) lists the core CGTP 
requirements, and Sec.  1271.150(c) addresses compliance with 
applicable requirements for those entities subject to CGTPs. Section 
1271.150(d) explains the relationship between the CGTP rule and 
regulations specifically applicable to biological drugs or devices, and 
paragraph (e) defines the term ``where appropriate'' in relation to the 
rule. Section 1271.150(b) through (e) will not generate any compliance 
costs for the HCT/P industry because no specific requirements are 
specified.
    b. Section 1271.155--exemptions and alternatives. The CGTP final 
rule allows establishments to request an exemption or alternative from 
FDA for certain provisions of the rule. There is currently no basis for 
predicting the number of industry requests for exemptions or 
alternatives, or for predicting the effect of these actions on 
compliance costs. Because of a high degree of similarity between CGTPs 
and current voluntary industry standards, FDA anticipates that very few 
establishments will consider it appropriate to be exempted from the 
provisions of this final rule.
    c. Section 1271.160--establishment and maintenance of a quality 
program. The final rule requires that establishments establish and 
maintain a quality program. The quality program must include: 
Procedures relating to core CGTP requirements, procedures for 
exchanging information with other establishments known to have 
recovered cells or tissue from the same donor, appropriate corrective 
actions related to core CGTP requirements, proper training and 
education of personnel involved in activities related to core CGTP 
requirements, appropriate monitoring systems, investigation and 
documentation of HCT/P deviations related to core CGTP requirements, 
audits, computer software validation or verification, and other 
procedures specific to the quality program. Several 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 industry sectors have the appropriate facilities, 
equipment, and systems to support a quality program, but only those 
already following industry standards are expected to have comprehensive 
quality programs in place. Some establishments may need to upgrade 
their quality program for several of the CGTP requirements. These 
include procedures for sharing information, corrective actions, and 
investigations. Further, some establishments may need to take 
additional steps to administer corrective actions and conduct 
investigations if they currently do so only when major deficiencies 
arise.
    Although the sharing of information is an industry-wide practice, 
some small establishments, particularly those not following current 
industry standards, may not have written procedures and forms for this 
task. FDA estimates that 95 percent of eye banks, 23 percent of 
conventional tissue banks not following the current AATB standards, and 
80 percent of the hematopoietic stem/progenitor cell establishments not 
following the FACT or AABB standards, will need to prepare a major 
procedure to address this requirement.
    Although FDA anticipates that most industry establishments take 
steps to administer corrective actions and conduct investigations, some 
may currently do so only when major deficiencies arise.
    FDA estimates that 95 percent of eye banks, 23 percent of 
conventional tissue banks, and 80 percent of hematopoietic stem/
progenitor cell establishments not following industry standards will 
need to invest additional time to meet these new requirements. The 
incremental time burden to administer corrective actions and document 
these activities is estimated to be an additional 1/2-hour per month of 
laboratory director time at establishments that already perform this 
activity to a lesser extent, and an additional hour per month at all 
other establishments that will be newly affected by this provision. As 
discussed in the background papers prepared by FDA and Eastern Research 
Group (ERG), and shown in table 4 of this document, for newly required 
investigations in tissue establishments, FDA estimates an additional 
cost per year of $2,214 for an additional 2 hours per month for the 
laboratory director to investigate and document deficiencies, and an 
additional 1/2 hour each for the laboratory supervisor and lab 
technician to participate in the investigations.
    A number of establishments will also need to institute other 
requirements of the quality program, including periodic audits, 
computer software validation or verification, and procedures specific 
to the quality program. Audits are part of the industry standards 
published by the AATB, EBAA, FACT, and AABB. However, some 
establishments following these standards may need to do some additional 
recordkeeping, and establishments not following standards will need to 
begin to conduct audits. Referring to table 4 of this document, FDA 
assumes that up to 95 percent of eye banks will increase their audit 
efforts, including additional lab director time to prepare for and 
perform the periodic audit. An estimated 23 percent of conventional 
tissue banks will allocate additional resources for audits, with a 
higher allocation of hours at larger establishments, to prepare for, 
and to conduct, the audit. For hemapoietic stem/progenitor cell 
establishments, FDA estimates that there will be no additional auditing 
required at establishments following FACT or AABB standards, but an 
estimated 80 percent of establishments not following industry standards 
will need to spend additional time to prepare for and to conduct 
periodic audits.
    Section 1271.160 of the CGTP final rule further stipulates that 
establishments must validate or verify, as appropriate, the computer 
software used in their operations when it is used in the performance of 
core (good tissue practice (GTP) functions. Validation would be 
required for custom software used in core GTP functions. However, for 
off the shelf commercial software packages (e.g., for data storage and 
retrieval, recordkeeping, etc.) used as intended by the software 
manufacturer, it would be adequate for the establishment, when using 
such products in the performance of core GTP functions, to verify the 
product's performance. Such products are already validated or verified 
by the software vendor.
    FDA assumes that none of the affected establishments currently 
validate or verify their custom software and that approximately 10 
percent of eye banks, conventional tissue banks and hematopoietic stem/
progenitor cell establishments have developed custom software that will 
require full validation or verification under this final rule. Because 
we received no specific comments regarding these assumptions in 
response to the proposed rule, we have retained them here. Although the

[[Page 68658]]

scope of such work can vary, FDA estimates that the custom software in 
use has a limited scope of application, and that an average of 60 hours 
of work by the laboratory supervisor will be required to validate or 
verify custom computer software at an establishment. Detailed 
presentations of these assumptions are provided in section 2.4.3 of the 
background papers (see footnote 1 of this document) 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 indicated that establishments have quality systems 
in place, but that most establishments are not aware of some minor 
elements of CGTPs that should be included in their 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 banks, and up to 80 
percent of hematopoietic stem/progenitor cell establishments will have 
minor deficiencies that will require them to revise one minor and one 
major procedure. In addition, FDA estimates that 5 percent of all eye 
banks, and conventional tissue banks and hematopoietic stem/progenitor 
cell establishments not following voluntary industry standards may 
identify major deficiencies, and will need to prepare five minor 
procedures and one major procedure to address those problems.
    The agency further assumes that establishments may generally need 
to perform some additional quality control work to comply with the 
quality program requirements in the CGTP final rule. Although some 
tasks will not require any additional time to perform, FDA estimates 
that approximately 1 hour per month each for the laboratory director 
and supervisor may be needed. The agency estimates that 95 percent of 
all eye banks, 23 percent of conventional tissue banks, and 
approximately 80 percent of hematopoietic stem/progenitor cell 
establishments will need to allocate additional staff time for this 
purpose.
    d. Section 1271.170--personnel. This final rule requires 
establishments to employ sufficient personnel with the necessary 
education, experience, and training to ensure competent performance of 
their assigned functions. The EBAA, AATB, FACT, 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 eye banks, conventional tissue 
banks and hematopoietic stem/progenitor cell establishments will 
already be compliant with these provisions of the CGTP rule. Those 
establishments in the conventional tissue and hematopoietic stem/
progenitor cell manufacturing sectors that do not follow industry 
standards will incur new costs. The cost of this staffing effort is 
estimated to be approximately $15,560 per affected establishment.
    FDA anticipates that the 23 percent of conventional tissue banks 
and 95 percent of hematopoietic stem/progenitor cell establishments not 
following industry standards will incur new training costs to comply 
with the personnel provisions of the CGTP final rule. For a small 
tissue establishment, these costs are estimated to average $2,476. The 
CGTP final rule also requires that records of personnel qualifications 
and training be maintained, but because existing industry standards 
address personnel recordkeeping, FDA assumes that the cost to comply 
with this requirement will be negligible. Details of these assumptions 
are provided in section 2.4.4 of the background papers (see footnote 1 
of this document) by FDA and ERG.
    e. Section 1271.180--procedures: general requirements. The CGTP 
final rule requires establishments to establish and maintain written 
procedures appropriate to meet core CGTP requirements for all steps 
performed in the manufacture of HCT/Ps. FDA anticipates a negligible 
incremental cost for most establishments following industry standards, 
and an additional 120 hours of laboratory director time for 
establishments not following the current industry standards. FDA 
estimates that 5 percent of eye banks will need to expand their current 
efforts, and that 23 percent of conventional tissue banks and 95 
percent of hematopoietic stem/progenitor cell establishments will incur 
new costs.
    f. Section 1271.190--facilities. This final rule stipulates a 
number of requirements regarding facilities covering operations, size, 
construction, location, lighting, ventilation, plumbing, drainage and 
access to sinks and toilets. A facility used in the manufacture of HCT/
Ps must be of suitable size, construction, and location to prevent 
contamination of HCT/Ps with communicable disease agents and to ensure 
orderly handling of HCT/Ps without mix-ups. Cleaning and sanitation 
requirements are also outlined, including requirements for written 
procedures, schedules, and documentation of these activities.
    Based on discussions with industry experts, FDA estimates that 
nearly all establishments that follow industry standards will not incur 
any new costs under these provisions of the CGTP final rule. However, 
some establishments that generally adhere to cleaning standards do not 
have written procedures. Thus, FDA estimates that 5 percent of all eye 
banks, in addition to 23 percent of the conventional tissue banks and 
95 percent of all hematopoietic stem/progenitor cell establishments, 
will incur the cost of writing a minor procedure for cleaning. The 
facilities provision of the CGTP final rule also requires that records 
of cleaning be maintained. This requirement is met by establishments 
following industry standards, and is expected to have a negligible 
impact on establishments not following the current voluntary standards.
    g. Section 1271.195--environmental control and monitoring. Where 
environmental conditions could reasonably be expected to cause 
contamination or cross-contamination, or accidental exposure of HCT/Ps 
to communicable disease agents, environmental conditions must be 
adequately controlled. The final rule also requires that environmental 
control systems be monitored and periodically inspected, and that 
environmental control and monitoring activities be documented. The 
impact of this provision of the CGTP rule varies by industry sector. 
For affected eye banks, the EBAA standards already contain similar 
provisions, however, some additional costs may be incurred for periodic 
inspection of 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 of equipment. 
FDA anticipates that conventional tissue banks following AATB standards 
will experience no new costs, but that the remaining 23 percent of 
establishments will need to prepare a minor procedure for control and 
monitoring of ventilation and air filtration.
    The current FACT and AABB standards do not require written 
procedures for environmental control and monitoring. FDA therefore 
estimates that 95 percent of all hematopoietic stem/progenitor cell 
establishments will need to develop a minor procedure for control and 
monitoring of ventilation and air filtration systems to comply with the 
CGTP rule. However, because the industry standards do provide for 
appropriate environmental controls, FDA assumes that some 
establishments

[[Page 68659]]

are performing the necessary control and monitoring activities. The 
agency estimates that as many as half of the establishments currently 
following industry standards may already be conducting routine 
inspections of their environmental control equipment. It is assumed 
that the remaining 50 percent of those establishments, and 95 percent 
of hematopoietic stem/progenitor cell establishments assumed not to be 
following industry standards, will incur additional costs to 
periodically inspect equipment and perform recordkeeping related to 
environmental control. Table 4 of this document provides estimates of 
cost per establishment associated with these efforts.
    h. Section 1271.200--equipment. This final rule requires that 
appropriate equipment be used in processing HCT/Ps to prevent the 
introduction, transmission, or spread of communicable disease. 
Cleaning, sanitizing, maintenance, and calibration of equipment must be 
performed according to established schedules and procedures; equipment 
must be regularly inspected for adherence to applicable procedures and 
schedules; and all such activities must be documented. In addition, 
establishments must keep records of each use of each piece of 
equipment, including the identification of each HCT/P manufactured with 
that piece of equipment.
    The standards related to equipment, as specified by AATB, EBAA, 
FACT, and AABB, generally address maintenance procedures, and 
recordkeeping related to maintenance. However, this final rule extends 
beyond industry standards of EBAA, FACT, and AABB in the areas of 
equipment inspection and recordkeeping. Based on information provided 
by industry sources, FDA believes that some of the larger HCT/P 
establishments may already be performing the required equipment 
inspection and recordkeeping.
    FDA therefore estimates that 95 percent of all eye banks will 
allocate an additional 1/2-hour per month for the laboratory supervisor 
to inspect equipment, an additional 1/2-hour per month of technician 
time to document equipment cleaning and calibration, and 2 additional 
hours per month for a technician to record each use of the equipment.
    The estimated 23 percent of conventional tissue banks that 
currently do not follow AATB standards will also incur new costs 
related to the equipment provisions. FDA estimates that small 
establishments will prepare one minor procedure for calibration, and 
for cleaning and other maintenance for each of six pieces of equipment. 
In addition, small establishments 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 of technician time to 
record each use of the equipment. FDA estimates that large 
establishments will need to write minor procedures for each of eight 
pieces of equipment, will 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 
establishments simultaneously preparing multiple procedures related to 
equipment will 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 required to prepare six to 
eight minor equipment maintenance procedures.
    It is expected that hematopoietic stem/progenitor cell 
establishments will also be required to perform additional work to 
align current practice with the CGTP requirements. Current FACT 
procedures provide for routine maintenance and calibration of 
equipment. In addition, the AABB standards recommend that SOPs be 
established for proper equipment maintenance and monitoring. To further 
develop procedures to address routine maintenance and recordkeeping 
under the CGTP rule, FDA estimates that 95 percent of all hematopoietic 
stem/progenitor cell establishments will prepare a minor procedure for 
calibration of each of six pieces of equipment. In addition to the 
preparation of procedures, lab personnel will be involved in carrying 
out the necessary maintenance work, estimated to require an additional 
1/2 hour of lab supervisor time per month for routine inspection of 
equipment, an additional 1/2 hour per month for lab technicians to 
document cleaning and calibration work, and an additional 4 hours per 
month of lab technician time to record each use of equipment. In 
addition, most cell establishments that do not currently follow FACT or 
AABB standards will incur the cost of preparing a minor procedure for 
cleaning and sanitizing, and for routine maintenance of each of six 
pieces of equipment. Section 2.4.8 of the FDA and ERG background papers 
(see footnote 1 of this document) provide detailed presentations of 
these assumptions.
    i. Section 1271.210--supplies and reagents. The CGTP rule requires 
manufacturers to verify that supplies and reagents used in the 
manufacture of HCT/Ps meet specifications designed to prevent 
circumstances that increase the risk of introduction, transmission, or 
spread of communicable disease. Verification of quality may be 
accomplished by the establishment that uses the supply or reagent, or 
the vendor of the supply or reagent. This final rule also requires 
documentation of the receipt and verification of supplies or reagents 
used in HCT/P processing, and of the lot of supply or reagent used in 
the manufacture of each HCT/P.
    The existing industry standards address some or all of these 
activities, and the estimated impact per establishment varies 
accordingly. EBAA standards specify that sterilized supplies and 
reagents must contain sterilization dates and method, or appropriate 
expiration dates. However, the agency estimates that up to 95 percent 
of eye banks will need to devote additional resources to receipt and 
verification activities, and will devote additional staff time to 
recording the receipt of supplies and reagents. Similarly, FACT 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 
hematopoietic stem/progenitor cell establishments will expand on their 
current supply and reagent related recordkeeping to comply with these 
CGTP provisions.
    The current AATB standards address most of the requirements for 
supplies and reagents included in the final rule. FDA assumes that the 
estimated 23 percent of conventional tissue establishments that do not 
follow these standards will require additional resources for in-house 
reagent receipt and verification, and will devote additional staff time 
to keeping records of the receipt and verification of supplies and 
reagents. The estimated costs per establishment for these provisions 
are presented in table 4 of this document.
    j. Section 1271.215--recovery. The CGTP final rule requires that 
each HCT/P be recovered in a way that does not cause contamination or 
cross contamination during recovery, or otherwise increase the risk of 
the introduction, transmission, or spread of

[[Page 68660]]

communicable disease through the use of the HCT/P. Because this section 
does not impose any specific requirements it is not expected to impose 
any identifiable compliance costs.
    k. Section 1271.220--processing and process controls. The CGTP 
final rule requires establishments to process HCT/Ps in a way that does 
not cause contamination or cross-contamination during processing, and 
that prevents the introduction, transmission, or spread of communicable 
disease. An establishment processing HCT/Ps is responsible for ensuring 
that each in-process HCT/P is controlled until the results of any 
required inspections, testing, verification activities or approvals are 
received and documented. The standards for tissue banking specified by 
the AATB include activities to address these process controls, but the 
EBAA, FACT, and AABB standards do not include specific requirements for 
in-process monitoring. FDA estimates that 95 percent of eye banks, 23 
percent of conventional tissue banks, and 95 percent of hematopoietic 
stem/progenitor cell establishments will need to prepare a minor 
procedure related to process monitoring.
    l. Section 1271.225--process changes. This final rule requires 
establishments to verify or validate any changes to established 
procedures to ensure that the change does not create an adverse impact 
elsewhere in the operation. Process changes must be approved before 
implementation by a responsible person and approved changes must be 
communicated to appropriate personnel in a timely manner. The current 
standards for AATB, FACT, and the AABB provide for SOPs for process 
changes, although recordkeeping procedures are not specified. Current 
EBAA standards do not provide for SOPs for process changes. FDA 
therefore estimates that nearly all eye banks will need to prepare a 
major procedure for process changes, and will allocate an additional 1/
2 hour of lab director time to document process changes.
    FDA anticipates that the 23 percent of conventional tissue banks 
not following the AATB standards will need to prepare a major procedure 
related to process changes, and that nearly all tissue banks will 
increase related recordkeeping. The agency estimates that small 
conventional tissue banks will spend an additional 1/2 hour per month 
of lab director time to document process changes, and that large 
establishments would allocate an additional hour of lab director time 
per month for this activity. FDA anticipates that almost all 
hematopoietic stem/progenitor cell establishments that do not follow 
FACT or AABB standards will need to prepare a major procedure to 
address process changes. In addition, FDA estimates that 95 percent of 
all hematopoietic stem/progenitor cell establishments will also 
allocate an additional half hour of lab director time per month to 
document process changes. The associated costs per establishment are 
presented in table 4 of this document.
    m. Section 1271.230--process validation. This final rule requires 
establishments to validate processes that cannot be verified through 
subsequent inspection and testing, and that the validation activities 
and results be documented. Current EBAA standards do not require 
process validation. Based on information provided by industry sources, 
FDA believes that some of the larger eye banks may already be 
performing the required process validation. Although current AATB, 
FACT, and AABB standards include provisions for process validation and 
related recordkeeping, industry experts indicate that additional 
validation work will be required at nearly all establishments under the 
CGTP final rule. FDA therefore estimates that 95 percent of all eye 
banks, conventional tissue banks, and all hematopoietic stem/progenitor 
cell establishments not following AABB or FACT voluntary standards, 
will prepare two major procedures related to process validation, and 95 
percent of conventional tissue banks and hematopoietic stem/progenitor 
cell establishments will revise two major procedures. Further, FDA 
estimates that 95 percent of all establishments in each sector of the 
HCT/P industry will devote additional staff time to perform process 
validation. Details of these assumptions are provided in section 2.4.12 
of the background papers (see footnote 1 of this document) by ERG and 
FDA.
    In addition to the initial validation work, the CGTP final rule 
requires revalidation when changes to a validated process occur. The 
agency estimates that approximately 95 percent of eye banks, 
conventional tissue banks, and hematopoietic stem/progenitor cell 
establishments will need to allocate an additional 20 to 40 hours of 
laboratory staff time annually for procedure revalidation. Costs for 
these provisions of the CGTP rule are presented in table 4.
    n. Section 1271.250--labeling controls. The CGTP rule requires 
establishments to establish and maintain written procedures for 
controlling the labeling of products. These procedures must ensure 
proper identification of products and include various checks and 
verifications. Each product must also be accompanied by a summary of 
donor eligibility information, if applicable.
    According to consultants and industry contacts, labeling controls 
are usual and customary practice in all sectors of the HCT/P industry. 
FDA anticipates that only about 5 percent of eye banks, conventional 
tissue banks and hematopoietic stem/progenitor cell processing 
establishments will need to perform additional work to comply with the 
CGTP labeling controls. FDA estimates that such establishments will 
need to revise a major procedure for proper identification of products.
    o. Section 1271.260--storage. The CGTP final rule requires that 
storage areas be controlled to prevent mixups, contamination, cross-
contamination, and to prevent an HCT/P from being improperly made 
available for distribution. Temperature must be monitored and limits 
established, including expiration dating where appropriate. Each of the 
relevant HCT/P industry standards contains provisions regarding storage 
practices. Based on agency review of current industry standards, and 
conversations with experts about current practices at HCT/P 
establishments, FDA anticipates that virtually all establishments 
already comply with these provisions of the CGTP rule. These provisions 
are therefore expected to produce no new cost impact for eye banks, 
conventional tissue banks and hematopoietic stem/progenitor cell 
processing establishments.
    p. Section 1271.265--receipt, predistribution shipment, and 
distribution. The CGTP final rule requires that procedures be 
established and maintained for receipt (e.g., determination of whether 
to accept, reject, or place the HCT/P in quarantine), predistribution 
shipment, and distribution of HCT/Ps. Documentation of each of the 
aforementioned activities, when performed, is also required. Packaging 
and shipping containers must be designed and constructed to protect the 
HCT/P from contamination, and appropriate shipping conditions must be 
established and maintained during transit. Procedures must 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 most provisions related to this area 
of quality control are included in each of the relevant industry 
standards.

[[Page 68661]]

    The primary impact of the CGTP provisions for product receipt, 
predistribution shipment, and distribution, thus, involves procedures 
development for establishments that do not currently follow industry 
standards. FDA estimates that 5 percent of eye banks, conventional 
tissue banks, and hematopoietic stem/progenitor cell establishments 
will increase lab supervisor time to document the receipt of products.
    The agency estimates that conventional tissue banks not following 
AATB standards will 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 hematopoietic stem/
progenitor cell establishments will write one major procedure 
addressing receiving activities. Establishments following FACT or AABB 
standards will also need to revise a major procedure for product 
distribution, while all other establishments will need to prepare a new 
major procedure for product distribution, as well as a minor procedure 
for the handling of products returned to inventory. Details of these 
assumptions are presented in section 2.4.15 of the background papers 
(see footnote 1 of this document) by ERG and FDA and the estimated 
costs per establishment for these activities are presented in table 4 
of this document.
    q. Section 1271.270--records. The CGTP rule requires that records 
be maintained for all steps required in this subpart and subpart C of 
this part. A records management system relating only to core CGTP 
requirements must be established and maintained. Records pertaining to 
a particular HCT/P must be maintained for at least 10 years after the 
date of administration, if known, or at least 10 years after the date 
of the HCT/P's distribution, disposition or expiration, whichever is 
latest. This final rule also requires that records be kept of any 
contracts or agreements. Although many components of the required 
recordkeeping system are addressed under individual provisions of the 
CGTP rule, there may be a few minor gaps in the records system of an 
establishment that would be addressed under this general provision. The 
agency therefore estimates that approximately 95 percent of all eye 
banks, conventional tissue banks, and hematopoietic stem/progenitor 
cell establishments that do not follow FACT or AABB standards, will 
write at least one minor procedure, and revise one major procedure 
related to recordkeeping.
    The agency also estimates that additional lab director time will be 
allocated (an estimated 40 hours at small establishments and 80 hours 
at large establishments) to set up enhanced recordkeeping where a 
system is already in place. System enhancement will be performed at an 
estimated 95 percent of eye banks, 23 percent of conventional tissue 
banks and 95 percent of hematopoietic stem/progenitor cell 
establishments.
    Various industry standards specify record retention, although the 
time periods vary somewhat. Of those establishments following industry 
standards, approximately 95 percent of eye banks and 75 percent to 80 
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 establishments, and the hematopoietic stem/progenitor cell 
establishments that do not currently follow industry standards, FDA 
estimates increased record retention costs based on the cost of storing 
an additional five boxes (2.4 cubic feet each) of records per year for 
5 years. The estimated record retention costs should be viewed as 
maximum potential burdens since affected entities have the option to 
retain the required records in more cost-effective (e.g., electronic) 
formats and because some establishments already retain records for 10 
years.
    The retention standards of FACT and AABB for records related to 
products are different from those concerned with facility and equipment 
maintenance, and personnel education and training. All records related 
to hematopoietic stem/progenitor cell products must be retained 
indefinitely whereas records related to facility and equipment 
maintenance and personnel training must be retained for only 5 years.
    FDA estimates that half of the records at hematopoietic stem/
progenitor cell establishments following industry standards will need 
to be retained for an additional 5 years, and that the annual cost will 
be comparable to that of other small eye banks and conventional tissue 
banks. The agency also estimates that nearly all hematopoietic stem/
progenitor cell establishments that are not following industry 
standards will need to increase record retention efforts. Almost all 
hematopoietic stem/progenitor cell establishments that do not follow 
industry standards are also expected to prepare at least one minor 
procedure and to revise a major procedure related to recordkeeping. The 
laboratory director at these establishments is expected to allocate 40 
hours of additional time to improving the establishment's current 
recordkeeping system.
    r. Section 1271.290--tracking. This final rule stipulates the steps 
needed to properly track a product from donor to consignee or final 
disposition and vice versa. The CGTP rule requires that establishments 
maintain a method for product tracking and that each product is 
assigned and labeled with a distinct identification code (identifier). 
If a new identifier is assigned during the manufacturing process, 
procedures must be in place for relating the new identifier to the old 
identifier. The establishment that manufactured the product must also 
keep track of the disposition of each product, so that the consignee 
can be easily identified. Establishments must also inform consignees in 
writing of the requirements of this section and of the established 
tracking method. In addition, labeling must include information 
designed to facilitate effective tracking from the donor to the 
recipient and from the recipient to the donor.
    Product ``traceability'' is a familiar concept and common practice 
in the eye banking, conventional tissue and hematopoietic stem/
progenitor cell processing industries. 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 banks will need to enhance current tracking systems, 
prepare one major procedure related to product tracking, spend 
additional staff time each month to identify and document consignee 
information, and allocate additional laboratory director time to inform 
the consignees who receive products and ensure the tracking 
requirements are met.
    Conventional tissue banks following AATB standards are able to 
trace all products from donation source to product recipient. 
Conventional tissue establishments not following AATB requirements will 
need to revise a major procedure to address product tracking, and to 
allocate additional staff time each month to obtain and record 
information about product consignees. The FACT and AABB standards for 
product tracking in hematopoietic stem/progenitor cell establishments 
recommend that the establishment 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

[[Page 68662]]

hematopoietic stem/progenitor cell establishments will, on a one-time 
basis, allocate an additional 20 hours of laboratory supervisor time to 
inform consignees who will receive products of tracking systems and 
requirements. In addition, FDA estimates that 95 percent of 
hematopoietic stem/progenitor cell establishments that are not 
following FACT or AABB standards will need to revise a major procedure 
related to product tracking, and will need to allocate additional staff 
hours each month for consignee documentation. The estimated costs per 
establishment to perform these activities are presented in table 4 of 
this document.
    s. Section 1271.320--complaint file. The CGTP final rule requires 
establishments to maintain procedures for the review, evaluation, and 
documentation of complaints relating to core CGTP requirements, and the 
investigation of complaints as appropriate. Establishments are required 
to review and evaluate complaints as soon as practical and to determine 
whether each complaint represents an event that must be reported to 
FDA. Documentation of the review and evaluation is required, even if no 
reporting is made. FDA finds that the AATB, FACT, and AABB standards 
explicitly address procedures for, or recordkeeping related to, 
complaints. Based on discussions with industry experts, the agency 
anticipates that nearly all establishments currently track, albeit 
informally, the complaints received from consignees and recipients. 
Establishments that must prepare new written procedures for review and 
handling of complaints would incur additional costs under these CGTP 
provisions. The agency estimates that the additional costs for 
establishments to maintain a complaint file would be negligible.
    To fully comply with these provisions of the CGTP rule, FDA 
estimates that 95 percent of all eye banks will revise a minor 
procedure to include the required handling of complaints, and allocate 
some additional staff time each year to review complaints. FDA assumes 
that conventional tissue banks following AATB standards will already be 
performing the necessary activities, but the estimated 23 percent of 
establishments not following AATB standards will need to prepare a 
minor procedure for complaint handling, and allocate additional 
laboratory director time each year to review any complaints received.
    Although the industry standards for hematopoietic stem/progenitor 
cell processing require that records be maintained of both donor and 
recipient complaints, the CGTP rule requires that establishments also 
have written procedures for complaint review. FDA therefore estimates 
that 95 percent of hematopoietic stem/progenitor cell establishments 
will write a minor procedure to handle complaints, and that 95 percent 
of all establishments that do not follow industry standards will also 
allocate additional time for yearly review and handling of complaints. 
Details of these assumptions are presented in section 2.4.18 of the 
background papers (see footnote 1 of this document) by FDA and ERG.
    t. Section 1271.350--reporting. This final rule requires 
establishments to investigate adverse reaction reports and report to 
FDA any adverse reactions, involving a communicable disease, that are 
fatal, life-threatening, result in permanent impairment of the body, or 
necessitate medical or surgical intervention, including 
hospitalization. In addition, the final rule requires establishments to 
investigate all HCT/P deviations and report to FDA any deviation 
related to core CGTP requirements if the deviation occurs in the 
establishment's facility or in a facility that performs a manufacturing 
step under contract, agreement, or other arrangement with the 
establishment. In our economic analysis of the proposed CGTP rule, we 
assumed that these provisions would result in negligible new costs for 
affected entities. However, because these are new FDA reporting 
requirements, the agency believes that additional costs will be 
incurred by all eye banks, conventional tissue banks, and hematopoietic 
stem/progenitor cell establishments. The agency further estimates that 
a typical affected establishment will submit an average of six Form FDA 
3500A (adverse reaction) reports and two Form FDA 3486 (HCT/P 
deviation) reports per year, requiring an additional 8 hours of 
laboratory director time. The associated costs are presented in table 4 
of this document.
    u. Section 1271.370--labeling. The CGTP rule requires that products 
be labeled clearly and accurately, with information including a 
description of the HCT/P along with its distinct identification code, 
the name and address of the manufacturer, a description of the product 
and the product expiration date. The storage temperature, appropriate 
warnings, and adequate instructions for use when related to the 
prevention of the introduction, transmission, or spread of communicable 
disease must also be provided on the label or on a package insert.
    Industry consultants inform FDA that the required elements are 
typically present on the labels of products manufactured by eye banks, 
conventional tissue banks, and hematopoietic stem/progenitor cell 
establishments. Proper labeling is considered very important to these 
industries, to prevent the misuse of their products. FDA assumes, 
therefore, that establishments in the various sectors of the HCT/P 
industry are already compliant with these provisions of the CGTP final 
rule, and that the cost impact will be negligible.
    v. Section 1271.400--inspections. FDA could conduct inspections of 
any facility subject to the CGTP final rule. FDA will typically 
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 this final rule. The agency estimates that all 
industry establishments, both domestic and foreign, will be subject to 
this provision of the CGTP final rule, and inspections will occur 
periodically. FDA estimates that up to 16 hours of laboratory 
technician time will 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 will be needed for 
activities related to the inspection. This is expected to impose a cost 
of approximately $768 per establishment per inspection.
    w. Section 1271.420--HCT/Ps offered for import. The CGTP final rule 
requires importers of HCT/Ps to notify the FDA district director having 
jurisdiction over the port of entry through which the HCT/P is imported 
or offered for import. The HCT/P must be held intact or transported 
under quarantine until it is inspected and released by FDA. There is 
currently very limited use of imported HCT/Ps that would trigger 
activities for compliance with this provision of the CGTP final rule. 
FDA therefore estimates the current cost for industry compliance with 
this requirement to be negligible.
    x. Section 1271.440--orders of retention, recall, and cessation of 
manufacturing. Firms in the HCT/P industry may incur costs to comply 
with orders issued under this provision. There is little available data 
on which to base estimates of the future frequency and scope of HCT/P 
industry conditions and practices that would necessitate such actions 
on the part of FDA. The agency anticipates that orders issued under 
this provision of the CGTP final rule will be rare. FDA estimates that 
the

[[Page 68663]]

yearly costs to the HCT/P industry resulting from such orders will 
therefore be negligible.
3. Estimated Impact on Reproductive Tissue Establishments
    As explained elsewhere in this preamble, establishments involved 
with reproductive tissue (e.g., ART establishments and semen banks) are 
subject only to the CGTP inspection and enforcement provisions of Sec.  
1271.400 as they apply to donor eligibility requirements under subpart 
C. The impact of these provisions is described in the following section 
and the estimated cost impact is presented in table 6 of this document.

    Table 6.--Estimated Cost Per Establishment and Estimated Percentage of Reproductive Tissue Establishments
                                         Affected By the CGTP Final Rule
----------------------------------------------------------------------------------------------------------------
          21 CFR Section                         Title                   ART Establishments       Semen Banks
----------------------------------------------------------------------------------------------------------------
1271.400                           Inspections                                    $768 (100%)        $768 (100%)
----------------------------------------------------------------------------------------------------------------

    a. Section 1271.400--inspections. FDA could conduct inspections of 
any facility subject to subpart F. This provision affects reproductive 
tissue establishments only insofar as it applies to the donor 
eligibility requirements under subpart C, and not to CGTPs generally. 
FDA will typically interact primarily with one responsible person for 
each establishment, but other personnel may also be involved in the 
inspection. FDA could inspect the donor eligibility related procedures 
and records of reproductive tissue establishments, and could review and 
copy any records required to be kept under this final rule.
    The agency estimates that all ART and semen bank establishments, 
whether domestic or foreign, will be subject to this provision of the 
CGTP final rule, and inspections will occur periodically. FDA estimates 
that up to 16 hours of laboratory technician time will be necessary, to 
accompany the FDA inspector through the establishment and to support 
the inspector's information needs, and that up to 4 hours of laboratory 
director time will be needed for activities related to the inspection. 
This is expected to impose a cost of approximately $768 per 
establishment per inspection. This is the only provision of the CGTP 
final rule that applies to establishments involved with reproductive 
tissues.
4. Summary of Estimated One-Time, Annual, and Annualized Cost Impacts
    The costs for each section of the CGTP final rule are computed as 
the product of the estimated number of affected establishments (table 3 
of this document), the estimated compliance cost per establishment, and 
the estimated percentage of establishments not currently following 
CGTPs (table 4 of this document), and are presented by HCT/P industry 
sector in tables 7 through 11 of this document. The total one-time and 
annual compliance costs, summed over all provisions of the CGTP rule, 
are also presented by HCT/P industry sector in these tables. The 
aggregate one-time and annual compliance costs for all sectors of the 
HCT/P industry are summarized in table 12 of this document. The total 
annualized cost estimates presented in tables 7 through 12 of this 
document include both the estimated annual and one-time costs, such as 
are incurred to prepare new procedures, and are annualized over 10 
years using both 7 percent and 3 percent discount rates.

                               Table 7.--Aggregate Compliance Costs for Eye Banks
----------------------------------------------------------------------------------------------------------------
                                                                                       Total           Total
  21 CFR Section               Title              One-Time Costs   Annual Costs     Annualized      Annualized
                                                                                     Costs\1\        Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.150           CGTP Requirements                          $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.155           Exemptions & Alternatives                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.160           Quality Program                      $159,038        $569,031        $591,674        $587,675
----------------------------------------------------------------------------------------------------------------
1271.170           Personnel                                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.180           Procedures                                 $0         $61,104         $61,104         $61,104
----------------------------------------------------------------------------------------------------------------
1271.190           Facilities                              2,328              $0            $331            $273
----------------------------------------------------------------------------------------------------------------
1271.195           Environmental Control &                    $0         $28,550         $28,850         $28,850
                    Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200           Equipment                                  $0        $138,248        $138,248        $138,248
----------------------------------------------------------------------------------------------------------------
1271.210           Supplies & Reagents                   $16,613         $22,150         $24,515         $24,098
----------------------------------------------------------------------------------------------------------------
1271.215           Recovery                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.220           Processing and Process                $48,374              $0          $6,887          $5,671
                    Controls
----------------------------------------------------------------------------------------------------------------
1271.225           Process Changes                       $96,748         $58,049         $71,824         $69,391
----------------------------------------------------------------------------------------------------------------
1271.230           Process Validation                   $409,906        $108,205        $166,566        $156,258
----------------------------------------------------------------------------------------------------------------
1271.250           Labeling Controls                      $2,456              $0            $362            $298
----------------------------------------------------------------------------------------------------------------

[[Page 68664]]

 
1271.260           Storage                                    $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.265           Receipt, Predistribution                   $0        $182,990        $182,990        $182,990
                    Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270           Records                              $479,603            $121         $68,405         $56,345
----------------------------------------------------------------------------------------------------------------
1271.290           Tracking                              $15,276         $11,578         $13,753         $13,368
----------------------------------------------------------------------------------------------------------------
1271.320           Complaint File                        $16,613         $77,398         $79,764         $79,364
----------------------------------------------------------------------------------------------------------------
1271.350           Reporting                                  $0         $81,472         $81,472         $81,472
----------------------------------------------------------------------------------------------------------------
1271.370           Labeling                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.400           Inspections                                $0        $102,912        $102,912        $102,912
----------------------------------------------------------------------------------------------------------------
1271.420           HCT/Ps Offered for Import                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.440           Orders of Retention, Recall,               $0              $0              $0              $0
                    Destruction and Cessation of
                    Manufacturing
----------------------------------------------------------------------------------------------------------------
Total              All Sections                       $1,247,044      $1,442,108      $1,619,659      $1,588,300
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.


                   Table 8.--Aggregate Compliance Costs for Conventional Tissue Establishments
----------------------------------------------------------------------------------------------------------------
                                                                                       Total           Total
  21 CFR Section               Title              One-Time Costs   Annual Costs     Annualized      Annualized
                                                                                     Costs\1\        Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.150           CGTP Requirements                          $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.155           Exemptions & Alternatives                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.160           Quality Program                      $127,960        $213,246        $231,464        $228,247
----------------------------------------------------------------------------------------------------------------
1271.170           Personnel                            $594,081        $101,444        $186,028        $171,088
----------------------------------------------------------------------------------------------------------------
1271.180           Procedures                                 $0        $348,202        $348,202        $348,202
----------------------------------------------------------------------------------------------------------------
1271.190           Facilities                            $14,838              $0          $2,113          $1,739
----------------------------------------------------------------------------------------------------------------
1271.195           Environmental Control &               $14,838          $8,124         $10,237          $9,863
                    Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200           Equipment                            $137,313        $101,411        $120,961        $117,508
----------------------------------------------------------------------------------------------------------------
1271.210           Supplies & Reagents                   $29,676          $8,124         $12,349         $11,603
----------------------------------------------------------------------------------------------------------------
1271.215           Recovery                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.220           Processing and Process                $20,516              $0          $2,921          $2,405
                    Controls
----------------------------------------------------------------------------------------------------------------
1271.225           Process Changes                       $41,033         $87,940         $93,782         $92,750
----------------------------------------------------------------------------------------------------------------
1271.230           Process Validation                   $437,574        $268,090        $330,391        $319,387
----------------------------------------------------------------------------------------------------------------
1271.250           Labeling Controls                      $4,460              $0            $635            $523
----------------------------------------------------------------------------------------------------------------
1271.260           Storage                                    $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.265           Receipt, Predistribution              $55,871        $237,058        $245,012        $243,607
                    Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270           Records                              $287,965            $687         $41,687         $34,446
----------------------------------------------------------------------------------------------------------------
1271.290           Tracking                              $78,550        $161,361        $172,544        $170,569
----------------------------------------------------------------------------------------------------------------
1271.320           Complaint File                        $14,837         $28,388         $30,500         $30,127
----------------------------------------------------------------------------------------------------------------
1271.350           Reporting                                  $0        $100,928        $100,928        $100,928
----------------------------------------------------------------------------------------------------------------

[[Page 68665]]

 
1271.370           Labeling                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.400           Inspections                                $0        $127,488        $127,488        $127,488
----------------------------------------------------------------------------------------------------------------
1271.420           HCT/Ps Offered for Import                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.440           Orders of Retention, Recall,               $0              $0              $0              $0
                    Destruction and Cessation of
                    Manufacturing
----------------------------------------------------------------------------------------------------------------
Total              All Sections                       $1,859,510      $1,792,489      $2,057,241      $2,010,480
----------------------------------------------------------------------------------------------------------------
\a.\ Over 10 years at 7 percent interest
\b.\ Over 10 years at 3 percent interest


           Table 9.--Aggregate Compliance Costs for Hematopoietic Stem/Progenitor Cell Establishments
----------------------------------------------------------------------------------------------------------------
                                                                                       Total           Total
     Section                   Title              One-Time Costs   Annual Costs     Annualized      Annualized
                                                                                     Costs\a\        Costs\b\
----------------------------------------------------------------------------------------------------------------
1271.150           CGTP Requirements                          $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.155           Exemptions & Alternatives                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.160           Quality Program                      $208,354        $457,200        $486,865        $481,625
----------------------------------------------------------------------------------------------------------------
1271.170           Personnel                            $739,100        $117,610        $222,841        $204,255
----------------------------------------------------------------------------------------------------------------
1271.180           Procedures                                 $0        $433,200        $433,200        $433,200
----------------------------------------------------------------------------------------------------------------
1271.190           Facilities                            $90,784        $665,000        $677,926        $675,643
----------------------------------------------------------------------------------------------------------------
1271.195           Environmental Control &               $90,784        $205,458        $218,383        $216,100
                    Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200           Equipment                            $450,621        $465,548        $529,706        $518,374
----------------------------------------------------------------------------------------------------------------
1271.210           Supplies & Reagents                  $135,185          $8,265         $27,512         $24,113
----------------------------------------------------------------------------------------------------------------
1271.215           Recovery                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.220           Processing and Process               $198,550              $0         $28,269         $23,276
                    Controls
----------------------------------------------------------------------------------------------------------------
1271.225           Process Changes                       $36,100        $119,130        $124,270        $123,362
----------------------------------------------------------------------------------------------------------------
1271.230           Process Validation                   $678,775        $297,825        $394,467        $372,398
----------------------------------------------------------------------------------------------------------------
1271.250           Labeling Controls                      $5,225              $0            $744            $613
----------------------------------------------------------------------------------------------------------------
1271.260           Storage                                    $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.265           Receipt, Predistribution             $482,861         $28,080         $96,829         $84,686
                    Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270           Records                              $178,956          $2,880         $28,359         $23,859
----------------------------------------------------------------------------------------------------------------
1271.290           Tracking                             $415,150        $164,160        $223,268        $212,828
----------------------------------------------------------------------------------------------------------------
1271.320           Complaint File                        $90,784        $158,840        $171,766        $169,483
----------------------------------------------------------------------------------------------------------------
1271.350           Reporting                                  $0        $167,200        $167,200        $167,200
----------------------------------------------------------------------------------------------------------------
1271.370           Labeling                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.400           Inspections                                $0        $211,200        $211,200        $211,200
----------------------------------------------------------------------------------------------------------------
1271.420           HCT/Ps Offered for Import                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.440           Orders of Retention, Recall,               $0              $0              $0              $0
                    Destruction and Cessation of
                    Manufacturing
----------------------------------------------------------------------------------------------------------------
Total              All Sections                       $3,801,230      $3,501,595      $4,042,805      $3,947,215
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.


[[Page 68666]]


                          Table 10.--Aggregate Compliance Costs for ART Establishments
----------------------------------------------------------------------------------------------------------------
                                                                                       Total           Total
  21 CFR Section               Title              One-Time Costs   Annual Costs     Annualized      Annualized
                                                                                     Costs\1\        Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.400           Inspections                                $0        $307,200        $307,200        $307,200
----------------------------------------------------------------------------------------------------------------
Total              All Sections                               $0        $307,200        $307,200        $307,200
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.


                              Table 11.--Aggregate Compliance Costs for Semen Banks
----------------------------------------------------------------------------------------------------------------
                                                                                       Total           Total
  21 CFR Section               Title              One-Time Costs   Annual Costs     Annualized      Annualized
                                                                                     Costs\1\        Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.400           Inspections                                $0         $84,480         $84,480         $84,480
----------------------------------------------------------------------------------------------------------------
Total              All Sections                               $0         $84,480         $84,480         $84,480
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.


                      Table 12.--Aggregate Compliance Costs for All HCT/P Industry Sectors
----------------------------------------------------------------------------------------------------------------
                                                                                       Total           Total
  21 CFR Section               Title              One-Time Costs   Annual Costs     Annualized      Annualized
                                                                                     Costs\1\        Costs\2\
----------------------------------------------------------------------------------------------------------------
1271.150           CGTP Requirements                          $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.155           Exemptions & Alternatives                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.160           Quality Program                      $495,351      $1,239,477      $1,310,003      $1,297,547
----------------------------------------------------------------------------------------------------------------
1271.170           Personnel                          $1,333,181        $219,054        $408,869        $375,343
----------------------------------------------------------------------------------------------------------------
1271.180           Procedures                                 $0        $842,506        $842,506        $842,506
----------------------------------------------------------------------------------------------------------------
1271.190           Facilities                           $107,950        $665,000        $680,370        $677,655
----------------------------------------------------------------------------------------------------------------
1271.195           Environmental Control &              $105,622        $242,432        $257,470        $254,814
                    Monitoring
----------------------------------------------------------------------------------------------------------------
1271.200           Equipment                            $587,933        $705,206        $788,914        $774,130
----------------------------------------------------------------------------------------------------------------
1271.210           Supplies & Reagents                  $181,473         $38,539         $64,377         $59,813
----------------------------------------------------------------------------------------------------------------
1271.215           Recovery                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.220           Processing and Process               $267,440              $0         $38,077         $31,352
                    Controls
----------------------------------------------------------------------------------------------------------------
1271.225           Process Changes                      $173,881        $265,118        $289,875        $285,503
----------------------------------------------------------------------------------------------------------------
1271.230           Process Validation                 $1,526,255        $674,120        $891,424        $853,044
----------------------------------------------------------------------------------------------------------------
1271.250           Labeling Controls                     $12,231              $0          $1,741          $1,434
----------------------------------------------------------------------------------------------------------------
1271.260           Storage                                    $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.265           Receipt, Predistribution             $538,732        $448,128        $524,831        $511,284
                    Shipment & Distribution
----------------------------------------------------------------------------------------------------------------
1271.270           Records                              $946,524          $3,688        $138,452        $114,649
----------------------------------------------------------------------------------------------------------------
1271.290           Tracking                             $508,976        $337,098        $409,565        $396,766
----------------------------------------------------------------------------------------------------------------
1271.320           Complaint File                       $122,235        $264,626        $282,029        $278,956
----------------------------------------------------------------------------------------------------------------
1271.350           Reporting                                  $0        $349,600        $349,600        $349,600
----------------------------------------------------------------------------------------------------------------
1271.370           Labeling                                   $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------
1271.400           Inspections                                $0        $833,280        $833,280        $833,280
----------------------------------------------------------------------------------------------------------------
1271.420           HCT/Ps Offered for Import                  $0              $0              $0              $0
----------------------------------------------------------------------------------------------------------------

[[Page 68667]]

 
1271.440           Orders of Retention, Recall,               $0              $0              $0              $0
                    Destruction and Cessation of
                    Manufacturing
----------------------------------------------------------------------------------------------------------------
Total              All Sections                       $6,907,784      $7,127,872      $8,111,384      $7,937,674
----------------------------------------------------------------------------------------------------------------
\1\ Over 10 years at 7 percent interest.
\2\ Over 10 years at 3 percent interest.

    As shown in table 7 of this document, the total one-time costs for 
the eye banking industry are estimated to be $1.25 million, and annual 
costs are estimated at $1.44 million. These figures generate a total 
annualized cost estimate of $1.59 million to $1.62 million. For the 
conventional tissue industry (table 8 of this document), aggregate one-
time costs and annual costs are estimated at $1.86 million and $1.79 
million, respectively. These figures correspond to an estimated 
annualized cost of $2.01 million to $2.06 million. The hematopoietic 
stem/progenitor cell industry (table 9 of this document) is estimated 
to incur a one-time cost of $3.8 million and annual costs of $3.5 
million, yielding an annualized cost estimate of $3.95 million to $4.04 
million. ART establishments and semen banks are expected to incur no 
one-time costs under the CGTP final rule because they are subject only 
to the inspection and enforcement provisions as they relate to donor 
eligibility requirements under subpart C. The total annual and 
annualized costs for ART establishments and semen banks are estimated 
to be $0.31 million and $0.08 million, respectively. These cost 
estimates are presented in tables 10 and 11 of this document.
    Table 12 of this document summarizes the total estimated cost 
impacts for all HCT/P industry sectors. FDA estimates the aggregate 
one-time compliance costs of the CGTP final rule to be $6.9 million. 
Annual costs, aggregated across all sectors of the HCT/P industry, are 
estimated to be $7.13 million. These estimates correspond to a total 
annualized cost estimate of $7.94 million to $8.1 million for the CGTP 
final rule applied to all major sectors of the HCT/P industry.

C. Estimated Benefits of the CGTP Final Rule

    The purpose of the CGTP final rule is to prevent the introduction, 
transmission, or spread of communicable disease through the use of HCT/
Ps. Although voluntary industry standards exist for most of the 
affected products, FDA finds that public safety cannot be assured or 
effectively protected through reliance on these informal mechanisms. 
The existing industry standards also vary to some extent in their 
comprehensiveness, and there are variations in the extent to which 
firms in the affected industry sectors follow these voluntary 
standards.
    For example, most industry consultants providing input for this 
analysis agreed that quality standards, such as those in the CGTP final 
rule, and similar standards recommended by industry, could 
substantially reduce the risk of HCT/P product contamination by 
communicable disease agents. However, most of these experts also agreed 
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 
establishments are not currently following adequate quality control 
procedures. A regulatory requirement for quality systems and 
recordkeeping would provide the incentives needed to bring marginal 
establishments to a more uniform and appropriately high standard of 
quality in HCT/P processing.
    The primary beneficiaries of the CGTP final rule are the patients 
who receive HCT/Ps. Benefits to patients result from improved outcomes 
due to reduced risks of communicable disease transmission. Society as a 
whole will benefit from implementation of CGTPs due to improved safety 
of the supply of HCT/Ps, and reductions in health care and other costs 
associated with treating the complications arising from the use of 
contaminated tissue products. The discussion that follows considers 
some of the potential benefits of CGTPs based on a survey of the 
clinical literature.
    Recent clinical literature indicates that each type of HCT/P 
affected by the CGTP final rule has documented communicable disease 
transmission risk that may be the result of contamination or other 
problems resulting from processing, or other steps in manufacturing. 
Although the limited number of adverse events reported in the clinical 
literature suggests a relatively low risk of communicable disease 
transmission associated with HCT/Ps, it is important to note that this 
evidence is generally based on analysis of a limited number of 
voluntarily reported incidents. The reported HCT/P problems provide a 
basis for assessing the magnitude of the potential benefit from further 
reducing the incidence of events that contribute to or increase the 
risk of communicable disease transmission. In some cases involving eye 
tissue, conventional tissue, or hematopoietic stem/progenitor cell 
products, HCT/P problems have required medical intervention to treat 
infection, or to replace an implanted HCT/P. In some clinical 
applications, HCT/P related problems have increased the risk of patient 
morbidity or mortality. In general, FDA anticipates that the risk of 
communicable disease transmission will decline, and patient outcomes 
will improve, as a result of industry compliance with the provisions of 
the CGTP final rule.
    The sections that follow describe specific product-related problems 
associated with communicable disease transmission that are at least 
partly attributable to a lack of uniform and enforceable standards in 
HCT/P manufacturing. The costs of correcting these problems are 
considered, to gauge the potential magnitude of the benefits associated 
with improvements in manufacturing processes brought about through 
implementation of CGTPs. The discussion is organized by type of HCT/P.
1. Eye Tissue
    Primary corneal graft failure is a key adverse outcome of concern 
following corneal tissue transplant. Such failures result in additional 
graft attempts, and each attempt increases the risk of communicable 
disease transmission by exposing the recipient to another HCT/P, and 
another surgical procedure. Although primary corneal graft failure is 
relatively uncommon, its occurrence has been attributed to several 
factors related

[[Page 68668]]

to tissue collection, processing, and product distribution. These 
factors include donor characteristics such as age (Ref. 5), donor 
infectivity (e.g., with Herpes Simplex Virus and CJD) (Refs. 8 and 31), 
length of product storage, type of storage medium, and shipping 
distance from the eye bank to the recipient site. In an analysis of 
factors contributing to primary corneal graft failure, Wilhelmus et al. 
(Ref. 5) found that ``the 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, 
even with modern eye bank screening and preservation procedures, a 
donor corneal storage time greater than 1 week increases the risk of 
primary corneal graft failure by more than two-fold.
    Wilhelmus et al. include in their analysis a summary of selected 
findings of studies published between 1971 and 1994 that report the 
incidence of primary graft failure for corneal transplants using 4 
degrees Celsius preservation, and a variety of preservation methods. 
The rates of primary graft failure reported ranged from 0.9 percent 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 verification 
of quality and documentation of the receipt of supplies and reagents 
used in HCT/P processing. The authors found that 86 cases 
(approximately 59 percent of all cases studied) of primary corneal 
graft failure shared preservation media from the same lots. These 
findings underline the importance of the CGTP requirement for 
verification of quality and documentation of receipt for each 
particular lot of processing media used in the manufacture of uniquely 
labeled and traceable products.
    Primary corneal graft failure typically requires repeat surgery to 
replace the failed graft. The Agency for Healthcare Research and 
Quality (AHRQ), reports 598 total discharges for Principal Procedure 
13, Corneal transplant, with a mean hospital length of stay (LOS) of 
3.5 days and a mean hospital charge of $14,233 in 2000 (Ref.7). The 
estimated rate of primary graft failure, which may result from one or 
more aspects of cornea collection, processing, or distribution, ranges 
from 0.1 percent (based on the number of cases voluntarily reported to 
EBAA for the period 1991-1993, and again in 2001) 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 45,897 corneal transplants 
reported by the EBAA in 1999, the estimated number of cases of primary 
graft failure may range from 46 cases [0.001 x 45,897] to 413 cases 
[0.009 x 45,897] per year. The lowest estimate of the incidence of 
primary corneal graft failure reported by Wilhelmus et al. (0.9 
percent) was used in this calculation to produce a conservative 
estimate of the number of cases, and in response to public comments on 
the proposed CGTP rule. The total cost of replacement of a failed 
corneal graft is estimated to include $654 of physician services 
(Ref.8), including an office visit to diagnose the graft failure before 
hospitalization, and initial and followup physician visits during 
patient hospitalization for the repeated corneal transplant. It also 
includes one followup physician office visit to assess the outcome of 
the second transplant. The patient is estimated to further incur at 
least 1 week of time lost from work for doctor visits, hospitalization, 
and recovery of visual function after surgery. The cost of this patient 
time loss is estimated at $957.20, based on a 40-hour work week and 
U.S. average employer costs for employee compensation of $23.93 (Ref. 
32). Thus, the current annual cost impact of primary corneal graft 
failure may range from $728,833 (46 x ($14,233 + $654 + $957.20)) to 
$6,543,655 (413 x ($14,233 + $654 + $957.20)).
    The risk, incidence, and cost of treating primary corneal graft 
failure will be reduced through the implementation of CGTPs, due to 
provisions requiring the validation of processing methods and process 
quality controls, the verification of supplies and reagents, and 
improved documentation. The total annualized cost to eye banks of 
implementing the CGTP final rule is estimated to be $1.61 million to 
$1.65 million, and the total cost of repeat surgery, hospitalization, 
physician's services and work loss associated with primary corneal 
graft failure is estimated to be $15,844.20 per occurrence ($14,233 + 
$654 + $957.20). Based on these estimates, if implementation of the 
CGTP final rule were to result in approximately 104 fewer cases ($1.65 
million / $15,844 per case) of primary corneal graft failure per year, 
the benefits realized (in the form of avoided health care costs and 
income loss due to time away from work) would exceed the total 
annualized cost to eye banks, thereby making the rule cost effective 
for this sector of the HCT/P industry.
    A reduction of 104 cases represents a 25 percent reduction (104 
fewer cases / 413 total cases) in the risk of corneal graft failure 
(from 0.9 percent to 0.675 percent) based on the lowest rate reported 
by Wilhelmus et al. Due to uncertainty with respect to the actual risk 
of primary corneal graft failure, and the degree to which CGTPs would 
reduce this already uncertain risk, FDA is not able to determine 
whether or not implementation of this final rule would generate this 
level of risk reduction. No attempt was made to estimate the benefits 
of any potential reduction in the risk of intraocular infection 
(another HCT/P-related problem associated with eye tissue) resulting 
from implementation of CGTPs due to a lack of data.
2. Conventional Tissue
    Conventional tissue refers to a wide range of HCT/Ps including 
pericardium, dura mater, heart valves, skin allograft, bone allograft, 
fascia, tendons, and ligaments. FDA's survey of the clinical literature 
indicates that bone, skin and heart valve allografts each present a 
different potential for communicable disease transmission risk and 
graft failure, and thus different levels of potential benefits from 
improved processing procedures and quality assurance steps in HCT/P 
manufacture. The discussion that follows considers these three distinct 
conventional tissue products and thus areas of potential benefit.
    a. Bone allograft. An analysis of the incidence, nature, and 
treatment of infection associated with bone allograft by Lord et al. 
(Ref.9), 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 patients) of the infected allografts 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 infected grafts), highlighting the critical 
need for HCT/Ps that are free from contamination by communicable 
disease agents. Other factors cited include duration of the

[[Page 68669]]

operation, loss of blood, injury to soft tissue, and skin sloughing 
during the operation.
    The importance of process validation is also implied by Hardin 
(Ref.10) in a review of banked bone allograft processes. In describing 
methods for sterilization, Hardin identifies ethylene oxide as one of 
the chemicals used, but indicates that its effectiveness may 
nonetheless be questionable, because of reports of graft failures in 
which residues of ethylene oxide have been implicated, 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 x 
an estimated 0.82 failure rate for infected bone allograft), and the 
conservative assumption that all graft failures would be treatable 
through repeat surgery to replace the bone allograft, the associated 
healthcare costs could be on the order of $60 million per year 
($59,679,928 = 0.057 x 44,000 x ($22,497 + $1,133)). This figure is 
based on a national level estimate of 44,000 bone allografts per year 
(Ref.11), and a mean hospital charge of $22,497 for Principle Procedure 
142, Partial excision of bone (Ref. 28). Physician costs per 
hospitalization are estimated to be $1,133, based on submitted charges 
per person served in the Orthopedic Surgery Physician Specialty 
category (Ref. 8).
    The reported average length of hospital stay for bone surgery is 
approximately 6.3 days (Ref. 28). The estimated cost of patient time 
lost assumes that repeat surgery would require at least 1 week of time 
away from work, at an estimated value of $957.20, based on a 40-hour 
work week and average hourly compensation of $23.93 (Ref.32). This 
yields an estimated total patient time cost of $2,400,658 (0.057 x 
44,000 x $9357.20). Thus, the total annual cost of bone allograft 
failure due to contamination is estimated to be approximately $62 
million ($62,080,586 = $59,679,928 + $2,400,658).
    If bone allograft failures result in amputation, the direct and 
indirect costs would be significantly higher. For example, the direct 
cost per hospitalization for lower extremity amputation is estimated to 
be $30,820 based on AHRQ Healthcare Cost and Utilization Project (HCUP) 
data (Ref. 23). Moreover, permanent disability following amputation 
imposes extremely high costs on the patient, the patient's family, and 
on society as a whole. The AHRQ HCUP data also report 5,200 in-hospital 
deaths and a 4.5 percent death rate associated with these amputation 
procedures.
    FDA is uncertain about the extent to which the estimated cost 
impact will be reduced through implementation of the CGTP final rule 
for two reasons. First, many graft failures result from transplantation 
procedures and other factors not related to bone allograft manufacture, 
or from a combination of factors. Second, some establishments may have 
already developed new bone processing methods that may greatly reduce 
infection risk. If as much as 90 percent of the estimated risk is 
actually attributable to other factors, or has already been addressed 
through better manufacturing processes, the benefit from CGTPs applied 
to the remainder of bone tissue processes and establishments would be 
on the order of $6.2 million ($62,080,586 x 0.10) per year. The total 
annualized cost of the CGTP final rule for all conventional tissue 
banks is estimated to be $2.03 million to 2.07 million, and the 
estimated total cost of treatment for infected bone allograft, 
including hospitalization, physician's office visits and work loss is 
$24,587.20 per occurrence. If implementation of the CGTP final rule 
resulted approximately 84 fewer cases of infected bone allograft 
requiring repeat surgery ($2,073,547 / $24,587.2 = 84.3), the benefits 
of CGTPs would exceed the estimated total annualized costs for all 
conventional tissue banks. This reduction in the number of cases of 
bone allograft infection corresponds to a 3.3 percent reduction (84.3 
fewer cases / 2,525.6 potential cases) in risk based on the information 
used as the basis for this analysis.
    b. Skin allograft. Skin allografts represent another type of HCT/P 
that is critically dependent on processing and quality controls to 
prevent the manufacture, distribution and/or use of contaminated 
products. The clinical literature reports cases of cytomegalovirus 
(CMV) transmission due to skin donor infection (Ref.12), and HIV 
contamination from infected donor skin tissue and subsequent tissue 
processing (Ref.13). 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 injuries and are therefore susceptible to potentially 
life-threatening CMV infections. These include pneumonitis, retinitis, 
gastroenteritis, hepatitis, and neurological complications (Ref. 12). 
Contamination of skin allograft can also significantly affect burn 
patient survival. Because the clinical literature does not provide 
summary estimates of the risk of contamination associated with skin 
allograft, the agency is unable to quantify the level of associated 
risk. Although implementation of the CGTP final rule is expected to 
reduce the risk of contaminated skin allograft, and thereby improve 
burn patient outcomes, FDA could not quantify this source of expected 
patient benefits due to a lack of necessary information.
    c. Heart Valve Allografts. Heart valve allografts, another of the 
many types of conventional tissue products, provides another compelling 
case for HCT/P production process validation and quality control. Human 
heart valve contaminants not effectively removed in tissue processing 
have resulted in serious infections that, at a minimum, require valve 
replacement and may also result in patient death. Sources of 
contamination of a heart valve allograft include the donor, the 
environment during harvesting and processing, and the operating room 
during implantation. Microbial contamination of human heart valves 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.14) common contaminants found before 
disinfection consist of gastrointestinal and skin flora (including 
coliforms), viridans group streptococci, Staphylococcus aureus, S. 
epidermidis, and Bacillus species. In general, bacterial contamination 
can be effectively removed through standard disinfection procedures 
used in most accredited conventional 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 of heart valve allograft 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 tissue 
disinfection regimens is not effective in eradicating fungal 
contamination.
    Fungal endocarditis is a rare but potentially fatal complication of 
allograft heart 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 0.85 percent). In one reported case, 
the infected patient needed subsequent surgery to replace

[[Page 68670]]

the valve and required treatment with 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 patients who had acquired fungal endocarditis after heart valve 
allograft implantation died within 2 weeks of diagnosis.
    In their study, Kuehnert et al. describe the process controls used 
by AATB-affiliated establishments including the establishment, 
validation and documentation of decontamination protocols. Because 
these regimens have not been found effective against fungal 
contamination, AATB-affiliated establishments routinely discard tissue 
with documented fungal contamination. However, according to Kuehnert et 
al., the supplier of over 85 percent of all heart valve allografts 
(approximately 41,000 since 1984) 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 results in tissue being distributed for use in patients.
    The CGTP final rule requires that all establishments use validated 
procedures and that HCT/Ps meet all release criteria before they are 
made available for distribution. Based on the rates of infection and 
mortality risk reported by Kuehnert et al., and an estimated 5,000 to 
6,000 human heart valve allografts per year (these figures were 
reported to the agency by the largest supplier of this type of HCT/P in 
their comment on the proposed rule), there may be an estimated 43 
(0.0085 x 5,000) to 51 (0.0085 x 6,000) cases of fungal endocarditis 
each year. These cases of fungal endocarditis may further cause an 
estimated 17 (0.0085 x 0.40 x 5000) to 20 patient deaths per year 
(0.0085 x 0.40 x 6,000). Fungal endocarditis may result from a variety 
of peri- or post-operative factors including infection of the valve 
allograft itself. While highly uncertain, one comment suggested that as 
many as one-third of all cases of fungal endocarditis may be caused by 
contaminated valve allografts. Based on this information, FDA expects 
that there may be as many as 14 to 17 cases of heart valve 
contamination causing fungal endocarditis along with 5 to 7 patient 
deaths each year. Changes in processing procedures based on the CGTP 
requirements will help to avoid cases of fungal endocarditis and, 
perhaps, some of the resulting deaths. Substantial health care cost 
savings will also be achieved through improved processing controls and 
avoided adverse events due to implementation of the CGTP final rule.
    AHRQ reports 82,874 total hospital discharges for Principle 
Procedure 43, Heart Valve Procedures in 2000 with a mean LOS of 11.1 
days and mean hospital charges of $78,494 (Ref. 24). The AHRQ also 
reports 4,986 in-hospital deaths (and a 6.0 percent death rate) 
associated with these procedures. If patients undergoing this procedure 
were to lose 2 weeks of time away from work, the value of this work 
loss, based on a 40-hour work week and an average hourly compensation 
of $ 23.93 (Ref. 32), would be $1,914 per case. Based on reported 
average charges of $78,494 per hospitalization for implantation of a 
heart valve allograft (Ref. 24), estimated physician charges of $6,796 
per case, including repeat surgery and patient care during the average 
11.1-day hospital stay, and 2 weeks of patient work loss, the total 
cost of treating cases of heart valve contamination causing fungal 
endocarditis would be between $1,220,862 (14 x ($78,494 + $6,796 + 
$1,914.4)) and $1,482,475 (17 x ($78,494 + $6,796 + $1,914.4)). These 
estimates should be viewed as conservative because they reflect only 
the costs associated with contaminated heart valve allografts causing 
fungal endocarditis, and do not consider the costs associated with the 
more common bacteria-induced early onset allograft valve endocarditis. 
No estimate of the potential benefit of CGTPs in reducing the cost of 
treating early onset allograft valve endocarditis was generated due to 
a lack of necessary information.
    The total annualized costs of the CGTP final rule for conventional 
tissue banks are estimated to be $2.03 million to $2.07 million. The 
total costs associated with infected bone allografts and contaminated 
heart valve allografts causing fungal endocarditis are estimated to be 
between $61.3 million ($60.1 million + $1.2 million) and $61.6 million 
($60.1 million + $1.5 million). If implementation of the CGTP final 
rule were to reduce these estimated costs by 3.3 percent, the estimated 
annual cost savings, or benefit, would exceed the estimated compliance 
costs. Thus, a 3.3 percent reduction in the cost associated with only 
two HCT/P-related problems would make the CGTP final rule cost 
effective for the conventional tissue industry.
3. Hematopoietic Stem/Progenitor Cells
    Promising outcomes from use of peripheral blood stem/progenitor 
cells (PBSC) and cord blood-derived stem/progenitor cells (CBSC) in 
lieu of bone marrow have resulted in increased collection and use of 
these products in hematopoietic stem/progenitor cell transplants. For 
example, recent studies have reported the use of PBSC (rather than bone 
marrow) in 54 percent (Ref. 15) and 62 percent of cases, respectively 
(Ref. 16). However, studies of hematopoietic stem/progenitor cell 
products indicate that products manufactured by this industry may 
become contaminated during collection and processing. Moreover, the 
therapy-induced immunosuppression of the oncology patients who receive 
these products places them at particularly high risk for serious 
infection and subsequent mortality. Manufacturing methods conforming to 
CGTP are necessary to prevent this threat to the safety and 
effectiveness of hematopoietic stem/progenitor cell therapies. For 
example, investigations of PBSC have reported that the large quantity 
of blood that must be processed to obtain adequate numbers of 
hematopoietic stem/progenitor 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. 20).
    Another quality concern with PBSC involves the maintenance of the 
sterile integrity of the apheresis catheter and component throughout 
the period of leukapheresis, cryopreservation, thawing, and transfusion 
(Espinosa et al., 1996) (Ref. 17). Webb et al. (Ref. 18) 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 bacteremia-induced fever and other clinical sequelae are 
generally considered reversible, infections present more serious risks 
for hematopoietic stem/progenitor cell recipients than for the overall 
population. Survival rates for hematopoietic stem/progenitor cell 
transplantation are significantly reduced for patients who become 
critically ill. In a study of survival rates among hematopoietic stem/
progenitor cell recipients admitted to an intensive care unit, Price et 
al. (Ref. 16) 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., controlling for other risk factors such as patient 
intubation, type of transplant, source of hematopoietic stem/progenitor 
cells, human leukocyte antigen compatibility, type of

[[Page 68671]]

malignancy and patient age, also found infection to be a significant 
predictor of mortality.
    Based on reported blood collection and transfusion statistics (Ref. 
25), a total of 32,291 units of PBSCs were collected, and 18,123 units 
transfused, in the United States in 1997 (the use of PBSCs has been 
increasing steadily since that time). Thus, an estimated 60 patients 
per year (18,123 PBSC transfusions x 0.024 x 0.137) 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 (Ref. 15), 
and 18,123 hematopoietic stem/progenitor cell transplants performed in 
1997. Costs of treating patients who become infected after receiving 
contaminated hematopoietic stem/progenitor cell products are estimated 
based on 8,985 AHRQ-reported total discharges for Principle Procedure 
3, Bacterial Infection, Unspecified Site, with average hospital charges 
of $21,221 per 6.9-day patient stay (Ref. 26). Estimated total health 
care costs also include physician costs of $918 assuming one initial 
in-hospital visit, and daily followup visits during the patient stay 
(Ref. 8). Patient income loss is valued at $1,914 based on estimated 
hourly compensation of $23.93 (Ref. 32) and an estimated 2 weeks away 
from work. Thus, the total annual cost impact of infection following 
transplant of contaminated PBSC products is estimated to be $1,443,180 
(60 x ($21,221 + $918 + $1,914)).
    In addition to health care and time away from work costs, reducing 
the risk of contaminated PBSC products could result in avoiding 26 
excess hematopoietic stem/progenitor cell patient deaths per year, due 
to infection. This number reflects the excess mortality risk reported 
for hematopoietic stem/progenitor cell recipients with infection versus 
those without infection. It is based on the following: (18,123 
transplant procedures per year) x (2.41 percent PBSC patients receiving 
contaminated product) x (13.7 percent patients receiving contaminated 
product develop infection) x (44 percent excess mortality risk for 
hematopoietic stem/progenitor cell recipients with a probable 
infection). This estimate suggests a risk of death due to infection 
resulting from a contaminated hematopoietic stem/progenitor cell 
transplant of approximately 0.14 percent (26 deaths / 18,123 
hematopoietic stem/progenitor cell transplants). FDA currently has no 
basis for predicting how many of these deaths might be avoided through 
implementation of the CGTP final rule.
    As bacterial contamination has also been documented in studies of 
cord blood processing, the CGTP requirements for staff training and 
process validation will likely support risk and cost reduction efforts 
across the 25 CBSC establishments. For example, a study by Kogler et 
al. (Ref. 18) found that, during the initial 6 months of a 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. Due to a lack of data regarding the incidence and risks 
associated with CBSC procedures, FDA currently has no basis for 
predicting the magnitude of benefits that might be realized from 
implementation of the CGTP final rule in this HCT/P industry sector.

D. Summary of cGTP Benefits

    This analysis of the potential benefits of the CGTP final rule has 
considered its impact on major sectors of the HCT/P industry by 
focusing on problems associated with HCT/Ps cited in the literature, 
and the costs of correcting those problems. This review suggests that 
current industry voluntary standards are not followed uniformly, and 
that implementation of the CGTP final rule has the potential to 
generate economic benefits by reducing communicable disease 
transmission risks, improving product safety, and by reducing the costs 
associated with correcting HCT/P related problems.
    Table 13 of this document provides a summary of the particular 
products, problems identified and their associated costs based on the 
agency's survey of the literature. FDA estimated the associated health 
care costs based on reported risks, national level database estimates 
of the numbers of patients undergoing related procedures, and estimates 
of the direct medical costs associated with those procedures. These 
estimates also reflect the cost of work loss experienced by patients 
undergoing treatment to correct HCT/P related problems.
    Rather than attempting to generate point estimates of the benefits 
of the CGTP rule, the agency has chosen to present the results of this 
analysis of potential benefits in cost-effectiveness or break-even 
terms. There are several reasons for this. First, the current or 
baseline risks associated with the various types of HCT/Ps are unknown 
because the data required to establish these risks is either not 
readily available or is not currently collected by any entity. The lack 
of comprehensive risk data for the HCT/P industry is due primarily to a 
lack of mandatory reporting requirements for adverse health events 
associated with human tissues, a situation that is addressed by the 
reporting requirements of the CGTP final rule. Second, given that the 
current baseline risks associated with various types of HCT/Ps are 
uncertain, FDA has no basis for determining defensible estimates of the 
degree to which implementation of the CGTP final rule might be expected 
to reduce these already uncertain risks. Finally, while limited data 
with which to characterize a few of the risks associated with a select 
few of the many and diverse HCT/Ps, it is not possible to fully 
characterize all of the potential problems associated with all of the 
HCT/Ps that would be affected by this rule. Thus, it is not possible to 
develop comprehensive estimates of the aggregate benefits of the CGTP 
final rule.

                                       Table 13.--Summary of CGTP Benefits
----------------------------------------------------------------------------------------------------------------
                                                                                                 Cost-Effective
 HCT/P Industry Sector    HCT/P-Related Problem      Avoided Treatment     Estimated Cost of   Percent Reduction
                                                          Outcome              Treatment          in Cost/Risk
----------------------------------------------------------------------------------------------------------------
Eye Tissue               Primary Corneal Graft    Repeat Surgery          $.729 to $6.5                      25%
                          Failure                                          million
                                                                          $15,844 per case
----------------------------------------------------------------------------------------------------------------
Conventional Tissue      Bone Allograft           Repeat Surgery/         $62 million                       3.2%
                          Infection/Graft          Amputation             $24,587 per case
                          Failure
----------------------------------------------------------------------------------------------------------------

[[Page 68672]]

 
Conventional Tissue      Heart Valve Fungal       Repeat Surgery (Death)  $1.2 to $1.5                      3.3%
                          Endocarditis                                     million
                                                                          $87,204 per case
----------------------------------------------------------------------------------------------------------------
Hematopoietic Stem/      PBSC Transplant          Hospitalization         $1.4 million                 Unable to
 Progenitor Cells         Infection                (Death)                $24,053 per case             Determine
                                                                          26 deaths
----------------------------------------------------------------------------------------------------------------

    Additional uncertainties associated with estimating the benefits of 
the CGTP final rule include: The actual extent of current compliance in 
each of the affected industry sectors, the direct impact of HCT/P 
related problems on patient outcomes, and the precise size of the 
affected patient populations. Because of the limits of available data, 
the forgoing analysis has focused on a limited set of HCT/Ps. It is not 
certain how well these data represent the most critical areas, or 
actual levels of risk, associated with the many and varied products 
produced by the HCT/P industry. For some products, such as 
demineralized bone, the industry has achieved important advances in 
processing that have improved the safety and effectiveness of products. 
Thus, the analysis of benefits based on problem reports from several 
years ago, may overstate the potential for improvements in the current 
industry practice. In other cases, the publication of the recent 
reports suggests that deficiencies still exist within current 
practices. These areas present important opportunities to avoid product 
failures due to HCT/P-related problems, which lead to unnecessary 
communicable disease transmission risks and greater health care costs.

E. Small Entity Impacts

    The Regulatory Flexibility Act requires agencies to assess whether 
a rule may have a significant economic impact on a substantial number 
of small entities. Based on size standards established by the SBA, a 
small establishment in this industry sector (NAICS code 621991, Blood 
and Organ Banks) has annual receipts of less than $8.5 million (Refs. 
21 and 22). In every sector of the HCT/P industry, the majority of 
establishments are estimated to be classified as small entities. 
However, because of the large number of entities currently following 
industry voluntary standards, the increase in costs is expected to be 
limited primarily to establishments that do not follow those existing 
standards. To assess the impact of the CGTP rule on small businesses, 
FDA first calculated the ratio of average compliance costs to average 
annual revenues, assuming that all establishments will incur similar 
costs. The small entity impacts estimated below also focus on 
establishments that will be newly compliant under the CGTP final rule, 
and thus will experience the greatest potential new cost burden. 
Although current quality management practices at nonaccredited 
establishments may vary, and not every facility will incur every new 
cost estimated in table 4 of this document, the analysis that follows 
also considers a worst-case scenario in which every estimated cost is 
incurred by an establishment, to provide additional insight as to the 
maximum potential impact on small entities. While some firms may have 
lower than estimated average revenues, making them potentially more 
sensitive to cost increases, FDA does not know the distribution of 
firms by revenues because this information is not readily available. 
Therefore, the agency requested detailed industry comment regarding our 
average annual revenue assumptions in the CGTP proposed rule. To the 
extent possible, information obtained during the comment period has 
been incorporated into this analysis of the small entity impacts of the 
CGTP final rule. The results of this analysis are summarized in table 
14 of this document.
    A 1995 study of conventional tissue banks (Ref. 19) reports average 
annual revenues of $1.23 million per establishment, which translates 
into $1.45 million per establishment (in the year 2002 dollars) based 
on inflation data reported by the Bureau of Labor Statistics (Ref. 27). 
Most eye banks, conventional tissue banks and hematopoietic stem/
progenitor cell establishments were assumed to have a comparable level 
of average revenues in the proposed rule, and that assumption is 
retained here.
    Within the eye banking industry, experts estimate that virtually 
all of the 134 establishments would be classified as small, and all are 
believed to follow the current industry (EBAA) standards. The average 
annual revenue per eye bank is estimated at $1.45 million. If an eye 
bank were to incur every new cost estimated for establishments in that 
industry sector, the total cost impact, including total one-time and 
annual costs, would be $39,750, which represents 2.7 percent ($39,750 / 
$1.45 million) of estimated annual revenues. Average annualized 
compliance costs are estimated to be $12,087 ($1,619,659 total 
annualized costs / 134 small eye banks), and represents 0.83 percent 
($12,087 / $1.45 million) of average annual revenues per firm.
    In the conventional tissue banking industry, an estimated 75 to 80 
percent of the total of 166 establishments may be classified as small 
entities. Industry experts also estimate that 75 to 80 percent of those 
establishments currently follow AATB standards, which generally meet or 
exceed the requirements of the CGTP final rule. Based on the assumed 
levels of increased effort and costs shown in table 4 of this document, 
the remaining 20 to 25 percent of small establishments that do not 
follow current AATB standards could incur up to $66,621 in total 
incremental costs, including both one-time and annual costs, assuming 
that every potential area of new quality management effort will be 
needed under the worst-case scenario. The average annual revenue per 
small conventional tissue bank is estimated at $1.45 million. Thus, the 
estimated maximum potential new costs would represent approximately 4.6 
percent ($66,621 / $1.45 million) of this average annual revenue 
figure. The average total annualized cost for a small conventional 
tissue bank is estimated to be $11,678 ($1,506,433 total annualized 
costs / 129 small conventional tissue banks), and represents 0.8 
percent ($11,678 / $1.45 million) of average annual revenues.
    The agency estimates that approximately 250 hematopoietic stem/
progenitor cell establishments may be classified as small entities, and 
that these establishments have average annual revenues of $1.45 
million. An

[[Page 68673]]

estimated 200 (or 80 percent) of these small establishments follow the 
current FACT or AABB standards but will incur some additional costs. If 
one of these establishments were to incur new costs for each of the 
relevant provisions identified in table 4 of this document, the total 
incremental cost per establishment, including total one-time and annual 
costs, would be approximately $21,602. This figure represents 
approximately 1.5 percent ($21,602 / $1.45 million) of estimated annual 
revenues. The estimated 50 (or 20 percent of) small hematopoietic stem/
progenitor cell establishments that do not currently comply with AABB 
or FACT standards will incur greater costs, as shown in table 4 of this 
document. If one of these establishments were assumed to incur every 
new cost identified in the cost analysis, the total one-time and annual 
costs would be approximately $83,483. This represents approximately 5.8 
percent ($83,483 / $1.45 million) of average annual revenues.
    The average annualized costs incurred by small hematopoietic stem/
progenitor cell establishments would also vary depending on current 
practices and the degree to which establishments follow AABB or FACT 
standards. If a small hematopoietic stem/progenitor cell establishment 
is currently following industry standards, the average annualized cost 
associated with the CGTP final rule is estimated to be $8,367 
($1,673,301 total annualized costs / 200 small hematopoietic stem/
progenitor cell establishments), and represents approximately 0.58 
percent ($8,367 / $1.45 million) of the average annual revenue of these 
firms. However, if a small establishment is not following the current 
industry standards, a greater level of new effort will be required for 
quality assurance and quality management. The average annualized cost 
per small establishment not following current industry standards is 
estimated to be $43,207 ($2,160,341 total annualized costs / 50 small 
hematopoietic stem/progenitor cell establishments), and represents 
about 3 percent ($43,207 / $1.45 million) of average annual revenue.
    Consultants estimate that two-thirds of all ART establishments 
could be classified as small entities, and have average annual revenues 
of approximately $2.1 million. A typical ART establishment is expected 
to incur average annual and annualized costs of $768. This figure 
represents approximately 0.04 percent ($768 / $2.1 million) of average 
annual revenues.
    According to estimates by a semen banking industry expert, 
approximately 100,000 total daily intake (TDI) units are produced each 
year from collected and processed semen donations. An estimated 95 
percent of that total production is handled by the largest 20 
commercial establishments. Nineteen of these largest 20 establishments 
are estimated to have average annual revenues of approximately $2.4 
million, and only 1 establishment is estimated to have revenues greater 
than $8.5 million per year. The remaining 5 percent of industry 
production, or 5,000 TDI units, are processed by very small semen banks 
that typically function within a physician office practice (e.g., that 
of an obstetrician/gynecologist (Ob/Gyn)). Semen banking in these 
establishments is generally offered as an additional service to 
patients receiving fertility treatment, and is not a primary line of 
business.
    The annual revenue for these individual physician practices is 
estimated to be $692,000 per year, based on the average annual practice 
revenue per self-employed physician in the Ob/Gyn specialty category 
reported as $627,000 in 1998 (Ref. 20), adjusted to year 2002 dollars 
based on inflation data reported by the Bureau of Labor Statistics 
(Ref. 27). Thus the majority of semen banks would be considered small 
entities.
    The average annual and annualized costs associated with the 
inspection and enforcement provisions are estimated to be $768 per 
affected ART establishment and semen bank. This figure represents 
approximately 0.03 percent ($768 / $2.4 million) of average annual 
revenues for the 19 small commercial semen banks, and about 0.11 
percent ($768 / $692,000) for individual Ob/Gyn ART establishments and 
small physician practice-based semen banks.
    Although these cost figures account for a much larger percentage of 
individual physician practice income, the semen banking provided by 
these establishments is considered to represent a small part of their 
overall business. For the smallest banks, the estimated 5,000 TDI units 
supplied by the estimated 90 establishments in this category translate 
to an average volume of 55 units per establishment per year. With an 
estimated price of $95 to $145 per TDI unit (Ref. 30) and an estimated 
profit of 15 percent, these banks would realize, on average, a net 
income of $12.40 to $19.00 per unit, or a total net income of $682 to 
$1,045 for 55 units. This income would represent only 0.1 percent ($682 
/ $692,000) to 0.15 percent ($1,045 / $692,000) of the estimated annual 
practice revenue per self-employed physician in the Ob/Gyn specialty 
category.
    In summary, the majority of establishments within each sector of 
the HCT/P industry are expected to qualify as small business entities. 
The actual cost impact on these entities is uncertain, because of the 
limited information available with which to describe current practices 
and the degree to which individual establishments follow voluntary 
industry standards within each HCT/P industry sector. Based on the 
limited available data and industry expert opinions, the agency 
estimates impacts that would result in an average annualized cost per 
small establishment subject to CGTPs in their entirety ranging from 
$8,367 to $12,087 for establishments that currently follow industry 
standards, and $43,207 for establishments that do not currently follow 
industry quality standards. These annualized costs represent 0.6 
percent to 0.83 percent of estimated average annual revenues for firms 
currently following industry standards, and 3 percent of average annual 
revenues for firms not following industry standards.
    The worst-case analysis assumes that an affected small entity will 
incur new costs for every provision of the CGTP final rule. While this 
represents a highly unlikely scenario for nearly all firms in the HCT/P 
industry sectors subject to CGTPs in their entirety, this analysis does 
provide a useful illustration of the maximum potential burden of the 
CGTP final rule. The agency estimates worst-case average annualized 
costs per small establishment ranging from $21,602 to $66,621 for 
establishments that currently follow industry standards, and $83,483 
for establishments that do not currently follow industry quality 
standards. These worst-case annualized costs for small entities, 
expressed as a percentage of estimated average annual revenue, range 
from 1.5 percent to 4.6 percent for firms currently following industry 
standards, and represent 5.8 percent of estimated average annual 
revenues for firms not following industry standards.
    Establishments handling reproductive tissue are subject only to the 
inspection and enforcement provisions of the CGTP final rule as they 
apply to donor eligibility requirements under subpart C of part 1271. 
Small ART establishments and semen banks are expected to incur average 
annualized costs of $768, which represent between 0.03 and 0.11 percent 
of average annual revenues. The results of FDA's analysis of small 
entity impacts are summarized in table 14 of this document.

[[Page 68674]]



                                  Table 14.--Summary of Small Business Impacts
----------------------------------------------------------------------------------------------------------------
                                                              Average
   No. of Small      Average Annual        Average        Annualized Cost    Worst-Case Costs   Worst-Case Costs
Establishments by  Revenue per Small   Annualized Cost    as a Percentage    for an affected    as a Percentage
  Industry Sector     Establishment       per Small          of Average           Small            of Average
                     (in millions)      Establishment         Revenue         Establishment         Revenue
----------------------------------------------------------------------------------------------------------------
Eye Banks (134                 $1.45            $12,087              0.83%            $39,750               2.7%
 Establishments)
----------------------------------------------------------------------------------------------------------------
Conventional                   $1.45            $11,678               0.8%            $66,621               4.6%
 Tissue (129
 Establishments)
----------------------------------------------------------------------------------------------------------------
Stem/Progenitor                $1.45             $8,367               0.6%            $21,602               1.5%
 Cell
 Establishments
 Following
 Industry
 Standards (200
 Establishments)
----------------------------------------------------------------------------------------------------------------
Stem/Progenitor                $1.45            $43,207                 3%            $83,483               5.8%
 Cell
 Establishments
 Not Following
 Industry
 Standards (50
 Establishments)
----------------------------------------------------------------------------------------------------------------
ART                             $2.1               $768              0.04%               $768              0.04%
 Establishments
 (260
 Establishments)
----------------------------------------------------------------------------------------------------------------
Ob/Gyn and small              $0.692               $768               0.11               $768               0.11
 physician based
 practices
----------------------------------------------------------------------------------------------------------------
Semen Banks (19                 $2.4               $768              0.03%               $768              0.03%
 Establishments)
----------------------------------------------------------------------------------------------------------------

    The agency is uncertain about the accuracy of these estimates, 
however, because of the lack of revenue data for individual 
establishments. Because of the importance of this information in 
accurately assessing the impact on small entities, the agency requested 
detailed industry comment on individual firm revenues, the percentage 
of establishments that qualify as small entities, the percentage of 
those establishments that comply with current industry quality 
standards and the extent of their compliance, and the specific areas 
where industry anticipates substantial differences between current 
manufacturing practices and the quality assurance elements specified 
under the CGTP final rule. For those areas of identified difference, 
the agency further requested estimates of the resources and costs 
required for establishment compliance. This analysis has incorporated 
information received during the comment period to the extent possible. 
Please see our responses to comments 172 through 197 at section III.F. 
of this document for details.
    Although the CGTP final rule will impose some costs on small 
entities involved in the manufacture of HCT/Ps, the agency believes 
that this approach represents an effective means of protecting patient 
safety and public health. The less burdensome alternatives to the CGTP 
final rule involve fewer requirements for small entities (the vast 
majority of entities in this industry), but fail to provide fundamental 
assurances of product quality and safety. Reliance on industry 
professional organization voluntary standards or published FDA guidance 
for good tissue practice, rather that establishing a regulatory 
requirement, would not ensure uniform or consistent compliance and 
would preclude the agency's ability to effectively monitor HCT/Ps to 
ensure public health and safety. Given that each trade organization 
varies in their standards or guidelines, regulatory requirements for 
good tissue practice would help to ensure consistency among 
manufacturers and across the various sectors of the HCT/P industry. 
Further, the adverse reaction reporting requirements of the CGTP final 
rule will provide valuable information that will allow the agency to 
identify and respond to emerging public health and safety risks 
associated with HCT/Ps. FDA finds that the CGTP final rule will enhance 
both public health and public confidence in the safety and quality of 
the nation's supply of HCT/Ps, while imposing only a minimum burden on 
the affected entities.
    Another alternative would involve waiving some of the requirements 
for small establishments. However, as noted previously, nearly all 
establishments in this industry are small. Moreover, this alternative 
would increase HCT/P safety risks if small establishments that 
currently follow voluntary industry standards for good tissue practice 
choose to discontinue this practice due to an FDA-granted waiver. 
Furthermore, documentation and record retention provisions ensure that 
HCT/Ps can be tracked to their source in the event of infection or 
other adverse reactions that result from donor tissue characteristics.
    In summary, the agency believes that abridged requirements for 
CGTP, based on voluntary standards or facility size criteria, would 
provide inadequate protection against the risk of communicable disease 
transmission. Most notably, the current absence of regulation allows 
some establishments handling human tissues to ignore the standards 
established by industry professional associations and followed by a 
majority of entities in all sectors of the HCT/P industry.
    FDA has made a number of revisions to this final rule, many in 
response to public comments on the proposed CGTP rule, that are 
expected to reduce the overall compliance burden on affected entities.
    Provisions under Sec.  1271.160(c) have been revised to require 
audits periodically rather than annually as stipulated under the CGTP 
proposed rule. However, the cost estimates presented in this analysis 
of economic impacts retain the assumption that audits will impose an 
annual burden so as to generate conservative estimates of overall 
compliance costs. The provisions proposed under Sec.  1271.160(f), 
requiring complete validation of custom computer software used for 
making HCT/P-related decisions or determinations, have been changed to 
a requirement for validation or verification as appropriate.

[[Page 68675]]

 Verification is a less burdensome alternative that would apply to 
software not relied upon for making donor eligibility or HCT/P 
suitability decisions or determinations (e.g., inventory).
    The proposed requirement under Sec.  1271.180 for an annual review 
of all procedures has been removed, as has the requirement for prior 
authorization of any deviation from an established procedure. 
Provisions proposed under Sec.  1271.220(b) (process controls) 
requiring procedures for the use and removal of processing material 
have been deleted in response to comments. Proposed provisions under 
Sec.  1271.230(e) requiring validation of all process changes and 
process deviations now require validation only of process changes. 
Requirements proposed under Sec.  1271.265(e) for HCT/P packaging 
validation now allow for packaging validation or verification (a less 
burdensome alternative) as appropriate.
    Provisions proposed under Sec.  1271.290(d) and (e) requiring 
establishments to ensure each HCT/P is tracked from donor to recipient 
and from recipient to donor, now only require that establishments have 
a method of tracking in place. This will reduce the burden on affected 
entities because they no longer bear the responsibility of ensuring 
tracking with respect to their consignees. The proposed requirement for 
the reporting of all HCT/P deviations under Sec.  1271.350(b) now only 
applies to distributed HCT/Ps and not to those still in inventory. 
Finally, language has been added to Sec.  1271.420(b) to allow 
transportation to the consignee under quarantine of HCT/Ps offered for 
import to facilitate more rapid release of imported tissue products.
    As part of the development process for this final rule, FDA 
conducted an extensive outreach program in an effort to inform affected 
small entities and to request input regarding the potential economic 
impact. Representatives from CBER have given presentations on good 
tissue practice related issues at the annual conferences of many of the 
professional associations representing affected entities including 
ASRM, AATB, EBAA, and others. The agency has also engaged in outreach 
activities directed toward interested consumer groups such as RESOLVE 
and the American Infertility Association. At their request, FDA also 
held individual meetings with ASRM, EBAA, and AATB to discuss specific 
concerns regarding the impact of the CGTP rule. Some of these 
presentation materials and meeting minutes are available on the CBER 
Web page at http://www.fda.gov/cber/tissue/min.htm. Additional 
materials associated with the CGTP rule are available online at http://www.fda.gov/cber/tissue/docs.htm. Finally, in the proposed rule, FDA 
requested industry comment regarding the many assumptions upon which 
this analysis of economic impacts was based. In particular, we 
requested detailed industry comment regarding our estimates of: The 
number and type of entities affected, the extent of CGTP, compliance 
rates for firms in various sectors of the HCT/P industry, and the level 
of compliance costs. To the extent possible, we have incorporated these 
comments and our responses into the preamble and analysis of economic 
impacts of this final rule.
    The specific requirements for good tissue practice, the required 
recordkeeping, and the required types of professional skills are 
described in the economic analysis provided previously. This analysis 
includes an accounting of all major cost factors, with the exception of 
the reduced potential liability currently encountered by those marginal 
tissue establishments that fail to provide the level of protection from 
infectious disease that is considered a standard of good practice in 
other sectors of the tissue-based product industry. The relevant 
Federal rules that are related to this final rule are discussed in 
section II of this document. This economic analysis provides a summary 
of the private industry standards that overlap this final Federal 
standard, but as discussed, there is no current regulation of tissue 
that will duplicate this final rule. Consequently, FDA finds that this 
final rule will enhance both public health and public confidence in the 
safety and utility of HCT/Ps, while imposing only a minimum burden on 
the affected industry sectors.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) and (j) that this 
action is of a type that is categorically excluded from the preparation 
of an environmental assessment because these actions, as a class, will 
not result in the production or distribution of any substance and 
therefore will not result in the production of any substance into the 
environment.

VII. Federalism Assessment

    Executive Order 13132, dated August 4, 1999, establishes the 
procedure that Federal agencies must follow when formulating and 
implementing policies that have federalism implications. The Executive 
order described nine fundamental federalism principles, stressing the 
importance and sovereignty of State and local governments, and the 
contributions of individual states and communities to the development 
of enlightened public policy. Principles of federalism are inherent in 
the very structure of the Constitution and formalized in and protected 
by the tenth amendment. Regulations have federalism implications 
whenever they have a substantial direct effect on the States, on the 
relationship between the National Government and the States, or on the 
distribution of power and responsibilities among the various levels of 
government. Whenever a regulation has this result, the agency must 
prepare a federalism assessment.
    The Executive order directs Federal agencies to:
     Encourage States to develop their own policies to achieve 
program objectives and to work with appropriate officials in other 
States;
     Where possible, defer to the States to establish 
standards;
     In determining whether to establish uniform national 
standards, consult with appropriate State and local officials as to the 
need for national standards and any alternatives that would limit the 
scope of national standards or otherwise preserve State prerogatives 
and authority; and
     Where national standards are required by Federal statutes, 
consult with appropriate State and local officials in developing those 
standards.
    In the proposed rule (66 FR 1508 at 1551), we made the statement 
that we had analyzed the proposed rule in accordance with the 
principles set forth in Executive Order 13132, and that the proposed 
rule may raise federalism implications because it could preempt States' 
laws regarding donated human cells and tissues. We then invited 
comments from elected State and local government officials on:
     The need for the proposed CGTP to prevent communicable 
disease transmission through HCT/Ps;
     Alternatives that would limit the scope of such national 
requirements or otherwise preserve State prerogatives and authority;
     The proposed CGTP provisions; and
     Any other issues raised by the proposed rule that could 
affect State laws and authorities.
    We received no comments from State officials on federalism issues.
    This final rule represents the exercise of a core Federal function: 
``prevent[ing] the introduction, transmission, or spread of 
communicable diseases from foreign countries into the States or 
possessions, or from one State or possession into any other State or 
possession'' (section 361(a) of the PHS

[[Page 68676]]

Act; 42 U.S.C. 264). To prevent the transmission of communicable 
disease in the United States, including the interstate transmission of 
disease, uniform national standards for HCT/Ps are necessary. No State 
official commented otherwise. For these reasons, this rule is 
consistent with the federalism principles expressed in Executive Order 
13132.
    However, we received two comments requesting that we clearly state 
that this rulemaking's provisions preempt state tissue regulations.
    We decline to make this statement. Section 361 was recently amended 
to provide,
    Nothing in this section or section 363 [42 U.S.C. 266], or the 
regulations promulgated under such sections, may be construed as 
superseding any provision under State law (including regulations and 
including provisions established by political subdivisions of 
States), except to the extent that such a provision conflicts with 
an exercise of Federal authority under this section or section 363.
(section 361(e); 42 U.S.C. 264(e)).
    Accordingly, consistent with this provision, establishments must 
comply with applicable State law and regulations, unless the State 
provisions conflict with this exercise of Federal authority under 
section 361. In the event of such a conflict, these regulations would 
preempt the State provisions under ordinary principles of preemption. 
(Geier v. Honda, 529 U.S. 861 (2000).)

VIII. The Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520). A 
description of these provisions is shown as follows 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.
    Title: Current Good Tissue Practice for Human Cell, Tissue, and 
Cellular and Tissue-Based Product Establishments; Inspection and 
Enforcement.
    Description: Under the authority of section 361 of the PHS Act, FDA 
is requiring certain HCT/P establishments to follow CGTP, which 
includes information collection provisions such as the establishment 
and maintenance of SOPs, recordkeeping, reporting, and labeling of the 
HCT/Ps. The CGTP information collection provisions in this rulemaking 
provide: (1) Additional measures for preventing the introduction, 
transmission, or spread of communicable diseases; (2) step-by-step 
consistency in the manufacturing of the HCT/P; (3) necessary 
information to FDA for the purpose of protecting public health and 
safety; (4) accountability in the manufacturing of HCT/Ps; and (5) 
information facilitating the tracking of an HCT/P back to its original 
source or to a consignee.
    Table 15 lists provisions that require reporting or disclosure of 
information to third parties, the Federal Government, or the public. 
Section 1271.155(a) permits 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. Section 1271.290(c) requires the 
establishment to affix a distinct identification code to each HCT/P 
relating the HCT/P to the donor and all records pertaining to the HCT/
P. Whenever an establishment initially distributes an HCT/P to a 
consignee, Sec.  1271.290(f) requires the establishment to inform the 
consignee, in writing, of the product tracking requirements and the 
methods the establishment uses to fulfill the requirements. Non-
reproductive HCT/P establishments described in Sec.  1271.10 are 
required under Sec.  1271.350(a)(1) and (b)(1) to report to FDA adverse 
reactions (defined in Sec.  1271.3(y)) and HCT/P deviations (defined in 
Sec.  1271.3(dd)). Section 1271.370(b) and (c) requires establishments 
to include specific information either on the HCT/P label or in the 
package insert.
    Table 16 lists recordkeeping provisions under this final rule. 
Nonreproductive HCT/P establishments are required to prepare and 
maintain written SOPs to meet the core CGTP requirements for all steps 
performed in the manufacturing of HCT/Ps. As calculated in table 16 of 
this document, the preparation of the SOPs would result in a one-time 
impact on establishments and, once composed and/or reviewed for 
compliance, SOPs would only be updated as necessary.
    The requirement for reporting, SOPs, and recordkeeping in proposed 
Sec. Sec.  1271.160(d)(3), 1271.160(f), 1271.170(d), 1271.195(a), 
1271.210(a) and (b), 1271.220(b), 1271.225(b), 1271.230(b) and (d), 
1271.270(c), 1271.290(f), and 1271.350(c) are not included in the final 
rule.
    The SOP provisions under part 1271 include: (1) Sec.  
1271.160(b)(2) (receiving, investigation, evaluating, and documenting 
information relating to core CGTP requirements received from other 
sources and for sharing information with consignees and other 
establishments); (2) Sec.  1271.180(a) (to meet core CGTP requirements 
for all steps performed in the manufacture of HCT/Ps); (3) Sec.  
1271.190(d)(1) (facility cleaning and sanitization); (4) Sec.  
1271.200(b) (cleaning, sanitizing, and maintenance of equipment); (5) 
Sec.  1271.200(c) (calibration of equipment); (6) Sec.  1271.230(a) 
(verification or validation of changes to a process); (7) Sec.  
1271.250(a) (controls for labeling HCT/Ps); (8) Sec.  1271.265(e) 
(receipt, pre-distribution shipment, availability for distribution, and 
packaging and shipping of HCT/Ps); (9) Sec.  1271.265(f) (suitable for 
return to inventory); (10) Sec.  1271.270(b) (records management 
system); (11) Sec.  1271.290(b)(1) (system of HCT/P tracking); and, 
(12) Sec.  1271.320(a) (review, evaluation, and documentation of all 
complaints).
    Part 1271 requires the following additional recordkeeping 
provisions listed under Table 16. Section 1271.155(f) requires an 
establishment operating under the terms of an exemption or alternative 
to maintain documentation of the terms and date of FDA approval. 
Section 1271.160(b)(3) requires documentation of corrective actions 
taken as a result of an audit of the quality program. Section 
1271.160(b)(6) requires documentation of HCT/P deviations. Section 
1271.160(d) requires documentation of computer validation or 
verification activities and results when computers are used to comply 
with the core CGTP requirements for its intended use. Section 
1271.190(d)(2) requires documentation of all significant facility 
cleaning and sanitation. Section 1271.195(d) requires documentation of 
environmental control and monitoring activities. Section 1271.200(e) 
requires documentation of all equipment maintenance, cleaning, 
sanitizing, calibration, and other activities. Section 1271.210(d) 
requires documentation of the receipt, verification, and use of each 
supply or reagent. Section 1271.230(a) requires documentation of 
validation activities when the results of a process cannot be fully 
verified by subsequent inspection and tests. Section 1271.230(c) 
requires documentation of the review and evaluation of a process and 
revalidation of the process, if necessary, when any changes to a 
validated process occur. Sections 1271.260(d) and (e) require 
documentation of the storage temperature of HCT/Ps and any corrective 
action taken when acceptable storage conditions are not met. Section 
1271.265(c)(1) requires documentation that all release criteria are met 
before distribution of an HCT/P. Section

[[Page 68677]]

1271.265(c)(3) requires documentation of any departure from a procedure 
at the time of occurrence. Section 1271.265(e) requires documentation 
of the receipt, pre-distribution shipment, distribution, and packaging 
and shipping of HCT/Ps. Section 1271.270(a) requires documentation of 
each step in manufacturing required in subparts C and D.
    Section 1271.270(e) requires documentation of the name and address, 
and a list of responsibilities of any establishment that performs a 
manufacturing step for you. Sections 1271.290(d) and (e) require 
documentation of the disposition of each non-reproductive HCT/P as part 
of its tracking method. Section 1271.320(b) requires an establishment 
to maintain a record of each complaint that it receives, including a 
review and evaluation.
    Section 1271.270(d) requires the retention of all records for a 
period of 10 years after their creation. Records pertaining to a 
particular nonreproductive HCT/P are required to be retained at least 
10 years after the date of administration. If the date of 
administration is not known, then records are required to be retained 
at least 10 years after the date of the HCT/P's distribution, 
disposition, or expiration, whichever is latest. This retention time is 
necessary because certain nonreproductive HCT/Ps 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 an HCT/P from a donor later determined to be at 
risk for communicable disease agents or diseases.
    Description of Respondents: For-profit and not-for-profit 
institutions.
    As required by section 3506(c)(2)(B) of the PRA, we provided an 
opportunity for public comment on the information collection 
requirements of the proposed rule (66 FR 1508 at 1548). No comments on 
the information collection burden estimate were submitted to the 
docket. However, we respond to comments on the utility of the 
information collection in section III of this document, e.g., response 
to comment 68 addresses the utility and burden of retaining facility 
cleaning and sanitation records for 10 years.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 15.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                         No. of        Annual Frequency     Total Annual        Hours per
  21 CFR Section      Respondents        per Response        Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
1271.155(a)                    1,302                  1              1,302                  3              3,906
----------------------------------------------------------------------------------------------------------------
1271.290(c)                       93               52.2              4,855               0.08                388
----------------------------------------------------------------------------------------------------------------
1271.290(f)                      227                  1                227                  1                227
----------------------------------------------------------------------------------------------------------------
1271.350(a)(1)                   792                  6              4,752                  1              4,752
----------------------------------------------------------------------------------------------------------------
1271.350(b)(1)                   792                  2              1,584                  1              1,584
----------------------------------------------------------------------------------------------------------------
1271.370(b) and                   93               52.2              4,855               0.25              1,214
 (c)
----------------------------------------------------------------------------------------------------------------
Total                                                                                                     12,071
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                               Table 16.--Estimated Annual Recordkeeping Burden\1\
----------------------------------------------------------------------------------------------------------------
                                                            Annual
            21 CFR Section                  No. of       Frequency per   Total Annual    Hours per   Total Hours
                                        Recordkeepers    Recordkeeping      Records        Record
----------------------------------------------------------------------------------------------------------------
One-time Burden (Creation of SOPs)                  93              12           1,116           16       17,856
                                      --------------------------------------------------------------------------
                                                   134               3             402           16        6,432
----------------------------------------------------------------------------------------------------------------
One-time Burden (Review of existing                699              12           8,388            8       67,104
 SOPs for compliance)
                                      --------------------------------------------------------------------------
                                                   134               9           1,206            8        9,648
----------------------------------------------------------------------------------------------------------------
SOP Maintenance (See previous list of              792              12           9,504            2       19,008
 12 SOPs)
----------------------------------------------------------------------------------------------------------------
1271.155(f)                                        792               1             792         0.25          198
----------------------------------------------------------------------------------------------------------------
1271.160(b)(3)                                      93              12           1,116            1        1,116
----------------------------------------------------------------------------------------------------------------
1271.160(b)(6)                                     227              12           2,724            1        2,724
----------------------------------------------------------------------------------------------------------------
1271.160(d)                                        227              12           2,724            1        2,724
----------------------------------------------------------------------------------------------------------------
1271.190(d)(2)                                      93              12           1,116            1        1,116
----------------------------------------------------------------------------------------------------------------
1271.195(d)                                        227              12           2,724            1        2,724
----------------------------------------------------------------------------------------------------------------
1271.200(e)                                         93              12           1,116            1        1,116
----------------------------------------------------------------------------------------------------------------

[[Page 68678]]

 
1271.210(d)                                         93              12           1,116            1        1,116
----------------------------------------------------------------------------------------------------------------
1271.230(a)                                        227              12           2,724            1        2,724
----------------------------------------------------------------------------------------------------------------
1271.230(c)                                        360               1             360            1          360
----------------------------------------------------------------------------------------------------------------
1271.260(d)                                        227              12           2,724         0.25          681
----------------------------------------------------------------------------------------------------------------
1271.260(e)                                         93             365          33,945         0.08        2,716
----------------------------------------------------------------------------------------------------------------
1271.265(c)(1)                                     227         1,079.8         245,105         0.08       19,608
----------------------------------------------------------------------------------------------------------------
1271.265(c)(3)                                     592               1             592            1          592
----------------------------------------------------------------------------------------------------------------
1271.265(e)                                         93         1,622.6         150,905         0.08       12,072
----------------------------------------------------------------------------------------------------------------
1271.270(a)                                        227         1,079.8         245,105         0.25       61,276
----------------------------------------------------------------------------------------------------------------
1271.270(e)                                        227               2             454          0.5          227
----------------------------------------------------------------------------------------------------------------
1271.290(d) and (e)                                 93         1,622.6         150,905         0.25       37,726
----------------------------------------------------------------------------------------------------------------
1271.320(b)                                         93               5             465            1          465
----------------------------------------------------------------------------------------------------------------
Total                                                                                                    271,329
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Under this final rule, 12 SOPs are required as previously 
described. FDA is assuming that approximately 93 nonreproductive HCT/P 
establishments would create all 12 SOPs, and 134 nonreproductive HCT/P 
establishments would create 3 SOPs, for a total of 1,518 records; and 
we estimate that it would take 16 hours per new SOP for a total of 
24,288 hours as a one-time burden. We estimate that up to 12 SOPs would 
already exist for each nonreproductive HCT/P establishment as a result 
of complying with current applicable regulations or following industry 
organizational standards. We estimate that approximately 699 
nonreproductive HCT/P establishments would review all 12 SOPs, and 134 
nonreproductive HCT/P establishments would revise 9 SOPs. Each review 
would take approximately 8 hours per SOP for a total one-time burden of 
76,752 hours.
    Once the SOPs are created, annual SOP maintenance of existing SOPs 
is estimated to involve 2 hours annually per SOP. An additional hour 
for clerical time is added to the 1 hour per SOP stated in the proposed 
rule. Annual total hours for maintaining the SOPs is estimated at 
19,008 hours.
    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 regulation may have. In 
estimating the burden, FDA compared the regulations with the current 
voluntary standards of a number of industry organizations, such as, 
AATB, EBAA, AABB, FACT, NMDP, and CAP. In those cases where a voluntary 
industry standard appears to be equivalent to a 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 rule may already be required to 
comply with regulations for manufacturers of human drugs or biological 
products, e.g., 21 CFR parts 210, 211, 312, 314, 600, and 606. FDA 
attributes the decrease in total burden hours in the final rule 
(283,400 hours) from the total burden hours in the proposed rule 
(621,573 hours) to:
     Not including certain proposed information collection 
burden in the final rule;
     Not applying the information collection burden to 
reproductive HCT/P establishments; and
     Industry strengthening their current standards.
    FDA has estimated the reporting (table 15 of this document) and 
recordkeeping (table 16 of this document) burdens based upon our 
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 non-reproductive HCT/Ps 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 semen banks and ART facilities.
    We have estimated that there are approximately 792 nonreproductive 
HCT/P manufacturers (approximately 166 conventional tissue 
establishments, 134 eye tissue establishments, 425 peripheral and cord 
blood stem/progenitor cells, and 67 manufacturers of licensed 
biological products or devices). For the number of respondents for 
requesting a variance under Sec.  1271.155(a) in table 15 of this 
document, we added 510 reproductive HCT/P establishments. FDA obtained 
these estimates of manufacturers (including percentage of members and 
nonmembers) from the various trade organizations and our registration 
systems for HCT/P, biological product, and device manufacturers. The 
total number of respondents and recordkeepers, 1,302, in the tables is 
decreased for each provision by the estimated number of establishments 
that follow, as usual and customary practice, the applicable 
established trade

[[Page 68679]]

organizational standards comparable to the GTP requirements, i.e., 
AATB, EBAA, FACT, AABB, NMDP, or CAP. FDA based the estimated numbers 
for ``Number of Respondents'' and ``Number of Recordkeepers'' on 
information provided by the trade organizations and FDA registration 
databases.
    FDA based the estimated numbers for ``Annual Frequency per 
Response,'' ``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 Record'' 
were calculated using comparable burdens under drug GMP regulations (21 
CFR part 211) and GMP for blood and blood components (21 Part 606) or 
by using the information provided by ERG, e.g., time spent on 
Sec. Sec.  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.
    The information collection requirements of this final rule have 
been approved by OMB. The OMB control number is 0910-0559; it expires 
11/30/07. An agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

IX. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday. (FDA has verified the 
Web site addresses, but we are not responsible for subsequent changes 
to the Web site after this document publishes in the Federal Register.)
    1. U.S. Department of Health and Human Services, Center for 
Disease Control and Prevention, ``Update: Allograft-Associated 
Bacterial Infections--United States,'' Morbidity and Mortality 
Weekly Report, vol. 51, no. 10, pp. 207-210, March 15, 2002.
    2. Diringer, H. and H.R. Braig, ``Infectivity of Unconventional 
Viruses in Dura Mater,'' Lancet, pp. 439-440, 1989.
    3. U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Devices and Radiological Health, ``Class 
II Special Controls Guidance Document: Human Dura Mater; Draft 
Guidance for Industry and FDA,'' October 2002.
    4. U.S. Department of Health and Human Services, Food and Drug 
Administration, Transmissible Spongiform Encephalopathies Advisory 
Committee Meeting Transcript, pp. 1-100, June 26, 2002.
    5. 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.
    6. Remeijer, L., P. Doornenbal, A. J. M. Geerards, W. A. 
Rijneveld, and W. H. Beekhuis, ``Newly Acquired Herpes Simplex Virus 
Keratitis After Penetrating Keratoplasty,'' Ophthalmology, vol. 104, 
No. 4, pp. 648-652, April 1997.
    7. Health Care Utilization Project (HCUP), Nationwide Inpatient 
Sample (NIS) for 2000, Outcomes for Principle Procedure 13, Corneal 
transplant, Available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
    8. Health Care Financing Review, 2000 Statistical Supplement, 
Submitted Charges per Person Served, Calendar Year 1998, U.S. 
Department of Health and Human Services, Center for Medicare and 
Medicaid Services, Table 59, pp. 226-227.
    9. 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.
    10. Hardin, C. K., ``Banked Bone,'' Otolaryngologic Clinics of 
North America, vol. 27, No. 5, pp. 911-925, October 1994.
    11. Detailed Diagnoses and Procedures Data, National Hospital 
Discharge Survey 2000, Series 13, No. 153, Table 46, p. 153, 
November 2002.
    12. Abecassis, M. M., ``Transmission of Cytomegalovirus by Skin 
Allograft,'' Tissue and Cell Report, vol. 2, No. 1, pp. 14-17, 1995.
    13. 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.
    14. 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.
    15. 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.
    16. 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.
    17. 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.
    18. 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.
    19. 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.
    20. American Medical Association, Center for Health Policy 
Research, Physician Socioeconomic Statistics, 2002 Edition, Table 
41, p. 83, 2002.
    21. North American Industry Classification System (NAICS), 
available online at http://www.naics.com.
    22. U.S. Small Business Administration, Office of Size 
Standards, Table of Size Standards, Sector 62, Health Care and 
Social Assistance, 2002.
    23. HCUP, NIS for 2000, Outcomes for Principle Procedure 157, 
Amputation of Lower Extremity, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
    24. AHRQ, HCUP, NIS for 2000, Outcomes for Principle Procedure 
43, Heart Valve Procedures, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
    25. ``Blood Collection and Transfusion in the United States in 
1997,'' Transfusion, vol. 42, pp. 1253-1300, 2002.
    26. AHRQ, HCUP, NIS for 2000, Outcomes for Principle Procedure 
3, Bacterial Infection, Unspecified Site, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
    27. U.S. Department of Labor, Bureau of Labor Statistics, 
Available online at http://www.bls.gov/cpi.
    28. AHRQ, HCUP, NIS for 2001, Outcomes for Principle Procedure 
142, Partial Excision of Bone, available online at http://www.hcup-us.ahrq.gov/nisoverview.jsp.
    29. U.S. Department of Health and Human Services, Centers for 
Disease Control and Prevention, American Society for Reproductive 
Medicine and RESOLVE, 1999 Assisted Reproductive Technology Success 
Rates: National Summary and Fertility Clinic Reports, 2000.
    30. Fee Schedule 1/98, Donor Semen 0.5cc and Donor Semen 0.8cc-
1.0cc, The Sperm Bank of California, at http://www.thespermbankofca.org/fees.html.
    31. Hogan, R. N., P. Brown, and E. Heck, ``Risk of Prion Disease 
Transmission From Ocular Donor Tissue Transplantation,'' Cornea, 
vol. 18, No. 1, 1999, pp. 2-11.
    32. U.S. Department of Labor, Bureau of Labor Statistics, 
``Employer Costs for Employee Compensation per hour worked for 
Civilian Workers in Private Industry and State and local 
Governments, March 2003, available online at http://www.bls.gov.

List of Subjects

21 CFR part 16

    Administrative practice and procedure.

[[Page 68680]]

21 CFR part 1270

    Communicable diseases, HIV/AIDS, Reporting and recordkeeping 
requirements.

21 CFR part 1271

    Communicable diseases, HIV/AIDS, Human cells, tissues, and cellular 
and tissue-based products, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, Chapter I of title 21 of the Code of 
Federal Regulations is amended as follows:

0
1. The authority citation for 21 CFR part 16 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394, 
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.

0
2. Section 16.1 is amended in paragraph (b)(2) by numerically adding an 
entry for Sec.  1271.440(e) to read as follows:


Sec.  16.1  Scope.

* * * * *
    (b) * * *
    (2) * * *
    Sec.  1271.440(e) relating to the retention, recall, and 
destruction of human cells, tissues, and cellular and tissue-based 
products (HCT/Ps), and/or the cessation of manufacturing HCT/Ps.

PART 1270--HUMAN TISSUE INTENDED FOR TRANSPLANTATION

0
3. The authority citation for 21 CFR part 1270 continues to read as 
follows:

    Authority: 42 U.S.C. 216, 243, 264, 271.

0
4. Section 1270.3 is amended by revising paragraph (j) introductory 
text to read as follows:


Sec.  1270.3  Definitions

* * * * *
    (j) Human tissue, for the purpose of this part means any tissue 
derived from a human body and recovered before May 25, 2005, which:
* * * * *

PART 1271--HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED 
PRODUCTS

0
5. The authority citation for 21 CFR part 1271 continues to read as 
follows:

    Authority: 42 U.S.C. 216, 243, 263a, 264, 271.

0
6. Section 1271.3 is amended by revising paragraphs (c) and (d) and by 
adding paragraphs (y) through (ll) to read as follows:


Sec.  1271.3  How does FDA define important terms in this part?

* * * * *
    (c) Homologous use means the repair, reconstruction, replacement, 
or supplementation of a recipient's cells or tissues with an HCT/P that 
performs the same basic function or functions in the recipient as in 
the donor.
    (d) Human cells, tissues, or cellular or tissue-based products 
(HCT/Ps) means articles containing or consisting of human cells or 
tissues that are intended for implantation, transplantation, infusion, 
or transfer into a human recipient. Examples of HCT/Ps include, but are 
not limited to, bone, ligament, skin, dura mater, heart valve, cornea, 
hematopoietic stem/progenitor cells derived from peripheral and cord 
blood, manipulated autologous chondrocytes, epithelial cells on a 
synthetic matrix, and semen or other reproductive tissue. The following 
articles are not considered HCT/Ps:
    (1) Vascularized human organs for transplantation;
    (2) Whole blood or blood components or blood derivative products 
subject to listing under parts 607 and 207 of this chapter, 
respectively;
    (3) Secreted or extracted human products, such as milk, collagen, 
and cell factors; except that semen is considered an HCT/P;
    (4) Minimally manipulated bone marrow for homologous use and not 
combined with another article (except for water, crystalloids, or a 
sterilizing, preserving, or storage agent, if the addition of the agent 
does not raise new clinical safety concerns with respect to the bone 
marrow);
    (5) Ancillary products used in the manufacture of HCT/P;
    (6) Cells, tissues, and organs derived from animals other than 
humans; and
    (7) In vitro diagnostic products as defined in Sec.  809.3(a) of 
this chapter.
* * * * *
    (y) Adverse reaction means a noxious and unintended response to any 
HCT/P for which there is a reasonable possibility that the HCT/P caused 
the response.
    (z) Available for distribution means that the HCT/P has been 
determined to meet all release criteria.
    (aa) Complaint means any written, oral, or electronic communication 
about a distributed HCT/P that alleges:
    (1) That an HCT/P has transmitted or may have transmitted a 
communicable disease to the recipient of the HCT/P; or
    (2) Any other problem with an HCT/P relating to the potential for 
transmission of communicable disease, such as the failure to comply 
with current good tissue practice.
    (bb) Distribution means any conveyance or shipment (including 
importation and exportation) of an HCT/P that has been determined to 
meet all release criteria, whether or not such conveyance or shipment 
is entirely intrastate. If an entity does not take physical possession 
of an HCT/P, the entity is not considered a distributor.
    (cc) Establish and maintain means define, document (in writing or 
electronically), and implement; then follow, review, and, as needed, 
revise on an ongoing basis.
    (dd) HCT/P deviation means an event:
    (1) That represents a deviation from applicable regulations in this 
part or from applicable standards or established specifications that 
relate to the prevention of communicable disease transmission or HCT/P 
contamination; or
    (2) That is an unexpected or unforeseeable event that may relate to 
the transmission or potential transmission of a communicable disease or 
may lead to HCT/P contamination.
    (ee) 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.
    (ff) Processing means any activity performed on an HCT/P, other 
than recovery, donor screening, donor testing, storage, labeling, 
packaging, or distribution, such as testing for microorganisms, 
preparation, sterilization, steps to inactivate or remove adventitious 
agents, preservation for storage, and removal from storage.
    (gg) Quality audit means a documented, independent inspection and 
review of an establishment's activities related to core CGTP 
requirements. The purpose of a quality audit is to verify, by 
examination and evaluation of objective evidence, the degree of 
compliance with those aspects of the quality program under review.
    (hh) Quality program means an organization's comprehensive system 
for manufacturing and tracking HCT/Ps in accordance with this part. A 
quality program is designed to prevent, detect, and correct 
deficiencies that may lead to circumstances that increase the risk of 
introduction, transmission, or spread of communicable diseases.
    (ii) Recovery means obtaining from a human donor cells or tissues 
that are intended for use in human implantation, transplantation, 
infusion, or transfer.
    (jj) Storage means holding HCT/Ps for future processing and/or 
distribution.
    (kk) Validation means confirmation by examination and provision of

[[Page 68681]]

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 HCT/P meeting its predetermined specifications.
    (ll) Verification means confirmation by examination and provision 
of objective evidence that specified requirements have been fulfilled.

0
7. Section 1271.10 is amended by revising paragraph (a)(3) to read as 
follows:


Sec.  1271.10  Are my HCT/Ps regulated solely under section 361 of the 
PHS Act and the regulations in this part, and if so what must I do?

    (a) * * *
    (3) The manufacture of the HCT/P does not involve the combination 
of the cells or tissues with another article, except for water, 
crystalloids, or a sterilizing, preserving, or storage agent, provided 
that the addition of water, crystalloids, or the sterilizing, 
preserving, or storage agent does not raise new clinical safety 
concerns with respect to the HCT/P; and
* * * * *

0
8. Section 1271.22 is revised to read as follows:


Sec.  1271.22  How and where do I register and submit an HCT/P list?

    (a) You must use Form FDA 3356 for:
    (1) Establishment registration,
    (2) HCT/P listings, and
    (3) Updates of registration and HCT/P listing.
    (b) You may obtain Form FDA 3356:
    (1) By writing to the Center for Biologics Evaluation and Research 
(HFM-775), Food and Drug Administration, 1401 Rockville Pike, 
Rockville, MD 20852-1448, Attention: Tissue Establishment Registration 
Coordinator;
    (2) By contacting any Food and Drug Administration district office;
    (3) By calling the CBER Voice Information System at 1-800-835-4709 
or 301-827-1800; or
    (4) By connecting to http://www.fda.gov/opacom/morechoices/fdaforms/cber.html on the Internet.
    (c)(1) You may submit Form FDA 3356 to the Center for Biologics 
Evaluation and Research (HFM-775), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448, Attention: Tissue 
Establishment Registration Coordinator; or
    (2) You may submit Form FDA 3356 electronically through a secure 
web server at http://www.fda.gov/cber/tissue/tisreg.htm.

0
9. Section 1271.45 is amended in paragraph (a), after the second 
sentence, by adding a sentence to read as follows:


Sec.  1271.45  What requirements does this subpart contain?

    (a) * * * Other CGTP requirements are set out in subpart D of this 
part.
* * * * *

0
10. Part 1271 is amended by adding subpart D, consisting of Sec. Sec.  
1271.145 through 1271.320, to read as follows:
Subpart D--Current Good Tissue Practice
Sec.
1271.145 Prevention of the introduction, transmission, or spread of 
communicable diseases.
1271.150 Current good tissue practice requirements.
1271.155 Exemptions and alternatives.
1271.160 Establishment and maintenance of a quality program.
1271.170 Personnel.
1271.180 Procedures.
1271.190 Facilities.
1271.195 Environmental control and monitoring.
1271.200 Equipment.
1271.210 Supplies and reagents.
1271.215 Recovery.
1271.220 Processing and process controls.
1271.225 Process changes.
1271.230 Process validation.
1271.250 Labeling controls.
1271.260 Storage.
1271.265 Receipt, predistribution shipment, and distribution of an 
HCT/P.
1271.270 Records.
1271.290 Tracking.
1271.320 Complaint file.

Subpart D--Current Good Tissue Practice


Sec.  1271.145  Prevention of the introduction, transmission, or spread 
of communicable diseases.

    You must recover, process, store, label, package, and distribute 
HCT/Ps, and screen and test cell and tissue donors, in a way that 
prevents the introduction, transmission, or spread of communicable 
diseases.


Sec.  1271.150  Current good tissue practice requirements.

    (a) General. This subpart D and subpart C of this part set forth 
current good tissue practice (CGTP) requirements. You must follow CGTP 
requirements to prevent the introduction, transmission, or spread of 
communicable diseases by HCT/Ps (e.g., by ensuring that the HCT/Ps do 
not contain communicable disease agents, that they are not 
contaminated, and that they do not become contaminated during 
manufacturing). Communicable diseases include, but are not limited to, 
those transmitted by viruses, bacteria, fungi, parasites, and 
transmissible spongiform encephalopathy agents. CGTP requirements 
govern the methods used in, and the facilities and controls used for, 
the manufacture of HCT/Ps, including but not limited to all steps in 
recovery, donor screening, donor testing, processing, storage, 
labeling, packaging, and distribution. The CGTP provisions specifically 
governing determinations of donor eligibility, including donor 
screening and testing, are set out separately in subpart C of this 
part.
    (b) Core CGTP requirements. The following are core CGTP 
requirements:
    (1) Requirements relating to facilities in Sec.  1271.190(a) and 
(b);
    (2) Requirements relating to environmental control in Sec.  
1271.195(a);
    (3) Requirements relating to equipment in Sec.  1271.200(a);
    (4) Requirements relating to supplies and reagents in Sec.  
1271.210(a) and (b);
    (5) Requirements relating to recovery in Sec.  1271.215;
    (6) Requirements relating to processing and process controls in 
Sec.  1271.220;
    (7) Requirements relating to labeling controls in Sec.  1271.250(a) 
and (b);
    (8) Requirements relating to storage in Sec.  1271.260 (a) through 
(d);
    (9) Requirements relating to receipt, predistribution shipment, and 
distribution of an HCT/P in Sec.  1271.265(a) through (d); and
    (10) Requirements relating to donor eligibility determinations, 
donor screening, and donor testing in Sec. Sec.  1271.50, 1271.75, 
1271.80, and 1271.85.
    (c) Compliance with applicable requirements--(1) Manufacturing 
arrangements (i) If you are an establishment that engages in only some 
operations subject to the regulations in this subpart and subpart C of 
this part, and not others, then you need only comply with those 
requirements applicable to the operations that you perform.
    (ii) If you engage another establishment (e.g., a laboratory to 
perform communicable disease testing, or an irradiation facility to 
perform terminal sterilization), under a contract, agreement, or other 
arrangement, to perform any step in manufacture for you, that 
establishment is responsible for complying with requirements applicable 
to that manufacturing step.
    (iii) Before entering into a contract, agreement, or other 
arrangement with another establishment to perform any step in 
manufacture for you, you must ensure that the establishment complies 
with applicable CGTP requirements. If, during the course of this 
contract, agreement, or other arrangement, you

[[Page 68682]]

become aware of information suggesting that the establishment may no 
longer be in compliance with such requirements, you must take 
reasonable steps to ensure the establishment complies with those 
requirements. If you determine that the establishment is not in 
compliance with those requirements, you must terminate your contract, 
agreement, or other arrangement with the establishment.
    (2) If you are the establishment that determines that an HCT/P 
meets all release criteria and makes the HCT/P available for 
distribution, whether or not you are the actual distributor, you are 
responsible for reviewing manufacturing and tracking records to 
determine that the HCT/P has been manufactured and tracked in 
compliance with the requirements of this subpart and subpart C of this 
part and any other applicable requirements.
    (3) With the exception of Sec. Sec.  1271.150(c) and 1271.155 of 
this subpart, the regulations in this subpart are not being implemented 
for reproductive HCT/Ps described in Sec.  1271.10 and regulated solely 
under section 361 of the Public Health Service Act and the regulations 
in this part, or for the establishments that manufacture them.
    (d) Compliance with parts 210, 211, and 820 of this chapter. With 
respect to HCT/Ps that are drugs (subject to review under an 
application submitted under section 505 of the Federal Food, Drug, and 
Cosmetic Act or under a biological product license application under 
section 351 of the Public Health Service Act) or that are devices 
(subject to premarket review or notification under the device 
provisions of the act or under a biological product license application 
under section 351 of the Public Health Service 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 
supplement, and do not supersede, each other unless the regulations 
explicitly provide otherwise. In the event that a regulation in part 
1271 of this chapter is in conflict with a requirement in parts 210, 
211, or 820 of this chapter, the regulations more specifically 
applicable to the product in question will supersede the more general.
    (e) Where appropriate. When a requirement is qualified by ``where 
appropriate,'' it is deemed to be ``appropriate'' unless you can 
document justification otherwise. A requirement is ``appropriate'' if 
nonimplementation of the requirement could reasonably be expected to 
result in the HCT/P not meeting its specified requirements related to 
prevention of introduction, transmission, or spread of communicable 
diseases, or in your inability to carry out any necessary corrective 
action.


Sec.  1271.155  Exemptions and alternatives.

    (a) General. You may request an exemption from or alternative to 
any requirement in subpart C or D of this part.
    (b) Request for exemption or alternative. Submit your request under 
this section to the Director of the appropriate Center (the Director), 
e.g., the Center for Biologics Evaluation and Research or the Center 
for Devices and Radiological Health. The request must be accompanied by 
supporting documentation, including all relevant valid scientific data, 
and must contain either:
    (1) Information justifying the requested exemption from the 
requirement, or
    (2) A description of a proposed alternative method of meeting the 
requirement.
    (c) Criteria for granting an 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 protecting the public health 
and/or preventing the introduction, transmission, or spread of 
communicable diseases and that:
    (1) The information submitted justifies an exemption; or
    (2) The proposed alternative satisfies the purpose of the 
requirement.
    (d) Form of request. You must ordinarily make your request for an 
exemption or alternative in writing (hard copy or electronically). 
However, if circumstances make it difficult (e.g., there is inadequate 
time) to submit your request in writing, you may make the request 
orally, and the Director may orally grant an exemption or alternative. 
You must follow your oral request with an immediate written request, to 
which the Director will respond in writing.
    (e) Operation under exemption or alternative. You must not begin 
operating under the terms of a requested exemption or alternative until 
the exemption or alternative has been granted. You may apply for an 
extension of an exemption or alternative beyond its expiration date, if 
any.
    (f) Documentation. If you operate under the terms of an exemption 
or alternative, you must maintain documentation of:
    (1) FDA's grant of the exemption or alternative, and
    (2) The date on which you began operating under the terms of the 
exemption or alternative.
    (g) Issuance of an exemption or alternative by the Director. In a 
public health emergency, the Director may issue an exemption from, or 
alternative to, any requirement in part 1271. The Director may issue an 
exemption or alternative under this section if the exemption or 
alternative is necessary to assure that certain HCT/Ps will be 
available in a specified location to respond to an unanticipated 
immediate need for those HCT/Ps.


Sec.  1271.160  Establishment and maintenance of a quality program.

    (a) General. If you are an establishment that performs any step in 
the manufacture of HCT/Ps, you must establish and maintain a quality 
program intended to prevent the introduction, transmission, or spread 
of communicable diseases through the manufacture and use of HCT/Ps. The 
quality program must be appropriate for the specific HCT/Ps 
manufactured and the manufacturing steps performed. The quality program 
must address all core CGTP requirements listed in Sec.  1271.150(b).
    (b) Functions. Functions of the quality program must include:
    (1) Establishing and maintaining appropriate procedures relating to 
core CGTP requirements, and ensuring compliance with the requirements 
of Sec.  1271.180 with respect to such procedures, including review, 
approval, and revision;
    (2) Ensuring that procedures exist for receiving, investigating, 
evaluating, and documenting information relating to core CGTP 
requirements, including complaints, and for sharing any information 
pertaining to the possible contamination of the HCT/P or the potential 
for transmission of a communicable disease by the HCT/P with the 
following:
    (i) Other establishments that are known to have recovered HCT/Ps 
from the same donor;
    (ii) Other establishments that are known to have performed 
manufacturing steps with respect to the same HCT/P; and
    (iii) Relating to consignees, in the case of such information 
received after the HCT/P is made available for distribution, shipped to 
the consignee, or administered to the recipient, procedures must 
include provisions for assessing risk and appropriate followup, and 
evaluating the effect this information has on the HCT/P and for the 
notification of all entities to whom the affected HCT/P was 
distributed, the

[[Page 68683]]

quarantine and recall of the HCT/P, and/or reporting to FDA, as 
necessary.
    (3) Ensuring that appropriate corrective actions relating to core 
CGTP requirements, including reaudits of deficiencies, are taken and 
documented, as necessary. You must verify corrective actions to ensure 
that such actions are effective and are in compliance with CGTP. Where 
appropriate, corrective actions must include both short-term action to 
address the immediate problem and long-term action to prevent the 
problem's recurrence. Documentation of corrective actions must include, 
where appropriate:
    (i) Identification of the HCT/P 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 
involved in activities related to core CGTP requirements;
    (5) Establishing and maintaining appropriate monitoring systems as 
necessary to comply with the requirements of this subpart (e.g., 
environmental monitoring);
    (6) Investigating and documenting HCT/P deviations and trends of 
HCT/P deviations relating to core CGTP requirements and making reports 
if required under Sec.  1271.350(b) or other applicable regulations. 
Each investigation must include a review and evaluation of the HCT/P 
deviation, the efforts made to determine the cause, and the 
implementation of corrective action(s) to address the HCT/P deviation 
and prevent recurrence.
    (c) Audits. You must periodically perform for management review a 
quality audit, as defined in Sec.  1271.3(gg), of activities related to 
core CGTP requirements.
    (d) Computers. You must validate the performance of computer 
software for the intended use, and the performance of any changes to 
that software for the intended use, if you rely upon the software to 
comply with core CGTP requirements and if the software either is custom 
software or is commercially available software that has been customized 
or programmed (including software programmed to perform a user defined 
calculation or table) to perform a function related to core CGTP 
requirements. You must verify the performance of all other software for 
the intended use if you rely upon it to comply with core CGTP 
requirements. You must approve and document these activities and 
results before implementation.


Sec.  1271.170  Personnel.

    (a) General. You must have personnel sufficient to ensure 
compliance with the requirements of this part.
    (b) Competent performance of functions. You must have personnel 
with the necessary education, experience, and training to ensure 
competent performance of their assigned functions. Personnel must 
perform only those activities for which they are qualified and 
authorized.
    (c) Training. You must train all personnel, and retrain as 
necessary, to perform their assigned responsibilities adequately.


Sec.  1271.180  Procedures.

    (a) General. You must establish and maintain procedures appropriate 
to meet core CGTP requirements for all steps that you perform in the 
manufacture of HCT/Ps. You must design these procedures to prevent 
circumstances that increase the risk of the introduction, transmission, 
or spread of communicable diseases through the use of HCT/Ps.
    (b) Review and approval. Before implementation, a responsible 
person must review and approve these procedures.
    (c) Availability. These procedures must be readily available to the 
personnel in the area where the operations to which they relate are 
performed, or in a nearby area if such availability is impractical.
    (d) Standard procedures. If you adopt current standard procedures 
from another organization, you must verify that the procedures meet the 
requirements of this part and are appropriate for your operations.


Sec.  1271.190  Facilities.

    (a) General. Any facility used in the manufacture of HCT/Ps must be 
of suitable size, construction, and location to prevent contamination 
of HCT/Ps with communicable disease agents and to ensure orderly 
handling of HCT/Ps without mix-ups. You must maintain the facility in a 
good state of repair. You must provide lighting, ventilation, plumbing, 
drainage, and access to sinks and toilets that are adequate to prevent 
the introduction, transmission, or spread of communicable disease.
    (b) Facility cleaning and sanitation. (1) You must maintain any 
facility used in the manufacture of HCT/Ps in a clean, sanitary, and 
orderly manner, to prevent the introduction, transmission, or spread of 
communicable disease.
    (2) You must dispose of sewage, trash, and other refuse in a 
timely, safe, and sanitary manner.
    (c) Operations. You must divide a facility used in the manufacture 
of HCT/Ps into separate or defined areas of adequate size for each 
operation that takes place in the facility, or you must establish and 
maintain other control systems to prevent improper labeling, mix-ups, 
contamination, cross-contamination, and accidental exposure of HCT/Ps 
to communicable disease agents.
    (d) Procedures and records. (1) You must establish and maintain 
procedures for facility cleaning and sanitation for the purpose of 
preventing the introduction, transmission, or spread of communicable 
disease. These procedures must assign responsibility for sanitation and 
must describe in sufficient detail the cleaning methods to be used and 
the schedule for cleaning the facility.
    (2) You must document, and maintain records of, all cleaning and 
sanitation activities performed to prevent contamination of HCT/Ps. You 
must retain such records 3 years after their creation.


Sec.  1271.195  Environmental control and monitoring.

    (a) Environmental control. Where environmental conditions could 
reasonably be expected to cause contamination or cross-contamination of 
HCT/Ps or equipment, or accidental exposure of HCT/Ps to communicable 
disease agents, you must adequately control environmental conditions 
and provide proper conditions for operations. Where appropriate, you 
must provide for the following control 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; and
    (4) Maintenance of equipment used to control conditions necessary 
for aseptic processing operations.
    (b) Inspections. You must inspect each environmental control system 
periodically to verify that the system, including necessary equipment, 
is adequate and functioning properly. You must take appropriate 
corrective action as necessary.
    (c) Environmental monitoring. You must monitor environmental 
conditions where environmental conditions could reasonably be expected 
to cause contamination or cross-contamination of HCT/Ps or equipment, 
or accidental exposure of HCT/Ps to communicable

[[Page 68684]]

disease agents. Where appropriate, you must provide environmental 
monitoring for microorganisms.
    (d) Records. You must document, and maintain records of, 
environmental control and monitoring activities.


Sec.  1271.200  Equipment.

    (a) General. To prevent the introduction, transmission, or spread 
of communicable diseases, equipment used in the manufacture of HCT/Ps 
must be of appropriate design for its use and must be suitably located 
and installed to facilitate operations, including cleaning and 
maintenance. Any automated, mechanical, electronic, or other equipment 
used for inspection, measuring, or testing in accordance with this part 
must be capable of producing valid results. You must clean, sanitize, 
and maintain equipment according to established schedules.
    (b) Procedures and schedules. You must establish and maintain 
procedures for cleaning, sanitizing, and maintaining equipment to 
prevent malfunctions, contamination or cross-contamination, accidental 
exposure of HCT/Ps to communicable disease agents, and other events 
that could reasonably be expected to result in the introduction, 
transmission, or spread of communicable diseases.
    (c) Calibration of equipment. Where appropriate, you must routinely 
calibrate according to established procedures and schedules all 
automated, mechanical, electronic, or other equipment used for 
inspection, measuring, and testing in accordance with this part.
    (d) Inspections. You must routinely inspect equipment for 
cleanliness, sanitation, and calibration, and to ensure adherence to 
applicable equipment maintenance schedules.
    (e) Records. You must document and maintain records of all 
equipment maintenance, cleaning, sanitizing, calibration, and other 
activities performed in accordance with this section. You must display 
records of recent maintenance, cleaning, sanitizing, calibration, and 
other activities on or near each piece of equipment, or make the 
records readily available to the individuals responsible for performing 
these activities and to the personnel using the equipment. You must 
maintain records of the use of each piece of equipment, including the 
identification of each HCT/P manufactured with that equipment.


Sec.  1271.210  Supplies and reagents.

    (a) Verification. You must not use supplies and reagents until they 
have been verified to meet specifications designed to prevent 
circumstances that increase the risk of the introduction, transmission, 
or spread of communicable diseases. 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 HCT/
Ps must be sterile, where appropriate.
    (c) In-house reagents. You must validate and/or verify the 
processes used for production of in-house reagents.
    (d) Records. You must maintain the following records pertaining to 
supplies and reagents:
    (1) Records of the receipt of each supply or reagent, including the 
type, quantity, 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 
certificate of analysis from the vendor; and
    (3) Records of the lot of supply or reagent used in the manufacture 
of each HCT/P.


Sec.  1271.215  Recovery.

    If you are an establishment that recovers HCT/Ps, you must recover 
each HCT/P in a way that does not cause contamination or cross-
contamination during recovery, or otherwise increase the risk of the 
introduction, transmission, or spread of communicable disease through 
the use of the HCT/P.


Sec.  1271.220  Processing and process controls.

    (a) General. If you are an establishment that processes HCT/Ps, you 
must process each HCT/P in a way that does not cause contamination or 
cross-contamination during processing, and that prevents the 
introduction, transmission, or spread of communicable disease through 
the use of the HCT/P.
    (b) Pooling. Human cells or tissue from two or more donors must not 
be pooled (placed in physical contact or mixed in a single receptacle) 
during manufacturing.
    (c) In-process control and testing. You must ensure that specified 
requirements, consistent with paragraph (a) of this section, for in-
process controls are met, and that each in-process HCT/P 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 HCT/Ps must be representative of the 
material to be evaluated.
    (d) Dura mater. (1) When there is a published validated process 
that reduces the risk of transmissible spongiform encephalopathy, you 
must use this process for dura mater (or an equivalent process that you 
have validated), unless following this process adversely affects the 
clinical utility of the dura mater.
    (2) When you use a published validated process, you must verify 
such a process in your establishment.


Sec.  1271.225  Process changes.

    Any change to a process must be verified or validated in accordance 
with Sec.  1271.230, to ensure that the change does not create an 
adverse impact elsewhere in the operation, and must be approved before 
implementation by a responsible person with appropriate knowledge and 
background. You must communicate approved changes to the appropriate 
personnel in a timely manner.


Sec.  1271.230  Process validation.

    (a) General. Where the results of processing described in Sec.  
1271.220 cannot be fully verified by subsequent inspection and tests, 
you must validate and approve the process according to established 
procedures. The validation activities and results must be documented, 
including the date and signature of the individual(s) approving the 
validation.
    (b) Written representation. Any written representation that your 
processing methods reduce the risk of transmission of communicable 
disease by an HCT/P, including but not limited to, a representation of 
sterility or pathogen inactivation of an HCT/P, must be based on a 
fully verified or validated process.
    (c) Changes. When changes to a validated process subject to 
paragraph (a) of this section occur, you must review and evaluate the 
process and perform revalidation where appropriate. You must document 
these activities.


Sec.  1271.250  Labeling controls.

    (a) General. You must establish and maintain procedures to control 
the labeling of HCT/Ps. You must design these procedures to ensure 
proper HCT/P identification and to prevent mix-ups.
    (b) Verification. Procedures must include verification of label 
accuracy, legibility, and integrity.
    (c) Labeling requirements. Procedures must ensure that each HCT/P 
is labeled in accordance with all applicable labeling requirements, 
including those in Sec. Sec.  1271.55, 1271.60, 1271.65,

[[Page 68685]]

1271.90, 1271.290, and 1271.370, and that each HCT/P made available for 
distribution is accompanied by documentation of the donor eligibility 
determination as required under Sec.  1271.55.


Sec.  1271.260  Storage.

    (a) Control of storage areas. You must control your storage areas 
and stock rooms to prevent:
    (1) Mix-ups, contamination, and cross-contamination of HCT/Ps, 
supplies, and reagents, and
    (2) An HCT/P from being improperly made available for distribution.
    (b) Temperature. You must store HCT/Ps at an appropriate 
temperature.
    (c) Expiration date. Where appropriate, you must assign an 
expiration date to each HCT/P based on the following factors:
    (1) HCT/P type;
    (2) Processing, including the method of preservation;
    (3) Storage conditions; and
    (4) Packaging.
    (d) Corrective action. You must take and document corrective action 
whenever proper storage conditions are not met.
    (e) Acceptable temperature limits. You must establish acceptable 
temperature limits for storage of HCT/Ps at each step of the 
manufacturing process to inhibit the growth of infectious agents. You 
must maintain and record storage temperatures for HCT/Ps. You must 
periodically review recorded temperatures to ensure that temperatures 
have been within acceptable limits.


Sec.  1271.265  Receipt, predistribution shipment, and distribution of 
an HCT/P.

    (a) Receipt. You must evaluate each incoming HCT/P for the presence 
and significance of microorganisms and inspect for damage and 
contamination. You must determine whether to accept, reject, or place 
in quarantine each incoming HCT/P, based upon pre-established criteria 
designed to prevent communicable disease transmission.
    (b) Predistribution shipment. If you ship an HCT/P within your 
establishment or between establishments (e.g., procurer to processor) 
and the HCT/P is not available for distribution as described in 
paragraph (c) of this section, you must first determine and document 
whether pre-established criteria designed to prevent communicable 
disease transmission have been met, and you must ship the HCT/P in 
quarantine.
    (c) Availability for distribution. (1) Before making an HCT/P 
available for distribution, you must review manufacturing and tracking 
records pertaining to the HCT/P, and, on the basis of that record 
review, you must verify and document that the release criteria have 
been met. A responsible person must document and date the determination 
that an HCT/P is available for distribution.
    (2) You must not make available for distribution an HCT/P that is 
in quarantine, is contaminated, is recovered from a donor who has been 
determined to be ineligible or for whom a donor-eligibility 
determination has not been completed (except as provided under 
Sec. Sec.  1271.60, 1271.65, and 1271.90), or that otherwise does not 
meet release criteria designed to prevent communicable disease 
transmission.
    (3) You must not make available for distribution any HCT/P 
manufactured under a departure from a procedure relevant to preventing 
risks of communicable disease transmission, unless a responsible person 
has determined that the departure does not increase the risk of 
communicable disease through the use of the HCT/P. You must record and 
justify any departure from a procedure at the time of its occurrence.
    (d) Packaging and shipping. Packaging and shipping containers must 
be designed and constructed to protect the HCT/P from contamination. 
For each type of HCT/P, you must establish appropriate shipping 
conditions to be maintained during transit.
    (e) Procedures. You must establish and maintain procedures, 
including release criteria, for the activities in paragraphs (a) 
through (d) of this section. You must document these activities. 
Documentation must include:
    (1) Identification of the HCT/P and the establishment that supplied 
the HCT/P;
    (2) Activities performed and the results of each activity;
    (3) Date(s) of activity;
    (4) Quantity of HCT/P subject to the activity; and
    (5) Disposition of the HCT/P (e.g., identity of consignee).
    (f) Return to inventory. You must establish and maintain procedures 
to determine if an HCT/P that is returned to your establishment is 
suitable to be returned to inventory.


Sec.  1271.270  Records.

    (a) General. You must maintain records concurrently with the 
performance of each 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 is subject to the requirements 
of this section. All records must be accurate, indelible, and legible. 
The records must identify the person performing the work and the dates 
of the various entries, and must be as detailed as necessary to provide 
a complete history of the work performed and to relate the records to 
the particular HCT/P involved.
    (b) Records management system. You must establish and maintain a 
records management system relating to core CGTP requirements. Under 
this system, records pertaining to a particular HCT/P must be 
maintained in such a way as to facilitate review of the HCT/Ps history 
before making it available for distribution and, if necessary, 
subsequent to the HCT/Ps release as part of a followup evaluation or 
investigation. Records pertinent to the manufacture of HCT/Ps (e.g., 
labeling and packaging procedures, and equipment logs) must also be 
maintained and organized under the records management system. If 
records are maintained in more than one location, then the records 
management system must be designed to ensure prompt identification, 
location, and retrieval of all records.
    (c) Methods of retention. You may maintain records required under 
this subpart electronically, as original paper records, or as true 
copies such as photocopies, microfiche, or microfilm. Equipment that is 
necessary to make the records available and legible, such as computer 
and reader equipment, must be readily available. Records stored in 
electronic systems must be backed up.
    (d) Length of retention. You must retain all records for 10 years 
after their creation, unless stated otherwise in this part. However, 
you must retain the records pertaining to a particular HCT/P at least 
10 years after the date of its administration, or if the date of 
administration is not known, then at least 10 years after the date of 
the HCT/Ps distribution, disposition, or expiration, whichever is 
latest. You must retain records for archived specimens of dura mater 
for 10 years after the appropriate disposition of the specimens.
    (e) Contracts and agreements. You must maintain the name and 
address and a list of the responsibilities of any establishment that 
performs a manufacturing step for you. This information must be 
available during an inspection conducted under Sec.  1271.400.


Sec.  1271.290  Tracking.

    (a) General. If you perform any step in the manufacture of an HCT/P 
in which you handle the HCT/P, you must track each such HCT/P in 
accordance with this section, to facilitate the

[[Page 68686]]

investigation of actual or suspected transmission of communicable 
disease and take appropriate and timely corrective action.
    (b) System of HCT/P tracking. (1) You must establish and maintain a 
system of HCT/P tracking that enables the tracking of all HCT/Ps from:
    (i) The donor to the consignee or final disposition; and
    (ii) The consignee or final disposition to the donor.
    (2) Alternatively, if you are an establishment that performs some 
but not all of the steps in the manufacture of an HCT/P in which you 
handle the HCT/P, you may participate in a system of HCT/P tracking 
established and maintained by another establishment responsible for 
other steps in the manufacture of the same HCT/P, provided that the 
tracking system complies with all the requirements of this section.
    (c) Distinct identification code. As part of your tracking system, 
you must ensure: That each HCT/P that you manufacture is assigned and 
labeled with a distinct identification code, e.g., alphanumeric, that 
relates the HCT/P to the donor and to all records pertaining to the 
HCT/P; and that labeling includes information designed to facilitate 
effective tracking, using the distinct identification code, from the 
donor to the recipient and from the recipient to the donor. Except in 
the case of autologous or directed donations, you must create such a 
code specifically for tracking, and it may not include an individual's 
name, social security number, or medical record number. You may adopt a 
distinct identification code assigned by another establishment engaged 
in the manufacturing process, or you may assign a new code. If you 
assign a new code to an HCT/P, you must establish and maintain 
procedures for relating the new code to the old code.
    (d) Tracking from consignee to donor. As part of your tracking 
system, you must establish and maintain a method for recording the 
distinct identification code and type of each HCT/P distributed to a 
consignee to enable tracking from the consignee to the donor.
    (e) Tracking from donor to consignee or final disposition. As part 
of your tracking system, you must establish and maintain a method for 
documenting the disposition of each of your HCT/Ps, to enable tracking 
from the donor to the consignee or final disposition. The information 
you maintain must permit the prompt identification of the consignee of 
the HCT/P, if any.
    (f) Consignees. At or before the time of distribution of an HCT/P 
to a consignee, you must inform the consignee in writing of the 
requirements in this section and of the tracking system that you have 
established and are maintaining to comply with these requirements.
    (g) Requirements specific to dura mater donors. You must archive 
appropriate specimens from each donor of dura mater, under appropriate 
storage conditions, and for the appropriate duration, to enable testing 
of the archived material for evidence of transmissible spongiform 
encephalopathy, and to enable appropriate disposition of any affected 
nonadministered dura mater tissue, if necessary.


Sec.  1271.320  Complaint file.

    (a) Procedures. You must establish and maintain procedures for the 
review, evaluation, and documentation of complaints as defined in 
Sec. 1271.3(aa), relating to core current good tissue practice (CGTP) 
requirements, and the investigation of complaints as appropriate.
    (b) Complaint file. You must maintain a record of complaints that 
you receive in a file designated for complaints. The complaint file 
must contain sufficient information about each complaint for proper 
review and evaluation of the complaint (including the distinct 
identification code of the HCT/P that is the subject of the complaint) 
and for determining whether the complaint is an isolated event or 
represents a trend. You must make the complaint file available for 
review and copying upon request from FDA.
    (c) Review and evaluation of complaints. You must review and 
evaluate each complaint relating to core CGTP requirements to determine 
if the complaint is related to an HCT/P deviation or to a adverse 
reaction, and to determine if a report under Sec.  1271.350 or another 
applicable regulation is required. As soon as practical, you must 
review, evaluate, and investigate each complaint that represents an 
event required to be reported to FDA, as described in Sec.  1271.350. 
You must review and evaluate a complaint relating to core CGTP 
requirements that does not represent an event required to be reported 
to determine whether an investigation is necessary; an 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, you must maintain a record that includes the 
reason no investigation was made, and the name of the individual(s) 
responsible for the decision not to investigate.

0
11. Part 1271 is amended by adding subpart E, consisting of Sec. Sec.  
1271.330 through 1271.370, to read as follows:
Subpart E--Additional Requirements for Establishments Described in 
Sec.  1271.10
Sec.
1271.330 Applicability.
1271.350 Reporting.
1271.370 Labeling.

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


Sec.  1271.330  Applicability.

    The provisions set forth in this subpart are being implemented for 
nonreproductive HCT/Ps described in Sec.  1271.10 and regulated solely 
under section 361 of the Public Health Service Act and the regulations 
in this part, and for the establishments that manufacture those HCT/Ps. 
HCT/Ps that are drugs or devices regulated under the act, or are 
biological products regulated under section 351 of the Public Health 
Service Act, are not subject to the regulations set forth in this 
subpart.


Sec.  1271.350  Reporting.

    (a) Adverse reaction reports. (1) You must investigate any adverse 
reaction involving a communicable disease related to an HCT/P that you 
made available for distribution. You must report to FDA an adverse 
reaction involving a communicable disease if it:
    (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, including 
hospitalization.
    (2) You must submit each report on a Form FDA-3500A to the address 
in paragraph (a)(5) of this section within 15 calendar days of initial 
receipt of the information.
    (3) You must, as soon as practical, investigate all adverse 
reactions that are the subject of these 15-day reports and must submit 
followup reports within 15 calendar days of the receipt of new 
information or as requested by FDA. If additional information is not 
obtainable, a followup report may be required that describes briefly 
the steps taken to seek additional information and the reasons why it 
could not be obtained.
    (4) You may obtain copies of the reporting form (FDA-3500A) from 
the Center for Biologics Evaluation and Research (see address in 
paragraph (a)(5) of this section). Electronic Form

[[Page 68687]]

FDA-3500A may be obtained at http://www.fda.gov/medwatch or at http://www.hhs.gov/forms.
    (5) You must submit two copies of each report described in this 
paragraph to the Center for 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 HCT/P deviations. (1) You must investigate all HCT/P 
deviations related to a distributed HCT/P for which you performed a 
manufacturing step.
    (2) You must report any such HCT/P deviation relating to the core 
CGTP requirements, if the HCT/P deviation occurred in your facility or 
in a facility that performed a manufacturing step for you under 
contract, agreement, or other arrangement. Each report must contain a 
description of the HCT/P deviation, information relevant to the event 
and the manufacture of the HCT/P involved, and information on all 
follow-up actions that have been or will be taken in response to the 
HCT/P deviation (e.g., recalls).
    (3) You must report each such HCT/P deviation that relates to a 
core CGTP requirement on Form FDA-3486 available at http://www.fda.gov/cber/biodev/bpdrform.pdf, within 45 days of the discovery of the event 
either electronically at http://www.fda.gov/cber/biodev/biodevsub.htm 
or by mail 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.


Sec.  1271.370  Labeling.

    The following requirements apply in addition to Sec. Sec.  1271.55, 
1271.60, 1271.65, and 1271.90:
    (a) You must label each HCT/P made available for distribution 
clearly and accurately.
    (b) The following information must appear on the HCT/P label:
    (1) Distinct identification code affixed to the HCT/P container, 
and assigned in accordance with Sec.  1271.290(c);
    (2) Description of the type of HCT/P;
    (3) Expiration date, if any; and
    (4) Warnings required under Sec. Sec.  1271.60(d)(2), 
1271,65(b)(2), or 1271.90(b), if applicable.
    (c) The following information must either appear on the HCT/P label 
or accompany the HCT/P:
    (1) Name and address of the establishment that determines that the 
HCT/P meets release criteria and makes the HCT/P available for 
distribution;
    (2) Storage temperature;
    (3) Other warnings, where appropriate; and
    (4) Instructions for use when related to the prevention of the 
introduction, transmission, or spread of communicable diseases.

0
12. Part 1271 is amended by adding subpart F, consisting of Sec. Sec.  
1271.390 through 1271.440, 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 HCT/Ps 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 
HCT/Ps described in Sec.  1271.10 and regulated solely under section 
361 of the Public Health Service Act and the regulations in this part, 
and to the establishments that manufacture those HCT/Ps. HCT/Ps that 
are drugs or devices regulated under the act, or are biological 
products regulated under section 351 of the Public Health Service Act, 
are not subject to the regulations set forth in this subpart.


Sec.  1271.400  Inspections.

    (a) If you are an establishment that manufactures HCT/Ps described 
in Sec.  1271.10, whether or not under contract, you must permit the 
Food and Drug Administration (FDA) to inspect any manufacturing 
location at any reasonable time and in a reasonable manner to determine 
compliance with applicable provisions of this part. The inspection will 
be conducted as necessary in the judgment of the FDA and may include 
your establishment, facilities, equipment, finished and unfinished 
materials, containers, processes, HCT/Ps, procedures, labeling, 
records, files, papers, and controls required to be maintained under 
the part. The inspection may be made with or without prior notification 
and will ordinarily be made during regular business hours.
    (b) The frequency of inspection will be at the agency's discretion.
    (c) FDA 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 necessary to determine compliance 
with the provisions of this part.
    (d) FDA's representatives may take samples, may review and copy any 
records required to be kept under this part, and may use other 
appropriate means to record evidence of observations during inspections 
conducted under this subpart.
    (e) The public disclosure of records containing the name or other 
positive identification of donors or recipients of HCT/Ps will be 
handled in accordance with FDA's procedures on disclosure of 
information as set forth in parts 20 and 21 of this chapter.


Sec.  1271.420  HCT/Ps offered for import.

    (a) Except as provided in paragraphs (c) and (d) of this section, 
when an HCT/P is offered for import, the importer of record must 
notify, either before or at the time of importation, the director of 
the district of the Food and Drug Administration (FDA) having 
jurisdiction over the port of entry through which the HCT/P 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, and must provide sufficient information for FDA to 
make an admissibility decision.
    (b) Except as provided in paragraphs (c) and (d) of this section, 
an HCT/P offered for import must be held intact by the importer or 
consignee, under conditions necessary to prevent transmission of 
communicable disease, until an admissibility decision is made by FDA. 
The HCT/P may be transported under quarantine to the consignee, while 
the FDA district reviews the documentation accompanying the HCT/P. When 
FDA makes a decision regarding the admissibility of the HCT/P, FDA will 
notify the importer of record.
    (c) This section does not apply to reproductive HCT/Ps regulated 
solely under section 361 of the Public Health Service Act and the 
regulations in this part, and donated by a sexually intimate partner of 
the recipient for reproductive use.
    (d) This section does not apply to peripheral blood stem/progenitor 
cells regulated solely under section 361 of the Public Health Service 
Act and the regulations in this part, except that paragraphs (a) and 
(b) of this section apply when circumstances occur under which such 
imported peripheral blood stem/progenitor cells may present an 
unreasonable risk of communicable disease transmission which indicates 
the need to review the information referenced in paragraph (a) of this 
section.

[[Page 68688]]

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

    (a) Upon an agency finding that there are reasonable grounds to 
believe that an HCT/P is a violative HCT/P because it was manufactured 
in violation of the regulations in this part and, therefore, the 
conditions of manufacture of the HCT/P do not provide adequate 
protections against risks of communicable disease transmission; or the 
HCT/P is infected or contaminated so as to be a source of dangerous 
infection to humans; or an establishment is in violation of the 
regulations in this part and, therefore, does not provide adequate 
protections against the risks of communicable disease transmission, the 
Food and Drug Administration (FDA) may take one or more of the 
following actions:
    (1) Serve upon the person who distributed the HCT/P a written order 
that the HCT/P be recalled and/or destroyed, as appropriate, and upon 
persons in possession of the HCT/P that the HCT/P must be retained 
until it is recalled by the distributor, destroyed, or disposed of as 
agreed by FDA, or the safety of the HCT/P is confirmed;
    (2) Take possession of and/or destroy the violative HCT/P; or
    (3) Serve upon the establishment an order to cease manufacturing 
until compliance with the regulations of this part has been achieved. 
When FDA determines there are reasonable grounds to believe there is a 
danger to health, such order will be effective immediately. In other 
situations, such order will be effective after one of the following 
events, whichever is later:
    (i) Passage of 5 working days from the establishment's receipt of 
the order; or
    (ii) If the establishment requests a hearing in accordance with 
paragraph (e) of this section and part 16 of this chapter, a decision 
in, and in accordance with, those proceedings.
    (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 ordinarily provide that the HCT/P 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 HCT/P must not 
distribute or dispose of the HCT/P in any manner except to recall and/
or destroy the HCT/P consistent with the provisions of the order, under 
the supervision of FDA.
    (2) In lieu of paragraph (c)(1) of this section, other arrangements 
for assuring the proper disposition of the HCT/P may be agreed upon by 
the person receiving the written order and FDA. Such arrangements may 
include, among others, providing FDA with records or other written 
information that adequately ensure that the HCT/P has been recovered, 
processed, stored, and distributed in conformance with this part, and 
that, except as provided under Sec. Sec.  1271.60, 1271.65, and 
1271.90, the donor of the cells or tissue for the HCT/P has been 
determined to be eligible.
    (d) A written order issued under paragraph (a)(3) of this section 
will specify the regulations with which you must achieve compliance and 
will ordinarily specify the particular operations covered by the order. 
After receipt of an order that is in effect and issued under paragraph 
(a)(3) of this section, you must not resume operations without prior 
written authorization of FDA.
    (e) The recipient of an order issued under this section may request 
a hearing in accordance with part 16 of this chapter. To request a 
hearing, the recipient of the written order or prior possessor of such 
HCT/P must make the request 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 an HCT/P under 
paragraph (a)(2) of this section), in accordance with part 16 of this 
chapter. An order of destruction will be held in abeyance pending 
resolution of the hearing request. Upon request under part 16 of this 
chapter, FDA will provide an opportunity for an expedited hearing for 
an order of cessation that is not stayed by the Commissioner of Food 
and Drugs.
    (f) FDA will not issue an order for the destruction of reproductive 
tissue under paragraph (a)(1) of this section, nor will it carry out 
such destruction itself under paragraph (a)(2) of this section.

    Dated: June 17, 2004.
Lester Crawford,
Acting Commissioner of Food and Drugs.

    Dated: September 16, 2004.
Tommy G. Thompson,
Secretary of Health and Human Services.
[FR Doc. 04-25798 Filed 11-18-04; 12:30 pm]
BILLING CODE 4160-01-S