68612 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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.

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 (§ 1271.3)

C. Part 1271, Subpart D—Current 

Good Tissue Practice

D. Part 1271, Subpart E—Additional 

Requirements for Establishments 

Described in § 1271.10

E. Part 1271, Subpart F—Inspection 

and Enforcement of Establishments 

Described in § 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 § 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 

§§ 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 tissuebased products (now called human 

cells, tissues, and cellular and tissuebased 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 (donoreligibility 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68613

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 § 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 § 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 (§§ 1271.150(c) and 

1271.155) subparts D and E are not 

being implemented for reproductive 

HCT/Ps described in § 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 (donoreligibility 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 crosscontamination 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 riskbased 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 § 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

68614 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

§ 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 § 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 § 1271.3(d)(2) until 

January 21, 2004(68 FR 2690, January 

21, 2003), on which date § 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 

§ 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 § 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 reevaluated 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 

§ 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 

§ 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., § 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,

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68615

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 § 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 § 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 § 1271.220(b) 

Processing material and the definition 

of that term in proposed § 1271.3(hh);

• Adding paragraph (b) to § 1271.265;

• Adding language in § 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 §§ 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 § 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

68616 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 (§ 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 

§ 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 

§§ 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.

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

§ 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 

§ 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: 

§§ 1271.3(bb) and (kk), 1271.160, 

1271.200, 1271.210, 1271.220, 1271.260, 

1271.265, 1271.350, and 1271.420.

B. Definitions (§ 1271.3)

We have grouped all definitions 

pertinent to part 1271 in a single 

definitions section (§ 1271.3), among the 

general provisions of subpart A. The 

proposed rule contained proposed 

definitions from § 1271.3(ff) through (tt); 

these have been renumbered from 

§ 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 § 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 

§ 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 (§ 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 

§ 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 

§ 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,

68618 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

(§ 1271.3(z))

The proposed regulations in 

§ 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 

§ 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 

§ 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 (§ 1271.3(aa))

Proposed § 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 

§ 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 § 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 § 1271.3(ii)(3), which has been 

renumbered as § 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 § 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 (§ 1271.3(bb))

We proposed to define ‘‘distribution’’

in § 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68619

operating room in the same facility 

would be considered distribution.

5. Establish and Maintain (§ 1271.3(cc))

Proposed § 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 (§ 1271.3(dd))

Proposed § 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 § 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 § 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 § 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 § 1271.350(b).

7. Importer of Record (§ 1271.3(ee))

Proposed § 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 (§ 1271.3(ff))

Processing is one of the activities 

listed in the definition of ‘‘manufacture’’

in § 1271.3(e). The proposed rule would 

define ‘‘processing’’ in § 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 §§ 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 § 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 § 1271.220(b), and as a result 

are also deleting this definition.

10. Quality Audit (§ 1271.3(gg))

We proposed to define ‘‘quality audit’’

in § 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.

68620 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

(Comment 22) One comment 

recommended that we define 

‘‘independent’’ or insert a reference to 

proposed § 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 § 1271.160, 

which has been revised.

11. Quality Program (§ 1271.3(hh))

We proposed to define ‘‘quality 

program’’ in § 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 (§ 1271.3(ii))

Proposed § 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 § 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 (§ 1271.3(jj))

Storage is one of the activities listed 

in the definition of manufacture in 

§ 1271.3(e). We proposed to define 

‘‘storage’’ in § 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 (§ 1271.3(kk))

Proposed § 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., 

§§ 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68621

professional organizations and others to 

submit drafts of proposed guidance in 

this area for FDA to consider for 

possible adoption.

15. Verification (§ 1271.3(nn))

Proposed § 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 

§ 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 (§ 1271.150)

General (§ 1271.150(a))

Proposed § 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 § 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 allograftassociated 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 

(§ 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: § 1271.190(a) and (b) 

(relating to facilities); § 1271.195(a) 

(environmental controls); § 1271.200(a) 

(equipment); § 1271.210(a) and (b) 

(supplies and reagents); § 1271.215 

(recovery); § 1271.220 (processing and 

process controls); § 1271.250(a) and (b) 

(labeling controls); § 1271.260(a) 

through (d) (storage); § 1271.265(a) 

through (d) (receipt, predistribution 

shipment, and distribution); and 

§§ 1271.50, 1271.75, 1271.80, and 

1271.85 (donor eligibility 

determinations, donor screening, and 

donor testing).

Compliance With Applicable 

Requirements (§ 1271.150(c)(1))

Proposed § 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 

§ 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 an 

HCT/P

Follow CGTP (subparts C and D) (§ 1271.150(a)) as it relates to that step.

Perform only some and not all operations of 

manufacturing, and do not make the HCT/P 

available for distribution

1. Follow only those requirements applicable to the operations you perform (§ 1271.150(c)(1). 

2. When you receive the HCT/P, determine whether the HCT/P meets all pre-established criteria, designed to prevent communicable disease transmission, for acceptance or rejection, 

and place the HCT/P in quarantine as appropriate (§ 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 (§ 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 (§ 1271.350(b)(1) and (b)(2)).

Engage another establishment to perform any 

step in manufacturing for you under contract, agreement, or other arrangement

1. Enter into and maintain such an arrangement only with a reliable establishment that complies 

with applicable CGTP requirements. (§ 1271.150(c)(1)). 

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 (§ 1271.350(b)(1) and (b)(2)).

68622 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

TABLE 1A—Continued

If you: You must: 

Make the HCT/P available for distribution 1. Review manufacturing and tracking records to determine that the HCT/P meets all the release criteria (§§ 1271.150(c)(2) and 1271.265(c)) and maintain records relevant to the release determination (§ 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 (§§ 1271.150(c)(2) and 

1271.290).

3. Investigate and report any adverse reaction involving a communicable disease 

(§ 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 (§ 1271.350(b)(1) and (b)(2)).

(Comment 28) Several comments 

objected to the statement in proposed 

§ 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 

§ 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 

§ 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 § 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, § 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 §§ 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68623

purpose of this requirement, you may 

seek an exemption or alternative under 

§ 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 § 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 (§ 1271.150(c)(2))

Proposed § 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 

§ 1271.150(c)(2), we have added the 

responsibility for tracking (consistent 

with § 1271.290).

(Comment 31) Under proposed 

§ 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 § 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 

§ 1271.150(b)(2) (and renumbered it 

§ 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 (§§ 1271.80 and 

1271.85); matching the distinct 

identification code on the HCT/P 

container with the code in the summary 

of records (§ 1271.290)c); reviewing 

records pertaining to donor screening 

for risk factors for and clinical evidence 

of relevant communicable disease 

agents (§ 1271.75); reviewing records 

pertaining to storage temperature 

(§ 1271.260), processing (§ 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 § 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 § 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

68624 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

receives the finished HCT/P from a 

commercial tissue processor, and 

‘‘distributes’’ the HCT/P in the same 

facility, is excepted from these 

regulations (§ 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 (§ 1271.150(c)(3))

Paragraph (c)(3) of § 1271.150 states 

that with the exception of 

§§ 1271.150(c) and 1271.155 of this 

subpart, the regulations in this subpart 

are not being implemented for 

reproductive HCT/Ps described in 

§ 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 (§ 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 § 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 

§ 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 (§ 1271.150(e))

‘‘Where appropriate’’ in proposed 

§ 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(§ 1271.155)

Proposed § 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 § 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 § 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 § 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 § 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 § 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 

§ 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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., § 640.120 (21 CFR 

640.120) and 21 CFR 803.19). The time 

for our review of requests under 

§ 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 § 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 

§ 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 

(§ 1271.150(c)(1)).

We have, however, modified the 

criteria for granting an exemption or 

alternative in § 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 § 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 § 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 

§ 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 (§ 1271.160)

Proposed § 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 § 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 § 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 § 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 § 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 § 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

68626 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

§ 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 § 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 § 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 § 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 § 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 

§ 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 

§ 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 § 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 § 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 § 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 userdefined 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 (§ 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 § 1271.160(d) would 

not apply.

4. Organization and Personnel 

(§ 1271.170)

Proposed § 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 § 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 § 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 § 1271.170(b) 

with ‘‘training and documentation of 

competency.’’

(Response) We agree with the 

comment that ‘‘training’’ should be 

added to the requirements in 

§ 1271.170(b), and we have made this 

change; however, we disagree with the 

proposal to remove ‘‘education and 

experience.’’ As revised, § 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 § 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 

§ 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 (§ 1271.180)

Proposed § 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 § 1271.180 by 

dividing it into paragraphs for greater 

clarity and ease of reading. In addition, 

§ 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 

§ 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 

§ 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 § 1271.180(a).

(Comment 60) Proposed § 1271.180 

would require establishments to review

68628 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 (§§ 211.100 and 820.40) do 

not require an annual review of 

procedures. For this reason, we are 

deleting the proposed requirement in 

§ 1271.180 that all procedures be 

reviewed on an annual basis. However, 

we note that the periodic quality audit 

required under § 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 § 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 § 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 § 1271.270.

(Response) We have removed this 

requirement from the final regulation. 

However, although we do not require 

you to retain obsolete procedures, under 

§ 1271.270(d) you are required to retain 

records for 10 years unless otherwise 

stated.

6. Facilities (§ 1271.190)

Proposed § 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 § 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 § 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 § 1271.190, reflecting the 

suggested language. The first sentence of 

§ 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 § 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 § 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 

§ 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 § 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

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

§ 1271.190(c)(3) is contained in 

§ 1271.190(d)(1); and the requirement 

for record retention in proposed 

§ 1271.190(c)(4) is contained in 

§ 1271.190(d)(2).

(Comment 68) Another comment 

asked for clarification of the phrase 

‘‘significant cleaning and sanitation 

activities’’ in proposed § 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 

§ 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 (§ 1271.195)

Proposed § 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 § 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, § 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 § 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 

§ 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 

§ 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 

§ 1271.195(a)(5) has been moved to 

§ 1271.195(c).

8. Equipment (§ 1271.200)

Proposed § 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

68630 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 § 1271.200 should be 

limited to concerns of communicable 

disease transmission.

(Response) We agree with the 

comments that § 1271.200 should be 

limited to concerns of communicable 

disease transmission. Therefore, the first 

sentence of § 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 § 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 § 1271.200.

(Response) You may use vendor 

validation and maintenance records to 

demonstrate compliance with 

§ 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 § 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 

§ 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 § 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 § 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 

§ 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 § 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 crosscontamination 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 (§ 1271.210)

Proposed § 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 § 1271.210. The 

requirement for validation or 

verification of the production of inhouse 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 § 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 § 1271.210(a) no longer 

contains a requirement for procedures. 

However, § 1271.210(a) and (b) are core 

CGTP requirements listed in 

§ 1271.150(b); therefore, the requirement 

for establishing procedures under 

§ 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 

§ 1271.210 to apply more specifically to 

preventing the introduction, 

transmission, or spread of 

communicable diseases.

(Comment 82) Proposed § 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 (§ 1271.215)

This final rule includes a new section 

specific to the recovery of cells and 

tissues, § 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., 

§ 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 § 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 

(§ 1271.220)

Proposed § 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 § 1271.220 also 

contains requirements with respect to 

processing materials, pooling, and inprocess monitoring.

We have moved the provision on dura 

mater from proposed § 1271.230(c) to 

§ 1271.220(d); we address comments on 

the proposed provision with other 

comments on proposed § 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 § 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 § 1271.220(c). We 

have also removed references to 

specifications from § 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., § 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 

§ 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 crossVerDate jul<14>2003 16:32 Nov 23, 2004 Jkt 205001 PO 00000 Frm 00021 Fmt 4701 Sfmt 4700 E:\FR\FM\24NOR3.SGM 24NOR3
68632 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 § 1271.220(a) requested 

clarification of the term ‘‘manufacturing 

process.’’

(Response) We have re-examined our 

use of the phrase ‘‘manufacturing 

process’’ in § 1271.220(a) and have 

concluded that it is confusing. 

Processing is one of the steps in 

manufacture, as defined in § 1271.3(e). 

Because §§ 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 § 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 § 1271.220 and renumbered the 

paragraphs accordingly.

Pooling.

Proposed § 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 Rhnegative 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 crosscontamination; 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 § 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 immunosilent; 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 § 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 § 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 § 1271.155 in a request for an 

exemption or alternative to the 

prohibition on pooling in § 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 § 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 § 1271.220(b) under the 

provisions of § 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 § 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 § 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 

§ 1271.230(c) to § 1271.220(d) because it 

relates more closely to processing and 

process controls than to process 

validation.

(Comment 95) Three comments 

objected to proposed § 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 §§ 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,

68634 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

§ 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, 

§ 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 (§ 1271.225)

Proposed § 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 

§ 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 § 1271.150(b), an establishment 

need only comply with those 

requirements applicable to the 

operations in which it engages 

(§ 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 § 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 § 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 § 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 § 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 

§ 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 (§ 1271.230)

Where the results of a process cannot 

be fully verified by subsequent 

inspection and tests, proposed 

§ 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 § 1271.230. 

Paragraph (a) now refers to processing 

described in § 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 § 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 § 1271.230(e), now 

§ 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 § 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 

§ 1271.230 to take into account the 

uniqueness of various HCT/Ps. Thus, 

§ 1271.230(a) requires validation of a 

process where the results of processing 

described in § 1271.220 cannot be fully

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

§ 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 (§ 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 § 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 

§ 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 

§ 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 

§ 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 

§ 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 (§ 1271.250)

Proposed § 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 

§ 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 § 1271.55. We have 

modified § 1271.55 in the donoreligibility 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

68636 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 (§ 1271.260)

Proposed § 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 

§ 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 (§ 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 

§ 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 § 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 

(§ 1271.265)

Proposed § 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 § 1271.265. One comment 

indicated that the provisions are 

worthwhile, and another comment 

supported documenting the identity of 

the consignee.

We have reorganized § 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 

§ 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 § 1271.265 as 

suggested by the comment, we have 

made a related change, by adding a new 

provision on ‘‘pre-distribution 

shipment’’ (§ 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 

§ 1271.265(b) would require each 

incoming HCT/P to be inspected 

according to established procedures. 

Two comments on proposed 

§ 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 § 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 § 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 § 1271.265.

(Comment 111) One comment on 

proposed § 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 

§ 1271.265(c) are intended to apply to 

the establishment that first makes an 

HCT/P available for distribution 

(defined in § 1271.3(z)). This 

establishment, which may or may not be 

the actual distributor, needs to have 

procedures in place under § 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 §§ 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 § 1271.60, 

§ 1271.65, or § 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 

§ 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 

§ 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 

§ 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 § 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 § 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 

§ 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 (§ 1271.270)

Proposed § 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 

§ 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 § 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 § 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 

§ 1271.270 would relate to the donoreligibility requirements in subpart C of 

part 1271. In the donor-eligibility final 

rule (69 FR 29786 at 29831), we 

incorporated the contents of proposed 

§ 1271.270(c) into the records 

requirements in § 1271.55 and 

responded to these comments. We are 

now removing proposed paragraph (c) 

from § 1271.270.

(Comment 117) Proposed 

§ 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

68638 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 § 1271.270(e) has 

been renumbered § 1271.270(d).

(Comment 118) Three comments 

pointed out that the record retention 

requirement in proposed § 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 § 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 (§ 1271.290)

Proposed § 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 deidentified health information for any 

purpose and includes requirements for 

determining whether information is deidentified. (45 CFR 164.502(d), 

164.514(a)-(c)). Further, a covered entity 

may assign a code to otherwise deidentified 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 deidentified in accordance with 45 CFR 

164.514(a)-(c), including a distinct 

identification code that meets the 

requirements of 45 CFR 164.514(c).

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

§ 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 § 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 batchprocessed 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 § 1271.155. The requestor should 

show that the proposed alternative 

tracking method satisfies the purposes 

of the requirement in § 1271.290(e).

(Comment 128) Proposed 

§ 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

68640 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 § 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 

§ 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 

§ 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 § 1271.290.

Several comments questioned how 

proposed § 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 (§ 1271.320)

Proposed § 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 

§ 1271.3(ii) and have made several 

changes to that definition, now 

renumbered § 1271.3(aa), which are 

discussed at Comment 13.

We have revised § 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 § 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 § 1271.10

1. Applicability (§ 1271.330)

Proposed § 1271.330 explained that 

the regulations in subpart E would be 

applicable only to HCT/Ps described in 

§ 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68641

§ 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 

§ 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 (§ 1271.350)

Proposed § 1271.350(a) sets out 

requirements for reporting adverse 

reactions, and § 1271.350(b) deals with 

reports of product deviations (now 

called ‘‘HCT/P deviations’’).

(Comment 134) One comment on 

proposed § 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 

(§ 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 § 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 § 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 § 1271.3(y), and 

reporting would not be required under 

§ 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 § 1271.350(a). If, 

after you have made a required report, 

you discover additional information, 

you must report this information to the 

agency under § 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 

§ 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 

§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 

§ 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 lifethreatening, 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 § 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 

§ 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 

§ 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 § 1271.350(a). We have inserted 

this language into § 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

68642 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 § 1271.350.

HCT/P Deviation Reporting 

(§ 1271.350(b))

(Comment 142) One comment on 

proposed § 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 

§ 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 

§ 1271.350(b) and the biologic product 

deviations final rule, and suggested that 

reporting requirements be harmonized.

(Response) We have largely 

harmonized § 1271.350(b) with 

§ 600.14(b), as suggested by the 

comment. In addition, we have clarified 

in § 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 

§ 1271.160(b)(2).

3. Labeling (§ 1271.370)

Proposed § 1271.370 would have 

required clear and accurate labels for 

each HCT/P.

Proposed § 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 § 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 

§ 1271.290(c) that you label each HCT/

P with a distinct identification code, we 

have added to § 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 

§ 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 

§ 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 §§ 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 § 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 § 1271.370(b)(4), which lists, as 

information that must appear on the 

label, warnings required under 

§ 1271.60, § 1271,65, or § 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 

§ 1271.370 to strengthen the connection 

between the labeling requirements and 

the prevention of communicable 

disease. For example, § 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68643

spread of communicable disease. We 

have removed proposed paragraph (b); 

§ 1271.370 no longer covers claims.

(Comment 149) One comment on 

proposed § 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 § 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 § 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 § 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 

§ 1271.10.

(Comment 150) Two comments 

asserted that proposed § 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 

§ 1271.370. ‘‘Homologous use’’ is 

defined in § 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 

§ 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 § 1271.10

1. Applicability (§ 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 § 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 (§ 1271.400)

Proposed § 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 thirdparty 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 § 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 

§ 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 § 1271.400(a). For 

example, the inspection of an 

establishment that engages solely in 

processing would address processingrelated 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

68644 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 § 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 

§ 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 

§ 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 

§ 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 § 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 

§ 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 

§ 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 

§ 1271.400(d) that FDA also may take 

samples.

4. Imports (§ 1271.420)

When an HCT/P is offered for entry, 

proposed § 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 

§ 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 § 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 § 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 (§ 1271.15(a)); 

moreover, § 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 

§ 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 

§ 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 

§ 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 § 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 

§ 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 (§ 1271.440)

Proposed § 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

68646 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

§ 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 

(§ 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). 

(§ 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 § 1271.440(e).) 

As a technical amendment, we are 

revising § 16.1(b)(2) by adding 

§ 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 (§ 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 §§ 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 § 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 § 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 

§ 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 

§ 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 

§ 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 

§ 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 § 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

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

§ 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 

§ 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 § 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

68648 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 bankrelated 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

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

68650 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

§ 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 § 1271.3(d) that are 

regulated solely under the authority of 

section 361 of the PHS Act (as described 

in § 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 §§ 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 

§ 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 § 1270.3(j) and 

recovered before May 25, 2005. We have 

amended § 1270.3(j) to implement this 

provision. Products that meet the 

definition of HCT/P in § 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 § 1271.350(a), as 

well as reports of HCT/P deviations 

required in § 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

Type of HCT/P Number of Establishments1 Number of Donors Number of Products 

Produced Annually 

Eye Tissue2 134 47,796 94,186

Conventional Tissue3 166 20,000 750,000

Hematopoietic Stem/Progenitor Cells4 425 5,700 6,031

Reproductive Tissue5 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. 2EBAA, 1999.

3AATB, 1999.

4AABB/FACT, 1999.

5The 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 * * * allograftassociated 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.

68652 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 INFORMATION1

Type of HCT/P 

Number of

Transplants

Number of

Infections

Number of

Graft Failures

Additional Surgeries

Required

Ocular (Eye)2 33,035 9 37 37

Musculoskeletal4 NDF3 52 NDF 4

Heart Valve Allografts5 4,000 26 41 41

Hematopoeitic Stem/Progenitor Cells; Peripheral 

Blood6

18,123 (in 1997) NDF NDF NDF

Hematopoeitic Stem/Progenitor Cells; Cord Blood7 2000 (from 1988 to 

2002, inclusive)

NDF NDF NDF

1Annual data except as noted otherwise.

2EBAA, 2001 Statistical Report.

3 NDF: Denotes No Data Found or Available.

4AATB, 2001.

5FDA, CDRH, Office of Surveillance and Biometrics, 2001.

6Transfusion, 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

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

68654 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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

Affected Industry 

Relevant Voluntary

Industry Standards

Percentage of Firms Following

Voluntary Industry Standards

Eye Tissue: 134 FDA Registered Establishments EBAA 100 %

Conventional Tissue: (e.g., pericardium, dura mater, heart valves, skin 

allograft, bone allograft, fascia, tendons, ligaments, other viable) 

166 FDA Registered Establishments

AATB 75 to 80%

Stem/Progenitor Cells: 

Peripheral Blood (PB): 400 establishments

Cord Blood (CB): 25 establishments

AABB or FACT 

AABB or FACT

85 % of accredited PB establishments 

100 % of all CB establishments

Reproductive Tissue: 

Semen Banks: 110 establishments

AATB; CAP accreditation;State Licensed (e.g., NY, CA); and/or 

CLIA-certified

20 largest establishments (accounting for 95% of total production)

Reproductive Tissue: 

ART Establishments: 400 establishments

CAP accreditation; State Licensed 

(e.g., NY, CA); ASRM guidelines

80 %

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).

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68655

TABLE 4.—ESTIMATED COST PER ESTABLISHMENT AND ESTIMATED PERCENTAGE OF ESTABLISHMENTS AFFECTED BY THE

CGTP FINAL RULE1

21 CFR

Section Title 

Eye Tissue

Establishments

Conventional Tissue

Sm./Lrg.

Stem/Progenitor 

Cell

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 Deficiencies ....................................... $511 (95%) $511/$1,278 (23%) $511 (80%)

-Establishment with Major Deficiencies ....................................... $2,498 (5%) $2,498/$4,832 (5%) $2,498 (5%)

-Cost for Additional Quality Control Work .................................... $1,344 (95%) $1,344 (23%) $1,344 (80%)

(b)(2) Procedures for Sharing Information ............................................. $380 (95%) $760/$2,172 (23%) $760 (80%)

(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 Software ........................................... $2,160 (10%) $2,160 (10%) $2,160 (10%)

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 Requirements ............................................... $9,120 (5%) $9,120 (23%) $9,120 (95%)

1271.190 Establishments: ................................................................................

(d)(1) Cleaning and Sanitation Procedures ........................................... $348 (5%) $348/$532 (23%) $348 (95%)

(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—Cleaning, Sanitizing and Maintenance — $1,460/$2,979 (23%) $1,460 (95%)

(c) Calibration .................................................................................... — $1,460/$2,979 (23%) $1,460 (95%)

(d) Inspections ................................................................................... $216 (95%) $432/$684 (23%) $216 (95%)

(e) Records ........................................................................................

-of Cleaning, Sanitizing and Calibration Activities .................... $174 (95%) $348/$696 (23%) $174 (95%)

-of the Use of Each Piece of Equipment .................................. $696 (95%) $1,392/$2,784 (23%) $1,392 (95%)

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, Verification, and Lot .................................... $174 (95%) $174/$348 (23%) $174 (95%)

1271.220 Process Controls: .............................................................................

In-Process Monitoring Procedures ............................................... $380 (95%) $380/$1,086 (23%) $760 (95%)

1271.225 Process Changes: ............................................................................

Validation of Process Changes .................................................... $760 (95%) $760/$2,172 (23%) $760 (95%)

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 Process Changes ............................... $850 (95%) $1,700 (95%) $1,140 (95%)

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 Documentation ............................................. $864 (5%) $1,728/$3,456 (5%) $3,456 (5%)

(a) Procedures—Receiving Activities ................................................ — $380/$1,086 (23%) $760 (95%)

(c) Procedures—Availability for Distribution ...................................... — $380/$1,086 (23%) $760 (95%)

(d) Packaging and Shipping .............................................................. $1,392 (95%) $1,392 (95%) $576 (95%)

(f) Procedures—Return to Inventory ................................................. — $348/$532 (23%) $348 (95%)

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%)

68656 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

1A 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 4.—ESTIMATED COST PER ESTABLISHMENT AND ESTIMATED PERCENTAGE OF ESTABLISHMENTS AFFECTED BY THE

CGTP FINAL RULE1—Continued

21 CFR

Section Title 

Eye Tissue

Establishments

Conventional Tissue

Sm./Lrg.

Stem/Progenitor 

Cell

Establishments

(d) Length of Retention ...................................................................... $18 (5%) $18 (23%) $18 (95%)

1271.290 Tracking: ..........................................................................................

(b)(c) System of Product Tracking: General Requirements .................. $760 (5%) $380/$1,086 (23%) $380 (95%)

(d)(e) System of Product Tracking: Specific Requirements .................. $1,728 (5%) $3,456/$6,912 (23%) $3,456 (95%)

(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 Complaints ......................................... $608 (95%) $608/$1,216 (23%) $608 (95%)

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.— ——

1Only 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

TABLE 5.—ESTIMATED LEVEL OF EFFORT AND COST PER PROCEDURE REVISED OR PREPARED TO COMPLY WITH THE

CGTP FINAL RULE

Category: 

Minor Procedures Major Procedures 

Revise

Existing Prepare New 

Revise

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

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

68658 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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

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

68660 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 inprocess 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.

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

68662 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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

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

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

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 & Monitoring $0 $28,550 $28,850 $28,850

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 Controls $48,374 $0 $6,887 $5,671

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

68664 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

TABLE 7.—AGGREGATE COMPLIANCE COSTS FOR EYE BANKS—Continued

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

1271.260 Storage $0 $0 $0 $0

1271.265 Receipt, Predistribution Shipment & Distribution $0 $182,990 $182,990 $182,990

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, Destruction and Cessation of Manufacturing$0 $0 $0 $0

Total All Sections $1,247,044 $1,442,108 $1,619,659 $1,588,300

1Over 10 years at 7 percent interest.

2Over 10 years at 3 percent interest.

TABLE 8.—AGGREGATE COMPLIANCE COSTS FOR CONVENTIONAL TISSUE ESTABLISHMENTS

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

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 & Monitoring $14,838 $8,124 $10,237 $9,863

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 Controls $20,516 $0 $2,921 $2,405

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 Shipment & Distribution $55,871 $237,058 $245,012 $243,607

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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68665

TABLE 8.—AGGREGATE COMPLIANCE COSTS FOR CONVENTIONAL TISSUE ESTABLISHMENTS—Continued

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

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, Destruction and Cessation of Manufacturing$0 $0 $0 $0

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

Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costsa

Total 

Annualized 

Costsb

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 & Monitoring $90,784 $205,458 $218,383 $216,100

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 Controls $198,550 $0 $28,269 $23,276

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 Shipment & Distribution $482,861 $28,080 $96,829 $84,686

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, Destruction and Cessation of Manufacturing$0 $0 $0 $0

Total All Sections $3,801,230 $3,501,595 $4,042,805 $3,947,215

1Over 10 years at 7 percent interest.

2Over 10 years at 3 percent interest.

68666 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

TABLE 10.—AGGREGATE COMPLIANCE COSTS FOR ART ESTABLISHMENTS

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

1271.400 Inspections $0 $307,200 $307,200 $307,200

Total All Sections $0 $307,200 $307,200 $307,200

1Over 10 years at 7 percent interest.

2Over 10 years at 3 percent interest.

TABLE 11.—AGGREGATE COMPLIANCE COSTS FOR SEMEN BANKS

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

1271.400 Inspections $0 $84,480 $84,480 $84,480

Total All Sections $0 $84,480 $84,480 $84,480

1Over 10 years at 7 percent interest.

2Over 10 years at 3 percent interest.

TABLE 12.—AGGREGATE COMPLIANCE COSTS FOR ALL HCT/P INDUSTRY SECTORS

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

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 & Monitoring $105,622 $242,432 $257,470 $254,814

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 Controls $267,440 $0 $38,077 $31,352

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 Shipment & Distribution $538,732 $448,128 $524,831 $511,284

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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 68667

TABLE 12.—AGGREGATE COMPLIANCE COSTS FOR ALL HCT/P INDUSTRY SECTORS—Continued

21 CFR Section Title One-Time 

Costs Annual Costs 

Total 

Annualized 

Costs1

Total 

Annualized 

Costs2

1271.440 Orders of Retention, Recall, Destruction and Cessation of Manufacturing$0 $0 $0 $0

Total All Sections $6,907,784 $7,127,872 $8,111,384 $7,937,674

1Over 10 years at 7 percent interest.

2Over 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

68668 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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

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

68670 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 AATBaffiliated 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 falsenegative 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 postoperative 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 inhospital 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 therapyinduced 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

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

HCT/P Industry Sector HCT/P-Related Problem Avoided Treatment Outcome Estimated Cost of 

Treatment 

Cost-Effective 

Percent Reduction 

in Cost/Risk 

Eye Tissue Primary Corneal Graft Failure Repeat Surgery $.729 to $6.5 million 

$15,844 per case

25%

Conventional Tissue Bone Allograft Infection/Graft 

Failure

Repeat Surgery/Amputation $62 million 

$24,587 per case

3.2%

68672 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

TABLE 13.—SUMMARY OF CGTP BENEFITS—Continued

HCT/P Industry Sector HCT/P-Related Problem Avoided Treatment Outcome Estimated Cost of 

Treatment 

Cost-Effective 

Percent Reduction 

in Cost/Risk 

Conventional Tissue Heart Valve Fungal EndocarditisRepeat Surgery (Death) $1.2 to $1.5 million 

$87,204 per case

3.3%

Hematopoietic Stem/Progenitor 

Cells

PBSC Transplant Infection Hospitalization (Death) $1.4 million 

$24,053 per case

26 deaths

Unable to 

Determine

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

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

68674 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

TABLE 14.—SUMMARY OF SMALL BUSINESS IMPACTS

No. of Small Establishments by

Industry Sector

Average Annual 

Revenue per 

Small

Establishment (in 

millions)

Average 

Annualized Cost 

per Small

Establishment

Average 

Annualized Cost 

as a Percentage 

of Average

Revenue

Worst-Case Costs 

for an affected 

Small

Establishment

Worst-Case Costs 

as a Percentage 

of Average

Revenue

Eye Banks (134 Establishments) $1.45 $12,087 0.83% $39,750 2.7%

Conventional Tissue (129 Establishments) $1.45 $11,678 0.8% $66,621 4.6%

Stem/Progenitor Cell Establishments 

Following Industry Standards (200 

Establishments) $1.45 $8,367 0.6% $21,602 1.5%

Stem/Progenitor Cell Establishments 

Not Following Industry Standards 

(50 Establishments) $1.45 $43,207 3% $83,483 5.8%

ART Establishments (260 Establishments) $2.1 $768 0.04% $768 0.04%

Ob/Gyn and small physician based 

practices $0.692 $768 0.11 $768 0.11

Semen Banks (19 Establishments) $2.4 $768 0.03% $768 0.03%

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 § 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 

§ 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.

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

§ 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 

§ 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 

§ 1271.230(e) requiring validation of all 

process changes and process deviations 

now require validation only of process 

changes. Requirements proposed under 

§ 1271.265(e) for HCT/P packaging 

validation now allow for packaging 

validation or verification (a less 

burdensome alternative) as appropriate.

Provisions proposed under 

§ 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 

§ 1271.350(b) now only applies to 

distributed HCT/Ps and not to those still 

in inventory. Finally, language has been 

added to § 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

68676 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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, § 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 § 1271.10 

are required under § 1271.350(a)(1) and 

(b)(1) to report to FDA adverse reactions 

(defined in § 1271.3(y)) and HCT/P 

deviations (defined in § 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 

§§ 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) § 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) § 1271.180(a) (to 

meet core CGTP requirements for all 

steps performed in the manufacture of 

HCT/Ps); (3) § 1271.190(d)(1) (facility 

cleaning and sanitization); (4) 

§ 1271.200(b) (cleaning, sanitizing, and 

maintenance of equipment); (5) 

§ 1271.200(c) (calibration of equipment); 

(6) § 1271.230(a) (verification or 

validation of changes to a process); (7) 

§ 1271.250(a) (controls for labeling HCT/

Ps); (8) § 1271.265(e) (receipt, predistribution shipment, availability for 

distribution, and packaging and 

shipping of HCT/Ps); (9) § 1271.265(f) 

(suitable for return to inventory); (10) 

§ 1271.270(b) (records management 

system); (11) § 1271.290(b)(1) (system of 

HCT/P tracking); and, (12) § 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

Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 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 BURDEN1

21 CFR Section 

No. of

Respondents

Annual Frequency

per Response

Total Annual

Responses

Hours per

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 (c) 93 52.2 4,855 0.25 1,214

Total 12,071

1There are no capital costs or operating and maintenance costs associated with this collection of information.

TABLE 16.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1

21 CFR Section 

No. of

Recordkeepers

Annual

Frequency per 

Recordkeeping

Total Annual

Records

Hours per

Record Total Hours 

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 SOPs for compliance) 699 12 8,388 8 67,104

134 9 1,206 8 9,648

SOP Maintenance (See previous list of 12 SOPs) 792 12 9,504 2 19,008

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

68678 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

TABLE 16.—ESTIMATED ANNUAL RECORDKEEPING BURDEN1—Continued

21 CFR Section 

No. of

Recordkeepers

Annual

Frequency per 

Recordkeeping

Total Annual

Records

Hours per

Record Total Hours 

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

1There 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 nonreproductive 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 

§ 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

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

68680 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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.

■ 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:

■ 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.

■ 2. Section 16.1 is amended in 

paragraph (b)(2) by numerically adding 

an entry for § 1271.440(e) to read as 

follows:

§ 16.1 Scope.

* * * * *

(b) * * *

(2) * * *

§ 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

■ 3. The authority citation for 21 CFR 

part 1270 continues to read as follows:

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

■ 4. Section 1270.3 is amended by 

revising paragraph (j) introductory text 

to read as follows:

§ 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

■ 5. The authority citation for 21 CFR 

part 1271 continues to read as follows:

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

271.

■ 6. Section 1271.3 is amended by 

revising paragraphs (c) and (d) and by 

adding paragraphs (y) through (ll) to read 

as follows:

§ 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 § 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

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

■ 7. Section 1271.10 is amended by 

revising paragraph (a)(3) to read as 

follows:

§ 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

* * * * *

■ 8. Section 1271.22 is revised to read as 

follows:

§ 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.

■ 9. Section 1271.45 is amended in 

paragraph (a), after the second sentence, 

by adding a sentence to read as follows:

§ 1271.45 What requirements does this 

subpart contain?

(a) * * * Other CGTP requirements 

are set out in subpart D of this part.

* * * * *

■ 10. Part 1271 is amended by adding 

subpart D, consisting of §§ 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

§ 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.

§ 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 § 1271.190(a) and (b);

(2) Requirements relating to 

environmental control in § 1271.195(a);

(3) Requirements relating to 

equipment in § 1271.200(a);

(4) Requirements relating to supplies 

and reagents in § 1271.210(a) and (b);

(5) Requirements relating to recovery 

in § 1271.215;

(6) Requirements relating to 

processing and process controls in 

§ 1271.220;

(7) Requirements relating to labeling 

controls in § 1271.250(a) and (b);

(8) Requirements relating to storage in 

§ 1271.260 (a) through (d);

(9) Requirements relating to receipt, 

predistribution shipment, and 

distribution of an HCT/P in 

§ 1271.265(a) through (d); and

(10) Requirements relating to donor 

eligibility determinations, donor 

screening, and donor testing in 

§§ 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

68682 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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 

§§ 1271.150(c) and 1271.155 of this 

subpart, the regulations in this subpart 

are not being implemented for 

reproductive HCT/Ps described in 

§ 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.

§ 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.

§ 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 

§ 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 

§ 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

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

§ 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.

§ 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.

§ 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, crosscontamination, 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.

§ 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

68684 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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.

§ 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.

§ 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.

§ 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.

§ 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 inprocess 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.

§ 1271.225 Process changes.

Any change to a process must be 

verified or validated in accordance with 

§ 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.

§ 1271.230 Process validation.

(a) General. Where the results of 

processing described in § 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.

§ 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 §§ 1271.55, 1271.60, 1271.65,

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

§ 1271.55.

§ 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.

§ 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 preestablished 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 §§ 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.

§ 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 § 1271.400.

§ 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

68686 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

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.

§ 1271.320 Complaint file.

(a) Procedures. You must establish 

and maintain procedures for the review, 

evaluation, and documentation of 

complaints as defined in §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 

§ 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 

§ 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.

■ 11. Part 1271 is amended by adding 

subpart E, consisting of §§ 1271.330 

through 1271.370, to read as follows:

Subpart E—Additional Requirements for 

Establishments Described in § 1271.10

Sec.

1271.330 Applicability.

1271.350 Reporting.

1271.370 Labeling.

Subpart E—Additional Requirements 

for Establishments Described in 

§ 1271.10

§ 1271.330 Applicability.

The provisions set forth in this 

subpart are being implemented for 

nonreproductive HCT/Ps described in 

§ 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.

§ 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

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

§ 1271.370 Labeling.

The following requirements apply in 

addition to §§ 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 § 1271.290(c);

(2) Description of the type of HCT/P;

(3) Expiration date, if any; and

(4) Warnings required under 

§§ 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.

■ 12. Part 1271 is amended by adding 

subpart F, consisting of §§ 1271.390 

through 1271.440, to read as follows:

Subpart F—Inspection and Enforcement of 

Establishments Described in § 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 § 1271.10

§ 1271.390 Applicability.

The provisions set forth in this 

subpart are applicable only to HCT/Ps 

described in § 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.

§ 1271.400 Inspections.

(a) If you are an establishment that 

manufactures HCT/Ps described in 

§ 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.

§ 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.

68688 Federal Register / Vol. 69, No. 226 / Wednesday, November 24, 2004 / Rules and Regulations 

§ 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 

§§ 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