1508 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 1271

[Docket No. 97N–484P]

Current Good Tissue Practice for

Manufacturers of Human Cellular and

Tissue-Based Products; Inspection

and Enforcement

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing new

regulations to require manufacturers to

follow current good tissue practice,

which includes methods used in, and

the facilities and controls used for, the

manufacture of human cellular and

tissue-based products; recordkeeping;

and the establishment of a quality

program. The agency is also proposing

new regulations pertaining to labeling,

reporting, inspections, and enforcement

that will apply to manufacturers of

those human cellular and tissue-based

products that the agency is proposing to

regulate solely under the authority of

the Public Health Service Act (PHS Act)

and not as biological drugs or as

devices. The agency’s actions are

intended to improve protection of the

public health while permitting

significant innovation and keeping

regulatory burden to a minimum.

DATES: Submit written comments on the

proposed rule by May 8, 2001. Submit

written comments on the information

collection provisions by February 7,

2001.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852. Submit

written comments on the information

collection provisions to the Office of

Information and Regulatory Affairs,

OMB, New Executive Office Bldg., 725

17th St. NW., Washington, DC 20503,

Attn: Wendy Taylor, Desk Officer for

FDA.

FOR FURTHER INFORMATION CONTACT:

Paula S. McKeever, Center for Biologics

Evaluation and Research (HFM–17),

Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852–1448, 301–827–6210.

SUPPLEMENTARY INFORMATION:

I. Introduction

FDA is in the process of establishing

a comprehensive new system for

regulating human cellular and tissuebased products. In an earlier related

rulemaking, the agency proposed to

define a human cellular or tissue-based

product as a ‘‘product containing or

consisting of human cells or tissues that

is intended for implantation,

transplantation, infusion, or transfer

into a human recipient * * *’’

(‘‘Suitability Determination for Donors

of Human Cellular and Tissue-based

Products,’’ proposed rule (64 FR 52696,

September 30, 1999), hereinafter

‘‘donor-suitability proposed rule’’).

‘‘Transfer’’ is a term used with respect

to reproductive cells and tissues, and

has also been defined in another related

proposal (‘‘Establishment Registration

and Listing for Manufacturers of Human

Cellular and Tissue-based Products,’’

proposed rule (63 FR 26744 at 26754,

May 14, 1998), hereinafter ‘‘registration

proposed rule’’).

Examples of human cellular and

tissue-based products include cadaveric

ligaments, skin, bone, dura mater, heart

valves, corneas, blood hematopoietic

stem cells, manipulated autologous

chondrocytes, and spermatozoa. Certain

exclusions from the definition of human

cellular and tissue-based products may

be applicable and have been discussed

in earlier rulemakings (registration

proposed rule, 63 FR 26744 at 26748;

donor-suitability proposed rule, 64 FR

52696 at 52700).

The regulations now being proposed

would require all human cellular and

tissue-based products to be

manufactured in compliance with

current good tissue practice (CGTP). The

proposal also contains provisions

relating to establishment inspection and

enforcement, as well as certain labeling

and reporting requirements, which

would be applicable to those human

cellular and tissue-based products that

the agency is proposing to regulate

solely under the authority of section 361

of the PHS Act and not as biological

drugs or devices.

The agency also requests consultation

from the States on any preemption

issues raised by the proposed CGTP

rule, specifically with regard to: (1) the

need for CGTP requirements to prevent

communicable disease transmission

through human cellular and tissuebased products; (2) alternatives that

would limit the scope of such national

requirements or otherwise preserve

State prerogatives and authority; and (3)

any other issues raised by this proposed

rule that could affect State laws and

authorities.

A. Background

In February 1997, FDA proposed a

new, comprehensive approach to the

regulation of human cellular and tissuebased products. The agency announced

its regulatory plans in two documents:

‘‘Reinventing the Regulation of Human

Tissue’’ and ‘‘A Proposed Approach to

the Regulation of Cellular and Tissuebased Products’’ (hereinafter ‘‘proposed

approach document’’). FDA requested

written comments on its proposed

approach and, on March 17, 1997, held

a public meeting to solicit information

and views from the interested public (62

FR 9721, March 4, 1997).

Since that time, the agency has

published two proposed rules that

would implement aspects of the

proposed approach. On May 14, 1998,

the agency proposed regulations that

would create a new, unified system for

registering establishments that

manufacture human cellular and tissuebased products and for listing their

products (registration proposed rule at

63 FR 26744). On September 30, 1999,

FDA proposed regulations that would

require most cell and tissue donors to be

tested and screened for relevant

communicable diseases (donorsuitability proposed rule at 64 FR 52696

at 52719).

With the present rulemaking, the

agency is completing the set of

proposals that would implement the

new regulatory scheme. In the proposed

approach document, the agency stated

that it would require that cells and

tissues be handled according to

procedures designed to prevent

contamination and to preserve tissue

function and integrity. Thus, the agency

is now proposing to require that

establishments that manufacture human

cellular or tissue-based products comply

with CGTP, which would include,

among other things, proper handling,

processing, labeling, and recordkeeping

procedures. In addition, the proposed

regulations would require each

establishment to maintain a ‘‘quality

program’’ to ensure compliance with

CGTP.

The proposed CGTP regulations

would be contained in title 21 CFR in

new part 1271, along with provisions

relating to establishment registration

and donor suitability that have been

proposed previously. Subpart A of part

1271 would set forth scope and purpose

as well as definitions. Subpart B of part

1271 would contain registration

procedures. Subpart C of part 1271

would set forth provisions for the

screening and testing of donors in order

to determine their suitability. Subpart D

of part 1271 would contain the

provisions on CGTP now being

proposed. Subpart E of part 1271 would

contain certain labeling and reporting

requirements and subpart F of part 1271

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1509

would contain the inspection and

enforcement provisions applicable to

those human cellular and tissue-based

products regulated solely under the

authority of section 361 of the PHS Act.

The agency proposes to revoke part

1270 (21 CFR part 1270), which will be

superseded by new part 1271.

B. The Tiered, Risk-Based Regulatory

Approach

The proposed approach document set

out a tiered regulatory scheme, under

which human cellular and tissue-based

products would be subject to an

appropriate level of regulation based on

the degree of risk and the necessity for

FDA review. Certain human cellular and

tissue-based products (e.g., tissues that

are more than minimally manipulated)

would be regulated as biological drugs

or medical devices under the Federal

Food, Drug, and Cosmetic Act (the act)

and/or section 351 of the PHS Act (42

U.S.C. 262), and thus would be subject

to premarket review procedures, among

other requirements. FDA is proposing to

regulate other human cellular and

tissue-based products solely under the

authority of section 361 of the PHS Act

(42 U.S.C. 264), which authorizes the

agency to issue regulations to prevent

the introduction, transmission, or

spread of communicable diseases.

(These products are referred to in this

document as ‘‘361 products.’’)

The proposed tissue regulations

would apply to a wide range of human

cells and tissues. To simplify

terminology, the proposed regulations

refer generally to all human cells and

tissues, including reproductive tissue,

as ‘‘products,’’ and refer to persons who

recover, screen, test, process, store,

label, package, or distribute human

cellular and tissue-based products as

‘‘manufacturers.’’ The term ‘‘product’’ is

a term of art coined under Section 351

of the PHS Act, i.e., ‘‘biological

product,’’ while the term

‘‘manufacturer’’ is used in FDA’s

current regulations that affect biological

products, drugs, and devices. However,

Section 361 of the PHS Act, which gives

FDA the authority to make and enforce

regulations to prevent the spread of

communicable disease, does not require

use of the term ‘‘product’’ to define its

scope. The agency has received

comments to the first two proposed

rules to implement the proposed

approach objecting to the use of the

terms ‘‘product’’ and ‘‘manufacturer’’ as

applied to human cells and tissues. In

finalizing these rules, the agency will

consider whether alternative

terminology to describe the scope of the

regulations should be used.

FDA anticipates that determining the

regulatory process for certain cellular

and tissue-based products may be

complicated. To help answer questions

about how a particular cellular or tissuebased product will be regulated, the

agency developed the Tissue Reference

Group (TRG). The TRG is composed of:

(1) Three representatives from the

Center for Biologics Evaluation and

Research (CBER); (2) three

representatives from the Center for

Devices and Radiological Health

(CDRH); (3) the product jurisdictional

officer from each Center; and (4) a

liaison from the agency’s Office of the

Chief Mediator and Ombudsman

(OCMO), a nonvoting member. Other

FDA staff attend the TRG meetings as

needed to discuss issues related to

products in their area of expertise. The

TRG provides a single reference point

and makes recommendations to the

center directors regarding product

jurisdiction of specific tissue.

In addition, FDA recognizes that

further public discussion of how the

proposed tissue regulations would be

applied to certain categories of human

cells and tissues may be warranted due

to the complexity or sensitivity of the

issues. For example, the agency held a

public meeting to discuss how proposed

definitions for ‘‘minimally

manipulated’’ and ‘‘homologous use’’

should be applied to human bone

allograft products on August 2, 2000.

FDA intends to provide further

opportunities for public discussion of

how the regulatory approach should be

applied to reproductive cells and tissue.

FDA anticipates that there may be

additional needs for discussion through

public meetings, public hearings, or

guidance as the agency implements the

new regulations. The regulatory

categories applicable to human cellular

and tissue-based products are discussed

in greater detail in the registration and

donor-suitability proposed rules (63 FR

26744 at 26746; 64 FR 52696 at 52698).

Under the regulatory scheme being

proposed at part 1271, all human

cellular and tissue-based products,

regardless of the regulatory category in

which they belong, would be subject to

certain core requirements designed to

address concerns common to all such

products. (These core requirements will

cover registration procedures, donor

testing and screening, and CGTP, and

will be in subparts B, C, and D of part

1271.) Because of their nature as

derivatives of the human body, all

human cellular and tissue-based

products pose a potential risk of

transmitting communicable diseases.

Thus, the donor-suitability proposed

rule would require that most cell and

tissue donors be tested and screened for

evidence of relevant communicabledisease infection. Similarly, the CGTP

regulations now being proposed are

designed to prevent the introduction,

transmission, and spread of

communicable diseases. For example,

compliance with CGTP would require

such precautions as cleaning of facilities

and equipment, storage procedures

designed to prevent product mix-ups,

and controls over processing to prevent

product contamination and impairment

to function or integrity.

Those human cellular or tissue-based

products regulated solely under the

authority of section 361 of the PHS Act

would be subject only to the

requirements contained in part 1271. In

contrast, human cellular or tissue-based

products regulated as devices or

biological drugs would be subject not

only to the core requirements contained

in subparts B, C, and D of part 1271, but

also to other applicable statutory and

regulatory requirements.

C. Legal Authority

FDA is proposing to issue these new

regulations under the authority of

section 361 of the PHS Act. Under

section 361 of the PHS Act, FDA may

make and enforce regulations necessary

to prevent the introduction,

transmission, or spread of

communicable diseases between the

States or from foreign countries into the

States. (See sec. 1, Reorg. Plan No. 3 of

1966 at 42 U.S.C. 202 for delegation of

section 361of the PHS Act authority

from the Surgeon General to the

Secretary, Health and Human Services;

see 21 CFR 5.10(a)(4) for delegation

from the Secretary to FDA.) Intrastate

transactions may also be regulated

under section 361 of the PHS Act. (See

Louisiana v. Mathews, 427 F. Supp. 174,

176 (E.D. La. 1977).)

Certain diseases, such as those caused

by the human immunodeficiency virus

(HIV) and the hepatitis B and C viruses,

may be transmitted through the

implantation, transplantation, infusion,

or transfer of human cellular or tissuebased products derived from infected

donors. The agency has, in an earlier

rulemaking, proposed that most cell and

tissue donors be screened and tested for

these and other relevant communicable

diseases (donor-suitability proposed

rule, 64 FR 52696 at 52720). However,

donor screening and testing, although

crucial, are not sufficient to prevent the

transmission of disease by human

cellular and tissue-based products.

Rather, each step in the manufacturing

process needs to be controlled. Errors in

labeling, mix-ups of testing records,

failure to adequately clean work areas,

1510 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

and faulty packaging are all examples of

improper practices that could lead to a

product capable of transmitting disease

to its recipient. Similarly, as noted in

the proposed approach document,

improper handling of a human cellular

or tissue-based product can lead to

bacterial contamination of the product

or to cross-contamination between

products.

In addition to the direct transmission

of communicable disease agents by

human cellular and tissue-based

products to their recipients, the agency

is also concerned about the spread of

communicable disease through the use

of products whose function or integrity

have been impaired. When a product

does not work in a patient because it has

not been manufactured properly, the

risk of introducing, transmitting, or

spreading a communicable disease is

increased each time a procedure is

repeated for at least two reasons: (1)

Despite the best controls, there is a risk,

albeit smaller than without controls, of

communicable disease transmission,

and (2) a procedure for transfer or

transplant can carry an independent risk

of communicable disease transmission.

For example, use of a product whose

function or integrity may have been

compromised could create a

circumstance that increases a patient’s

need for an additional transfer or

transplant attempt. A repeat surgical

procedure necessitated by the damaged

product would further expose the

patient to the additional communicable

disease risks inherent in any such

procedure. Moreover, a patient in a

weakened state from the first

unsuccessful procedure is at greater risk

of contracting a communicable disease

by experiencing a repeat procedure.

Therefore, the agency considers that

requirements aimed at maintaining

product function and integrity are

necessary, and thus may be issued

under section 361 of the PHS Act.

The proposed CGTP regulations

would govern the methods used in, and

the facilities and controls used for, the

manufacture of human cellular and

tissue-based products. CGTP

requirements are a fundamental

component of FDA’s risk-based

approach to regulating human cellular

and tissue-based products. Products that

the agency is proposing to regulate

solely under section 361 of the PHS Act

and proposed part 1271, would be

subject to less rigorous agency oversight

than products also regulated under the

act and/or section 351 of the PHS Act.

By requiring that 361 products be

manufactured in compliance with

CGTP, in combination with the other

proposed requirements in part 1271, the

agency can be assured that 361 products

are subject to sufficient regulatory

controls to protect the public health.

FDA is proposing that the CGTP

regulations would supplement, but not

supersede, the current good

manufacturing practice (CGMP) and

quality system (QS) regulations

applicable to drugs and devices in parts

210, 211, and 820 (21 CFR parts 210,

211, and 820). Under the proposed rule,

human cellular and tissue-based

products regulated as biological drugs

under the act and section 351 of the

PHS Act, or as devices under the act,

would have to be manufactured in

accordance with CGTP, in addition to

existing requirements. Thus, in keeping

with the plan outlined in the proposed

approach document, those products

regulated as biological drugs or devices

would be subject to more

comprehensive regulation of

manufacturing than the 361 products.

In the donor-suitability proposed rule,

the agency proposed to amend the

existing CGMP regulations for drugs and

the QS requirements for devices to

incorporate the testing and screening

provisions of proposed part 1271,

subpart C. At that time, in order to

obviate the need for further revisions,

the agency also proposed to amend

those sections to incorporate the current

good tissue practice procedures of

proposed part 1271 subpart D. In

amending the CGMP and QS

regulations, FDA is relying both on the

authority provided by section 361 of the

PHS Act to make regulations to prevent

the spread of communicable disease,

and on its authority under the act to

issue CGMP regulations (section

301(a)(2)(B) and (h) of the act) (21 U.S.C.

351(a)(2)(B) and (h)), section 520(f)(1) of

the act (360j(f)(1)); section 701 of the act

(21 U.S.C. 371)).

Under proposed 21 CFR 210.1(c), the

manufacturer of a human cellular or

tissue-based product regulated as a drug

or biological drug would be required to

comply with the CGTP procedures in

part 1271, subpart D (donor suitability

proposed rule, (64 FR 52696 at 52699

and 52719)). Likewise, under proposed

21 CFR 820.1, the manufacturer of a

human cellular or tissue-based product

regulated as a device would be required

to comply with the same procedures

(donor suitability proposed rule (64 FR

52696 at 52699 and 52719)). If the

manufacturer failed to follow the CGMP

requirements, including the good tissue

practice procedures in part 1271, the

product would be adulterated under

section 501(a)(2)(B) of the act.

FDA is also relying on its authority

under section 361 of the PHS Act to

propose several reporting, labeling,

inspection, and enforcement provisions.

Because products regulated under the

act and/or section 351 of the PHS Act,

are subject to similar regulation

requirements, these provisions would

apply only to 361 products. Proposed

subpart E of part 1271 contains

regulations on reporting and labeling

pertaining to 361 products and is

discussed in section III of this

document. Proposed subpart F of part

1271 contains inspection and

enforcement provisions also applicable

only to 361 products; the relevant

discussion appears in section IV of this

document.

II. Summary of the Proposed CGTP

Regulations

The regulations being proposed

would require manufacturers of human

cellular and tissue-based products to

follow CGTP, which includes proper

handling, processing, storage, and

labeling of human cellular and tissuebased products, recordkeeping, and the

establishment of a quality program. The

proposed CGTP regulations are designed

to address issues common to all human

cellular and tissue-based products, and

so are intentionally broad in scope. The

agency anticipates that, as it implements

the new regulations, there may be

additional need for discussion, through

public meetings, public hearings, or

guidance, of how these general

regulations would apply to specific

types of products. In addition, there

may be specific elements of these

proposed requirements that some

readers may not consider appropriate to

general application. The agency

welcomes comments that will assist it in

achieving the proper balance between

generality and specificity in these

regulations.

A. General Provisions (Proposed

§§ 1271.150 and 1271.155)

Proposed § 1271.150 contains general

provisions intended to aid in the

interpretation of the requirements

contained in subparts C and D of part

1271. Proposed § 1271.155 sets out the

procedures for obtaining an exemption

or variance from one or more of these

requirements.

1. Current Good Tissue Practice

(Proposed § 1271.150(a))

Proposed § 1271.150(a) states that

CGTP requirements govern the methods

used in, and the facilities and controls

used for, the manufacture of human

cellular and tissue-based products.

CGTP requirements are intended to

prevent the introduction, transmission,

and spread of communicable disease

through the use of human cellular and

tissue-based products by helping to

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1511

ensure that: (1) The products do not

contain relevant communicable disease

agents; (2) they are not contaminated

during the manufacturing process; and

(3) the function and integrity of the

products are not impaired through

improper manufacturing, all of which

could lead to circumstances that

increase the risk of communicable

disease transmission. ‘‘Manufacture’’ as

defined in the registration proposed

rule, includes, but is not limited to, any

or all steps in the recovery, processing,

storage, labeling, packaging, or

distribution of any human cellular or

tissue-based product, and the screening

and testing of a cell or tissue donor

(proposed § 1271.3(f), 63 FR 26744 at

26754.) The definition of ‘‘human

cellular or tissue-based product’’ as

revised in the donor suitability

proposed rule, is intended to cover such

products at all stages of their

manufacture, from recovery through

distribution (see proposed § 1271.3(e)

(64 FR 52696 at 52719). For a human

cellular or tissue-based product to be

manufactured properly, CGTP must be

followed in each step of the

manufacturing process.

The word ‘‘current’’ is included in the

term ‘‘current good tissue practice’’

because the agency recognizes that

appropriate practices may change over

time, as research is conducted and new

manufacturing methods are developed.

These regulations are not intended to

require that practices considered current

at the time of issuance of the final

regulations be maintained indefinitely;

instead, the obligation on an

establishment is to maintain up-to-date

practices over time. Recognizing that

improved manufacturing techniques

may be developed, the agency has

generally refrained in these proposed

regulations from requiring specific

procedures, such as particular

processing methods or storage

temperatures. Instead, the proposed

regulations set out general objectives.

This approach not only allows for new

developments, but also affords

establishments flexibility in developing

procedures that are both appropriate to

their particular operations and that

comply with the regulations.

The proposed requirements are based

on current good industry practice and

are intended to address what the agency

considers important minimum criteria

for the manufacture of these products.

In developing these regulations, the

agency has reviewed several sets of

industry standards, including those

issued by the American Association of

Tissue Banks (AATB) and by the Eye

Bank Association of America (EBAA).

The agency expects that some

establishments will need to make only

small changes in their operations to

achieve compliance. Other

establishments may find that complying

with the new requirements entails

revising certain procedures and

recordkeeping practices, but few

operational changes. Another group of

establishments—for example, those that

have not previously been subject to

regulation and that do not belong to any

standard-setting or accrediting

organization—may need to revise their

procedures more completely, in order to

bring them into compliance with these

regulations and industry practice.

Proposed § 1271.150(a) states that

CGTP requirements are set forth in

subparts C and D of part 1271. The

CGTP provisions specifically governing

donor suitability, including donor

testing and screening, are set out

separately in subpart C of part 1271. The

agency notes that § 1271.90 contains

exceptions from required testing and

screening for two types of human

cellular and tissue-based product:

Banked cells and tissues for autologous

use, and reproductive cells or tissue

donated by a sexually-intimate partner

of the recipient for reproductive use (64

FR 52696 at 52723). (Donor testing and

screening are recommended, however.)

The agency specifically notes that the

exceptions in § 1271.90 apply only to

subpart C of part 1271 and do not

extend to the provisions of subpart D of

part 1271. Because the safety concerns

addressed by the proposed CGTP

requirements apply to all human

cellular and tissue-based products, no

exceptions are being proposed for any

particular category of product. Thus,

banked cells and tissues for autologous

use, and reproductive cells or tissue

donated by a sexually-intimate partner

of the recipient for reproductive use,

would be subject to the CGTP

requirements in subpart D of part 1271.

2. Compliance With Applicable

Requirements (Proposed § 1271.150(b))

FDA recognizes that several

establishments may be involved in the

manufacture of a single human cellular

or tissue-based product. For example,

one establishment may recover tissue

from a cadaver, another establishment

may make the donor-suitability

determination, a third may process the

tissue, and a fourth may distribute the

product. The agency has taken care, in

designing these proposed regulations, to

reflect the fact that manufacturing roles

might be divided up in a variety of

possible ways. Thus, under proposed

§ 1271.150(b), an establishment that

engages in only some operations subject

to the regulations in subparts C and D

of part 1271 need only comply with

those requirements applicable to the

operations in which it engages. Under

§ 1271.150(b), an establishment that

does not process cells or tissue would

not be obligated to establish and

maintain process controls under

proposed § 1271.220. However, an

establishment that engages another

establishment, under a contract,

agreement, or other arrangement, to

perform any step in the manufacturing

process, would be responsible for

ensuring that the work is performed in

compliance with the requirements in

subparts C and D of part 1271. One

method of accomplishing this might be

by performing periodic audits.

Given that the steps in manufacturing

a single human cellular or tissue-based

product may be carried out by several

establishments, FDA considers it

essential that additional safeguards be

established to ensure compliance with

regulatory requirements throughout the

manufacturing process. The agency has

considered various ways of allocating

regulatory responsibilities among the

establishments involved in

manufacturing a human cellular or

tissue-based product. The agency seeks

to permit establishments to maintain

flexibility in sharing manufacturing

responsibilities, while ensuring that

products made available for release

maintain their function and integrity,

are not contaminated, and do not

contain communicable disease agents.

The agency first considered assigning

overall responsibility for ensuring that a

human cellular and tissue-based

product is manufactured in compliance

with all applicable regulations to the

establishment that determines donor

suitability. However, the agency

recognized that the role this

establishment plays in the manufacture

of a human cellular or tissue-based

product occurs early in the sequence of

manufacturing events. As a practical

matter, the establishment that

determines donor suitability might not

be able to ensure that later

manufacturing steps, such as processing

and labeling, are performed in

compliance with the regulations. A

more pragmatic approach would be to

assign responsibility to the

establishment that makes a product

available for distribution.

Another option would be to permit

the establishments engaged in the

manufacturing process to decide among

themselves which party bears ultimate

responsibility for the product. However,

the agency is concerned that, under this

approach, there would be occasions

when no establishment would step

forward as the one ultimately

responsible, and that as a consequence

1512 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

compliance with certain requirements

might not be accomplished. As a result,

products might be released that pose a

risk of transmitting communicable

disease or otherwise increasing the risk

of disease transmission. For the same

reasons, FDA has rejected the idea that

designating a responsible establishment

is unnecessary.

The agency has also considered a

‘‘cascading’’ set of responsibilities.

Under this approach, an establishment

would be responsible for ensuring that

its own operations comply with

applicable requirements, and also

would bear the burden of proof that

operations performed by other

establishments prior to its receipt of the

cells or tissue were performed in

compliance with applicable

requirements.

After considering the unique nature of

the cell and tissue industry, and each of

the above options, the agency has

tentatively concluded that the best

approach is to assign ultimate

responsibility for the product to the

establishment that is responsible for

making the product available for

distribution. This is consistent with the

proposed approach document, which

stated that ‘‘[t]he establishment or

person responsible for determining

suitability of release of cells or tissues

would be responsible for ensuring that

required screening and testing had been

performed prior to final release of the

material.’’ Thus, proposed § 1271.150(b)

states that the establishment that

determines that a product meets release

criteria and makes the product available

for distribution, whether or not that

establishment is the actual distributor,

is responsible for ensuring that the

product has been manufactured in

compliance with the requirements of

subpart C and D of part 1271 and any

other applicable requirements.

The agency specifically requests

comments on the allocation of overall

manufacturing responsibility. Examples

of industry arrangements currently in

existence would be particularly useful

to the agency in evaluating the

comments on these proposed

regulations.

3. Compliance With Parts 210, 211,

and 820

The proposed CGTP regulations are

similar to the CGMP requirements

applicable to drugs and the QS

requirements for devices. However, the

CGMP and QS regulations do not

contain provisions specifically intended

to prevent the spread of communicable

disease. In contrast, the purpose of the

proposed CGTP regulations is limited to

preventing circumstances that increase

the risk of introduction, transmission,

and spread of communicable disease;

the proposed regulations are therefore

less extensive in scope than the CGMP

and QS regulations.

Proposed § 1271.150(c) states that,

with respect to human cellular and

tissue-based products regulated as

biological drugs or as devices, the

proposed CGTP procedures will

supplement, not supersede, the CGMP

and QS requirements. Proposed

§ 1271.150(c) states that, in the event

that it is impossible to comply with all

applicable regulations, the regulations

specifically applicable to the biological

drug or device in question shall

supersede the more general.

4. ‘‘Where Appropriate’’

Several of the requirements contained

in part 1271, subpart D, are qualified by

the term ‘‘where appropriate,’’ which as

explained in proposed § 1271.150(d),

are considered to be appropriate, and

must be followed, unless an

establishment can justify otherwise, and

maintains documentation of that

justification. Under proposed

§ 1271.150(d), a requirement is

‘‘appropriate’’ if nonimplementation

could reasonably be expected to result

in the: (1) Product’s not meeting its

specified requirements related to

preventing the introduction,

transmission, and spread of

communicable disease agents and

diseases; or (2) manufacturer’s inability

to carry out any necessary corrective

action.

5. Exemptions and Alternatives

(Proposed § 1271.155)

FDA recognizes the possibility that, as

technology and scientific knowledge

advance, new methods may be

developed that could be used in the

manufacture of human cellular and

tissue-based products, or other

unanticipated circumstances may arise

that warrant a departure from an

approach detailed in the regulations.

Some of these technical developments

may not be consistent with the terms of

the donor-suitability and CGTP

regulations, although the purpose of

those regulations might be satisfied. In

order to provide establishments with

flexibility, and to ensure that the agency

may respond appropriately to improved

technologies and increased scientific

knowledge, the agency proposes that

establishments may apply for

exemptions or alternatives from the

regulatory requirements contained in

subparts C and D of part 1271.

Proposed § 1271.155 sets out the

procedures for obtaining an exemption

or alternative from a requirement in

subpart C of part 1271, pertaining to

donor suitability, or in subpart D of part

1271, pertaining to CGTP. Under

proposed § 1271.155, an establishment

could demonstrate to the agency that it

should be exempted from an otherwise

applicable regulatory requirement or

permitted to satisfy the purpose of the

requirement in an alternative manner. A

request for an exemption or alternative

would need to be accompanied by

supporting documentation, including all

relevant valid scientific data. Requests

would be made in writing or

electronically, except that in limited

circumstances (e.g., emergencies) a

request might be made and granted

orally, with a written request and

acknowledgment of approval to follow.

Under proposed § 1271.155(c), the

Director of the Center for Biologics

Evaluation and Research (CBER) could

grant an exemption or alternative if he

or she found that doing so would be

consistent with the goals of preventing

circumstances that increase the risk of

the introduction, transmission, and

spread of communicable disease. In

addition, an exemption or alternative

would be conditioned on a finding by

the Director that the information

submitted justified an exemption or that

the proposed alternative satisfied the

purpose of the requirement. An

establishment that requested an

exemption or alternative could not

begin operating under its terms until the

exemption or alternative had been

granted. Some exemptions or

alternatives might have expiration dates,

in which case an extension could be

requested. An establishment operating

under the terms of an exemption or

alternative would be required to

maintain documentation that the

exemption or alternative had been

granted, and of the date on which the

establishment began operating under the

terms of the exemption or alternative.

B. Definitions (Proposed § 1271.3)

Definitions pertinent to part 1271 will

be contained in subpart A, in § 1271.3.

In the registration proposed rule, FDA

set out defined terms in paragraphs (a)

through (h) of § 1271.3. In the donorsuitability proposed rule, further

definitions were proposed, to be

contained in § 1271.3(i) through (ee),

and the proposed definition of human

cellular or tissue-based product in

paragraph (e) was revised.

Now, the agency is proposing new

paragraphs (ff) through (tt) in § 1271.3.

These new definitions are discussed

below, when the requirements to which

the defined terms relate are discussed.

C. Quality Program (Proposed

§ 1271.160)

Any establishment that manufactures

human cellular or tissue-based products

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1513

needs to have in place a method of

ensuring that its manufacturing

processes are performed properly and in

compliance with applicable regulations.

For devices, such a program is called a

‘‘quality system’’ (§ 820.1 et seq.). In

these regulations, FDA is proposing to

use ‘‘quality program’’ to refer to the set

of activities, including management

review, training, audits, and corrective

and preventive actions, that represent a

commitment on the part of an

establishment’s management to the

quality of its products. FDA proposes to

define ‘‘quality program’’ in § 1271.3(oo)

as ‘‘an organization’s comprehensive

system for manufacturing and tracking

human cellular and tissue-based

products. This program includes

preventing, detecting, and correcting

deficiencies that may lead to

circumstances that increase the risk of

the introduction, transmission, or

spread of communicable disease.’’

Proposed § 1271.160 would require an

establishment that performs any step in

the manufacture of human cellular and

tissue-based products to establish and

maintain a quality program that is

appropriate for the specific human

cellular and tissue-based products

manufactured and the manufacturing

steps performed and that meets the

requirements of this part. With

proposed § 1271.160, FDA intends to

require that a quality program perform

certain basic functions, but also intends

to provide each establishment with

flexibility to devise a program

appropriate to its particular activities

and characteristics. Thus, FDA expects

that quality programs may differ from

establishment to establishment,

depending on the size of the

establishment and the type of

manufacturing performed, among other

factors. A smaller company that

performs limited manufacturing steps

might have a less complex quality

program than a larger establishment that

processes a variety of products.

Some establishments may currently

have in place quality programs that

would meet the requirements of

proposed § 1271.160. An establishment

that manufactures human cellular and

tissue-based products regulated as

devices would likely find it unnecessary

to make major changes to its quality

system established in compliance with

§ 820.5 in order to comply with

proposed § 1271.160. Such an

establishment would not need to

maintain both a QS and a separate

quality program.

The functions of a quality program, as

listed in proposed § 1271.160(b),

include but are not limited to: (1)

Ensuring that required procedures are

established and maintained; (2)

ensuring the appropriate analysis and

sharing of information that could affect

the integrity and function of a human

cellular or tissue-based product,

possible contamination of the product,

or the potential transmission of

communicable disease by the product;

(3) ensuring that appropriate corrective

actions are taken and documented; (4)

ensuring the proper training and

education of personnel; (5) establishing

and maintaining appropriate monitoring

systems; (6) establishing and

maintaining a system for maintaining

records; (7) investigating and

documenting product deviations and

making certain required reports; and (8)

conducting evaluations, investigations,

audits, and other actions necessary to

ensure compliance with the regulations.

Proposed § 1271.160(b)(2) would

specifically require procedures to be

established for sharing and receiving

information that could affect the

integrity and function of a human

cellular or tissue-based product, the

possible contamination of the product,

or the potential transmission of

communicable disease by the product.

This would include information on

testing or screening results that could

make a donor unsuitable; such

information would need to be shared

with other establishments that are

known to have recovered cells or tissue

from the same donor. An establishment

would also need procedures in place in

order to respond appropriately (through

investigation, evaluation, possible

recall, reporting, etc.) if it received any

such information from another

establishment.

Proposed § 1271.160(b)(7) would

require establishments to investigate

and document all product deviations in

manufacturing. The term ‘‘product

deviation’’ is defined in proposed

§ 1271.3(kk) as ‘‘an event that represents

a deviation from current good tissue

practice, applicable standards, or

established specifications; or an

unexpected or unforeseeable event that

may relate to the transmission or

potential transmission of a

communicable disease agent or disease

from a human cellular or tissue-based

product to a recipient, may lead to

product contamination, or may

adversely affect the function or integrity

of the product.’’ Investigation would be

required to include a review and

evaluation of the product deviation in

manufacturing, the efforts made to

determine the cause, and the

implementation of corrective action

designed to address the event and

prevent its recurrence.

Certain product deviations in

manufacturing would be required to be

reported. The proposed requirement,

applicable to distributed 361 products,

for reporting product deviations in

manufacturing that could lead to

adverse reactions is discussed below in

section III of this document. Certain

product variations, referred to currently

as errors and accidents, involving

human cellular and tissue-based

products regulated as biological drugs

are required to be reported under 21

CFR 600.14 (currently undergoing

revisions; see 62 FR 49642, September

23, 1997). In addition, each

establishment would be required to

perform a periodic review and analysis

of all investigations of product

deviations in manufacturing, at least

once each year, for the purpose of

identifying trends and adopting

appropriate corrective and preventive

measures. Section 1271.160(b)(7)

specifies that this analysis shall be

available for review upon inspection

and for submission to FDA upon

request.

Under proposed § 1271.160(c), one or

more designated persons shall have

authority over the quality program, and

this person shall report to management

at least once a year on the performance

of the quality program. However, more

frequent reports may be necessary in

order to keep management informed of

the status of the program.

Audits are an important component of

a quality program. Under proposed

§ 1271.160(d), a comprehensive quality

audit of all activities would be required

at least once a year. FDA proposes to

define ‘‘quality audit’’ in proposed

§ 1271.3(nn), as ‘‘a documented,

independent inspection and review of

an establishment’s activities, including

manufacturing and tracking, performed

according to procedures, to verify, by

examination and evaluation of objective

evidence, the degree of compliance with

those aspects of the quality program

under review.’’ In addition to the annual

quality audit, special audits would be

performed as necessary to ensure that

quality program objectives are achieved.

Proposed § 1271.160(e) covers the use

of computers or automated data

processing systems used as part of the

quality program, as part of

manufacturing, or for maintaining

manufacturing data or records. An

establishment using such a computer or

automated system would be required to

validate the computer software for its

intended use according to an

established protocol, as well as all

software changes. Validation and results

would be required to be documented.

The agency proposes to define

1514 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

‘‘validation’’ in proposed § 1271.3(rr) as

‘‘confirmation by examination and

provision of objective evidence that

particular requirements can consistently

be fulfilled * * *’’.

D. Organization and Personnel

(Proposed § 1271.170)

Proposed § 1271.170 sets out general

requirements for the organization and

personnel of establishments that

manufacture human cellular and tissuebased products. Under this section, each

establishment would be required to

maintain an adequate organizational

structure and sufficient personnel to

ensure that the requirements of part

1271 are met. Moreover, an

establishment would need to have

sufficient personnel with the necessary

education and experience, or

combination thereof, to assure

competent performance of their

assigned functions.

Under proposed § 1271.170,

personnel would only be permitted to

perform those activities for which they

are qualified. Training of personnel to

perform their assigned responsibilities

adequately would be required, as would

any necessary retraining. Because of the

particular risks addressed by the

requirements of part 1271, the agency is

proposing to require that personnel be

educated about possible consequences

of improperly performing their duties;

e.g., the risk that an improperly handled

product could cause harm to the

product’s recipient, by transmitting a

communicable disease or by failing to

function adequately. A record of the

education, experience, training, and

retraining would need to be maintained

for all personnel.

E. Procedures (Proposed § 1271.180)

Under proposed § 1271.180, each

establishment would be required to

establish and maintain procedures for

all significant steps that it performs in

the manufacture of human cellular and

tissue-based products. The agency is

proposing to define ‘‘establish and

maintain’’ in § 1271.3(ll) as ‘‘define,

document (in writing or electronically),

and implement, then follow, review,

and as needed, revise on an ongoing

basis.’’ FDA intends, by using the

phrase ‘‘establish and maintain’’ in

these regulations, to indicate that, once

established, procedures must be

followed on an ongoing basis. Because

established procedures would, by

definition, be documented in writing or

electronically, the agency is proposing

to use the term ‘‘procedures’’ as

opposed to ‘‘written procedures.’’

Procedures required under proposed

§ 1271.180, and those specifically

required elsewhere in subpart D of part

1271, would be required to be designed

to prevent circumstances that increase

the risk of the introduction,

transmission, and spread of

communicable diseases through the use

of human cellular and tissue-based

products by ensuring that: (1) The

products do not contain relevant

communicable disease agents; (2) the

products do not become contaminated

during manufacturing; and (3) the

function and integrity of the products

are not impaired through improper

manufacturing. Procedures must be

designed to ensure compliance with the

requirements of part 1271.

The recovery of cells or tissue is an

example of an especially significant step

in the manufacture of a human cellular

or tissue-based product, for which

procedures would have to be

established. Under the terms of

proposed § 1271.180, such procedures

would need to include the use of

procurement techniques designed to

prevent the transmission of

communicable disease agents and

diseases by the product. In addition,

procedures for recovery would have to

be designed to ensure that the function

and integrity of the procured cells or

tissue are maintained during and after

procurement.

All procedures shall be reviewed and

approved by a responsible person prior

to implementation. At least once in a

12-month period, all procedures would

be required to be reviewed and, if

necessary, revised; such review would

need to be documented. Procedures

must be readily available to personnel

in the area where relevant operations

are performed, unless this would be

impractical. Any deviation from a

procedure must be authorized by a

responsible person, recorded, and

justified.

FDA is not prescribing the contents of

particular procedures, but is allowing

establishments to develop procedures

that suit their particular operations.

Alternatively, under proposed

§ 1271.180, an establishment could

adopt current standard procedures, e.g.,

those in a technical manual prepared by

another organization, so long as the

procedures are consistent with the

requirements of part 1271, at least as

stringent as those requirements, and

appropriate for the establishment’s

operations.

Any procedure that becomes obsolete

would be required to be archived for at

least 10 years. Since some tissues have

long expiration dates, they can be

transplanted many years after they were

recovered or processed. Should an

adverse reaction occur after

transplantation, it would be important

to know the procedures under which

the tissue was recovered or processed,

especially if those procedures differ

from the ones currently in place.

F. Facilities, Environmental Control and

Monitoring, Equipment, and Supplies

and Reagents

1. Facilities (Proposed § 1271.190)

Under proposed § 1271.190, any

facility used in the manufacture of

human cellular or tissue-based products

must be of suitable size, construction,

and location to facilitate cleaning,

relevant maintenance, and proper

operations. A facility that, for whatever

reason, cannot be adequately cleaned is

not appropriate for use in the

manufacture of human cellular and

tissue-based products, because of the

potential risk of product contamination.

‘‘Relevant maintenance’’ refers to those

actions that, if not taken, could lead to

potentially adverse effects on product

integrity or function, or to the accidental

exposure of human cellular and tissuebased products to communicable

disease agents, or to contamination or

cross-contamination with such agents.

Finally, any operation undertaken by a

manufacturing establishment needs to

be performed in a facility in which the

operation can be performed correctly.

For example, although not specifically

required to do so by these regulations,

an establishment may need to establish

gowning procedures for its employees,

in order that their functions be

performed properly. Such an

establishment would need to provide

employees with a dressing room and

gowning area.

Proposed § 1271.190 would also

require that a facility be maintained in

a good state of repair. Broken windows,

peeling paint, uneven flooring, and

improper electrical wiring are all

examples of maintenance problems that

could lead to product contamination or

impairment of product function or

integrity. In addition, adequate lighting,

ventilation, plumbing, drainage, and

washing and toilet facilities would all

be required.

Proposed § 1271.190(b) sets out

requirements for the location of

operations within a facility used in the

manufacture of human cellular or

tissue-based products. Such a facility

would need to be divided into separate

or defined areas of adequate size for

each operation that takes place in the

facility. As an alternative, however,

other control systems could be

established and maintained to prevent

improper labeling, mix-ups,

contamination, cross-contamination,

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1515

and accidental exposure of human

cellular and tissue-based products to

communicable disease agents. Examples

of different types of operations that an

establishment might perform, and

which would need to be conducted

either in separate locations or subject to

other controls, include: (1) Receipt,

identification, and storage of containers,

labels, supplies, and reagents; (2)

processing, including laboratory

functions; (3) storage of human cellular

and tissue-based products, both before

and after release from quarantine; (4)

product labeling; (5) storage and

disposal of biohazards and/or medical

waste; (6) irradiation; and (7)

sterilization and aseptic processing.

Proposed § 1271.190(c) contains basic

requirements for facility cleaning and

sanitation. Facilities must be

maintained in a clean, sanitary, and

orderly manner. Sewage, trash, and

other refuse must be disposed of in a

timely, safe, and sanitary manner.

Procedures for facility cleaning and

sanitation would be required to be

established and maintained. These

procedures would need to include an

assignment of responsibility for

sanitation, cleaning methods to be used,

and a cleaning schedule. Finally, all

significant cleaning and sanitation

activities that are done to prevent

contamination would need to be

documented, and records maintained.

2. Environmental Control and

Monitoring (Proposed § 1271.195)

Proposed § 1271.195 would require

monitoring and control over

environmental conditions where such

conditions (e.g., temperature, air

quality) could reasonably be expected to

have an adverse effect on the function

or integrity of human cellular and

tissue-based products, to cause

contamination or cross-contamination of

products or equipment, or to lead to

accidental exposure of products to

communicable disease agents. In these

situations, an establishment would be

required to establish and maintain

procedures to adequately control and

monitor environmental conditions and

to provide proper conditions for

operations.

Depending on the particular

environmental factors at a facility, and

the type of operations that take place

there, environmental controls and

monitoring could include one or more

of the following: Temperature and

humidity controls; ventilation and air

filtration; cleaning and disinfecting of

rooms and equipment to ensure aseptic

processing operations; maintenance of

equipment used to control conditions

necessary for aseptic processing

operations; and environmental

monitoring for organisms. Proposed

§ 1271.195(a) would require these

elements to be adopted, where

appropriate. Thus, under proposed

§ 1271.195, an establishment would be

required first to identify any

environmental conditions that require

monitoring and control, and then to

respond appropriately.

Periodic inspections of environmental

controls systems would be required. In

addition, environmental controls and

monitoring activities would have to be

documented, and records maintained.

3. Equipment (Proposed § 1271.200)

CGTP requirements for equipment are

set out in proposed § 1271.200. For

human cellular and tissue-based

products to be manufactured properly,

the equipment used in their

manufacture must be appropriate. Thus,

§ 1271.200(a) contains the general

requirement that equipment used in the

manufacture of human cellular and

tissue-based product be of appropriate

design for its use. Equipment must be

suitably located and installed to

facilitate operations, including cleaning

and maintenance. In addition,

equipment must not have any adverse

effect on the products being

manufactured.

Equipment used for inspection,

measuring, and testing must be capable

of producing valid results; such

equipment could include automated,

mechanical, electronic, computer, or

other kinds of equipment. Section

1271.200(c) would require regularly

scheduled calibration of equipment

used for inspection, measuring, and

testing. Thus, for example, a

thermometer used in a storage area

would be required to produce valid

results and would also be subject to

regularly scheduled calibration

procedures. ‘‘Equipment used for

inspection’’ would include any

equipment used to inspect a human

cellular or tissue-based product during

its manufacture or prior to making it

available for distribution.

Under § 1271.200(b), an establishment

would be required to establish and

maintain procedures for cleaning,

sanitizing, and maintaining equipment.

The purpose of these procedures is to

prevent equipment malfunctions,

contamination or cross-contamination,

accidental exposure of human cellular

and tissue-based products to

communicable disease agents, and other

events that could reasonably be

expected to have an adverse effect on

product function or integrity. Cleaning,

sanitizing, and maintenance of

equipment would be required to be

performed according to established

schedules.

Section 1271.200(d) sets out a

requirement for routine inspections of

equipment for cleanliness, sanitation,

and calibration, and to ensure

compliance with maintenance

schedules.

Section 1271.200(e) contains specific

requirements for records, to be

maintained in accordance with the

general records provisions in

§ 1271.270. All maintenance, cleaning,

sanitizing, calibration, and other

activities performed in accordance with

§ 1271.200 would be required to be

documented. Records of recent

maintenance, cleaning, sanitizing,

calibration, and other activities must be

available at each piece of equipment;

this requirement promotes both accurate

recordkeeping and ease of reference. In

addition, the use of each piece of

equipment must be documented, and

this record of use must identify each

human cellular or tissue-based product

manufactured using the equipment.

This requirement is necessary to ensure

that those products manufactured with

a particular piece of equipment may be

traced for follow-up and appropriate

corrective action, in the event that a

problem (e.g., contamination or

malfunction) is discovered after the

equipment is used.

4. Supplies and Reagents (Proposed

§ 1271.210)

Use of a contaminated or otherwise

defective supply or reagent in the

manufacture of a human cellular or

tissue-based product could adversely

affect the product; e.g., by introducing a

disease agent or by failing to properly

preserve the product. For this reason,

compliance with CGTP requires that

care be taken in receiving supplies and

reagents into an establishment, in

determining their appropriateness for

use, and in keeping track of the

products in whose manufacture they are

used. By ‘‘supplies and reagents,’’ the

agency refers to all of the products that

might be used during the manufacturing

process but excludes any material that

might be considered to become a

component of a human cellular or

tissue-based product. Supplies and

reagents would include, but not be

limited to, ‘‘processing material,’’ which

the agency is proposing to define at

§ 1271.3(hh) as ‘‘any material or

substance that is used in, or to facilitate,

processing, but which is not intended

by the manufacturer to be included in

the human cellular or tissue-based

product when it is made available for

distribution.’’

1516 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

Proposed § 1271.210 contains several

requirements with respect to supplies

and reagents used in the manufacture of

human cellular and tissue-based

products. An establishment would be

required to establish and maintain

procedures for receiving supplies and

reagents. Before using a supply or

reagent, the establishment must verify

that the supply or reagent meets

specifications that are designed to

prevent circumstances that increase the

risk of the introduction, transmission,

and spread of communicable disease

through product contamination or the

impairment of product function or

integrity. An establishment could verify

on its own that the supplies and

reagents that it uses meet specifications;

e.g., by testing the product.

Alternatively, verification could be

accomplished by the vendor of the

supply or reagent. ‘‘Verification’’ is

defined in proposed § 1271.3(ss) as

‘‘confirmation by examination and

provision of objective evidence that

specified requirements have been

fulfilled.’’

Section 1271.210(b) would require

that reagents used in processing and

preservation of human cellular and

tissue-based products be of appropriate

grade for their intended use and, if

appropriate, sterile. Some

establishments may produce their own

in-house reagents. These establishments

would be required to validate and/or

verify the procedures for producing

such reagents.

Section 1271.210(c) would require

that specific records relating to the

receipt, verification, and use of each

supply and reagent be maintained.

G. Processing

Three sections of the proposed CGTP

regulations address the processing of

human cellular and tissue-based

products. Proposed § 1271.220 would

require controls to be established over

processing. Requirements for making

changes to processes are contained in

proposed § 1271.225. Proposed

§ 1271.230 would require process

validation in place of verification in

some situations and sets out certain

specific requirements related to process

validation.

‘‘Processing’’ is defined in proposed

§ 1271.3(mm) as ‘‘any activity other than

recovery, donor screening, donor

testing, storage, labeling, packaging, or

distribution performed on a human

cellular or tissue-based product,

including, but not limited to,

preparation, sterilization, steps to

inactivate and remove adventitious

agents, preservation for storage, and

removal from storage.’’

1. Process Controls (Proposed

§ 1271.220)

Under proposed § 1271.220(a), any

establishment engaged in the processing

of human cellular and tissue-based

products would be required to develop,

conduct, control, and monitor its

manufacturing processes to ensure that

each product: (1) Conforms to its

specifications, (2) is not contaminated,

(3) maintains its function and integrity,

and (4) is manufactured so as to prevent

transmission of communicable disease

by the product. By ‘‘specifications,’’ the

agency refers to those criteria

established by a manufacturer for a

human cellular or tissue-based product

that must be met at defined stages in the

manufacturing process and before the

product is made available for

distribution.

Sections 1271.220(b) governs the

removal of processing materials. In

accordance with the definition proposed

in § 1271.3(hh), processing materials

would not be intended by the

manufacturer to be included in a human

cellular or tissue-based product when it

is made available for distribution. Under

§ 1271.220(b), where a processing

material could reasonably be expected

to have an adverse effect on a human

cellular or tissue-based product’s

function or integrity, the establishment

would be required to establish and

maintain procedures for the use and

removal of the processing material to

ensure that it is removed or limited to

an amount that does not adversely affect

the product’s function or integrity. Any

such removal or reduction would be

required to be documented.

Section 1271.220(c) would prohibit

the pooling of human cells or tissue

from two or more donors during

manufacturing. Pooling refers to placing

products in physical contact with each

other or mixing them in a single

receptacle. Such commingling of cells or

tissues from a single infected donor

with cells or tissues from other donors

can contaminate the entire pooled

quantity, greatly increasing the risk to

recipients of the pooled materials of

exposure to infectious agents. The

proposed regulation is consistent with

recommendations made by FDA’s

Transmissible Spongiform

Encephalopathy Advisory Committee, at

their meeting on October 6, 1997, with

respect to the pooling of dura mater.

Section 1271.220(d) would require

procedures to be established for inprocess monitoring, or monitoring of the

product during processing, for

compliance with specified

requirements. This requirement is

modified by the phrase ‘‘where

appropriate.’’ In other words, as

discussed in section II.A.4. of this

document, in-process monitoring would

be required unless the establishment

can justify, and document, that it would

be unnecessary under the terms of

§ 1271.150(d). The in-process product

would have to be controlled until the

completion of any required inspection,

tests, or other verification activities, or

until any necessary approvals are

received and documented. Any

sampling taken of the in-process

product for the purpose of testing or

inspection would be required to be

representative of the material being

evaluated.

2. Process Changes (Proposed

§ 1271.225)

Proposed § 1271.225 would require an

establishment to establish procedures

for making changes to a process. Any

such change would have to be verified

or validated, to ensure that the change

does not create an adverse impact

elsewhere in the operation. Any change

would also have to be approved by a

responsible person with appropriate

knowledge and background before being

implemented. Proposed § 1271.225(b)

would require that records be kept of all

such changes, and sets out the required

elements of such records (e.g., the

rationale for the change).

3. Process Validation (Proposed

§ 1271.230)

Proposed § 1271.230 contains

requirements related to the validation of

processes. Process validation, under

proposed § 1271.3(rr), means

‘‘establishing by objective evidence that

a process consistently produces a result

or product meeting its predetermined

specifications.’’

Proposed § 1271.230(a) would require

establishments to validate their

processes where verification is not

feasible; e.g., where verification cannot

be performed on each and every

finished product. Thus, § 1271.230(a)

states that, where the results of a

process cannot be fully verified by

subsequent inspection and tests, the

process must be validated and approved

according to established procedures,

and the validation activities must be

documented.

Under § 1271.230(b), any claim made

in labeling or promotional materials that

is related to the process used to

manufacture a human cellular or tissuebased product must be based on a

process that has been validated.

Validation must be documented, and

evidence of the validation must be

maintained at the establishment and

made available for review on inspection.

Examples of such process-related claims

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1517

include the claim that a product is

sterile or that it has undergone viral

inactivation.

The agency is proposing in

§ 1271.230(c) a requirement that would

apply specifically to establishments that

process dura mater. Donor screening

and testing requirements for donors of

dura mater have been proposed in the

donor-suitability proposed rule, but

additional processing safeguards are

necessary to prevent the transmission of

Creutzfeldt-Jakob disease (CJD) (64 FR

52696 at 52706). Proposed § 1271.230(c)

would require that dura mater be

processed using a validated procedure

to reduce CJD infectivity, while

preserving the clinical utility of the

product. Currently, an example of such

a procedure would be a sodium

hydroxide (NaOH) protocol that has

been validated to reduce CJD infectivity

(in an animal model) while preserving

the tissue’s clinical utility. In the future,

other methods that more effectively

reduce CJD infectivity may be

developed.

If processes are validated, in place of

verification, then procedures must be

established and maintained to ensure

that the specified requirements continue

to be met; this requirement appears in

proposed § 1271.230(d). Under

§ 1271.230(e), any change or deviation

from a validated process would require

a review and evaluation of the process

and, where appropriate, revalidation.

H. Labeling Controls (Proposed

§ 1271.250)

Under proposed § 1271.250, an

establishment would be required to

establish and maintain procedures to

control the labeling of human cellular

and tissue-based products. These

control procedures would be designed

to ensure that products are identified

properly and to prevent mix-ups. The

agency is not specifying how such

controls should be designed, but notes

that they would likely need to include

such elements as proper storage

methods to prevent deterioration of

adhesives, among other problems. In

addition, § 1271.250 would require

procedures to include verification of

label accuracy, legibility, and integrity.

Thus, for example, a labeled product

would be checked under such

verification procedures to ensure that its

label was affixed securely to the

container, could be read with ease, and

accurately identified the product by

identifier and product type.

Proposed § 1271.250 would also

require that procedures be established

and maintained to ensure that products

are labeled in accordance with all

applicable labeling requirements.

‘‘Applicable labeling requirements’’ for

human cellular and tissue-based

products regulated as biological drugs

include the labeling regulations in parts

201 and 610 (21 CFR parts 201 and 610);

for products regulated as devices, they

include those in part 801 (21 CFR part

801). Other labeling requirements

appear in several sections of proposed

part 1271, and these are listed in

proposed § 1271.250. For example,

§ 1271.90 is cross-referenced in

§ 1271.250; it would require that banked

cells and tissues for autologous use be

labeled ‘‘FOR AUTOLOGOUS USE

ONLY’’ (donor-suitability proposed rule

(64 FR 52723)). Procedures established

in compliance with proposed § 1271.250

would need to ensure that banked cells

and tissues for autologous use were

labeled with this statement.

I. Storage (Proposed § 1271.260)

Proposed § 1271.260 sets out storage

requirements. The proposed regulation

addresses three general areas of concern:

Control of storage areas; storage

temperature; and expiration date.

Under proposed § 1271.260, each

establishment would be required to

establish and maintain procedures for

the control of storage areas and stock

rooms in order to prevent mix-ups,

commingling, deterioration,

contamination, and cross-contamination

of human cellular and tissue-based

products and supplies, as well as any

other condition that might adversely

affect product function or integrity. In

addition, controls would be required to

prevent improper release for

distribution.

Storage at a proper temperature, in

order to preserve a product’s function

and integrity and prevent deterioration,

is an important aspect of CGTP. FDA

recognizes that appropriate

temperatures may differ for various

types of products. Thus, § 1271.260(b)

would require an establishment to

establish acceptable temperature limits

for the storage of human cellular and

tissue-based products at each step of the

manufacturing process. Monitoring of

storage temperatures would be required.

Temperatures would have to be

documented, and recorded temperatures

reviewed periodically to assure that

temperatures remained in the

permissible range.

Different products may be stored for

differing lengths of time before use. The

maximum storage period depends on

such factors as product type, processing

procedures and method of preservation,

storage conditions, and type of

packaging. Section 1271.260(c) would

require, where appropriate, that an

expiration date be assigned for each

human cellular or tissue-based product.

Under § 1271.260(d), corrective action

must be taken and documented

whenever proper storage conditions are

not met.

J. Receipt and Distribution (Proposed

§ 1271.265)

Proposed § 1271.265 covers the

receipt and distribution of human

cellular and tissue-based products.

Section 1271.265(a) contains general

requirements for procedures and

recordkeeping. Section 1271.265(b)

governs receiving activities.

Requirements that must be met prior to

making a product available for

distribution are contained in

§ 1271.265(c). The remaining paragraphs

deal with packaging, shipping

conditions, and the return of products to

inventory.

Under § 1271.265(a), procedures

would be required for receiving,

accepting or rejecting, and distributing

human cellular and tissue-based

products, as well as for the destruction

or other disposition of such products.

Each of these activities, when

performed, must be documented.

Required documentation would include

the identification of the human cellular

or tissue-based product, the activities

performed and the results of such

activities, the date or dates of the

activity, the quantity of product subject

to the activity, and the disposition of the

product. The disposition of the product

would include, for example, the identity

of the consignee. Complete and accurate

identification of a consignee would

include not only the consignee’s name,

but its address and telephone number.

Section 1271.265(b) contains specific

requirements with respect to the receipt

of human cellular and tissue-based

products for processing, distribution, or

any other step in the manufacturing

process. As part of its receiving

activities, an establishment would be

required to inspect incoming human

cellular and tissue-based products,

according to established procedures, for

damage, contamination, deterioration,

or any other indication that the integrity

of the product had been impaired. The

establishment would then determine

whether to accept or reject the product.

Acceptance or rejection of the incoming

product would need to be documented.

An establishment receiving a human

cellular or tissue-based product would

also be required to ascertain its status

and handle the product appropriately.

For example, a product that is shipped

under quarantine, pending completion

of the donor-suitability determination

required under subpart C of part 1271,

1518 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

would be required to be maintained in

quarantine after its receipt until the

determination was complete. Other

issues of product status (e.g., stage in

processing, results of donor screening

and testing) would dictate other

appropriate action with respect to the

product.

Proposed § 1271.265(c) deals with an

establishment’s determination that a

product is ‘‘available for distribution,’’ a

term that the agency is proposing to

define in proposed § 1271.3(ff). Under

that definition, a human cellular or

tissue-based product is ‘‘available for

distribution’’ if it has been determined

to meet all release specifications and to

be suitable for distribution. Under

§ 1271.265(c), an establishment would

be required to establish and maintain

procedures for making products

available for distribution, including

developing release criteria. These

procedures would be designed to

prevent the release of products that are

in quarantine, have deteriorated, or

otherwise have been manufactured in

violation of CGTP. They must also

prevent the release of products from

donors who have not been determined

to be suitable, except as provided under

proposed §§ 1271.65 and 1271.90.

Prior to making a human cellular or

tissue-based product available for

distribution, an establishment would be

required to review all records pertaining

to the product and to verify and

document that release criteria have been

met. The determination that a product is

available for distribution must be

documented and dated by a responsible

person.

Under § 1271.265(d), all packaging

and shipping containers would be

required to be designed, validated, and

constructed so as to ensure product

function and integrity and to protect the

product from damage, deterioration,

contamination, or other adverse effects

during customary conditions of

processing, storage, handling, and

distribution. Section 1271.265(e) would

require that appropriate shipping

conditions, to be maintained during

transit, be defined for each type of

product. And § 1271.265(f) would

require that an establishment develop

procedures for determining whether a

product that is returned to the

establishment may be returned to

inventory.

K. Records (Proposed § 1271.270)

Proposed § 1271.270 contains general

requirements for recordkeeping under

part 1271. Section 1271.270(a) would

require establishments to maintain

records concurrently with the

performance of each significant step

required in subparts C and D of part

1271. Many, but not necessarily all, of

the requirements for documenting a

manufacturing activity are specifically

noted elsewhere in the regulations. For

example, an establishment’s receipt of

tissue for processing would be a

significant step that needs to be

documented; proposed § 1271.265(a)

lists the specific documentation that

would be required. As noted in

proposed § 1271.270(a), any

requirement in part 1271 that an activity

be documented involves the creation of

a record, and that record would be

subject to the requirements of

§ 1271.270.

Section 1271.270(a) would require

records to be accurate, indelible, and

legible. Entries must be dated and the

person performing the work in question

must be identified. Records would have

to be sufficiently detailed to provide a

complete history of the work performed

and to relate the records to the

particular human cellular or tissuebased product involved. In order to

protect the privacy of both donors and

recipients, adequate record security

systems would be required.

Under § 1271.270(b), establishments

would have the flexibility to develop

individualized systems of maintaining

and organizing their records, so long as

certain objectives were achieved.

Records could be maintained in more

than one location, provided that the

records management system was

designed to ensure prompt

identification, location, and retrieval of

all records. Further, the records

management system would need to

facilitate the review of a particular

human cellular or tissue-based

product’s history both prior to its

release for distribution and, if necessary,

at a later date as part of a follow-up

evaluation or investigation. In addition

to records pertaining to individual

products, records for product types

would be required to be maintained and

organized. Thus, for example, a

manufacturer of several different types

of human cellular and tissue-based

products would be required to maintain,

for each product type, records of

pertinent procedures, product

specifications, labeling and packaging

procedures, and equipment logs. A

records management system could be as

simple as keeping all information

pertaining to the manufacture of one

product in one file folder, and keeping

all file folders for one product type, e.g.,

tendons, in one drawer of the file

cabinet. This drawer, labeled

‘‘Tendons’’, would also contain a folder

for ‘‘generic’’ procedures common to all

tendons. A more elaborate records

management system could utilize a

computer to generate files and subfiles.

Section 1271.270(d) and (e) deal with

methods and time frames for retaining

records. Under § 1271.270(d), records

could be maintained electronically, as

original paper records, or as true copies.

Examples of true copies include

photocopies, microfiche, and microfilm.

Suitable equipment would be required

to be available for reading and

photocopying any records maintained

on microfiche or microfilm. Records

stored in automated data processing

systems must be backed up to prevent

their loss. Any electronic record or

electronic signature would be subject to

the requirements in 21 CFR part 11.

Under § 1271.270(e), all records

would be required to be kept for 10

years after their creation. However,

consistent with proposed § 1271.55(b)

on records of donor-suitability

determinations, records pertaining to a

particular human cellular or tissuebased product must be retained at least

10 years after the date of implantation,

transplantation, infusion, or transfer of

the product. See donor-suitability

proposed rule (64 FR 52721). If the date

of implantation, transplantation,

infusion, or transfer is not known, then

the records must be retained at least 10

years after the date of the product’s

distribution, disposition, or expiration,

whichever is latest. The establishment

must make provisions for all records to

be maintained for the required period in

the event that the establishment ceases

operation. FDA requests comment on

whether there are specific types of

records for which a retention period

shorter than 10 years would be

appropriate and would not compromise

the agency’s ability to prevent the

introduction, transmission and spread

of communicable disease.

Section 1271.270(c) cross-references

records requirements proposed in

subpart C of part 1271 that relate to

donor testing and screening, in order to

make clear that records required under

subpart C of part 1271 are subject to the

recordkeeping requirements in

§ 1271.270. Section 1271.270(f) would

require an establishment to maintain

records of contracts, agreements, and

other arrangements with other

establishments under which any step in

the manufacturing process is performed

by the other establishment. These

records would need to contain not only

the name and address of the other

establishment, but also a description of

each party’s responsibilities.

L. Tracking (Proposed § 1271.290)

FDA considers product tracking to be

an essential component of its proposed

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1519

regulatory system for human cellular

and tissue-based products. Should the

recipient of such a product contract a

communicable disease, tracking would

permit appropriate follow-up, such as

an investigation to determine whether

the human cellular or tissue-based

product transmitted the disease agent

and, if so, would permit steps to be

taken to prevent the distribution of

other similarly infected products.

Similarly, if a donor is discovered, postdonation, to have had a communicable

disease, tracking would permit an

establishment to locate products from

that donor. Thus, a tracking system is

closely linked to the agency’s regulatory

objective of preventing the spread of

communicable disease.

As with other components of these

CGTP regulations, FDA is proposing

certain basic requirements, but is

allowing establishments flexibility in

designing tracking programs that suit

their particular activities. Auditing of an

establishment’s tracking method to

ensure its effectiveness would be

required under the quality program

(proposed § 1271.160(b)(8) and (d)).

FDA recognizes that some

establishments have already developed

and implemented tracking systems and

requests comments from those

establishments on the success or failure

of particular tracking methods.

Part 821 (21 CFR part 821) of FDA’s

regulations contains the medical device

tracking requirements. Except for dura

mater, human cellular and tissue-based

products regulated as devices generally

have not been subject to tracking under

part 821; thus, there will be little or no

duplication of tracking requirements.

When a human cellular or tissue-based

product is designated as a ‘‘tracked

device,’’ and subject to the device

tracking regulations, the manufacturer

would be required to satisfy both sets of

tracking requirements. However, given

the variety of methods that could be

devised to satisfy the tracking

requirements proposed in § 1271.290, it

is foreseeable that a single tracking

method could be adopted that conforms

with the requirements of both

§ 1271.290 and part 821.

Proposed § 1271.290 would require

each human cellular or tissue-based

product to be tracked. Section

1271.290(a) would place the tracking

obligation on each establishment that

performs any step in the manufacture of

a human cellular or tissue-based

product.

Proposed § 1271.290(b) would require

the establishment to establish and

maintain a method of product tracking

that enables the tracking of all human

cellular and tissue-based products from

the donor to the recipient or final

disposition and conversely from the

recipient or final disposition to the

donor. FDA recognizes, however, that

some establishments may be better

equipped than others to establish an

effective tracking system. For this

reason, the agency proposes to permit

an establishment that performs some,

but not all, of the steps in the

manufacturing process to participate in

a method of product tracking that has

been established by another

establishment responsible for other

steps in the manufacturing process,

provided that the tracking method meets

all the requirements of § 1271.290. One

possible method of tracking would be to

collect information about recipients on

cards that are returned to the tracking

establishment.

Section 1271.290(c) would require

that each human cellular or tissue-based

product be assigned and labeled with a

distinct identification code (e.g.,

alphanumeric) that relates the product

to the donor and to all records

pertaining to the product. Except in the

case of autologous or directed

donations, such a code must be created

specifically for tracking and may not

include an individual’s name, social

security or medical record number. An

establishment that receives a human

cellular or tissue-based product for

further manufacturing might use the

code already assigned or might assign a

new identifier to the product. The

regulation specifies, however, that an

establishment that assigns a new

identifier to a product shall establish

and maintain procedures for relating the

new identifier to the old identifier.

Section 1271.290(d) would require

establishments to ensure, through

agreements with consignees or through

other measures, that the code and type

of each human cellular or tissue-base

product that is implanted, transplanted,

infused, or transferred into a recipient

be recorded in the recipient’s medical

records, or in other pertinent records, to

enable tracking from the recipient to the

donor. Section 1271.290(e) would

require an establishment to document

and maintain records of the disposition

of each of its human cellular or tissuebased products to enable tracking from

the donor to the recipient or final

disposition. The information to be

maintained must permit the prompt

identification of the recipient of the

product.

Under § 1271.290(f), an establishment

would be required to inform its

consignees in writing of the

requirements in § 1271.290 and of the

tracking method that the establishment

is using to comply with those

requirements. For example, a statement

might be included in the materials

accompanying the consigned human

cellular or tissue-based product that

would describe applicable regulations

and the establishment’s tracking

method. The establishment would be

required to document that the consignee

agreed to participate in its tracking

method and to take all necessary steps

to ensure compliance with the

requirements of § 1271.290; this

agreement would need to be obtained

and documented upon initial

distribution of human cellular or tissuebased products to a consignee and

would not need to be obtained for each

subsequent consignment.

Proposed § 1271.290(g) contains a

requirement specific to donors of dura

mater, intended to address the

particular communicable-disease

concerns associated with that type of

product. Appropriate specimens from

the dura mater donor would be required

to be archived, under appropriate

storage conditions, and for the

appropriate duration, to enable future

testing of the archived material for

evidence of transmissible spongiform

encephalopathy (TSE) and appropriate

disposition of any affected dura mater

tissue, if necessary. Although archiving

samples may not immediately increase

the assurance of safety for a dura mater

graft, it would permit later testing for

TSE-induced changes using improved or

new methods as they become available.

In the event that a dura graft recipient

became ill with CJD, such testing of

archival donor material would be

needed to confirm whether the dura

graft was the source of infection, so that

no additional grafts from the affected lot

would be distributed. At this time,

based on currently available

information, FDA recommends that

samples of donor brain and dura mater

tissues be archived at a temperature

equal to or less than minus 70 1⁄2C for

16 years beyond the product’s

expiration date.

Ideally, archived samples should be

retained for the lifetime of the graft

recipient, because the maximum

incubation period is not certain. To

date, the longest known incubation

period is 16 years (Ref. 1). FDA believes

that it may be unrealistic to expect a

manufacturer to maintain an archive for

such a long time. FDA suggests that

establishment of a nationally supported

archive be considered for prolonged

storage of these materials, in order to

further the study of iatrogenic

transmission of spongiform

encephalopathies.

1520 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

M. Complaint Files (Proposed

§ 1271.320)

Proposed § 1271.320 would require

establishments to maintain records of,

and review, all complaints.

‘‘Complaint’’ is defined in proposed

§ 1271.3(ii) as:

any written, oral, or electronic

communication that alleges: (1) that a

human cellular or tissue-based product

has transmitted or may have transmitted

a communicable disease to the recipient

of the product; (2) that the function or

integrity of a human cellular or tissuebased product may have been impaired;

or (3) any other problem with a human

cellular or tissue-based product that

could result from the failure to comply

with current good tissue practice.

A communication from a physician

expressing concern about possible

product contamination would be a

‘‘complaint.’’

The proposed regulation would

require establishments to establish and

maintain procedures for the prompt

review, evaluation, and documentation

of all complaints. Records of each

complaint that the establishment

receives would be required to be

maintained in a file designated for

complaints. The complaint file would

be required to contain sufficient

information about each complaint for

proper review and evaluation of the

complaint, including the identifier of

the human cellular or tissue-based

product that is the subject of the

complaint. For example, the complaint

file should include the date of each

report, the unique product identifier,

and the name of the person or

establishment that submitted the

complaint. Proposed § 1271.320 would

require that the complaint file be made

available for review and copying upon

request from an authorized employee of

FDA. Section 1271.320(c) sets out

requirements for the review and

evaluation of complaints.

III. Additional Requirements With

Respect to 361 Products

Proposed subpart E of part 1271

contains reporting and labeling

requirements that would apply only to

those establishments that manufacture

human cellular and tissue-based

products as described in proposed

§ 1271.10 (registration proposed rule (63

FR 26754)). Such products would be

products that: (1) Are minimally

manipulated, (2) are not promoted or

labeled for any use other than a

homologous use, (3) are not combined

with or modified by the addition of any

nontissue or noncellular component

that is a drug or a device, and (4) do not

have a systemic effect. The agency

proposes to regulate such products

solely under the authority of section 361

of the PHS Act and not as biological

drugs or devices. Thus the heading of

subpart E of part 1271 is ‘‘Additional

Requirements for Establishments

Described in § 1271.10.’’ Human cellular

and tissue-based products regulated as

biological drugs or as medical devices

will continue to be subject to reporting

and labeling requirements that are

currently in place.

Although the title of proposed subpart

E of part 1271 refers to ‘‘additional’’

requirements for establishments

described in § 1271.10, the proposed

reporting and labeling requirements are

designed to be less extensive and

burdensome than the current

requirements applicable to products

regulated as biological drugs or as

devices. This approach is in keeping

with the agency’s expressed plans to put

in place a tiered regulatory scheme,

under which human cellular and tissuebased products would be subject to an

appropriate level of regulation based on

the degree of risk. At the same time, the

proposed reporting and labeling

requirements for 361 products have

been drafted to be generally consistent

with existing biological drug and device

regulations.

A. Reporting Requirements (Proposed

§ 1271.350)

In order to stay informed of potential

problems with human cellular and

tissue-based products related to

communicable-disease transmission,

and to be able to take appropriate steps

in response, FDA needs to receive

information from establishments on

adverse reactions and certain product

deviations that could result in adverse

reactions. For this reason, FDA is

proposing to require two different kinds

of reports from establishments that

manufacture human cellular and tissuebased products regulated solely under

section 361 of the PHS Act: the

reporting of adverse reactions, and the

reporting of product deviations.

1. Adverse Reactions

Under proposed § 1271.350(a),

establishments would be required to

report adverse reactions to CBER. The

agency is engaged in an ongoing effort

to enhance agency-wide consistency in

the collection of safety data and, where

possible, consistency with the

definitions, reporting periods, formats,

and standards recommended by the

International Conference on

Harmonisation of Technical

Requirements of Registration of

Pharmaceuticals for Human Use (ICH).

See ‘‘Expedited Safety Reporting

Requirements for Human Drug and

Biological Products,’’ final rule (62 FR

52237, October 7, 1997). In order to

achieve a degree of uniformity

throughout the agency and to simplify

reporting requirements for firms, FDA

has modeled the procedures in

§ 1271.350(a) on the reporting

requirements for other regulated

products (i.e., drugs, devices, and

biological products) and is proposing to

require use of the same standard

reporting form that is already in use

(FDA Form-3500A).

Proposed § 1271.3(gg) would define

an adverse reaction as ‘‘a noxious and

unintended response to any human

cellular or tissue-based product for

which there is a reasonable possibility

that the response may have been caused

by the product (i.e., the relationship

cannot be ruled out).’’ This definition

reflects the agency’s intention to shift

from adverse experience reporting to

adverse reaction reporting, consistent

with ICH guidelines (62 FR 52237 at

52238), and is consistent with the ICH

E2A guideline’s definitions of ‘‘adverse

drug reaction,’’ International Conference

on Harmonisation; Guideline on

Clinical Safety Data Management;

Definitions and Standards for Expedited

Reporting, availability (60 FR 11284 at

11285, March 1, 1995). Under the

proposed definition, not all

unsuccessful outcomes would be

considered ‘‘adverse reactions.’’ For

example, the agency recognizes that a

recipient may reject a human cellular or

tissue-based product, or that there may

be a failure to engraft (e.g., of

hematopoietic stem cells), for reasons

that are unrelated to the product itself.

Or a procedure may fail for reasons that,

whether or not specifically identified,

are known not to be product-related. On

the other hand, if the relationship

between the product and the noxious

and unintended response cannot be

ruled out, the response would be

considered an adverse reaction under

the proposed definition.

The phrase ‘‘the relationship cannot

be ruled out’’ is included in the

proposed definition to clarify which

individual cases should be reported to

FDA. Instances of probable, possible,

remote, or unlikely relationships would

all be considered adverse reactions,

because there would be at least a

reasonable possibility that the noxious

and unintended response may have

been caused by the human cellular or

tissue-based product, even though

causality has not been established.

Under proposed § 1271.350(a), only

those adverse reactions that involved

the transmission of a communicable

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1521

disease, product contamination, or the

failure of a human cellular or tissuebased product’s function or integrity

would be required to be reported.

Moreover, reporting would be limited to

those adverse reactions that are fatal or

life-threatening, that result in

permanent impairment of a body

function or permanent damage to body

structure, or that necessitate medical or

surgical intervention.

In order to determine which adverse

reactions are required to be reported,

each establishment would be required to

review all adverse reaction reports. The

source of the information is not

relevant; all reports, regardless of

source, would have to be considered.

The procedures proposed for

reporting adverse reactions are modeled

on those used for other products

regulated by the agency. Reports to the

agency would be required within 15

calendar days of initial receipt of the

information, with a possible follow-up

report. Reports would be submitted to

CBER. The proposed regulation

provides addresses and information on

obtaining forms.

With respect to human cellular and

tissue-based products regulated as

biological drugs, the reporting

requirements in 21 CFR 600.80 continue

to apply. For those products regulated

as devices, the medical device reporting

requirements in 21 CFR part 803 apply.

The agency notes that the transmission

of a serious communicable disease

would constitute an event that is

required to be reported under current

regulations.

2. Product Deviations

FDA is proposing to require, in

§ 1271.350(b), that those product

deviations that could reasonably be

expected to lead to a reportable adverse

reaction be reported to CBER, along

with information on corrective actions.

A definition of the term ‘‘product

deviation’’ is proposed in § 1271.3(kk)

and has been discussed at section II.C of

this document.

In the proposed approach document,

FDA indicated that establishments

would be required to maintain records

of errors and accidents, a term that is

incorporated in this proposal within the

meaning of ‘‘product deviation’’ (see

proposed § 1271.3(kk)), and to make

them available for inspection, but that

no reports to the agency would be

required. The General Accounting

Office, in its report on human tissue

banks, criticized the agency for not

requiring that such records be reported

(Ref. 2).

The agency is now proposing to

require the reporting of certain product

deviations: those that are of the type

that could reasonably be expected to

lead to a reportable adverse reaction. In

addition, required reporting would be

limited to product deviations involving

human cellular or tissue-based products

that have been distributed. The agency

considers that these limitations on the

reporting obligation will lessen the

burden on establishments and on the

agency, making it possible for the

agency to receive meaningful

information and respond appropriately

(e.g., by monitoring recalls and assisting

in their implementation as necessary

and appropriate).

Proposed § 1271.350(b) sets out the

requirements for reporting product

deviations that could give rise to an

adverse reaction and provides the

address to be used. Reports of such

product deviations would be expected

as soon as possible. Although no

particular reporting form would be

required, § 1271.350(b)(2) states that

each report shall contain a description

of the product deviation and

information on all corrective actions

that have been or will be taken in

response to the product deviation, such

as recalls.

B. Labeling and Claims

Proposed § 1271.370 contains

requirements for product labeling and

would govern promotional claims made

for human cellular and tissue-based

products regulated solely under the

authority of section 361 of the PHS Act.

Section 1271.370(a) describes the

required contents of product labels and

accompanying materials. The types of

claims that may be made for human

cellular and tissue-based products are

addressed in § 1271.370(b).

The agency considers regulation of

labeling and promotion to be an

essential part of its proposed tiered,

risk-based regulatory system for human

cellular and tissue-based products.

Labeling and promotional materials

which contain incomplete, unclear,

inaccurate, unbalanced, or misleading

information can increase the risk of the

introduction, transmission, or spread of

communicable disease by misleading

the public into inappropriate or unsafe

practices regarding these products (e.g.,

storing a product at an incorrect

temperature) or by hindering corrective

action which might become necessary

(e.g., by delaying identification of the

establishment distributing an unsafe

product).

For these reasons, the agency

considers that section 361 of the PHS

Act provides the agency with sufficient

authority to issue these requirements.

1. Labeling Information

Proposed § 1271.370(a) would require

each human cellular or tissue-based

product made available for distribution

to be labeled clearly and accurately. In

addition, certain basic information

would be required to appear on the

product label: (1) The name and address

of the establishment that determined

that the product met release criteria and

made the product available for

distribution, (2) a description of the type

of product, and (3) the product’s

expiration date, if any. The agency

considers each of these items to be of

sufficient importance that they warrant

placement on the product label itself

instead of in materials that accompany

the product. The first two items are

crucial for accurately identifying the

product and responsible establishment

in the event of any necessary follow-up

action (e.g., adverse reaction reports).

Requiring products to be labeled with

their expiration dates helps to ensure

that they maintain their function and

integrity at the time of use.

Recognizing that space on the product

label may be limited, the agency

proposes to require that the following

information appear either on the

product label or in a package insert: (1)

Storage temperature, (2) warnings,

where appropriate, and (3) instructions

for use. Information on storage

temperature will help prevent errors in

handling and help ensure that the

product maintains its integrity and

functions properly in the recipient.

Warnings and instructions for use will

inform the physician of the proper use

of the product and would increase the

probability of a successful procedure.

2. Claims

Section 1271.370(b) deals with claims

for human cellular and tissue-based

products in labeling, advertising, and

promotional materials. Consistent with

the agency’s plans outlined in the

proposed approach document, this

provision would require that any such

claim be clear, truthful, balanced, and

not misleading. A ‘‘balanced’’ claim for

a product would, for example, reflect an

objective, unbiased view of the product,

including not only claims for the

product’s benefits but also explanations

of any hazards. A claim may be

considered to be misleading if it omits

important information.

Proposed § 1271.370(b)(2) is intended

to clarify one of the four criteria that

must be met for a human cellular or

tissue-based product to be regulated

solely under the authority of section 361

of the PHS Act. Under proposed

§ 1271.10, a 361 product is one that, in

1522 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

addition to meeting other criteria, is not

promoted or labeled for any use other

than a homologous use (registration

proposed rule (63 FR 26744 at 26754)).

Section 1271.370(b)(2) explains that a

labeling claim or promotional materials

regarding the therapeutic or clinical

outcome of a human cellular or tissuebased product (other than for

reconstruction, replacement, repair, or

supplementation of cells or tissue)

would be considered a claim for a use

other than a homologous use. A product

for which such a claim was made would

be subject, along with its labeling, to

regulation under the act and/or section

351 of the PHS Act.

3. Labeling of Biological Drugs and

Devices

Proposed § 1271.370 applies only to

361 products; human cellular and

tissue-based products regulated as

biological drugs or as devices will

continue to be subject to labeling

requirements currently in place. Parts

201 and 610 (21 CFR parts 201 and 610)

will apply to human cellular or tissuebased products regulated as biological

drugs, as will relevant statutory

provisions and any conditions of

product licensure. Human cellular and

tissue-based products regulated as

devices will be subject to the labeling

requirements in part 801, in addition to

the provisions of the act and any

applicable conditions of approval or

clearance.

In order to ensure that all human

cellular and tissue-based products,

regardless of regulatory category, bear

certain basic relevant information, FDA

proposes to interpret several current

regulations as encompassing the

information set out in proposed

§ 1271.370(a). The agency would expect

the information listed in proposed

§ 1271.370(a) to appear on the label or

package insert of those products

regulated as biological drugs or devices.

The paragraphs below set out each

item listed in proposed § 1271.370(a),

along with the parallel regulation

applicable to biological drugs or

devices. The agency expects that few if

any changes will need to be made to

current labeling to ensure that the

information listed in proposed

§ 1271.370(a) is provided. Where there

is a difference in required placement of

the information (e.g., on the label or in

a package insert), the placement

required in the biological drug or device

regulation will apply.

a. Name and address of the

establishment that determines that the

product meets release criteria and

makes the product available for

distribution. For biological drugs,

§§ 610.60(a)(2), 610.61(b), and 610.63

require the name, address, and license

number of the manufacturer or, in the

case of divided manufacturing

responsibilities, all manufacturers.

Section 610.64 permits the name of the

distributor to appear. For human

cellular and tissue-based products, FDA

considers the establishment that

determines that the product meets

release criteria and makes the product

available for distribution to be a

manufacturer and will expect that

manufacturer’s name and address to

appear on the product label.

Section 801.1(a) requires the label of

a device to specify the name and place

of business of the manufacturer, packer,

or distributor. FDA proposes to interpret

this requirement, with respect to human

cellular and tissue-based products

regulated as devices, as requiring the

name of the establishment that

determines that the product meets

release criteria and makes the product

available for distribution.

b. Description of the type of product.

For biological drugs, §§ 610.60(a)(1) and

610.61(a) require the proper name of the

product to appear on the container and

package label. The product’s proper

name will serve as an adequate

description of the type of product. For

devices, section 502(e)(2) and (e)(4) of

the act (21 U.S.C. 352(e)(2) and (e)(4))

requires products to be labeled with

their established name, or if there is no

established name, then with the

common or usual name of the device;

either will suffice, so long as it

adequately describes the type of

product.

c. Expiration date. For biological

drugs, §§ 610.60(a)(4) and 610.61(d)

require products to be labeled with their

expiration dates. For devices,

§ 801.109(c) requires products to be

labeled with information on ‘‘any

relevant * * * precautions’’; FDA

proposes to interpret this provision as

requiring a product’s expiration date, if

the product has one, because the

expiration date is effectively a

precaution against use of an out-of-date

product.

d. Storage temperature. For biological

drugs, § 610.61(h) requires the

recommended storage temperature to

appear on the package label. For

devices, FDA proposes to interpret

§ 801.109(c), which requires information

for use, including precautions, to

include the proper storage temperature.

e. Warnings, where appropriate. For

biological drugs, § 210.57(e) requires

warnings. For devices, § 801.109(c)

requires information on hazards,

contraindications, side effects, and

precautions, which FDA proposes to

interpret as including any appropriate

warnings.

f. Instructions for use. For biological

drugs, § 610.61(i), (j), and (k), as well as

§ 201.57(c), requires instructions for use.

For devices, instructions for use are

required in § 801.109(b)(2) and (c).

IV. Inspection and Enforcement

Provisions

Proposed subpart F of part 1271

contains provisions on inspections;

human cellular and tissue-based

products offered for import; and orders

of retention, recall, destruction, and

cessation of manufacturing. Subpart F of

part 1271 would apply only to those

establishments described in proposed

§ 1271.10; i.e., those establishments that

manufacture human cellular and tissuebased products regulated under the

authority of section 361 of the PHS Act

and proposed part 1271, but not as

biological drugs or as devices. Products

that the agency is regulating as devices

or biological drugs will be subject to the

enforcement provisions of the act and

applicable regulations.

The proposed inspection and

enforcement provisions are based on

those contained in part 1270, subpart D,

which are currently applicable to

human tissue intended for

transplantation. These provisions were

fully discussed in the rulemaking on

part 1270 (‘‘Human Tissue Intended for

Transplantation,’’ interim rule (58 FR

65514 and 65517 to 65518, December

14, 1993); ‘‘Human Tissue Intended for

Transplantation,’’ final rule (62 FR

40429 and 40439 to 40440, July 29,

1997).

Authority for the enforcement of

section 361 of the PHS Act is provided

for in part under section 368 of the PHS

Act (42 U.S.C. 271). Under section

368(a) of the PHS Act, any person who

violates a regulation prescribed under

section 361 of the PHS Act may be

punished by imprisonment for up to 1

year (42 U.S.C. 271(a)). Individuals may

also be punished for violating such a

regulation by a fine of up to $100,000

if death has not resulted from the

violation or up to $250,000 if death has

resulted (18 U.S.C. 3559, 3571(b)).

Organizations may be fined up to

$200,000 per violation not resulting in

death and $500,000 per violation

resulting in death (18 U.S.C. 3559,

3571(c)). In addition, Federal District

Courts have jurisdiction to enjoin

individuals and organizations from

violating regulations implementing

section 361 of the PHS Act.

A. Inspections (Proposed § 1271.400)

Proposed § 1271.400 addresses the

inspectional process. In large part,

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1523

inspections of establishments that

manufacture human cellular and tissuebased products would be conducted in

the same manner as inspections of firms

dealing in other FDA-regulated

commodities.

Establishments subject to inspection

include those that perform any step in

the manufacture of human cellular and

tissue-based products, including

recovery, donor screening, donor

testing, processing, storage, labeling,

packaging, and distribution. All of these

establishments, including any location

performing contract services, would be

required to permit inspections by an

authorized FDA representative at any

reasonable time and in a reasonable

manner. The FDA representative would

determine which areas of the

establishment to inspect in order to

determine compliance with the

provisions of part 1271; these might

include, but would not necessarily be

limited to, the establishment’s facilities,

equipment, processes, products,

procedures, labeling, and records.

Inspections would be made with or

without prior notification and would

ordinarily occur during regular business

hours. The frequency of inspection

would be at the agency’s discretion.

The FDA representative would call

upon the most responsible person

available at the time of inspection of the

establishment and could question the

personnel of the establishment as the

representative deems necessary. The

FDA representative could review and

copy any records required to be kept

under part 1271, and could take

photographs or make video tapes. The

agency notes that, under the policy

expressed in Compliance Policy Guide

7151.02, ‘‘FDA Access to Results of

Quality Assurance Program Audits and

Inspections,’’ the FDA representative

would not ordinarily review or copy an

establishment’s records and reports that

result from audits of the establishment’s

quality program established under

proposed § 1271.160, when such audits

are conducted according to the

establishment’s written quality program.

This policy is intended to encourage the

establishment to conduct quality

program audits that are candid and

meaningful. The agency would continue

to have access to all information

required to be maintained under

proposed part 1271, such as complaint

files, information on product deviations,

and information on corrective actions.

At the end of the inspection, if

possible violations of the regulations are

found, the FDA representative would

issue to the most responsible person at

the establishment a list of ‘‘Inspectional

Observations’’ (Form FDA–483),

describing the observations of the

representative that represent an

observed or potential problem with the

facility or with the human cellular and

tissue-based products. After the report

of the FDA representative is reviewed,

FDA may issue additional

correspondence to the establishment

describing the violations to the

regulations and requesting appropriate

follow-up action.

The public disclosure of records

containing the name or other positive

identification of donors or recipients of

human cellular or tissue-based products

would be handled in accordance with

FDA’s procedures on disclosure of

information as set forth in 21 CFR part

20. Under these procedures, FDA takes

necessary precautions to protect the

privacy of names of donors and

recipients prior to public disclosure of

records containing identifiers of the

donor and recipients. FDA recognizes

the sensitive nature of information that

would identify a human tissue donor or

recipient. FDA may copy records

containing identification of the donors

or recipients if such records are needed;

for example, to document the

distribution of potentially infectious

human cellular and tissue-based

products.

The agency invites additional

comments on possible alternative

inspection and enforcement provisions

that would leverage agency resources,

be cost-effective, and achieve the public

health goals of the proposed rule. The

agency welcomes comments on the

advantages and disadvantages of various

types of programs, such as joint agencythird party inspectional programs and

joint Federal-State inspectional and

enforcement programs, as well as any

other alternative approach that would

help ensure compliance with the

proposed rule.

B. Imports (Proposed § 1271.420)

Proposed § 1271.420, which is

derived from § 1270.42, is intended to

clarify the administrative steps for the

importation of human cellular and

tissue-based products into the United

States. Human cellular and tissue-based

products that have been recovered from

sources outside the United States can

enter the country, and products that

have been recovered from sources in the

United States and then sent outside the

United States for processing can reenter

the country, consistent with the

provisions of part 1271. All imported

human cellular and tissue-based

products would be required to be

accompanied by appropriate records

identifying the donor and the status of

donor testing and screening in

accordance with the records

requirements proposed in the donorsuitability proposed rule.

As with other imports, when a human

cellular or tissue-based product is

offered for entry, the importer of record

must notify the director of the FDA

district having jurisdiction over the port

of entry through which the product is

imported or offered for import.

‘‘Importer of record’’ is defined in

proposed § 1271.3(tt). The human

cellular or tissue-based product offered

for import must be held intact, under

conditions necessary to maintain

product function and integrity, prevent

contamination, and prevent

transmission of communicable disease,

until it is released by FDA.

Human cellular and tissue-based

products that are offered for import and

found to be in violation of part 1271

would be subject to recall and

destruction in accordance with

§ 1271.440.

C. Orders of Retention, Recall,

Destruction, and Cessation of

Manufacturing (Proposed § 1271.440)

Proposed § 1271.440 describes the

procedures for the retention, recall, and

destruction of human cellular and

tissue-based products and for the

cessation of manufacturing operations,

and is derived in large part from

§ 1270.43. Section 1271.440(a) states

that, upon a finding that a human

cellular or tissue-based product or an

establishment is in violation of the

regulations in this part (and thus poses

a risk of spreading a communicable

disease), the agency may issue an order

that the product be recalled and/or

destroyed, as appropriate, or that it be

retained until it is recalled by the

distributor, destroyed, or disposed of as

agreed by FDA, or until the safety of the

product is confirmed. Alternatively, the

agency may take possession of and/or

destroy the violative product.

Section 1271.440(c) describes in

further detail the order of retention,

recall, or destruction, and describes

possible alternatives to destruction.

Section 1271.440(e) provides an

opportunity for a hearing under 21 CFR

part 16 and states that, if such a hearing

is requested, any possible destruction of

human cellular and tissue-based

products would be held in abeyance

pending resolution of the hearing

request.

Proposed § 1271.440(a)(3) contains a

provision not found in § 1270.43: an

‘‘order to cease manufacturing until

compliance with the regulations of this

part has been achieved.’’ This type of

order would bar an establishment from

continuing its manufacturing operations

1524 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

until the agency has determined that

compliance has been achieved. The

order will specify the regulations at

issue, and will ordinarily specify the

particular operations covered by the

order (e.g., distribution, labeling, etc.).

Operations may not resume without

prior authorization of FDA.

Authority for this new provision

derives from section 361 of the PHS Act,

which states that, ‘‘[f]or purposes of

carrying out and enforcing such

regulations, the Surgeon General may

provide for such inspection, * * *

destruction * * *, and other measures,

as in his judgment may be necessary.’’

The agency considers these new

measures to be a necessary component

of its new comprehensive approach to

cell and tissue regulation, which

includes the proposed establishment

registration and product listing and the

proposed CGTP requirements.

The agency recognizes that an order to

retain particular human cellular and

tissue-based products suspected of

being in violation of the regulations may

be appropriate in some instances, and

intends to continue to issue such orders

as necessary. However, such a limited

action against a product or products

may be an inadequate enforcement tool

in some instances; e.g., when an

establishment fails to comply with

CGTP. In that situation, it may be more

appropriate to take action directly

against the establishment, rather than

against the products of the

establishment.

For example, an order to cease

operations would be appropriate in the

case of an establishment that failed to

establish and maintain proper

procedures under proposed

§ 1271.260(a) for storage of human

cellular and tissue-based products in

such a way as to prevent their crosscontamination. Such a failure to comply

with CGTP would cause potential

serious communicable-disease risk from

all of the establishment’s products. An

order to retain or destroy particular

products would not prevent the

establishment from continuing its faulty

practices and could therefore be

inadequate.

The agency expects that, typically, an

order of cessation may be directed only

at the distribution of human cellular or

tissue-based products and would not

affect the rest of an establishment’s

operations. However, in some cases, the

order might cover a particular step in

the manufacturing process. And in

egregious cases involving serious CGTP

deficiencies, the order might cover all of

a firm’s operations.

V. Proposed Revocation of Part 1270

Part 1270 contains regulations

governing infectious disease testing,

donor screening, recordkeeping, and

enforcement for human tissue intended

for transplantation. Products currently

subject to the provisions in part 1270

would be considered human cellular

and tissue-based products under the

definition in § 1271.3(e) and would be

regulated under proposed part 1271.

The agency has previously announced

its intention that proposed part 1271

would supersede the regulations in part

1270 (donor suitability proposed rule

(64 FR 52696)). After the regulations in

part 1271 go into effect, the regulations

in part 1270 will be unnecessary,

confusing, and duplicative. For these

reasons, the agency now proposes to

revoke part 1270.

VI. Proposed Effective Date

FDA proposes that any final rule that

may issue based on this proposal

become effective 180 days after the date

of its publication in the Federal

Register.

VII. Environmental Impact

The agency has determined under 21

CFR 25.30(h) that this action is of a type

that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

VIII. Analysis of Economic Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612), and under the

Unfunded Mandates Reform Act (Public

Law 104–4). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). The Regulatory

Flexibility Act requires agencies to

analyze whether a rule may have a

significant impact on a substantial

number of small entities and, if it does,

to analyze regulatory options that would

minimize the impact. The Unfunded

Mandates Reform Act requires that

agencies prepare a written statement

under section 202 (a) of anticipated

costs and benefits before proposing any

rule that may result in an annual

expenditure by State, local and tribal

governments, in the aggregate, or by the

private sector, of $100 million in any

one year (adjusted annually for

inflation).

The agency believes that this final

rule is consistent with the principles

identified in Executive Order 12866.

The Office of Management and Budget

(OMB) has determined that the final

rule is a significant regulatory action as

defined by the Executive Order and so

is subject to review. Because the rule

does not impose mandates on State,

local, or tribal governments, or the

private sector, that will result in an

expenditure in any one year of $100

million or more, FDA is not required to

perform a cost-benefit analysis

according to the Unfunded Mandates

Reform Act. Many of the establishments

within the tissue industry would be

classified as small business entities, and

a number of these facilities will incur

new costs. Because of the limits of

information to characterize the current

quality management practices at many

of these facilities, and thus the

increased effort required to meet the

standards of CGTP, the cost impact on

small business entities is uncertain. The

FDA has therefore prepared an Initial

Regulatory Flexibility Analysis.

A. Estimated Cost Impact

With the proposed CGTP rule, the

FDA is furthering completion of the set

of proposals that represent a

comprehensive new system of

regulating human cellular and tissuebased products. Manufacturers of tissue

products may need to make certain

changes to their operations to comply

with the rule, such as creating new

procedures and providing additional

documentation. The proposed rule

affects several industries involved in the

manufacture of human cellular and

tissue-based products. These include:

Eye banks, conventional tissue banks,

hematopoietic stem cell facilities, and

reproductive tissue facilities.

FDA estimates are based on available

administrative data on the number of

facilities within each industry sector

and the number accredited by various

industry associations. Where good

statistical data are not available, FDA’s

cost impact estimates have incorporated

the quantified judgments of individual

experts identified through contacts with

the industry associations. Because of the

lack of comprehensive data to

characterize patterns of current practice

within each affected industry sector,

and the importance of this data in

development of an accurate assessment

of cost impact, FDA requests detailed

industry comment on the number of

facilities involved in the manufacture of

cellular and tissue products, and the net

change in quality assurance efforts

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1525

1Based on the National Inpatient Sample of

hospital discharge data collected by the Agency for

Health Care Policy Research (AHCPR) in the Health

Care Utilization Project (HCUP), a total of 7,300

stem cell transplants were performed in 1994, the

most recent year reported. With the number of stem

cell facilities ranging from 400 to 200, this would

translate to a range of 18 to 37 transplants per

facility per year. Based on the implied volume of

product per facility per year, a total of as many as

400 facilities would seem unlikely if the number of

transplants in 1994 were representative of the

current volume of demand for stem cell products.

needed for those facilities to comply

with the proposed rule.

1. The Number and Type of Entities

Affected

The economic impact of the proposed

rule is organized around four subgroups:

eye banks, conventional tissue banks,

stem cell facilities, and reproductive

tissue facilities. The number of facilities

and the percent of facilities that follow

current industry standards are

summarized in table 1 of this document.

In estimating net new costs for facilities,

it is critical to account for facility

adherence to current industry standards.

In a number of tissue manufacturing

sectors the industry standards for many

manufacturing operations meet or

exceed the specifications in the

proposed rule. Facilities following those

standards should experience very little

impact in complying with FDAproposed standards.

As presented in table 1 of this

document, FDA estimates that there are

114 eye banks currently operating in the

United States, although the EBAA

believes that the number of banks is

declining and may currently be closer to

100. According to EBAA, virtually all

operating eye banks currently comply

with the industry (EBAA) medical and

procedural standards for quality control.

For eye banks, the costs associated with

following the proposed rule result from

additional quality assurance steps and

process documentation as specified

under the CGTP.

FDA estimates that 110 tissue banks

are involved in the manufacture of other

conventional tissue, e.g., pericardium,

dura mater, heart valves, skin allografts,

bone allografts, fascia, tendon, and

ligaments (hereafter referred to as

‘‘conventional tissue banks’’). Industry

sources report that approximately 75 to

80 percent of these facilities currently

follow the standards for tissue banking

established by the AATB. For these

facilities, there will be some additional

cost associated with review of the

proposed FDA rule and with alignment

of their current procedures to FDA’s

requirements. There may also be some

additional recurring cost, where

documentation and quality control

required under the proposed rule extend

beyond current practice. For the

remaining 20 to 25 percent of facilities

not following the industry standard, the

cost of compliance would be somewhat

higher. These facilities may need to

establish more formal procedures and

quality control steps, and may need to

devote added staff hours to performing

these procedures and processing

controls.

Facilities that produce stem cell

products from peripheral blood or from

umbilical cord blood would also be

affected by the proposed rule. FDA finds

that available data to estimate the

number of peripheral blood stem cell

(PBSC) facilities and current practices

are quite limited. The actual number of

PBSC facilities may range from 200 to

400. Of the estimated total involved in

peripheral blood stem cell production,

approximately 150 are currently

accredited by the AABB and an

estimated 130 have applied for

accreditation by the Foundation for the

Accreditation of Hematopoietic Cell

Therapy (FAHCT). Industry sources

estimate that approximately 80 of these

facilities are seeking dual AABB/

FAHCT accreditation, indicating an

unduplicated count of approximately

200 PBSC facilities assumed to be

accredited by AABB and/or FAHCT.

However, the manufacturing practices of

non-accredited facilities are unknown.

The International Bone Marrow

Transplant Registry/Autologous Blood

and Marrow Transplant Registry

(IBMTR/ABMTR) estimates that the

total number of peripheral blood or

bone marrow facilities may be as high

as 4001 (i.e., 200 more than the number

estimated to be accredited by AABB or

FAHCT), but the number of IBMTR/

ABMTR-estimated facilities that

actually process peripheral blood (as

opposed to bone marrow) is uncertain.

In addition, the proposed rule would

apply to facilities involved with

reproductive tissue, primarily sperm

banks and Assisted Reproduction

Technology (ART) facilities. For

purposes of this discussion, references

to ART facilities include infertility

clinics, and andrology and embryology

laboratories. The American Society of

Reproductive Medicine (ASRM) has a

membership of approximately 330 ART

facilities. The ASRM also has a 1996 list

of approximately 110 sperm banks

operating in the United States. Based on

conversations with consultants, most

commercial sperm banking and most

ART facilities currently adhere to

industry standards similar to those in

the proposed rule. The 20 largest sperm

banks are estimated to handle 95

percent of the total volume of product

for the industry, and these facilities are

believed to follow industry standards

that are comparable to the CGTP.

According to industry consultants,

approximately one-third of the 20

largest sperm banks are accredited by

the AATB, and the remaining two-thirds

are licensed by State health agencies,

including the California Department of

Health and the New York Department of

Health. Sperm banks are also regulated

under the Clinical Laboratory

Improvement Amendment (CLIA) of

1988.

Andrology laboratories at ART

facilities are also subject to CLIA 1988.

The Committee on Laboratory

Accreditation (COLA) and the Joint

Commission on Accreditation of Health

Care Organization (JCAHO), also inspect

embryo laboratories for accreditation.

The requirements for accreditation by

the College of American Pathologists

(CAP), which also accredits ART

facilities, closely resemble those in the

proposed CGTP rule, with a few

exceptions. Consultants estimate that as

many as 80 percent of ART facilities

may currently comply with the CAP

requirements.

TABLE 1.—ESTIMATED NUMBER OF FACILITIES THAT FOLLOW INDUSTRY

STANDARDS

Affected

Industry

Relevant

Industry

Standards

Percent of

Firms

Following

Industry

Standards

Eye Tissue:

100–114

facilities

EBAA1 100% facilities estimated compliant

Conventional

Tissue:

(e.g., pericardium,

dura

mater,

heart

valves,

skin

allograft,

bone

allograft)

110 facilities

AATB2 75–80% facilities estimated compliant

Stem Cells

Peripheral

Blood

(PB): 400

facilities

[uncertain]

Cord Blood

(CB): 25

facilities

AABB or

FAHCT3

FAHCT

85% accredited facilities estimated compliant

100% CB

facilities

compliant

1526 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

TABLE 1.—ESTIMATED NUMBER OF FACILITIES THAT FOLLOW INDUSTRY

STANDARDS—Continued

Affected

Industry

Relevant

Industry

Standards

Percent of

Firms

Following

Industry

Standards

Reproductive

Tissue

Sperm

Banks: 110

facilities

AATB; CAP4

accreditation; State

Licensed

(e.g.,

NY,CA);

CLIA5-certified

20% facilities

estimated

compliant

(accounting

for 95% of

all production)

TABLE 1.—ESTIMATED NUMBER OF FACILITIES THAT FOLLOW INDUSTRY

STANDARDS—Continued

Affected

Industry

Relevant

Industry

Standards

Percent of

Firms

Following

Industry

Standards

Reproductive

Tissue

ART6 Facilities: 330

facilities

CAP accreditation; State

licensed

(e.g.,

NY,CA);

ASRM7

guidelines

approximately

80% facilities estimated compliant

1Eye Bank Association of America

2American Association of Tissue Banks

3Foundation for the Accreditation of

Hematopoietic Cell Therapy

4College of American Pathologists

5Clinical Laboratory Improvement Amendments of 1988 6Assisted Reproductive Technology

7American Society for Reproductive

Medicine

2. Estimated Impact on Industry

Facilities

In the sections that follow, the agency

considers each of the provisions of the

proposed rule its estimated impact on

facilities in the identified sectors of the

tissue industry. The impact analysis

distinguishes expected cost impacts

based on both facility size and estimated

current adherence with industry

standards. As defined by the U.S. Small

Business Administration, a small

facility has revenues less that $5.0

million.

TABLE 2.—ESTIMATED COST PER FACILITY AND ESTIMATED PERCENTAGE OF FACILITIES THAT WOULD BE AFFECTED BY

PROPOSED CURRENT GOOD TISSUE PRACTICES1

Section Title Eye Banks Conventional Tissue (Small/Large)

Stem Cell Facilities (Compliant/

noncompliant)

Sperm Banks ART2 Facilities

(Small/Large)

1271.150 CURRENT GOOD TISSUE

PRACTICE: GENERAL

– – – – – – – – – –

1271.155 EXEMPTIONS AND ALTERNATIVES– – – – – – – – – –

1271.160 ESTABLISHMENT AND MAINTENANCE OF A QUALITY

PROGRAM

(b)(2) Functions—Procedures

for sharing information

$349 (95%) $698/ $2,004

(23%)

$0/ $698 (0%/

80%)

$698 (5%) $698/ $0 (5%/ 0%)

(b)(3) Functions—Corrective actions$414 (95%) $828 (23%) $0/ $828 (0%/

80%)

$828 (5%) $828/ $0 (5%/ 0%)

(b)(7) Functions—Investigations $2,022 (95%) $2,022 (23%) $0/ $2,022 (0%/

80%)

$2,022 (5%) $2,022 /$0 (5%/

0%)

(d)(1) Audits—Annual $414 (95%) $828/ $1,656

(23%)

$0/ $828 (0%/

80%)

$828 (5%) $828/ $1,656 (50%)

(d)(3) Audits—Report $138 (95%) $276 /$552 (23%) $207 (95%) $207 (5%) $207/ $414 (50%)

(e) Computers—Validate customized software$2,040 (10%) $2,040 (10%) $2,040 (10%) $2,040 (5%) $2,040 (5%)

(f) Procedures—Quality program

—Facility with minor deficiencies$449 (95%) $449/ $1,159

(23%)

$449 (80%) $449 (80%) $449/ $1,159 (80%)

—Facility with major deficiencies$2,191 (5%) $2,191/ $4,359

(5%)

$0/ $2191 (0%/

5%)

$2,191 (5%) $2,191/$4,359 (5%)

—Cost for additional quality control work$1,236 (95%) $1,236 (23%) $1,236 (80%) $1,236 (80%) $1,236 (80%)

1271.170 ORGANIZATION AND PERSONNEL

(b) Competent performance

of functions—Sufficient

personnel

– – $15,560 (23%) $0/ $15,560 (0%/

95%)

$15,560 (5%) $15,560 (5%)

(c) Training – – $2,348/ $3,104

(23%)

$0/ $2,348 (0%/

95%)

$2,348 (5%) $2,348/ $0 (5%/

0%))

(d) Records—Personnel – – – –- – – – – – –

1271.180 PROCEDURES—GENERAL

REQUIREMENTS

$8,280 (5%) $8,280 (23%) $0/ $8,280 (0%/

95%)

$8,280 (50%) $8,280 (50%)

1271.190 FACILITIES

(a) General – – – – – – $14,000 (5%) $14,000/$28,000

(5%/ 5%)

(b) Operation-Separation

of Operations

– – – – $0/$14,000 (0%/

95%)

14,000 (5%) $14,000/$28,000

(5%/ 15%)

(b) General-Separation – – – –

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1527

TABLE 2.—ESTIMATED COST PER FACILITY AND ESTIMATED PERCENTAGE OF FACILITIES THAT WOULD BE AFFECTED BY

PROPOSED CURRENT GOOD TISSUE PRACTICES1—Continued

Section Title Eye Banks Conventional Tissue (Small/Large)

Stem Cell Facilities (Compliant/

noncompliant)

Sperm Banks ART2 Facilities

(Small/Large)

(c)(3) Facility cleaning and sanitation—Procedures$299 (5%) $299/ $471 (23%) $299 (95%) $299 (5%) $299/ $471 (5%)

(c)(4) Facility cleaning and sanitation—Records– – – – – – – – – –

1271.195 ENVIRONMENTAL CONTROL

AND MONITORING

(a) General—Procedures for

ventilation and air filtration

– – $299/ $471 (23%) $299 (95%) $299 (80%) $299/ $471 (80%)

(b) Inspections—Environmental control systems$1,000 (5%) – – $1,000 ( 50%/

95%)

$1,000 (20%) $1,000/$2,000

(20%)

(c) Records—Environmental

control and monitoring

activities

$162 (95%) $162/ $324 (23%) $162 ( 95%) $162 (80%) $162/ $324 (80%)

1271.200 EQUIPMENT

(b) Procedures and schedules—Cleaning, sanitizing, and maintenance– – $1,254/ $2,638

(23%)

$0/ $1,254 (0%/

95%)

$1,343 (90%) $1,343/$2,261

(90%)

(c) Calibration of equipment – – $1,254/ $2,638

(23%)

$1,254 (95%) $1,343 (5%) $1,343/

$2,261(50%)

(d) Inspections—Routine $204 (95%) $408/ $816 (23%) $204 (95%) $204 (5%) $204/ $408 (5%)

(e) Records—Maintenance,

cleaning, sanitizing, and

calibrating activities

—Keeping records of

cleaning and calibration

activities

$162 (95%) $324/ $648 (23%) $162 (95%) $162 (5%) $162/ $324 (5%)

—Keeping records of the

use of each piece of

equipment

$648 (95%) $1,296/ $2,592

(23%)

$1,296 (95%) $1,296 (100%) $1,296/$2,592

(100%)

1271.210 SUPPLIES AND REAGENTS

(a) Receipt and verification—

Procedures

$100 (95%) $299/ $471 (23%) $100/ $299 (95%/

95%)

$299 (5%) $299/ $471 (80%)

(b) Reagents—Procedures inhouse– – $299/ $471 (23%) $299 (95%)

(c)(1) Records—Receipt of supply or reagent$162 (95%) $162 / $324 (23%) $0 / $162 (0%/

95%)

$162 (5%) $162 / $324 (5%)

1271.220 PROCESS CONTROLS

(b) Processing material—Procedures for the use and

removal of damaging

processing materials

$299 (95%) $299/ $471 (23%) $299 (95%) $299 (90%) $299/ $471 (90%)

(d) In-process monitoring—

Procedures

$349 (95%) $349/ $1,002

(23%)

$698 (95%) $349 (5%) $349/ $1,002 (5%)

1271.225 PROCESS CHANGES

(a) Procedures—Process

changes

$698 (95%) $698/ $2,004

(23%)

$0 /$698 (0%/

95%)

$698 (5%) $698/ $2,004 (90%)

(b) Change records $414 (95%) $414/ $828 (95%) $414 (95%) $414 (90%) $414/ $828 (90%)

1271.230 PROCESS VALIDATION

(a) General $1,570 (95%) $1,570 (95%) $1,570 (95%) – – – –

(d) Procedures $1,396 (95%) $698 / $2004

(95%)

$698/ $1,396

(95%/ 95%)

(e) Changes and deviations—

Revalidation

$785 (95%) $1,570 (95%) $1,055 (95%)

1271.250 LABELING CONTROLS—

PROCEDURES

$349 (5%) $349 / $1,002

(5%)

$349 (5%) $349 (5%) $349 / $1,002 (5%)

1271.260 STORAGE – – – – – – – – – –

1271.265 RECEIPT AND DISTRIBUTION

(a)(1) General—Document identification of product$816 (5%) $1,632/ $3,264

(5%)

$1,632/ $3,264

(5%)

$1,632 (5%) $1,632/ $3,264

(5%)

1528 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

2A detailed presentation of level of effort and cost

assumptions are provided in FDA’s ‘‘Cost Impacts

of the Proposed Current Good Tissue Practices Rule

on Eye Banks, Conventional Tissue Banks and Stem

Cell Facilities: Background Paper,’’ April 1999, and

in ‘‘Cost Impacts of the Proposed Current Good

Tissue Practice Rule on Sperm Banks and ART

Facilities,’’ February 1999, prepared by Eastern

Research Group, Inc. These documents will be

available on the CBER website.

TABLE 2.—ESTIMATED COST PER FACILITY AND ESTIMATED PERCENTAGE OF FACILITIES THAT WOULD BE AFFECTED BY

PROPOSED CURRENT GOOD TISSUE PRACTICES1—Continued

Section Title Eye Banks Conventional Tissue (Small/Large)

Stem Cell Facilities (Compliant/

noncompliant)

Sperm Banks ART2 Facilities

(Small/Large)

(b) Receiving activities—Procedures– – $349/ $1,002

(23%)

$698 (95%) $698 (5%) $698/ $2,004 (5%)

(c) Availability for distribution—Procedures– – $349/ $1,002

(23%)

$349/ $698 (95%) $698 (5%) $698/ $2,004 (5%)

(d) Packaging—Validation $1,296 (95%) $1,296 (95%) $544 (95%) $544 (100%) $544 (100%)

(f) Return to inventory—Procedures– – $299/ $471 (23%) $0/$399 (0%/

95%)

$299 (5%) $299/$471 (100%)

1271.270 RECORDS

(a) General $648 (95%) $0/ $648 (0%/

95%)

$648 (95%) – – – –

(b) Records management

systems

$2,760 (95%) $0/ $2,760 (0%/

95%)

$2,760 (95%) $2,760 (5%) $2,760/$5,520

(50%)

(e) Length of retention $18 (5%) $18 (50%/ 95%) $18 (95%) $18 (5%) $18/$36 (5%)

1271.290 TRACKING

(b)(1) Method of product tracking-General method$698 (5%) $0/ $349 (0%/

95%)

$349 (95%) $349 (80%) $349/ $1,002 (80%)

(e) Recipient information $1,632 (5%) $0/ $3,264 (0%/

95%)

$3,264 (95%) – – – –

(f) Consignees $1,380 (5%) $1,380 (23%) $1,380 (95%) $1,380 (80%) $1,380 (80%)

1271.320 COMPLAINT FILE

(a) Procedures $100 (95%) $299/ $471 (23%) $299 (95%) $299 (5%) $299/ $471 (5%)

(b) Complaint file – – – – – – – – – –

(c) Review and evaluation of

complaints

$552 (95%) $552 / $1,104

(23%)

$552 (95%) $552 (5%) $552 / $1,104 (5%)

E—ADDITIONAL REQUIREMENTS FOR ESTABLISHMENTS DESCRIBED IN 1271.10

1271.350 REPORTING – – – – – – – – – –

1271.370 LABELING AND CLAIMS – – – – – – – – – –

F—INSPECTION AND ENFORCEMENT OF ESTABLISHMENTS DESCRIBED IN 1271.10

1271.400 INSPECTIONS

(a) Inspections—General $708 (100%) $708 (100%) $708 (100%) $708 (100%) $708 (100%)

1271.420 HUMAN CELLULAR AND TISSUE-BASED PRODUCTS

OFFERED FOR IMPORT

– – – – – – – – – –

1271.440 ORDERS OF RETENTION,

RECALL, DESTRUCTION,

AND CESSATION OF MANUFACTURING

– – – – – – – – – –

1Only sections estimated to have compliance costs for these industries are shown. No cost is estimated for a section (indicated by a double

dash‘‘—’’) if the background analysis (see a detailed presentation of cost assumptions provided in FDA’s Cost Impacts of the Proposed Current

Good Tissue Practices Rule on Eye Banks, Conventional Tissue Banks and Stem Cell Facilities: Background Paper, April 1999, and in Cost Impacts of the Proposed Current Good Tissue Practice Rule on Sperm Banks and ART Facilities, February 1999, prepared by Eastern Research

Group, Inc. ) shows that the requirements: (1) Do not apply, (2) have no new cost impact, or (3) are met by another section of the proposed rule. 2Assisted Reproductive Technology

As indicated by the information in

table 2, the impact of the proposed rule

varies, depending upon the sector of the

tissue industry and the particular

provisions of the proposed rule. For

many of the proposed provisions, the

facility level impact will entail

development of new procedures, or

revision of existing procedures. The

scope and degree of complexity may

vary. FDA expects that the staff

typically involved in the development

and finalization of facility procedures

will include technicians, clerical staff,

lab supervisors, and the lab director. For

purposes of industry-wide estimation,

the agency’s analysis relies on

standardized estimates of the level of

effort and cost for establishing

procedures. Table 3 summarizes the

agency’s assumptions, based on input

from industry consultants.2

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1529

TABLE 3.—ESTIMATED LEVEL OF EFFORT AND COST PER PROCEDURE REVISED OR PREPARED TO COMPLY WITH THE

PROPOSED CURRENT GOOD TISSUE PRACTICE1

Size Category Minor Procedures Major Procedures

Small Facility Revise Existing Prepare New Revise Existing Prepare New

Staff level of effort 2.0 hrs. 6.0 hrs. 8.0 hrs. 16.0 hrs.

Cost $99.50 $298.50 $349.0 $698.00

Large Facility

Staff level of effort 4.0 hrs. 12.0 hrs. 27.0 hrs. 54.0 hrs.

Cost $157.00 $471.00 $1,002.00 $2,004.00

1Small facilities are those with revenues less than $5.0 million. The distinction between major and minor procedures is described in the report by

Eastern Research Group, Inc.

The analysis of impact is summarized

below through a discussion of the

proposed rule provisions and expected

type and extent of industry impact. The

pertinent section of the proposed rule is

noted to facilitate reference to the

related estimates in table 2.

a. Section 1271.150—current good

tissue practice: general. The proposed

rule would require manufacturers of

human cellular and tissue-based

products to follow CGTP. Section

1271.150(a) gives an overview of CGTP

but does not present specific

compliance requirements. The specific

requirements are addressed in

subsequent sections. Section

1271.150(b) would require that

manufacturers ensure compliance on

the part of contractors and proposes the

establishment that should be

responsible for compliance. FDA

expects that facilities would use

accredited referral laboratories to ensure

compliance with the CGTP rule, and

therefore new costs would be associated

with § 1271.150(b). Section1271.150(c)

explains the relationship of the

proposed rule to regulations specifically

applicable to biological drugs or devices

and paragraph (d) defines the term

‘‘where appropriate’’ in relation to the

rule. Neither § 1271.150(c) nor (d)

would generate any costs for this

industry because no compliance

requirements are specified.

b. Section 1271.155—exemptions and

alternatives. The proposed rule would

allow establishments to request an

exemption or alternative from FDA for

any of the requirements of the rule.

There is currently no basis for

predicting industry requests for

exemptions or alternatives, or for

predicting the effect of these actions on

compliance costs. FDA anticipates that

very few facilities will consider it

appropriate to be exempted from the

quality standards specified in the

proposed rule.

c. Section 1271.160—establishment

and maintenance of a quality program.

The proposed rule would require that

facilities establish and maintain a

quality program. The quality program

would include: Procedures for each step

in the manufacturing process,

procedures for exchanging information

with other establishments known to

have recovered cells from the same

donor, corrective action and

documentation, training and education

of personnel, appropriate monitoring

systems, maintenance of records,

investigation and documentation of all

product deviations, other actions

necessary to assure compliance with the

quality program; assignment of

authority over the quality control

program, audits, computer software

validation, and other procedures

specific to the quality program. A

number of these functions are further

specified in subsequent provisions of

the rule, and the impact is estimated in

the context of those provisions.

In general, FDA anticipates that

almost all of the establishments in the

affected industries have the appropriate

facilities, equipment, and systems to

support comprehensive quality

management, but only those already

estimated to be following industry

standards are expected to have

comprehensive quality programs in

place. Some facilities may need to

upgrade their quality program for

several of the proposed requirements.

These include: Procedures for sharing

information, corrective actions, and

investigations. Further, some facilities

may need to take additional steps to

administer corrective actions and

conduct investigations, if they currently

do so only when major deviations arise.

Although sharing of information is an

industry-wide practice, some small

facilities, particularly those not

following current industry standards,

may not have written procedures and

reporting forms for this task. FDA

estimates that 95 percent of industry eye

banks would need to revise a major

procedure; 23 percent of other

conventional tissue banks, not following

the current AATB standard, would need

to write a major procedure to comply

with this requirement; 80 percent of the

peripheral blood stem cell facilities not

following the FAHCT or AABB

standards would need to prepare a

major procedure; and 5 percent of sperm

banks and 5 percent of ART facilities

would need to prepare a major

procedure to address this requirement.

Although FDA anticipates that most

industry facilities take steps to

administer corrective actions and

conduct investigations, some may

currently do so only when major

deviations arise.

FDA estimates that 95 percent of eye

banks, 23 percent of conventional tissue

banks, 80 percent of stem cell facilities,

and 5 percent of sperm banks and ART

facilities, would need to invest

additional time. The incremental time

for the laboratory director to administer

corrective actions and document these

activities is estimated to be an

additional half-hour per month of

laboratory director time at eye banks

that already perform this activity to a

lesser extent, and an additional hour per

month at all other facilities that will be

newly affected by this provision. As

shown in table 2 in § 1271.160(b)(7) of

the background papers prepared by FDA

and Eastern Research Group Inc., (ERG)

for newly required investigations in

tissue facilities, FDA estimates an

additional cost per year of $2,022 for an

additional 2 hours per month for the

laboratory director to investigate and

document deviations, and an additional

half hour each for the laboratory

supervisor and technician to participate

in the investigations.

A number of facilities would also

institute other requirements of the

quality program, including audits,

computer software validation, and

procedures specific to the quality

program. Audits are part of the industry

standards published by the AATB, the

EBAA, by FAHCT and the AABB.

However, some facilities following these

standards may need to do some

additional recordkeeping, and facilities

not following standards would begin to

conduct audits. Referring to table 2,

FDA assumes that up to 95 percent of

eye banks would increase their audit

efforts, including additional lab director

time to perform the audit and additional

1530 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

hours of preparation for the annual

audit. An estimated 23 percent of

conventional tissue banks, and an

estimated 50 percent of ART facilities,

would allocate additional resources for

annual audits, with a higher allocation

of hours at larger facilities, to prepare

for, and to conduct the audit. For stem

cell facilities, FDA estimates that there

would be no additional auditing

required at facilities following FAHCT

or AABB standards, but an estimated 80

percent of facilities not following

industry standards would need to spend

additional time to prepare for and to

conduct an audit each year. It is also

assumed that approximately 5 percent

of sperm banks would allocate

additional staff hours for these auditrelated activities.

In addition to performing the annual

audit, the proposed rule would require

preparation of an annual audit report.

Facilities following current industry

standards may need to increase the time

for reporting.

FDA estimates that 95 percent of

industry eye banks will experience an

increase of approximately 2 hours per

year of lab director time for preparing

the audit report. The 23 percent of

conventional tissue facilities not

following AATB standards are estimated

to devote 4 hours of lab director time,

in the case of small facilities, and 8

additional hours of lab director time at

large facilities for the preparation of an

annual audit report. Laboratory

directors of 95 percent of the stem cell

facilities, 5 percent of sperm banks, and

33 percent of ART facilities, would

spend an estimated additional 3 hours

to prepare the annual audit report.

Approximately 17 percent of ART

facilities would also be affected, with an

increase of approximately 6 hours per

year of staff time for audit report

preparation.

Section 1271.160 of the proposed rule

further stipulates that facilities would

be required to validate the computer

software used in their operations. The

FDA assumes that off-the-shelf

commercial software packages for

particular applications are already

validated by the software vendor, but

that a facility’s custom software would

require complete software validation.

FDA assumes that none of the affected

facilities currently validate their custom

software and that approximately 10

percent of eye, conventional tissue and

stem cell facilities, and approximately 5

percent of reproductive tissue facilities

have developed custom software that

would require full software validation

under the proposed rule. While the

scope of such work can vary, FDA

estimates that the custom software in

use has a limited scope of application,

and an average of 60 hours of work by

the laboratory supervisor would be

required to validate custom software at

a facility. Detailed presentations of these

assumptions are provided in section

2.4.3 of the background reports by FDA

and ERG.

The last requirement for the quality

control program is for procedures that

stipulate how the quality program

should be operated. Industry

consultants indicate that facilities have

quality systems in place, but that most

facilities are not aware of some minor

elements that should be included in the

procedures. Consequently, inspectors

for accreditation groups often find a few

deficiencies during initial visits. FDA

estimates that about 95 percent of eye

banks, 23 percent of conventional

tissue, and up to 80 percent of stem cell

facilities, sperm banks and ART

facilities will have minor deficiencies

that would require them to revise one

minor and one major procedure. In

addition, FDA estimates that 5 percent

of all eye banks, conventional tissue,

reproductive tissue facilities, and

industry non-compliant stem cell

facilities, may identify major

deficiencies, and would need to prepare

five minor procedures and one major

procedure to address those problems.

The agency further assumes that

facilities may generally need to do some

additional quality control work to

comply with the quality control

program requirements in the CGTP rule.

Although some tasks would not take any

additional time to perform, FDA

estimates that one additional hour per

month each for the laboratory director

and supervisor may be needed. FDA

estimates that 95 percent of all eye

banks, 23 percent of conventional tissue

banks and approximately 80 percent of

stem cell facilities and reproductive

tissue facilities would allocate this

additional staff time.

d. Section 1271.170—organization

and personnel. The proposed rule

would require facilities to employ

sufficient personnel with the necessary

education and experience to complete

their tasks. Personnel would be trained

to perform their work adequately. The

EBAA, AATB, FAHCT, and AABB

standards for quality assurance all

include provisions for appropriate

personnel qualifications and training,

and recordkeeping related to this

requirement. It is expected that most

facilities for eye banking, conventional

tissue banking, and stem cell production

already follow these practices as

proposed. The fraction of facilities in

conventional tissue and stem cell

manufacturing that do not follow

industry standards would incur new

costs. Similarly, 5 percent of the

facilities in the reproductive tissue

industries would incur some new costs

associated with hiring staff that meet

formal training requirements. The cost

of this staffing effort is estimated to be

approximately $15,560 per affected

facility.

FDA anticipates that the 23 percent of

conventional tissue facilities, 95 percent

of industry-noncompliant stem cell

facilities, 5 percent of sperm banks, and

5 percent of small ART facilities would

incur new training costs in complying

with the proposed rule. For a small

tissue establishment, these costs are

estimated to average $2,348. The

proposed CGTP would also require that

records of personnel qualifications and

training be maintained, but because the

incremental record keeping is minimal,

FDA assumes that the cost to comply

with this requirement would be

negligible. Detailed presentations of

these assumptions are provided in

section 2.4.4 of the background reports

by FDA and ERG.

e. Section 1271.180—procedures:

general requirements. The proposed rule

would require establishments to keep

written procedures for all steps

performed during manufacturing of

human cellular or tissue-based

products, and to perform an annual

review. FDA anticipates a negligible

incremental cost for most facilities

following industry standards, and an

additional 120 hours by the laboratory

director for facilities not following the

current industry standards. FDA

estimates that 5 percent of eye banks

would need to expand their current

review efforts, and that 23 percent of

conventional tissue banks, 95 percent of

stem cell facilities, and 50 percent of

reproductive tissue facilities would

incur new costs for an annual review.

f. Section 1271.190—facilities. The

proposed rule stipulates a number of

requirements regarding the construction

of facilities, covering size, location,

lighting, ventilation, plumbing,

drainage, and toilet and washing

facilities. The facility would also be

required to have properly divided areas

for appropriate quality control. Cleaning

requirements are also outlined,

including requirements for written

procedures and schedules for cleaning

and documentation of cleaning

activities. Based on discussions with

industry experts, FDA estimates that

nearly all facilities that follow industry

standards would not incur new costs

under the proposed CGTP rule.

However, some establishments that

generally adhere to cleaning standards

do not have written procedures. FDA

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1531

estimates that 5 percent of all eye banks,

in addition to 23 percent of the

conventional tissue banks, 95 percent of

all stem cell facilities, and 5 percent of

reproductive tissue facilities would

incur the cost of writing a minor

procedure for cleaning. The facilities

provision of the CGTP also would

require that records of cleaning be

maintained. This proposed requirement

is currently practiced by most facilities,

and is expected to have a negligible

impact on facilities not following

industry standards.

g. Section 1271.195—environmental

control and monitoring. The proposed

rule would require that procedures be

written for environmental control and

monitoring activities or systems where

an environmental condition could have

an adverse effect on the human cellular

or tissue-based product. The rule also

would require that environmental

control systems be regularly inspected

and that control and monitoring

activities be documented. The impact of

this provision of the CGTP varies by

industry sector. For eye banking, the

EBAA standards already contain

relevant provisions, however, some

additional costs may be incurred for

annual inspection of the environmental

control systems and for keeping records

of environmental control and

monitoring activities. It is estimated that

5 percent of eye banks may incur new

costs for inspection and certification of

equipment. FDA anticipates that the

conventional tissue facilities following

AATB standards would experience no

new costs, but that the remaining 23

percent of facilities would need to

prepare a minor procedure to control

and monitor ventilation and air

filtration.

The current FAHCT and AABB

standards do not provide for written

procedures for environmental control

and monitoring. FDA therefore

estimates that 95 percent of all stem cell

facilities would need to develop a minor

procedure to control and monitor

ventilation and air filtration to comply

with the CGTP. However, because the

industry standards provides for

appropriate environmental controls,

FDA assumes that some facilities are

currently performing control activities.

The agency estimates that as many as

half of the facilities currently following

standards may already be conducting

routine inspections of their

environmental control equipment. It is

assumed that the remaining 50 percent

of those facilities, and 95 percent of

facilities assumed not to be following

industry standards, would incur

additional costs to inspect equipment

and perform recordkeeping related to

environmental control.

The agency also assumes that most

reproductive tissue facilities would

need to prepare written procedures, and

do additional recordkeeping in

compliance with the CGTP. FDA

estimates that 80 percent of all sperm

banks and ART facilities would incur

costs to comply with this provision of

the proposed rule. FDA also estimates

that 20 percent of ART facilities would

increase ventilation systems inspection

activities. Table 2 provides estimates of

cost per facility associated with these

efforts.

h. Section 1271.200—equipment. The

proposed rule stipulates that

appropriate equipment be used and any

equipment used be validated. Cleaning,

maintenance, and calibration of

equipment would be performed

according to established schedules and

procedures; equipment would be

regularly inspected for adherence to

applicable procedures and schedules;

and all such activities would be

documented. In addition, facilities

would be required to keep records of

each use of each piece of equipment,

including the identification of each

human cellular or tissue-based product

manufactured with that piece of

equipment.

The standards related to equipment,

as specified by AATB, EBAA, FAHCT,

and AABB generally address

maintenance procedures, and

recordkeeping related to maintenance.

However, the proposed rule extends

beyond the industry standard for EBAA,

FAHCT and AABB in the areas of

equipment inspection and

recordkeeping. FDA therefore estimates

that 95 percent of all eye banks would

allocate an additional half-hour per

month for the laboratory supervisor to

inspect equipment, an additional half

hour per month of technician time to

documenting equipment cleaning and

calibration, and two additional hours of

technician time per month in recording

each use of the equipment.

The estimated 23 percent of

conventional tissue facilities that

currently do not follow AATB standards

would also incur new costs related to

equipment quality control. FDA

estimates that small facilities would

prepare one minor procedure for

calibration, and for cleaning and other

maintenance for each of six pieces of

equipment. In addition, small facilities

will allocate an additional hour per

month of lab supervisor time for routine

inspection of equipment, an additional

hour per month of technician time for

documentation of cleaning and

calibration, and 4 hours per month

recording each use of the equipment.

FDA estimates large facilities would

write minor procedures for each of eight

pieces of equipment, and would allocate

an additional 2 hours per month of lab

supervisor time for routine inspection of

equipment, an additional 2 hours per

month of technician time to record

cleaning and calibration activities, and

an additional 8 hours of technician time

per month to record each use of each

piece of equipment. It is anticipated that

the facilities simultaneously preparing

multiple procedures related to

equipment would realize some

economies of scale because of

similarities across procedures. This is

expected to result in a savings of 30

percent in the total amount of staff time

to prepare six to eight equipment

maintenance procedures at one time.

Stem cell facilities also would be

expected to perform some additional

work to align current practice with the

proposed CGTP requirements. Current

FAHCT procedures provide for routine

maintenance and calibration of

equipment. In addition, the AABB

standards recommend that standard

operating procedures (SOP’s) be

established for proper equipment

maintenance and monitoring. To further

develop procedures to address routine

maintenance and recordkeeping under

the proposed CGTP, FDA estimates that

95 percent of all stem cell facilities

would prepare a minor procedure for

calibration of each of six pieces of

equipment. In addition to the

preparation of procedures, lab personnel

would carry out the maintenance work,

estimated to require an additional half

hour of supervisor time per month in

routine inspection of equipment, an

additional half hour per month for

technicians to document cleaning and

calibration work, and an added 4 hours

per month of technician time to record

each use of equipment. In addition,

most stem cell facilities that do not

currently follow FAHCT or AABB

standards would incur the cost of

preparing a minor procedure for

cleaning, for sanitizing and for routine

maintenance of six pieces of equipment.

In the reproductive tissue industry,

the agency estimates that all facilities

have the appropriate equipment to

process the tissue products, but that

only a small percentage currently

conduct recordkeeping and have written

procedures related to maintenance,

calibration and other activities as

specified under the proposed CGTP.

The agency estimates that 90 percent of

sperm banks and ART facilities would

develop additional procedures, and that

100 percent of these facilities would

need to perform additional

1532 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

recordkeeping related to equipment use.

In addition, an estimated 5 percent of

sperm banks, and 50 percent of ART

facilities would devote additional

resources to routine calibration of

equipment. An estimated 5 percent of

facilities would need to also increase

efforts in routine inspection, and record

keeping related to equipment cleaning

and maintenance. The costs per facility

associated with each of these areas of

activity are presented in table 2. Section

2.4.8 of the ERG background paper

provides a detailed presentation of these

assumptions.

i. Section 1271.210—supplies and

reagents. The proposed rule would

require that procedures be established

for receipt of supplies and reagents used

in the manufacture of human cellular

and tissue-based products. In particular,

manufacturers would be required to

verify that supplies and reagents meet

specifications designed to prevent

transmission of communicable disease

and impairment of product function and

integrity. Verification of supply or

reagent quality could be accomplished

with a certificate of analysis. The

proposed rule would also require

documentation of receipt, verification,

and each use of a supply or reagent in

product processing.

The existing industry standards

address some or all of these activities,

and the estimated impact per facility

varies accordingly. EBAA standards

specify that sterilized supplies and

reagents should contain sterilization

dates, method or appropriate expiration

dates. However, the agency estimates

that up to 95 percent of eye banks

would be required to develop additional

procedures related to receipt and

verification, and would devote

additional staff time to recording the

receipt of supplies and reagents.

Similarly, FAHCT and AABB standards

contain provisions for quality control in

the storage, handling and use of

supplies and reagents, including

maintenance of records. However, FDA

expects that approximately 95 percent

of stem cell facilities may be required to

expand on their current SOP’s and

recordkeeping in order to comply with

the CGTP provisions.

The current AATB standards address

most of the requirements for supplies

and reagents included in the proposed

rule. FDA assumes that the estimated 23

percent of facilities that follow these

standards would be required to prepare

additional procedures for in-house

reagent verification, for receipt and

verification, and would devote

additional staff time to keeping records

of the receipt of supplies and reagents.

Based on consultant estimates that 95

percent of commercial sperm banks

follow AATB guidelines, the agency

estimates that only 5 percent of sperm

banks and 80 percent of ART facilities

would need to take new steps to comply

with this proposed CGTP provision. For

these facilities, the agency anticipates

that each facility would need to prepare

new procedures for receipt and

verification of supplies and reagents,

and each will devote additional staff

time to recording the receipt of these

materials. The estimated costs per

facility are presented in table 2.

j. Section 1271.220—process controls.

The proposed rule would require

facilities to monitor manufacturing

processes to ensure that specified

requirements for the product are met.

This includes having written procedures

for the use and removal of processing

material that can damage products, and

procedures for in-process monitoring.

The standards for tissue banking

specified by the AATB include activities

to address these process controls, but

the EBAA, FAHCT, and AABB

standards do not include specific

requirements for monitoring and

removal of processing material that may

damage the product. FDA estimates that

95 percent of eye banks, 23 percent of

conventional tissue banks, 95 percent of

stem cell facilities, and 90 percent of

sperm banks and ART facilities would

need to prepare a minor procedure

related to monitoring and removal of

damaging processing material.

Consultants estimate that most

reproductive tissue facilities have

procedures for in-process monitoring,

and in these industries, an estimated 5

percent of reproductive tissue facilities

would need to prepare procedures to

address this activity.

k. Section 1271.225—process

changes. The proposed regulation

would require establishments to

institute process change procedures that

will govern modifications to established

operations. Changes to processes would

be documented with the date of the

change, the date of implementation, the

rationale for the change, and

appropriate approval signatures. The

current standards for AATB, FAHCT

and the AABB provide for SOP’s for

process changes, although

recordkeeping procedures are not

specified. Current EBAA standards do

not provide for SOP’s for process

changes. FDA therefore estimates that

nearly all eye banks would be required

to prepare a major procedure for process

changes, and would allocate an

additional half hour of lab director time

to document process changes.

FDA anticipates that conventional

tissue banks not following the AATB

standard would need to prepare a major

procedure related to process changes,

and nearly all tissue banks would

increase related recordkeeping. The

agency estimates that small

conventional tissue banks would spend

an additional half hour per month of lab

director time to document process

changes, and large facilities would

allocate an additional hour of lab

director time for this. FDA anticipates

that almost all stem cell facilities that do

not follow FAHCT or AABB standards

would need to prepare a major

procedure to address process changes.

In addition, FDA estimates that 95

percent of all stem cell facilities would

allocate an additional half hour of

laboratory director time to document

process changes.

According to industry contacts, most

sperm banks already have established

written procedures for process changes,

and would therefore be in compliance

with this proposed provision. FDA is

also informed that ART facilities follow

standards for process changes, but the

procedures may not be in writing. In

addition, industry consultants estimate

that many reproductive tissue facilities

may not keep written records of their

process changes. Based on these

characterizations, FDA estimates that

approximately 5 percent of sperm banks

and 90 percent of ART facilities would

need to develop a written procedure for

process changes. In addition, the agency

estimates that 90 percent of sperm banks

and ART facilities would need to

allocate additional staff time (an

estimated one half-hour per month at

small facilities and one hour per month

at large facilities) to record changes. The

associated costs per facility are

presented in table 2.

l. Section 1271.230—process

validation. The proposed rule would

require facilities to validate processes

that cannot be verified through

subsequent inspection and testing.

Current EBAA standards do not require

process validation. Although current

AATB, FAHCT, and AABB standards

include provisions for process

validation and related recordkeeping,

industry experts indicate that additional

validation work would be required at

nearly all facilities under the proposed

rule. FDA therefore estimates that 95

percent of all eye banks, of all

conventional tissue banks and all stem

cell facilities, not compliant with AABB

or FAHCT, would need to prepare two

major procedures related to process

validation, and 95 percent of

conventional tissue banks and AABB/

FAHCT-compliant stem cell facilities

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1533

would need to revise two major

procedures. FDA estimates that 95

percent of all facilities in the tissue

industry would devote additional staff

time for process validation.

In addition to the initial validation

work, CGTP would require revalidation

of procedures. The agency estimates that

95 percent of eye banks, conventional

tissue banks and stem cell facilities

would need to allocate an additional

amount (on the order of 20 to 40 hours)

of laboratory staff time for annual

revalidation.

Reproductive tissue industry

consultants considered that the process

validation requirement would have

limited application to this industry

because the tissues involved in

laboratory processes (e.g., sperm and

ova) are not uniform in quality.

However, quality control through inprocess monitoring (under § 1271.220)

would be applicable to these tissues.

m. Section 1271.250—labeling

controls: procedures. The proposed rule

would require facilities to establish and

maintain written procedures for

controlling the labeling of products. The

procedures would ensure proper

identification of products and include

various checks and verifications. Each

product would also be accompanied by

donor suitability information, if

applicable. Other labeling requirements

would also be met, such as labeling

products appropriately with the

required information.

According to consultants and industry

contacts, labeling controls are usual and

customary practice in the industry. FDA

anticipates that only about 5 percent of

all facilities in eye banking, in

conventional tissue banking, in stem

cell processing and in the reproductive

tissue industries would need to do

additional work to comply with the

proposed labeling controls. FDA

estimates that such facility would need

to revise a major procedure for proper

identification of products.

n. Section 1271.260—storage. The

proposed rule would require that

storage areas be controlled to prevent

mix-ups and contamination.

Temperature should be monitored and

limits established, including expiration

dating where appropriate. Each of the

relevant industry standards contains

provisions regarding storage practices.

Based on agency review of current

industry standards, and conversations

with experts about current practices at

facilities, FDA anticipates that virtually

all facilities follow industry standards

that would comply with this provision

of the proposed CGTP. These provisions

of the proposed rule are therefore

expected to produce no new cost impact

for facilities in eye banking,

conventional tissue banking, stem cell

processing, and reproductive tissue.

o. Section 1271.265—receipt and

distribution. The proposed rule would

require that procedures be established

and maintained for receiving, rejecting,

distributing, and disposing of human

cellular or tissue-based products.

Documentation of each of those

activities, when performed, would also

be required. Packaging and shipping

containers would be validated and

appropriate shipping conditions must

be defined. Procedures would also be

established to determine whether

products returned to an establishment

are suitable to be returned to inventory.

Agency review of current industry

standards indicates that provisions

related to this area of quality control,

except for package validation, are

included in each of the relevant

standards.

The primary impact of the proposed

CGTP provisions for product receipt and

distribution thus involves packaging

validation for most facilities, and

procedures development for facilities

that do not currently follow industry

standards. FDA estimates that 95

percent of eye banks, conventional

tissue banks and stem cell facilities

would allocate approximately 4 extra

hours per month for a laboratory

technician to validate packaging,

particularly packaging changes. In

addition, an estimated 5 percent of eye

banks, conventional tissue banks, and

stem cell facilities would increase lab

supervisor time to document receipt of

products.

The agency estimates that

conventional tissue banks not following

AATB standards would need to revise

one major procedure for receiving

products, revise one major procedure

related to distribution of products, and

prepare a minor procedure for return of

products to inventory. FDA estimates

that 95 percent of stem cell facilities

would need to write one major

procedure addressing receiving

activities. Facilities following FAHCT or

AABB standards would also need to

revise a major procedure for product

distribution, while all other facilities

would need to prepare a new major

procedure for product distribution as

well as a minor procedure for handling

of products returned to inventory.

According to industry contacts, most

sperm banks and ART facilities have a

protocol for receiving and distributing

reproductive tissue products, however,

an estimated 5 percent of facilities

would need to write a major procedure

for receiving activities and one for

distribution. Similarly, an estimated 5

percent of facilities do not currently

follow industry standards for product

documentation. The agency estimates

that an additional 4 to 8 hours of staff

time per month would be required by

those facilities, for documentation

activities. Industry consultants indicate

that although most reproductive tissue

facilities utilize ‘‘dry shippers’’ for

shipped products, most do not perform

formal packaging validation. FDA

therefore estimates that all facilities

would be required to perform packaging

validation, in compliance with the

proposed CGTP. Experts in the

reproductive tissue industry also

consider it unusual for a product to be

returned to inventory; given the

potential risk of product deterioration or

damage. It is expected that most sperm

banks already have a formal procedure

for handling returned product, and that

ART facilities generally have an

established protocol, but not a written

procedure. The agency estimates that

approximately 5 percent of sperm banks

and 100 percent of ART facilities

therefore would be required to write a

minor procedure to comply with this

proposed CGTP requirement. The costs

per facility for these activities are

presented in table 2.

p. Section 1271.270—records. The

proposed rule would require that

records be maintained for any

significant step in the manufacturing

process. A records management system

would need to be in place and

procedures would need to be

established for keeping records

associated with donor suitability record

keeping requirements. Records would

be maintained for at least 10 years. The

proposed rule would also require that

records be kept of any contracts or

agreements. Although many

components of the required

recordkeeping system are addressed

under separate provisions of the

proposed CGTP, there may be a few

minor gaps in the records system of a

facility that would be addressed under

this general provision. FDA therefore

estimates that approximately 95 percent

of all eye banks, conventional tissue

banks, and stem cell facilities that

follow FAHCT or AABB standards,

would be required to write at least one

minor procedure, and revise one major

procedure related to recordkeeping.

The agency also estimates that

additional lab director time would be

allocated (estimated 40 hours at small

facilities and 80 at large facilities) to set

up enhanced recordkeeping where a

system is already in place. System

enhancement would be performed at an

estimated 95 percent of eye banks, 23

percent of conventional tissue facilities,

1534 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

95 percent of stem cell facilities, 5

percent of sperm banks, and 50 percent

of the ART facilities.

Various industry standards specify

record retention, although the time

periods vary somewhat. Of those

facilities following industry standards,

approximately 95 percent of eye banks

and the 77 percent of conventional

tissue banks retain records for at least 10

years, and the remainder retain records

for a minimum of 5 years. For these

facilities, and the stem cell facilities that

do not currently follow industry

standards, FDA estimates increased

record retention costs based on the cost

of storing an additional 5 boxes (2.4

cubic feet each) of records per year for

5 years. The retention standards of

FAHCT and AABB for records related to

products are different from those

concerned with facility and equipment

maintenance and personnel training. All

records related to the product should be

retained indefinitely and records related

to facility and equipment maintenance

and personnel training should be

retained for only 5 years.

FDA estimates that a half of the

records at stem cell facilities following

industry standards would need to be

retained for an additional 5 years, and

the annual cost will be comparable to

that of other small tissue facilities. The

agency also estimates that nearly all

stem cell facilities that are not following

industry standards will increase record

retention. Almost all stem cell facilities

that do not follow industry standards

would be required to prepare at least

one minor procedure and to revise a

major procedure related to record

keeping. The laboratory director at these

facilities would be expected to allocate

40 hours of time to improving the

facility’s current recordkeeping system.

Consultants estimate that within the

reproductive tissue industries all

facilities have some record management

system, and many facilities have

systems that meet the requirements of

the proposed rule. Consultants estimate

that most sperm banks and the currently

accredited ART facilities have adequate

records management systems in place,

but that approximately 5 percent of

sperm banks, and about 50 percent of

the ART facilities would need to

allocate additional laboratory staff time

(i.e., 40 hours at small facilities and 80

hours at larger facilities) to enhance

their current recordkeeping system in

compliance with the proposed rule.

In addition, FDA is informed that the

usual and customary practice in most

ART facilities is to retain donor records

for an indefinite period. Usual and

customary practice in sperm banks is to

retain records for at least 15 years, thus

more than the 10-year period specified

in the proposed rule. It is estimated that

only 5 percent of sperm banks and ART

facilities would need to extend record

retention by an estimated 5 years. The

additional cost of storing these files is

based on an assumption of 5 boxes (each

approximately 2 cubic feet)

accumulated per year at small facilities,

and 10 boxes per year at large facilities,

for an additional 5 years, at a cost of 30

cents per cubic foot per year. The

estimated costs per affected facility are

summarized in table 2.

q. Section 1271.290—tracking. The

proposed rule stipulates the steps

needed to properly track a product from

donor to recipient and vice versa. The

proposed CGTP would require that

facilities maintain a method for product

tracking and that each product be

assigned and labeled with a unique

identifier. If a new identifier is assigned

during the manufacturing process,

procedures would be required for

relating the new identifier to the old

identifier. Records of product transfers

would be kept in the recipient’s medical

records. The facility that manufactured

the product would also keep track of the

disposition of each product, so that the

recipient of the product can be easily

identified. Facilities would be required

to inform consignees of the established

tracking method and would be required

to document that consignees agreed to

participate in their tracking method.

Product ‘‘traceability’’ is a familiar

concept and common practice in eye

banking, in conventional tissue banking,

and in the stem cell processing industry.

Eye banks following EBAA standards

maintain records with information that

permits tracing of product from the

donor source to the patient recipient,

working through the surgeon who

performed the procedure. FDA

anticipates that only 5 percent of eye

facilities would need to enhance current

tracking, and would be required to

prepare one major procedure related to

product tracking, spend additional staff

time each month to identify and

document recipient information, and

would allocate additional laboratory

director time to institute agreements for

information sharing with the consignees

who will receive products.

Conventional tissue facilities

following AATB standards are able to

trace all products from donation source

to product recipient. Conventional

tissue facilities not following AATB

requirements would be required to

revise a major procedure to address

product tracking, allocate additional

staff time each month to obtain and

record information about product

recipients, and allocate some additional

laboratory director time (on a one-time

basis) to institute formal contracts with

consignees. The FAHCT and AABB

standards for product tracking in stem

cell facilities recommend that the

facility be able to trace products to final

distribution or disposition, but do not

specify that formal agreements be

established with consignees to assure

timely tracking of products. FDA

therefore estimates that 95 percent of

stem cell facilities would, on a one-time

basis, allocate an additional 20 hours of

laboratory supervisor time to institute

agreements for information sharing with

the consignees who will receive

products. In addition, FDA estimates

that 95 percent of stem cell facilities

that are not following FAHCT or AABB

standards would need to revise a major

procedure related to product tracking,

and would need to allocate additional

staff hours each month for recipient

identification and documentation.

Consultants for the reproductive

tissue industry indicate that although

sperm banks and ART facilities

generally perform product tracking and

adhere to the practice of documenting

recipient information for products,

current practices in assigning and

documenting products with unique

identifiers throughout tissue processing

may widely vary, and there may be little

documentation of tracking agreements

with consignees. Most reproductive

tissue facilities therefore would need to

review current systems and perform

some enhancements. It is estimated that

80 percent of reproductive tissue

facilities would need to revise a major

procedure related to product tracking,

and would allocate additional staff

hours each month for recipient

identification and documentation. In

addition, approximately 80 percent of

facilities would need to allocate lab

supervisor time to institute agreements

for information sharing with the

consignees who will receive products.

The estimated cost per facility to

perform these activities are presented in

table 2.

Hospitals generally handle all

categories of cellular and tissue-based

products. For accreditation by the Joint

Commission on Accreditation of

Healthcare Organizations (JCAHO),

organizations that store tissue must keep

records that permit tracing of any tissue

from the donor or source facility to all

recipients or other final dispositions.

The records must include

documentation of tissue use in the

patient’s clinical record. Most hospitals

are accredited and, therefore, are

presumed to be tracking tissue to

recipient. We believe that hospitals not

accredited tend to be specialized

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1535

facilities not handling cellular and

tissue-based products. Because we know

of no hospital receiving tissues and not

currently tracking tissue to recipient, we

expect hospitals to incur no additional

costs as a result of this regulation.

However, as some of our sources (Ref.

45) lack conclusive data on the

adequacy of hospital recordkeeping, we

welcome comment on this matter.

The proposed rule would also require

that specimens of dura mater be

archived for the appropriate duration

under appropriate conditions to enable

future testing for evidence of TSE. FDA

recommends that the specimens be

archived for 16 years beyond the

expiration date. As CDRH guidance

already recommends that such

specimens be archived for 10 years, this

requirement would not impose an

additional tracking burden. FDA

assumes the incremental cost of the

longer storage time to be extremely

small and the overall cost impact to be

negligible.

r. Section 1271.320—complaint file.

The proposed rule would require

facilities to maintain procedures for

reviewing and evaluating complaints

and to maintain a file for these

complaints. Facilities would be required

to review and evaluate complaints and

to determine whether each complaint

represents an event that should be

reported to FDA. Documentation of the

review and evaluation would be

required, even if no investigation is

made. FDA finds that the AATB,

FAHCT, and AABB standards explicitly

address procedures or recordkeeping

related to complaints. Based on

discussions with industry experts, the

agency assumes that nearly all facilities

currently track, albeit informally, the

complaints received from consignees

and recipients. Facilities that would be

required to prepare written procedures

for handling complaints, and to review

complaints on a yearly basis, would

incur additional costs. The agency

estimates that additional costs for

facilities to maintain a complaint file

would be negligible.

To fully comply with provisions in

the proposed rule, FDA estimates that

95 percent of all eye banks would revise

a minor procedure to include the

required handling of complaints, and

would allocate some additional staff

time each year to review complaints.

FDA assumes that conventional tissue

facilities following AATB standards

would already perform the necessary

activities, but the estimated 23 percent

of facilities not following AATB

standards would need to prepare a

minor procedure for complaint

handling, and would allocate additional

laboratory director time each year to

review complaints that are received.

Although the industry standards for

stem cell processing provide that

records be maintained of both donor

and recipient complaints, the proposed

rule requires that facilities also have

written procedures for complaint

review. FDA therefore estimates that 95

percent of all stem cell facilities would

be required to write a minor procedure

to handle complaints, and that 95

percent of all facilities would also be

required to allocate additional time for

yearly review and handling of

complaints.

Consultants assessing the impact of

the proposed rule on the reproductive

tissue industry estimate that about 95

percent of sperm banks and ART

facilities already have written

procedures for dealing with complaints,

and that 5 percent of facilities would

need to prepare a minor procedure for

complaint handling, and would allocate

additional laboratory director time each

year to review complaints that are

received. The estimated costs per

affected facility are presented in table 2.

s. Section 1271.350—reporting. The

proposed rule would require facilities to

review adverse reaction reports and

report any adverse reactions, or product

deviations, involving transmission of

disease, or of the failure of a product

that is fatal, life-threatening, results in

permanent impairment of the body, or

requires surgical intervention. Based on

expert assessments of current industry

practices, and the inclusion of adverse

event reporting in current industry

standards, the agency expects that this

requirement, within the proposed CGTP

framework for quality management,

would impose a negligible cost on

facilities in the industry.

t. Section 1271.370—labeling and

claims. The proposed rule would

require that products be labeled clearly

and accurately, with information

including name and address of the

manufacturer, a description of the

product, and product expiration date.

The storage temperature, warnings, and

instructions would be required on the

label or on a package insert. The rule

would also require that any claims on

labeling be truthful and that any

therapeutic claim or claim of a clinical

outcome of a product would be subject

to regulation under section 351 of the

PHS Act and/or the act.

Industry consultants inform FDA that

such elements are typically present on

the labels of products manufactured by

eye banks, conventional tissue banks,

stem cell facilities, sperm banks and

ART facilities. Proper labeling is

considered very important to these

industries, to prevent misuse of the

product. In addition, these industries

generally do not make therapeutic or

related claims for their products. FDA

assumes, therefore, that the industry

would be in compliance with this

provision of the proposed CGTP rule,

and estimates that the cost impact

would be negligible.

u. Section 1271.400—inspections.

FDA could conduct inspections of any

facility subject to the proposed CGTP

rule. FDA would interact primarily with

one responsible person for each

establishment, but other personnel may

also be involved in the inspection. FDA

could inspect facilities, equipment,

processes, products, procedures,

labeling, and records, and could review

and copy any records required to be

kept under the proposed rule. The

agency estimates that all industry

facilities would be subject to this

provision of the proposed CGTP, and

that inspections would occur annually.

FDA estimates that up to 16 hours of

laboratory technician time could be

necessary, to accompany the FDA

inspector through the facility and to

support the inspector’s information

needs, and that up to 4 hours of

laboratory director time would be

needed for activities related to the

inspection. This is expected to yield a

cost of approximately $702 per facility.

v. Section 1271.420—human cellular

and tissue-based products offered for

import. The proposed rule would

require importers of human cellular and

tissue-based products to notify the FDA

district director having jurisdiction over

the port of entry through which the

product is imported or offered for

import. The product would be held

intact until it is inspected and released

by FDA.

In the cellular and tissue-based

product industries there is currently

very little use of imported tissue that

would trigger activities for facility

compliance with this provision of the

proposed CGTP. FDA therefore

estimates the current cost for industry

compliance with this proposed

requirement would be negligible.

w. Section 1271.440—orders of

retention, recall, and cessation of

manufacturing. Industry firms could

incur costs to comply with orders under

this proposed provision. There is little

available data on which to base

estimates of the future frequency and

scope of tissue industry conditions and

practices that would necessitate such

actions on the part of FDA. The agency

anticipates that product orders under

this provision would be rare. FDA

estimates that the yearly costs to

1536 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

industry resulting from such orders

would therefore be negligible.

3. Summary of One-Time and Yearly

Cost Impacts

The costs for each subsection of the

proposed rule are the product of the

estimated number of affected

establishments in the industry (table 1),

the establishment noncompliance rate

by CGTP provision, by industry sector,

and the compliance cost per

establishment (table 2). Total

compliance costs, summed by provision

of the proposed rule, are presented by

sector in tables 4 through 8. The

aggregate compliance costs for all tissue

industries are summarized in table 9.

The total annualized costs presented in

these summary tables include the

reported one-time costs, such as are

incurred to prepare new procedures,

annualized over 10 years using a 7

percent discount rate.

TABLE 4.—AGGREGATE COMPLIANCE COSTS FOR EYE BANKS

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.150 Current good tissue practice:

general $0 $0 $0

1271.155 Exemptions and alternatives $0 $0 $0

1271.160 Establishment and maintenance of a quality program $122,111 $457,459 $474,845

1271.170 Organization and personnel $0 $0 $0

1271.180 Procedures—General requirements $0 $47,196 $47,196

1271.190 Facilities $1,701 $0 $242

1271.195 Environmental control and

monitoring $0 $23,245 $23,245

1271.200 Equipment $0 $109,816 $109,816

1271.210 Supplies and reagents $10,776 $17,545 $19,079

1271.220 Process Controls $70,124 $0 $9,984

1271.225 Process changes $75,593 $44,836 $55,599

1271.230 Process validation $321,218 $85,016 $130,750

1271.250 Labelling Controls—Procedures $1,989 $0 $283

1271.260 Storage $0 $0 $0

1271.265 Receipt and distribution $0 $145,008 $145,008

1271.270 Records $369,032 $103 $52,644

1271.290 Tracking $11,845 $9,302 $10,989

1271.320 Complaint file $10,776 $59,782 $61,316

1271.350 Reporting $0 $0 $0

1271.370 Labelling and claims $0 $0 $0

1271.400 Inspections $0 $80,712 $80,712

1271.420 Human cellular and tissuebased products offered for

import $0 $0 $0

1271.440 Orders of retention, recall, destruction, and cessation of

manufacturing $0 $0 $0

Total $995,165 $1,080,020 $1,221,708

TABLE 5.—AGGREGATE COMPLIANCE COSTS FOR CONVENTIONAL TISSUE FACILITIES

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.150 Current good tissue practice:

general $0 $0 $0

1271.155 Exemptions and alternatives $0 $0 $0

1271.160 Establishment and maintenance of a quality program $77,800 $137,655 $148,732

1271.170 Organization and personnel $393,668 $63,751 $119,801

1271.180 Procedures—General requirements $0 $209,484 $209,484

1271.190 Facilities $8,544 $0 $1,216

1271.195 Environmental control and

monitoring $8,544 $5,030 $6,247

1271.200 Equipment $79,352 $62,969 $74,267

1271.210 Supplies and reagents $17,088 $5,030 $7,463

1271.220 Process Controls $21,128 $0 $3,008

1271.225 Process changes $25,169 $53,096 $56,679

1271.230 Process validation $268,024 $164,065 $202,226

1271.250 Labelling Controls—Procedures $2,736 $0 $390

1271.260 Storage $0 $0 $0

1271.265 Receipt and distribution $33,713 $146,448 $151,248

1271.270 Records $172,967 $455 $25,082

1271.290 Tracking $47,498 $101,347 $108,110

1271.320 Complaint file $8,544 $17,140 $18,356

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1537

TABLE 5.—AGGREGATE COMPLIANCE COSTS FOR CONVENTIONAL TISSUE FACILITIES—Continued

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.350 Reporting $0 $0 $0

1271.370 Labelling and claims $0 $0 $0

1271.400 Inspections $0 $77,880 $77,880

1271.420 Human cellular and tissuebased products offered for

import $0 $0 $0

1271.440 Orders of retention, recall, destruction, and cessation of

manufacturing $0 $0 $0

Total $1,164,775 $1,044,350 $1,210,189

TABLE 6.—AGGREGATE COMPLIANCE COSTS FOR STEM CELL INDUSTRIES

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.150 Current good tissue practice:

general $0 $0 $0

1271.155 Exemptions and alternatives $0 $0 $0

1271.160 Establishment and maintenance of a quality program $188,166 $473,119 $499,909

1271.170 Organization and personnel $739,100 $111,530 $216,761

1271.180 Procedure—General requirements $0 $393,300 $393,300

1271.190 Facilities 77,983 $665,000 $676,103

1271.195 Environmental control and

monitoring $77,983 $202,323 $213,426

1271.200 Equipment $387,080 $434,198 $489,309

1271.210 Supplies and reagents $113,430 $7,695 $23,845

1271.220 Process Controls $260,336 $0 $37,066

1271.225 Process changes $33,155 $108,158 $112,878

1271.230 Process validation $625,670 $275,619 $364,700

1271.250 Labeling Controls—Procedures $4,799 $0 $683

1271.260 Storage $0 $0 $0

1271.265 Receipt and distribution $446,405 $26,520 $90,078

1271.270 Records $161,856 $2,880 $25,925

1271.290 Tracking $377,103 $155,040 $208,731

1271.320 Complaint file $77,983 $144,210 $155,313

1271.350 Reporting $0 $0 $0

1271.370 Labeling and claims $0 $0 $0

1271.400 Inspections $0 $194,700 $194,700

1271.420 Human cellular and tissuebased products offered for

import $0 $0 $0

1271.440 Orders of retention, recall, destruction, and cessation of

manufacturing $0 $0 $0

Total $3,571,049 $3,194,292 $3,702,727

TABLE 7.—AGGREGATE COMPLIANCE COSTS FOR ART1 FACILITIES

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.150 Current good tissue practice:

general $0 $0 $0

1271.155 Exemptions and alternatives $0 $0 $0

1271.160 Establishment and maintenance of a quality program $272,904 $586,854 $625,709

1271.170 Organization and personnel $256,740 $25,358 $61,912

1271.180 Procedures—General requirements $0 $1,366,200 $1,366,200

1271.190 Facilities $5,909 $621,600 $622,441

1271.195 Environmental control and

monitoring $94,536 $146,342 $159,802

1271.200 Equipment $767,022 $583,549 $692,756

1271.210 Supplies and reagents $94,536 $3,596 $17,056

1271.220 Process Controls $115,834 $0 $16,492

1271.225 Process changes $341,302 $165,434 $214,028

1271.230 Process validation $0 $0 $0

1271.250 Labeling Controls-Procedures $9,481 $0 $1,350

1271.260 Storage $0 $0 $0

1538 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

TABLE 7.—AGGREGATE COMPLIANCE COSTS FOR ART1 FACILITIES—Continued

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.265 Receipt and distribution $335,612 $36,230 $84,014

1271.270 Records $612,720 $400 $87,637

1271.290 Tracking $516,010 $0 $73,468

1271.320 Complaint file $5,909 $12,254 $13,096

1271.350 Reporting $0 $0 $0

1271.370 Labeling and claims $0 $0 $0

1271.400 Inspections $0 $233,640 $233,640

1271.420 Human cellular and tissuebased products offered for

import $0 $0 $0

1271.440 Orders of retention, recall, destruction, and cessation of

manufacturing $0 $0 $0

Total $3,428,515 $3,781,457 $4,269,601

1Assisted Reproductive Technology

TABLE 8.—AGGREGATE COMPLIANCE COSTS FOR SPERM BANKS

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.150 Current good tissue practice:

general $0 $0 $0

1271.155 Exemptions and alternatives $0 $0 $0

1271.160 Establishment and maintenance of a quality program $12,105 $23,661 $25,384

1271.170 Organization and personnel $15,560 $2,348 $4,563

1271.180 Procedures-General requirements $0 $82,800 $82,800

1271.190 Facilities $299 $28,000 $28,042

1271.195 Environmental control and

monitoring $4,776 $6,592 $7,272

1271.200 Equipment $25,522 $26,286 $29,920

1271.210 Supplies and reagents $299 $162 $204

1271.220 Process Controls $5,722 $0 $815

1271.225 Process changes $698 $7,452 $7,551

1271.230 Process validation $0 $0 $0

1271.250 Labeling Controls-Procedures $349 $0 $50

1271.260 Storage $0 $0 $0

1271.265 Receipt and distribution $12,575 $1,632 $3,422

1271.270 Records $2,760 $18 $411

1271.290 Tracking $27,664 $0 $3,939

1271.320 Complaint file $299 $552 $594

1271.350 Reporting $0 $0 $0

1271.370 Labeling and claims $0 $0 $0

1271.400 Inspections $0 $14,160 $14,160

1271.420 Human cellular and tissuebased products offered for

import $0 $0 $0

1271.440 Orders of retention, recall, destruction, and cessation of

manufacturing $0 $0 $0

Total $108,628 $193,663 $209,127

TABLE 9.—SUMMARY OF AGGREGATE COMPLIANCE COSTS FOR ALL TISSUE INDUSTRIES

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.150 Current good tissue practice:

general $0 $0 $0

1271.155 Exemptions and alternatives $0 $0 $0

1271.160 Establishment and maintenance of a quality program $673,085 $1,678,748 $1,774,580

1271.170 Organization and personnel $1,405,068 $202,987 $403,038

1271.180 Procedures—General requirements $0 $2,098,980 $2,098,980

1271.190 Facilities $94,435 $1,314,600 $1,328,046

1271.195 Environmental control and

monitoring $185,839 $383,532 $409,991

1271.200 Equipment $1,258,976 $1,216,819 $1,396,069

1271.210 Supplies and reagents $236,129 $34,028 $67,648

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1539

TABLE 9.—SUMMARY OF AGGREGATE COMPLIANCE COSTS FOR ALL TISSUE INDUSTRIES—Continued

Section Title One-Time Costs Annual Costs Total Annualized Costs

1271.220 Process Controls $473,145 $0 $67,365

1271.225 Process changes $475,917 $378,976 $446,735

1271.230 Process validation $1,214,911 $524,700 $697,675

1271.250 Labelling Controls—Procedures $19,354 $0 $2,756

1271.260 Storage $0 $0 $0

1271.265 Receipt and distribution $828,305 $355,838 $473,770

1271.270 Records $1,319,336 $3,856 $191,700

1271.290 Tracking 980,120 265,690 405,237

1271.320 Complaint file $103,510 $233,937 $248,675

1271.350 Reporting $0 $0 $0

1271.370 Labelling and claims $0 $0 $0

1271.400 Inspections $0 $601,092 $601,092

1271.420 Human cellular and tissuebased products offered for

import $0 $0 $0

1271.440 Orders of retention, recall, destruction, and cessation of

manufacturing $0 $0 $0

Total $9,268,130 $9,293,783 $10,613,357

B. Estimated Benefits of the Proposed

Rule

The overall purpose of the CGTP rule

is to prevent the introduction,

transmission, or spread of

communicable disease through the use

of human cellular and tissue-based

products. Although industry quality

standards exist for most of the affected

products, not all members of the

industry follow these standards. FDA

finds that public safety cannot be

assured or effectively protected through

reliance on this less formal and

voluntary mechanism for quality

assurance. The existing industry

standards vary to some extent in their

comprehensiveness. Moreover, there are

variations in the extent to which the

industry follows these standards.

For example, most industry

consultants for the cost analysis agree

that quality standards, such as those

proposed by the FDA, and similar

standards recommended by industry,

could substantially reduce the risk of

product contamination and product

failure. However, most experts also

opined that, because additional costs are

associated with maintaining higher

quality standards, and because there is

no explicit patient demand for higher

quality standards to prevent

contamination risks, some facilities are

not currently following adequate quality

control standards. A regulatory

requirement for quality systems would

provide the incentive needed to bring

all facilities to a more uniform and

appropriately high standard of quality.

The primary beneficiaries of the

proposed CGTP rule would be the

patients who receive the cellular and

tissue-based products. Benefits to

patients would result from the reduced

risk of communicable disease by

avoiding product contamination or

product failure through CGTP. The

discussion that follows considers the

potential benefit of avoided problems

with tissue products, based on a survey

of the clinical literature.

Recent clinical literature indicates

that each type of tissue product

considered in the proposed rule has

documented contamination or other

product problems resulting from

processing, or other steps in

manufacturing. These reported quality

problems provide a basis for assessing

the magnitude of the potential benefit

from further reducing events that

increase the risk of communicable

disease transmission. In cases involving

eye tissue, conventional tissue, or stem

cell products, problems have required

medical intervention to treat infection,

or to replace an implanted defective

product. In some clinical applications,

product failures have increased the risk

of patient mortality. In other

applications, such as embryo

processing, poor product quality is

associated with lower success rates (i.e.,

pregnancy rates) among treated patients,

which results in an increase in transfer

attempts. In general, FDA anticipates

that the risk of communicable disease

transmission from product quality

problems will decline as a result of

compliance with the proposed CGTP.

The sections that follow describe

product-related problems associated

with communicable disease

transmission that are at least partly

attributable to a lack of uniform quality

standards in manufacturing. The costs

related to correcting these problems are

considered, in order to gauge the

potential magnitude of the benefits

associated with improved quality in

manufacturing. The discussion is

organized by types of tissue product.

1. Eye Tissue Products

Primary corneal graft failure is a key

adverse outcome of concern following

corneal tissue transplant. Such failures

result in additional graft attempts. Each

attempt increases the risk of

communicable disease transmission by

exposing the recipient to another tissue

product and to another surgical

procedure. Although primary corneal

graft failure is relatively uncommon, its

occurrence has been attributed to

several factors related to tissue

collection, processing and product

distribution. These factors include

donor characteristics such as age (Ref.

3), donor infectivity (e.g., with Herpes

Simplex Virus) (Ref. 4) length of

product storage, storage medium, and

shipping distance from the eye bank to

the recipient site. In a recent analysis of

factors contributing to primary corneal

graft failure, Wilhelmus et al. found that

‘‘[T]he duration of donor corneal

preservation may have a significant

effect on endothelial vitality,’’ citing

studies that demonstrate endothelial

cell loss in chondroitin-supplemented

storage media after 7 to 10 days of

storage. The authors suggest that, with

modern eye bank screening and

preservation procedures, a donor

corneal storage time greater than 1 week

increases the risk of primary failure by

more than twofold.

Wilhelmus et al. include in their

analysis a summary of selected findings

of studies published between 1971 and

1540 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

3These AHCPR estimates are based on data from

the Healthcare Cost and Utilization Project (HCUP–

3) National Inpatient Sample. This is a FederalState-industry partnership to assemble health care

data, based on a nationwide inpatient sample of

hospital discharge records for 1994, from 20 percent

of U.S. community hospitals from 17 States. The

HCUP–3 estimated hospital charges do not include

physician payments.

4An estimated submitted charge of $76 per office

visit for ophthalmology care is based on HFCA

allowed payments for Medicare beneficiaries in the

Health Care Financing Review 1997 Statistical

Supplement Table 62, adjusted to estimate

submitted charges.

5An estimated initial hospital visit charge of $214

and subsequent visit charge of $88, based on HFCA

allowed payments for Medicare beneficiaries in the

Health Care Financing Review 1997 Statistical

Supplement Table 62, adjusted to estimate

submitted charges.

6This estimate is based on the 1994 average total

compensation of $36,834 adjusted by 2.9 percent

annual increase between 1994 and 1997, per the

U.S. Statistical Abstract. ($36,834 × 1,0293/2080) =

$19.3

7 Detailed Diagnoses and Procedures, National

Hospital Discharge Survey 1995, Series 13: Data

from the National Health Survey, No. 13, November

1997, table 4, p. 131.

1994 reporting primary graft failure for

corneal transplants using 4 °C

preservation, and using a variety of

preservation methods. The rates of

primary graft failure ranged from 0.9 to

3.1 percent, and a combined rate of 2.1

percent was estimated across all

preservation methods. In their analysis

of factors associated with corneal graft

failures reported to the EBAA for 1991

to 1993, the findings of Wilhelmus et al.

illustrate the importance of

documentation of the receipt of supplies

and reagents used in tissue processing.

The authors found the identical

manufacturer’s lot number for the

preservation medium among 2 media in

34 cases, among 3 media in 36 cases,

and among 4 media in 16 cases. Thus,

86 cases (approximately 59 percent of

cases) with primary graft failure shared

preservation media from the same lots.

The lot number was unique in 45 cases

(31 percent) and was not recorded in 16

cases (10 percent of cases) involving

product failure. These findings also

underline the importance of the

proposed CGTP-required verification of

quality and documentation of each

particular lot of processing media used

in the manufacture of a uniquely labeled

and traceable product.

Primary corneal graft failure typically

requires repeat surgery to replace the

failed graft. According to the Agency for

Health Care Policy Research (AHCPR)3

(Ref. 5), an estimated 7,443 corneal

transplants were performed in 1994,

with a mean hospital length of stay

(LOS) of 2 days, and a mean total

hospital charge equal to $7,530. The

estimated rate of primary graft failure

resulting from one or more aspects of

product collection, processing, or

distribution ranges from 0.1 percent (the

number of cases officially reported to

EBAA for the period 1991 to 1993) to as

much as 2.1 percent (combined failure

rate reported in the literature, across the

range of preservation media currently

used in eye tissue processing, cited in

Wilhelmus et al.). Based on the AHCPRreported 1994 volume of corneal

transplants, the estimated cases of

primary graft failure may range from 7

cases [0.001 × 7,443] to 156 cases [0.021

× 7,443]. The total cost of replacement

of a failed corneal graft is estimated to

include $454 of physician services,

including an office visit to diagnose the

graft failure prior to hospitalization4

(Ref. 6), and initial and follow-up

physician visits during patient

hospitalization5 (Ref. 6) for the repeated

corneal transplant. It also includes one

follow-up physician office visit to assess

the outcome of the second transplant.

The patient is estimated to further incur

at least one week of time lost from work

for the doctor visits, hospitalization and

recovery of visual function after surgery.

The cost of $772 for this patient time

loss is estimated based on a 40-hour

work week and average hourly

compensation of $19.30.6 Thus, the

current cost impact of corneal graft

failure may range from $61,292 [7 ×

($7,530 + $454 + $772)] to $1,365,936

[156 × ($7,530 + $454 + $772)].

These estimates provide an indication

of the potential cost savings from

avoided eye tissue product failures,

based on corneal transplants. Tissue

quality would improve through the

institution of multiple good quality

practices, including the validation of

processing methods, the verification of

processes quality control, and improved

documentation. Since these events

represent only one type of eye tissue

product, the potential for benefit across

all products in the eye tissue industry

may be greater. The estimated benefits

of CGTP applied to eye tissue, measured

in terms of avoided corneal graft

failures, therefore provide a lowerbound estimate of the potential benefits

of the proposed rule. Based on just this

one type of eye tissue product, the cost

of graft failures that may be avoidable

through a universal application of good

tissue practices ranges from $61,292 per

year, with the lower estimated failure

rate, to $1,365,936 per year, based on

the higher rate of primary graft failure

reported in the clinical literature.

2. Conventional Tissue Products

Conventional tissue includes a wide

range of products including bone

allograft, skin allograft, heart valves, and

other products. FDA’s survey of the

clinical literature indicates that bone,

skin and heart valve allograft each

presents a different potential for product

failure and thus different kinds of

benefits from improved quality

assurance in product manufacture. The

discussion that follows considers three

distinct areas of benefit.

a. Bone allograft products. An

analysis of the incidence, nature, and

treatment of infection in bone allograft

(Ref. 7) by Lord et al. demonstrates the

importance of quality standards and

process requirements to prevent tissue

contamination. Of the 283 patients in

their analysis who had received a

massive allograft of bone, infection

developed in 33 cases (11.7 percent).

The final outcome for those 33 patients

was poor compared to the 250

uninfected patients. About 82 percent

(27 of the 33) of the infected allograft

were considered failures of treatment

because amputation or resection of the

graft was required to control the

infection. Potential sources of

contamination cited in the study

include donor infection or

contamination introduced during

processing (estimated to occur in as

many as 7 percent of the grafts), in

addition to factors such as the duration

of the operation, loss of blood, injury to

soft tissue, and skin sloughing during

the operation. These risk factors

highlight the critical need for tissue

products that are both sterile and viable.

The importance of processing

validation is implied by Hardin (Ref. 8)

in a review of banked bone allograft

processes. In describing methods for

sterilization, Hardin lists ethylene oxide

as one of the most commonly used

chemicals, but indicates that its

effectiveness may nonetheless be

questionable, because of reports of graft

failures in which residues of ethylene

oxide have been blamed, and some

experimental evidence indicating

toxicity of ethylene oxide in human

tissues.

Based on an average rate of 0.057 for

bone allograft failure due to

contamination (based on an estimated

allograft infection rate of 0.07 and an

estimated 0.82 failure rate for infected

bone allograft), and the assumption that

all failures would be treatable through

repeat surgery to replace the bone graft,

the associated costs could be on the

order of $33 million per year

[$33,069,348 = 0.057 × 39,000 ×

($13,538 + $1,338)]. This is based on a

national estimate of 39,000 bone

allograft per year7 (Ref. 9), and an

estimated $13,538 per hospitalization

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1541

8An estimated cost of $135 per service based on

average submitted charges per service for‘‘All

Other Physician’’ specialty groups is used to

estimate specialist office visit charges. This cost per

service is reported in the Health Care Financing

Review 1997 Statistical Supplement Table 59.

9See Health Care Financing Review 1997

Statistical Supplement Table 59, Submitted

Charges, for Orthopedic Surgery.

for repeat surgery (AHCPR HCUP–3

NIS). Physician costs per hospitalization

are estimated to be $1,338 including

$135 for each of two specialty physician

office visits: one prior to, and one

following hospitalization8 (Ref. 6); and

$1,068 for surgeon services while

hospitalized, based on HCFA-reported

average submitted charges per person

served for orthopedic surgery9 (Ref. 6).

The reported average length of stay for

bone surgery is approximately 5 days.

The estimated cost of patient time lost

assumes that repeat surgery would

require at least 1 week of time from

work, at an estimated value of $772,

based on a 40-hour work week and

average hourly compensation of $19.30

(see footnote 6). This yields a total

estimated patient time cost of

$1,716,156 [0.057 × 39,000 × $772]. The

total annual cost of bone allograft failure

due to contamination is therefore

estimated to be nearly $35 million

[$34,785,504 = $33,069,348 +

$1,716,156].

If bone allograft failures result in

amputation, the direct and indirect costs

would be significantly higher. For

example, the cost per hospitalization for

lower extremity amputation is estimated

to be $24,178, based on the AHCPR

HCUP–3 data. Moreover, permanent

disability following amputation imposes

extremely high costs on the patient, and

on society.

FDA is uncertain about the extent to

which the estimated cost impact will be

reduced through CGTP for two reasons.

First, some tissue graft failures may

result from the transplant procedures

rather than the bone allograft

manufacture. Second, some facilities

may have already developed new bone

processing methods that may greatly

reduce infection risk. If as much as 75

to 80 percent of the estimated risk is

actually attributable to other factors, or

has already been addressed through

better manufacturing procedures at

many facilities, the net benefit from the

proposed CGTP rule applied to the

remainder of bone tissue processes and

facilities would be approximately $8

million [$34,785,504 × 0.23] per year.

b. Skin allograft products. Skin

allograft represent another type of tissue

product that is critically dependent on

quality controls to prevent the

manufacture and distribution of

contaminated or defective products. The

clinical literature reports cases of

cytomegalovirus (CMV) transmission

through skin donor infection (Ref. 10),

and HIV contamination from infected

donor tissue and subsequent skin tissue

handling (Ref. 11). CMV infections are

usually not life-threatening in healthy

individuals, but present grave risks to

the types of patients who typically

require skin grafts. In general, patients

who have suffered severe burns and

require skin grafts are

immunosuppressed as a result of their

injury and are therefore susceptible to

potentially life-threatening CMV

infections. These include pneumonitis,

retinitis, gastroenteritis, hepatitis, and

neurological complications (Ref. 10).

Contamination of skin allograft can

significantly affect burn patient

survival. Because the clinical literature

does not provide summary estimates of

the risk of contamination of skin

allografts, the agency is unable to

quantify overall risk. The agency

welcomes comment on the rate and

severity of skin tissue contamination.

c. Heart valve allograft. Heart valve

allograft, another conventional tissue

product, provide another compelling

case for process validation and quality

control. Valve tissue contaminants not

effectively removed in tissue processing

have resulted in serious infections that,

at minimum, require valve replacement

and that may also result in patient

death.

Sources of contamination of a valve

allograft include the donor, the

environment during harvesting and

processing, and the operating room

during implantation. Microbial

contamination of valve tissue is

common at tissue harvesting, with

reports of over 50 percent

contamination among valves retrieved

in open mortuary areas. According to a

study by Kuehnert et al. (Ref. 12)

common contaminants found before

disinfection consist of gastrointestinal

and skin flora, including coliforms,

viridans group streptococci,

Staphylococcus aureus, Staphylococcus

epidermidis, and Bacillus species. In

general, bacterial contamination can be

effectively removed through standard

disinfection procedures used in most

tissue banks. However, tissue that

remains contaminated with these

pathogens, particularly Staphylococcus

and Streptococcus species, can cause

early onset allograft valve endocarditis.

In contrast to bacterial contamination,

reported rates of fungal contamination

are relatively low. However, Kuehnert et

al. report that rates vary widely (1.7

percent to 28.0 percent), and that the

inclusion of anti-fungal drugs in the

tissue disinfection regimen is not

effective in eradicating fungal

contamination.

Fungal endocarditis is a rare but

potentially fatal complication of

allograft valve replacement. According

to Kuehnert et al., the incidence of

fungal endocarditis following surgery

for heart valve replacement with

allograft is estimated to range from 0.3

percent to 1.4 percent (midpoint

estimate of 0.0085). In one reported

case, the infected patient needed

subsequent surgery to replace the valve

and required intravenous amphotericin

B for the following 8 weeks. In many

cases, treatment is not successful and

death results. In one review, cited by

Kuehnert et al., over 40 percent of the

patients who had acquired fungal

endocarditis after valve allograft

implantation died within 2 weeks of

diagnosis.

In their study, Kuehnert et al. describe

the process controls used by AATBaffiliated facilities, including the

establishment, validation, and

documentation of decontamination

protocols. Because these regimens have

not been found effective against fungal

contamination, AATB-affiliated

facilities routinely discard tissue with

documented fungal contamination.

However, according to Kuehnert et al.,

the supplier of over 85 percent of all

heart valve allograft does not follow

AATB standards, but instead follows a

decontamination protocol that is

reported to be proprietary. This protocol

apparently includes efforts to disinfect

rather than discard tissue with fungal

contamination. However, efforts to

eradicate fungal contamination

identified in processing can be

unsuccessful, and in this case, a falsenegative culture following processing

resulted in the tissue being distributed

for patient use.

The proposed rule would require that

all facilities validate the effectiveness of

each step in processing, and would

require that contaminated tissue that

cannot be effectively disinfected be

discarded or otherwise removed from

processing for distribution. Based on the

rates of infection and mortality risk

reported by Kuehnert et al., and a total

of 61,000 heart valve allografts reported

per year by the National Hospital

Discharge Survey (Ref. 13), there may be

an estimated 519 cases per year [0.0085

× 61,000] of heart valve contamination

causing fungal endocarditis. These

contaminated valves may further cause

an estimated 207 deaths per year

[0.0085 x 0.40 x 61,000]. Changes in

processing based on the proposed CGTP

requirements would help to avoid these

deaths. Substantial health care cost

1542 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

10Based on AHCPR HCUP–3 National Inpatient

Survey for 1994 hospital charges by principal

diagnosis, ‘‘bacterial infection, unspecified site’’

($17,891), http://www.ahcpr.gov/data/

94dcchpr.htm. 1998.

11Physician charges are based on estimates of

physician submitted charges using data reported in

the Health Care Financing Review Statistical

Supplement, 1997, table 62. Initial inpatient visit

charge is estimated to be $214, and daily follow-up

visits in the hospital are estimated to be $88 per

visit. Thus total physician charges for care during

the 9-day hospital stay are estimated to be $918.

savings could also be achieved through

improved processing controls. Based on

an average cost of $63,096 per

hospitalization for implantation of a

heart valve allograft (Ref. 5), and

estimated physician charges of $6,796

per case, including repeat surgery and

patient care during the average 13-day

hospital stay. If the CGTP requirements

avoided 80 percent of these valve

infections, this might result in health

care cost savings of up to $29 million

[0.8 x 519 x $63,096 + $6,796)].

3. Stem Cell Products

According to the National Center for

Health Statistics National Hospital

Discharge Survey, approximately 8,000

stem cell transplant procedures were

performed in 1994. Based on the

AHCPR HCUP–3 NIS data for 1994 (Ref.

5), the average length of hospital stay for

bone marrow transplant procedures was

35 days, with an average cost per stay

of $168,573.

Promising outcomes from use of

peripheral blood stem cells (PBSC) and

cord blood-derived stem cells (CBSC) in

lieu of bone marrow have resulted in

increased collection and use of these

products in stem cell transplants. For

example, recent studies have

respectively reported use of PBSC

(rather than bone marrow) in 54 percent

(Ref. 14) and 62 percent (Ref. 15) of

cases. However, studies of stem cell

products indicate that products

manufactured by this industry can

become contaminated during collection

and processing. Moreover, the therapyinduced immunosuppression of the

oncology patients who receive these

products places them at particular risk

for serious infection and subsequent

mortality. Manufacturing methods

conforming to good tissue practice are

necessary to prevent this threat to the

safety and effectiveness of stem cell

therapies. For example, earlier

investigations of PBSC reported that the

large quantity of blood that must be

processed to obtain adequate numbers

of stem cells resulted in large volumes

of cryopreserved cells received by

patients. This process posed the risk of

increased toxicity, because of the

amount of dimethyl sulfoxide used for

cryopreservation (Ref. 16).

Another quality concern with PBSC

involves the maintenance of sterile

integrity of the apheresis catheter and

component throughout the period of

leukopheresis, cryopreservation,

thawing, and transfusion (Espinosa et

al., 1996). Webb et al. (Ref. 14) reported

a 2.41 percent rate of bacterial

contamination in PBSC products, and a

13.7 percent rate of infection of patients

receiving contaminated products.

Although the bacteremia-induced

fever and other clinical sequelae are

considered reversible, infections present

more serious risks in stem cell

recipients than for the general

population. Survival rates for

hematopoietic stem cell transplantation

are significantly reduced for patients

that become critically ill. In a study of

survival rates among stem cell

recipients admitted to an intensive care

unit, Price et al. (Ref. 15) found that

patients with probable infection had a

significantly higher death rate (57

percent) compared to patients with no

probable infection (13 percent).

Multiple regression analyses by Price et

al., to predict probability of death

controlling for other risk factors such as

patient intubation, type of transplant,

source of stem cells, human leukocyte

antigen compatibility, type of

malignancy and patient age, also found

infection to be a significant predictor of

mortality.

An estimated 15 patients per year

could suffer infection following receipt

of contaminated PBSC, based on the

reported rates of 2.4 percent of patients

receiving contaminated PBSC, 13.7

percent of those patients subsequently

developing infection, and 8,000 stem

cell transplants reported for 1994, and

assuming that 58 percent of stem cell

transplants (the average of the two

reported rates of PBSC transplant cited

above) involve PBSC. Costs of treating

patients who become infected after

receiving contaminated stem cell

product are based on an average

AHCPR-reported hospital charge10 (Ref.

5) of $17,981 per 9-day patient stay for

treatment of bacterial infection.

Estimated health care costs also include

physician costs of $918 assuming one

initial hospital visit, and daily followup visits during the patient stay11 (Ref.

6). Patient time loss during the

hospitalization is valued at $1,387,

based on estimated hourly

compensation of $19.30 (see footnote 4)

and a 9-day hospital stay. Thus, the total

annual cost impact of patient infection

following transplant of contaminated

PBSC products is estimated to be

$304,290 [15 × ($17,981 + $918 +

$1,387)].

In addition to avoided health care

costs, eliminating the risk of

contaminated products could yield a

potential of seven avoided stem cell

patient deaths per year, due to infection.

This number reflects the excess

mortality risk reported for stem cell

recipients with infection versus those

without infection. It is based on the

following: (8,000 transplant procedures

per year) × (58 percent of procedures

with PBSC) × (2.41 percent PBSC

patients receiving contaminated

product) × (13.7 percent patients

receiving contaminated product develop

infection) × (57 percent to 13 percent)

excess rate of death for stem cell

recipients given presence of infection.

As bacterial contamination has also

been documented in a study of cord

blood processing, the proposed CGTP

requirements for staff training and

process validation would support

similar risk reduction efforts across

CBSC facilities. For example, a study by

Kogler et al. (Ref. 17) found that during

the initial 6 months of an unrelated CB

collection program, the median bacterial

contamination rate was 18 percent.

After extensive training in sterile

procedures for the staff who collect cord

blood, the contamination rate was

reduced to 1 percent.

4. Reproductive Tissue Products

Most aspects of cellular and tissue

product manufacturing in the

reproductive tissue industry would

become newly regulated under the

proposed CGTP rule. The affected

establishments within this industry

include sperm banks and ART facilities.

Reports of the sensitivity of product

quality to variations in tissue collection,

technician skill, processing methods,

environmental conditions, and other

factors (Ref. 22), indicate that the risk of

communicable disease transmission

would be reduced by improving the

proposed overall product quality, and

economic benefits would be seen

through improved patient outcomes

from facility compliance with the

proposed CGTP requirements.

The tissue used in commercial sperm

banks is washed, processed, and

cryopreserved donor sperm used for

therapeutic donor insemination (TDI).

The sperm are obtained generally from

paid donors who have been screened

and tested for infectious disease and

certain genetic disease risks.

The tissues used in ART facilities

include fresh or cryopreserved oocytes,

sperm, zygotes, and embryos. The

handling of tissues include but are not

limited to: Retrieval of oocytes from a

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1543

female, collection of sperm from a male,

in vitro fertilization (IVF),

cryopreservation of fertilized oocytes

not transferred in the same treatment

cycle, and thawing of frozen fertilized

oocytes. The success of in vitro

fertilization, measured as the number of

deliveries per IVF cycle, has gradually

increased over the past decade or so,

from 11 percent in 1985 to 18 percent

in 1994 (Ref. 18). More recently, the

Centers for Disease Control and

Prevention (CDC) have reported average

live birth pregnancy rates for ART

clinics to be as high as 19.6 percent per

cycle in 1995 and 22.6 percent per cycle

in 1996 (Refs. 19 and 20).

Despite the increasing effectiveness of

infertility treatment through ART,

problems can occur in tissue processing.

Adverse outcomes owing to problems

with product quality can result from

contamination that produces infection

(e.g., HIV transmission) in the infertility

patient (Ref. 21). Problems with ART

facility processing of sperm or oocytes

can also lead to reduced rates of

fertilization, and unsuccessful IVF

attempts, which would ultimately

increase the number of transfer

attempts. Each additional transfer

attempt increases the risk of

communicable disease with each

attempt.

Where quality problems in tissue

processing result in reduced embryo

quality and lower probability of

pregnancy, the patient, on average,

needs to undergo more cycles of IVF to

achieve a pregnancy that produces a live

birth. The estimated patient cost per

cycle ranges from $8,000 to $10,000

(Refs. 24 to 26).

The number of Americans who would

potentially benefit from improved

reproductive tissue processing is

substantial. According to the 1995

National Survey of Family Growth

(NSFG), (Ref. 28) 15.4 percent of

American women 15 to 44 years of age,

approximately 9.3 million women, have

reported receiving infertility services.

Approximately 600,000 women report

receiving ART’s, defined in NSFG to

include artificial insemination and IVF

services. The number of ART

procedures annually has been

increasing in recent years. According to

the CDC (Ref. 29) a total of over 64,000

cycles of ART were performed by U.S.

facilities in 1996, compared to

approximately 60,000 cycles in 1995.

The proposed CGTP rule, therefore, has

the potential to benefit thousands of

infertile couples.

Processes that affect product quality.

Recent clinical literature reports a

number of factors in the manufacturing

process that could affect tissue quality.

These factors include technician skill,

equipment accuracy and reliability,

methods used in laboratory processing,

and environmental controls affecting

product quality. Following process

validation and quality controls that

would be required under the proposed

rule is expected to substantially reduce

or eliminate detrimental variations, and

thereby improve product quality.

Sperm processing occurs in both

commercial sperm banks and ART

facilities. Commercial sperm banks

generally screen, wash, and

cryopreserve donor sperm. ART

facilities typically include an andrology

laboratory that performs semen analysis

and conducts IVF. Variations in

methods and technician skills at various

stages of sperm processing have been

associated with variations in quality.

Poor sperm quality increases the

probability that additional tissue

transfer procedures will be necessary.

For example, in a study conducted to

establish quality controls in semen

analysis, Yeung et al. found that the

subjective thresholds for judging sperm

motility (a key measure of sperm

function for diagnosis and treatment)

differed for each technician performing

the analysis (Ref. 30). The establishment

of values for threshold velocities, and

standards for technician training were

identified as methods to improve

consistency in technician assessments.

A study by Mahmoud et al. (Ref. 31)

compared 10 different methods for

estimation of sperm concentration

(another key indicator of sperm quality)

and reported substantial differences in

the accuracy of laboratory assessments,

depending upon the type of pipette and

the method used. They found that

although a few devices and methods

produced accurate, low-variability

estimates, others had a tendency to

overestimate or to underestimate sperm

concentration. These findings strongly

support the need for equipment

calibration and laboratory method

validation.

In addition to processing steps related

to the sperm quantity and quality,

sperm processing for IVF typically

requires that sperm be purified,

removing semen fluid, cellular debris,

white blood cells, and other

contaminants that may interfere with

fertilization. Many sperm separation

methods have been developed and are

in use in ART programs, including basic

sperm washing, swim-down and swimup techniques, refrigeration/heparin

techniques, separation with Sephadex

and Ficoll columns, separation with

glass wool and Percoll gradient

centrifugation (Refs. 32 to 34). No single

method has become the standard,

although some approaches may be more

effective than others in preserving

functional integrity. For example, when

King et al. (Ref. 35) compared the effect

of different antibiotics used in sperm

washing, they found that some agents

produced severe adverse effects on

sperm motility and actually decreased

sperm fertilizing capacity. The

importance of product quality in this

step of processing offers another

example of the value of process

validation in ensuring sperm product

viability and thus successful fertility

treatment for patients.

Environmental controls present

another area with a demonstrated need

for quality control in reproductive tissue

processing. Environmental

contamination may come from many

sources, including the air, water or

laboratory supplies. A study of

laboratory air quality in ART facilities

by Cohen et al. (Ref. 36) found that over

300 volatile organic compounds were

detectable in spite of the use of

centralized high efficiency particulate

air (HEPA) filtration, generic but

centralized carbon and pre-filtration,

and numerous ionization units placed at

strategic points in the laboratory.

Potential sources of contaminants

included vehicle and industrial

emissions in outside air, use of plastics

and disposable plasticware in the

laboratory, equipment (e.g., freon

leakage from refrigeration units),

cleaning agents and equipment

lubricants, and air flows from activities

in adjacent areas of the building.

A more detailed study of these factors

by Cohen et al. was prompted in part by

the sudden and significant declines in

clinical pregnancy and implantation

rates that occurred at two points in time

at an ART facility. In those instances,

the pregnancy rate had declined by

about 50 percent and subsequent

implantation rates also declined. Their

investigation revealed that, in the first

instance of decline, a fumigation with

pesticides had taken place in areas of

the building adjacent to the ART

facility, without notification given to the

ART facility. The second episode of

sudden decline corresponded to the

installation of a redesigned air filter in

the facility. Further air sampling also

revealed that chemical contaminants

produced in another area of the

building, which was used as an

outpatient surgery center and was not

part of the ART clinic, could be detected

in the embryo laboratory when more

sensitive monitoring equipment was

used. Cohen et al. proposed various

measures to counter these potential

sources of chemical air contamination

in both the laboratory and the embryo

1544 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

12Estimated hourly compensation of $19.30 is

based on the 1994 average total compensation of

$36,834, adjusted by 2.9 percent annual increase

reported in the 1997 U.S. Statistical Abstract.

incubators. Laboratories without

adequate environmental monitoring and

controls would not be able to detect

such degradations in air quality.

An earlier study of mouse embryos by

Francis et al. reported that some brands

of nonpowdered surgical gloves appear

to be embryotoxic (Ref. 37).

Temperature fluctuations during cell

culture, and to a lesser extent, the time

between retrieval and transfer, may also

affect tissue quality and thus increase

the probability of additional transfer

attempts (Ref. 39).

The lack of experience and training of

laboratory personnel also could increase

the need for additional transfer attempts

due to poor tissue quality. One study

found that new embryologists needed

several months to gain the experience to

consistently predict nuclear maturity

from cumulus-coronal morphology.

Moreover, even when a stable

prediction rate was reached, it rarely

exceeded 72 percent accuracy (Ref. 40).

Yet consistent assessments of product

quality and transfer of high quality

embryos to the patient are critical to

increasing the overall success of IVF

treatment and to minimizing transfer

attempts.

Although there has been some Federal

and some private sector standard setting

and oversight in the reproductive tissue

industry, existing standards do not

provide the level of quality management

and process quality assurance that

would be required under the proposed

CGTP rule for all tissue establishments.

A voluntary accreditation program

jointly offered by the CAP and the

ASRM has been available to ART

laboratories since 1992 (Refs. 41 and

42), and the number of facilities seeking

accreditation has been increasing in

recent years. The problems with product

processing cited in recent clinical

literature, however, suggest that

although there is increasing interest in

quality assurance, there are still

substantial gains that could be made in

tissue facilities, by implementing the

proposed CGTP rule.

In addition to the benefits that would

accrue directly from implementation of

this proposed rule, individuals may

reap ancillary benefits that could arise

indirectly from the rule. Although the

proposed rule would provide a direct

benefit from the decreased risk of

communicable disease transmission, the

public, particularly couples seeking

assistance in beginning a pregnancy,

could receive an indirect economic

benefit. Such ancillary economic

benefit, although not certain, would be

seen as an increase in ART facility

success rates and a decrease in health

costs associated with a reduction in the

number of IVF attempts per live birth.

FDA cannot predict the precise

impact from implementation of the

proposed CGTP rule. To obtain an

estimate of benefits and to capture a

level of uncertainty, this analysis

considers three potential scenarios and

presents the results a range of possible

outcomes. In general, it is assumed that

the rule will affect the facilities with the

lowest success rates and that these

facilities would improve to some

minimal level of performance from the

implementation of good practices. In

one scenario, benefits are assumed to be

limited to the worst-performing quarter

of all facilities. These facilities would

improve to the level of the facility just

better than the bottom one-fourth. In

another scenario, the half of all facilities

with the lowest success rates would

improve to where they would be as good

as the median facility. In a third

scenario, implementation of the rule

would not change ART facility success

rates.

The scenarios consider only the

cycles of treatment for younger women

(age less than 35) for whom patient age

is not likely to be a confounding factor

affecting oocyte quality. Of the 22,811

fresh nondonor cycles of treatment for

these patients at the 300 ART facilities

reporting data for 1996, the average

success rate was 28.65 live births per

100 cycles, and the median live birth

pregnancy rate was 26.3 percent per

cycle.

Scenario 1 assumes that the facilities

currently achieving the lowest success

rates (i.e., the lowest quartile of success

rates reported for ART establishments)

are able to increase their average success

rate to the rate corresponding to the

25th percentile rate. This would

represent a first step and as technology

and techniques continue to improve, so

would success rates. In the 1996 report,

the 25th percentile rate was 19.7 live

births per 100 cycles. FDA finds that

raising the bottom quartile of 75

facilities, to 19.7 live births per 100

cycles, would reduce the IVF attempts

from a reported 4,756 to an estimated

3,591 treatment cycles. This

improvement would decrease transfer

attempts and yield an estimated savings

of $10.5 million for patients and other

payers, based on an estimated average

cost of $9,000 per cycle, and an

estimated 1,165 avoided cycles

[4,756¥3,591].

Scenario 2 assumes that facilities in

the lower half of the industry

distribution are able to bring their

success rates up to the median rate of

26.3 live births per 100 cycles. The

increased success rate is assumed to be

achieved through improvement in staff

training and skill, processing validation,

and quality control throughout the

facility in accordance with the proposed

CGTP rule. Under this scenario, the

affected 150 facilities would reduce the

number of IVF attempts from a reported

10,414 cycles to an estimated 7,662

treatment cycles, to achieve the same

number of successful treatments. This

would yield an estimated cost savings of

$24.8 million for patients and other

payers. This is based on an estimated

2,752 avoided cycles of treatment

[10,414¥7,662] and assumed average

cost of $9,000 per cycle of IVF

treatment.

At the other end of the spectrum,

Scenario 3 provides for the possibility

that this proposed rule would have no

effect on success rates at ART facilities

or the number of IVF attempts per live

birth. In such a case, there would be no

additional economic benefit beyond the

benefits previously discussed, including

an anticipated decrease in

communicable disease transmission.

Couples seeking infertility care incur

an indirect cost of time lost (e.g., work

time) while undergoing treatment. Using

an average hourly wage of $19.3012 and

assuming 6 hours of time (e.g., 4 hours

for the female and 2 hours for the male

patient) per couple per cycle of IVF

treatment, the estimated value of the

lost time would be as follows. Under

Scenario 1, the estimated 1,665 avoided

treatment cycles would yield a time gain

valued at $192,807 [1,665 × $19.30 × 6].

Under Scenario 2, the 2,752 potentially

avoided treatment cycles would yield a

time gain valued at $318,682 [2,752 ×

$19.30 × 6]. Under Scenario 3, there

would be no avoided treatment cycles

and, thus, no quantifiable benefits.

C. Summary of Potential Benefits

Resulting From Avoided Quality

Problems in Processing of Cellular and

Tissue Based Products

This analysis of benefits of the

proposed CGTP rule has considered its

impact on major sectors of the tissue

industry by focusing on product quality

problems cited in the literature. This

review suggests that industry standards

are not applied uniformly resulting in

uneven product quality.

Table 10 provides a summary of the

particular products and problems

identified in the agency’s survey of

literature. FDA estimated the potential

benefits of avoiding quality problems

based on reported risks and national

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1545

data-based estimates of the number of

patients undergoing related procedures.

Depending on the particular industry

sector, the potential quantified benefits

from reduced health care costs are

estimated to range from approximately

$61,000 per year, to approximately

$33.5 million per year. The total

estimated potential quantified benefits

range from a total of $41.9 million to

$68.0 million. The actual level of

benefits that would be realized through

wide application of CGTP is uncertain,

however, as the agency’s projections are

sensitive to numerous assumptions that

appear plausible, but remain to be

tested.

TABLE 10.—SUMMARY OF POTENTIAL BENEFITS OF PROPOSED CURRENT GOOD TISSUE PRACTICE BASED ON TISSUE

PROBLEMS CITED IN REVIEWED LITERATURE

Tissue Industry Sector Tissue(s) Considered Avoided Problems with

Tissue

Avoided Treatment or

Outcome

Potential Cost Savings/

Year

Eye Tissue corneal graft graft failure repeat surgery; increased

graft attempts

$61,000 to $1.4 million

Conventional Tissue bone allograft bone infection; graft failure repeat surgery/amputation;

increased graft attempts

$8 million

Conventional Tissue heart valve allograft fungal endocarditis repeat surgery/patient

death; increased

transplant attempts

$29.6 million

176 excess deaths

Peripheral Blood and Cord

Blood Stem Cells

stem cell transplant infection in cancer patients hospitalization/patient

death

$304,000

7 excess deaths

Reproductive Tissue sperm, oocytes, zygotes,

embryos

IVF1 failure additional IVF treatment

cycles

$0 to 24.8 million

Total Potential Cost Savings/Year$41.9 to $68.0 million

1 In vitro fertilization

Uncertainties affecting the true level

of benefit include: The actual extent of

current CGTP compliance in each of the

affected industries, the lack of more

complete information about the

incidence and severity of problems from

processing of tissue products, the net

impact of those quality problems on

patient outcomes, and the size of the

affected patient population. Because of

the limits of available data, the

foregoing analysis has focused on a

limited set of tissue products. It is not

certain how well these data represent

the most critical areas or actual scale of

risks in the tissue industry. For some

products, such as demineralized bone,

the industry has achieved important

advances in processing that have

improved the safety and effectiveness of

its products. Thus, the analysis of

benefits based on problem reports from

several years ago may overstate the

potential for improvements in the

current best industry practice. In other

cases, the publication of the recent

problem reports suggests that

deficiencies still exist within current

practices. These areas present important

opportunities to avoid unnecessary

patient risks and health care costs.

D. Small Entity Impacts

The Regulatory Flexibility Act (RFA)

requires agencies to determine whether

a proposed rule may have a significant

effect on a substantial number of small

entities. Tissue and blood banks are

classified in North American Industry

Classification System (NAICS) 621991.

In this industry category, any firm with

annual revenues less than $5.0 million

is considered small by the U.S. Small

Business Administration. In every sector

of the cell and tissue product industry,

the majority of establishments are

estimated to be classified as small

entities. However, because of the high

level of current compliance with

industry standards, the increase in costs

is expected to be limited primarily to

facilities that do not comply with

industry standards. To measure the

impact of CGTP on small businesses,

FDA calculated the ratio of industry

compliance costs to industry revenues,

assuming that all facilities incurred the

same cost. The small entity impacts

estimated below focus on the facilities

that will be newly compliant under the

proposed CGTP, and thus will

experience the highest potential new

costs. In addition, although current

quality management practices at nonaccredited or less-than-fully compliant

facilities may vary, and not every

facility will incur every new cost

estimated in table 2, the analysis that

follows considers a high-cost scenario

where every estimated cost is incurred,

in order to produce a conservative

estimate of the potential impact on

small entities. While some firms may

have lower than average revenues,

making them potentially more sensitive

to cost increases, FDA does not know

the distribution of firms by revenues.

FDA welcomes comments on this issue.

Within the eye banking industry,

experts estimate that virtually all

facilities would be classified as small,

and believe all are to be compliant with

the industry EBAA standards. The

average annual revenue per eye bank is

estimated at $1.2 million (Ref. 44). If an

eye bank were to incur every new cost

estimated for facilities in that industry,

the total cost impact, including total

one-time costs and the yearly cost,

would be $36,738, which represents an

estimated 3 percent (0.03) of estimated

annual revenues. Average annualized

compliance costs per eye bank are

estimated to be $10,717, or 0.89 percent

of annual revenue per firm.

In the conventional tissue industry,

an estimated 75 to 80 percent of the

total of 110 facilities would be classified

as small entities. Industry experts also

estimate that 75 to 80 percent of those

facilities currently comply with the

AATB standards, which generally meet

or exceed the requirements of the

proposed CGTP rule. Based on the

assumed levels of increased effort and

costs shown in table 2, the remaining 23

percent of small facilities that do not

comply with AATB standards would

incur up to $62,662 in total new costs,

including both the total one-time cost

and the yearly cost, assuming that every

potential area of new quality

management effort would be needed at

every one of these facilities. The average

annual revenue per small conventional

tissue bank is estimated at $1.2 million

(Ref. 44). The estimated total new costs

would represent approximately 5

percent of this annual revenue figure.

The average annualized compliance cost

for a small conventional tissue bank is

estimated to be $10,310, representing

0.86 percent of firm revenues.

1546 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

The agency anticipates that all stem

cell facilities would be classified as

small entities, and estimates that these

establishments have annual revenue

averaging $1.2 million (Ref. 44).

Establishments that comply with the

current FAHCT or AABB standards

would incur some additional costs. If

each of these facilities were to incur

new costs for every provision identified

in table 2, the total cost per facility,

including total one-time and yearly

costs, would be approximately $20,270.

This figure represents approximately 2

percent of estimated annual revenues.

Stem cell facilities that do not currently

comply with AABB or FAHCT

standards would incur greater costs, as

shown in table 2. If each of these

facilities were assumed to incur every

new cost identified in the cost analysis,

the total one-time cost plus annual cost

would be approximately $79,337. This

figure is equal to approximately 7

percent of estimated annual revenues.

The average annualized compliance

costs incurred by stem cell facilities

would similarly vary depending on

current facility practices and

compliance with AABB or FAHCT

standards. If a facility is currently

compliant with these industry

standards, the average annualized cost

of compliance with the proposed rule is

estimated to be about $7,407,

representing 0.62 percent of the yearly

revenue of these firms. However, if a

facility is not currently compliant with

the requirements of the current industry

standards, a greater level of new effort

would be required for quality assurance

and quality management. The average

annualized cost per facility is estimated

to be $40,721, which would represent

3.39 percent of an average annual

revenue of $1.2 million.

Consultants estimate that

approximately two-thirds of all ART

facilities (approximately 200) would be

classified as small entities, and have

average annual revenues of $2.5 million.

Based on the project levels of

compliance with various provisions of

CGTP, as described in the cost analysis,

if a facility were to incur every potential

new cost, as shown in table 2, the total

one-time plus annual cost to the facility

would be $83,302. This total would

represent approximately 3 percent of

average annual revenues. The average

annualized compliance cost per facility

is estimated to be $11,342, representing

approximately 0.45 percent of annual

revenues.

According to recent estimates by a

sperm banking industry expert,

approximately 100,000 TDI units are

produced each year from collected and

processed sperm donations. An

estimated 95 percent of that total

production is handled by the largest 20

facilities. Nineteen of the largest 20

facilities are estimated to have average

annual revenues of approximately $2

million, and only 1 of the 20 is

estimated to have revenues greater than

$5 million per year. The remaining 5

percent of industry production, or 5,000

TDI units, are processed by very small

banks described by an industry expert

as typically functioning within a

physician office practice (e.g., that of an

obstetrician (ob) or a gynecologist (gyn)).

The sperm banking in these facilities is

generally offered as an additional

service to patients receiving fertility

treatment, and is not the primary line of

business of these establishments. The

annual revenue for these individual

physician practices is estimated to be

$252,000 per year, based on the mean

physician income of $215,000 after

expenses and before taxes for the ob/gyn

specialty category, reported in the 1992

American Medical Association (AMA)

survey (Ref. 45), adjusted to 1998

assuming an average annual wage

inflation of 2.7 percent, based on yearly

rates reported by the Bureau of Labor

Statistics. Thus the majority of sperm

banks would be considered small

entities.

If each of the small sperm banks were

to incur every potential new cost of

compliance with the proposed CGTP

rule, as shown in table 2, the total onetime cost plus annual cost would equal

$83,302, which would be approximately

4 percent of the $2 million in annual

revenues for the ‘‘larger’’ small facilities.

The average annualized cost to these

banks is estimated to be $11,007,

representing approximately 0.55 percent

of annual revenues. Although these cost

figures would account for a much larger

percentage of individual physician

practice income, the sperm banking

provided by these establishments is

considered to represent a small and

generally nonessential part of their

business. For the smallest banks, the

estimated 5,000 TDI units supplied by

the estimated 90 facilities translates to

an average volume of 55 units per

facility per year. With an estimated

price of $95 to $145 per TDI unit (Ref.

46) and an estimated profit of 15

percent, the banks would realize a net

income of $12.40 to $19.00 per unit, or

average net income of $682 to $1,045 for

55 units. This income would represent

only 0.3 percent (0.0027) to 0.4 percent

(0.0041) of the estimated $252,000 in

annual net income for the ob/gyn

physician practice. Thus, it seems likely

that physician practices that currently

operate small-scale sperm banking may

prefer to discontinue banking, and refer

their patients to a commercial bank for

this service.

In summary, the majority of facilities

within each sector of the tissue industry

are expected to qualify as small entities.

The actual cost impact on each facility

is uncertain because of the limited

information available to describe the

current practices and compliance with

industry standards at each of these

facilities and within each distinct

industry sector. Based on the limited

available data and expert opinions, the

agency estimates impacts that would

result in an average annualized cost per

facility ranging from $ 7,000 to $11,000

for facilities that currently comply with

an industry standard, to over $40,000 in

average annualized costs for facilities

that do not currently comply with most

industry quality standards. These

annualized costs represent 0.45 to 3.39

percent of the estimated total average

annual revenues.

The agency is uncertain about the

accuracy of these estimates, however,

because of the lack of good data on

revenues for these facilities. Because of

the importance of this information in

accurately assessing the impact on small

entities, the agency requests that

industry provide detailed comment on

the percentage of facilities that qualify

as small entities in the eye tissue,

conventional tissue, stem cell, and

reproductive tissue industries; the

percentage of those facilities that fully

comply with current industry standards;

and the specific areas where industry

anticipates substantial differences

between current manufacturing

practices and the quality assurance

elements specified under the proposed

rule. For those areas of identified

difference, the agency further requests

estimates of the resources and costs that

will be required for facility compliance.

Although the proposed rule would

impose some costs on small entities

involved in the manufacture of cellular

and tissue-based products, the agency

believes that the proposed approach

represents an effective means of

protecting patient safety and public

health in the manufacture of human

cellular and tissue-based products. The

less burdensome alternative to the

proposed approach, i.e., continue with

the use of trade organizational standards

by industry, involve fewer requirements

for small entities (the vast majority of

facilities in this industry), but fail to

provide fundamental aspects of product

safety. Reliance on trade organization

voluntary standards for good tissue

practice, rather than establishing a

regulatory requirement, would not

ensure uniform or consistent

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1547

compliance and would preclude the

agency’s ability to effectively monitor

tissue products to ensure public health

and safety. While each trade

organization varies in their standards or

guidelines, regulatory requirements for

good tissue practice would help ensure

consistency among manufacturers. FDA

finds that this proposed rulemaking

would enhance both public health and

public confidence in the safety and

quality of cellular and tissue-based

products, while imposing only a

minimum burden on the affected

industry sectors.

IX. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Centers for Disease Control and

Prevention, ‘‘Creutzfeldt-Jakob Disease

Associated with Cadaveric Dura Mater

Grafts—Japan, January 1979–May 1996,’’

Morbidity and Mortality Weekly Report; vol.

46; pp. 1066–1069, 1997.

2. General Accounting Office, ‘‘Human

Tissue Banks; FDA Taking Steps to Improve

Safety, but Some Concerns Remain,’’

December 1997.

3. Wilhelmus, K. R., R. D. Stulting, J. Sugar,

and M. M. Khan, ‘‘Primary Corneal Graft

Failure,’’ Archives of Ophthalmology, vol.

113, pp. 1497–1502, December 1995.

4. Remeijer, L., P. Doornenbal, A. J. M.

Geerards, W. A. Rijneveld, and W. H.

Beekhuis, ‘‘Newly Acquired Herpes Simplex

Virus Keratitis After Penetrating

Keratoplasty,’’ Ophthamology, vol. 104, No.

4, pp. 648–652, April 1997.

5. Statistics From the HCUP–3 Nationwide

Inpatient Sample for 1994: Principal

Procedures, http://www.ahcpr.gov/data/

94pcchpr.htm, current as of September 1997,

AHCPR Pub. No. 97–0057.

6. Health Care Finance Review 1997

Statistical Supplement, U.S. Department of

Health and Human Services, Health Care

Financing Administration, Office of Research

and Demonstrations, Baltimore, MD,

November 1997.

7. Lord, C. F., M. C. Gebhardt, W. W.

Tomford, and H. J. Mankin, ‘‘Infection in

Bone Allograft: Incidence, Nature and

Treatment,’’ The Journal of Bone and Joint

Surgery, vol. 70–A, No. 3, pp. 369–376,

March 1988.

8. Hardin, C. K., ‘‘Banked Bone,’’

Otolaryngologic Clinics of North America,

vol. 27, No. 5, pp. 911–925, October 1994.

9. Vital and Health Statistics, Detailed

Diagnoses and Procedures, National Hospital

Discharge Survey, 1995, U.S. Department of

Health and Human Services, Centers for

Disease Control and Prevention, National

Center for Health Statistics, Series 13, No.

130, PHS–98–1791, November 1997.

10. Abecassis, M. M., ‘‘Transmission of

Cytomegalovirus by Skin Allograft,’’ Tissue

and Cell Report, vol. 2, No. 1, pp. 14–17,

1995.

11. Gala, J., A. Vandenbroucke, B.

Vandercam, J. Pirnay, N. Delferriere, and G.

Burronboy, ‘‘Human Immunodeficiency

Virus in Fresh or Cryopreserved Postmortem

Skin: Potential Implications for Skin

Handling and Allografting,’’ Journal of

Clinical Pathology, vol. 50, pp. 481–484,

1997.

12. Kuehnert, M. J., E. Clark, S. R.

Lockhart, D. R. Soll, J. Chia, and W. R. Jarvis,

‘‘Candida Albicans Endocarditis Associated

with a Contaminated Aortic Valve Allograft:

Implications for Regulation of Allograft

Processing,’’ Clinical Infectious Diseases, vol.

27, pp. 688–91, October 1998.

13. National Center for Health Statistics,

Detailed Diagnosis and Procedures, National

Hospital Discharge Survey (ICD–9–CM 35.2)

Series 13: Data from the National Health

Survey No. 130, November 1997.

14. Webb, I. J., F. S. Coral, J. W. Andersen,

A. D. Elias, R. W. Finberg, L. M. Nadler, J.

Ritz, and K. C. Anderson, ‘‘Sources and

Sequelae of Bacterial Contamination of

Hematopoietic Stem Cell Components:

Implications for the Safety of Hematotherapy

and Graft Engineering,’’ Transfusion, vol. 36,

pp. 782–788, 1996.

15. Price, K. J., P. F. Thall, S. K. Kish, V.

R. Shannon, and B. S. Andersson,

‘‘Prognostic Indicators for Blood and Marrow

Transplant Patients Admitted to an Intensive

Care Unit,’’ American Journal of Respiratory

Critical Care Medicine, vol. 158, pp. 876–

884, 1998.

16. Espinosa, M. T. F., R. Fox, R. J. Creger,

and H. M. Lazarus, ‘‘Microbiologic

Contamination of Peripheral Blood

Progenitor Cells Collected for Hematopoietic

Cell Transplantation,’’ Transfusion, vol. 36,

pp. 789–793, 1996.

17. Kogler, G., J. Callejas, P. Hakenberg, J.

Enczmann, O. Adams, W. Daubener, C.

Krempe, U. Gobel, T. Somville, and P.

Wernet, ‘‘Hematopoietic Transplant Potential

of Unrelated Cord Blood: Critical Issues,’’

Journal of Hematotherapy, vol. 5, pp. 105–

116, 1996.

18. Van Voorhis, B. J. et al, ‘‘Cost-effective

Treatment of the Infertile Couple,’’ Fertility

and Sterility, vol. 70, pp. 995–1005, 1998.

19. U.S. Department of Health and Human

Services, Centers for Disease Control and

Prevention, American Society for

Reproductive Medicine and RESOLVE, 1997,

1995 Assisted Reproductive Technology

Success Rates: National Summary and

Fertility Clinic Reports.

20. U.S. Department of Health and Human

Services, Centers for Disease Control and

Prevention, American Society for

Reproductive Medicine and RESOLVE.

1998.1996 Assisted Reproductive Technology

Success Rates: National Summary and

Fertility Clinic Reports.

21. Wortley, P. M., T. A. Hammett, and P.

L. Fleming, ‘‘Donor Insemination and Human

Immunodeficiency Virus Transmission,’’

Obstetrics and Gynecology, vol. 91, No. 4,

1998.

22. VanKooij, R. J., M. F. Peeters, and E.

R. Velde, ‘‘Twins of Mixed Races:

Consequences for Dutch IVF Laboratories,’’

Human Reproduction, vol. 12, No. 12, pp.

2585–2587, 1997.

23. Hu, Yunxia, W. S. Maxson, D. I.

Hoffman, S. J. Ory, S. Eager, J. Dupre, and C.

Lu, ‘‘Maximizing Pregnancy Rates and

Limiting Higher-order Multiple Conceptions

by Determining the Optimal Number of

Embryos to Transfer Based on Quality,’’

Fertility and Sterility, vol. 69, No. 4, pp. 650–

657, 1998.

24. Van Voorhis, B. J., D. W. Stovall, B. D.

Allen, and C. H. Syrop, and ‘‘Cost-effective

Treatment of the Infertile Couple,’’ Fertility

and Sterility, vol. 70, No. 6, pp. 995–1004.

1998.

25. Griffin, M., and W. F. Panak, ‘‘The

Economic Cost of Infertility-related Services:

An Examination of the Massachusetts

Infertility Insurance Mandate,’’ Fertility and

Sterility, vol. 70, No. 1, pp. 22–29, 1999.

26. Neumann, P. J., ‘‘Should Health

Insurance Cover IVF? Issues and Options,’’

Journal of Health Politics, Policy and Law,

vol. 22, No. 5, pp. 1215–1236, 1997.

27. Steinberg, E. P., P. M. Holtz, E. M.

Sullivan, and C. P. Villar, ‘‘Profiling Assisted

Reproductive Technology Outcomes and

Quality of Infertility Management,’’ Fertility

and Sterility, vol. 69, No. 4, pp. 617–623,

1998.

28. National Center for Health Statistics,

Centers for Disease Control and Prevention,

U. S. DHHS, Fertility, Family Planning and

Women’s Health: New Data From the 1995

National Survey of Family Growth, Series 23,

No. 19, table 55, May 1997.

29. National Center for Chronic Disease

Prevention and Health Promotion, Centers for

Disease Control and Prevention, U.S. DHHS,

1996 Assisted Reproductive Technology

Success Rates: National Summary and

Fertility Clinic Reports, December 1998.

30. Yeung, C. H., T. G. Cooper, and E.

Nieschlag, ‘‘A Technique for Standardization

and Quality Control of Subjective Sperm

Motility Assessments in Semen Analysis,’’

Fertility and Sterility, vol. 67, No. 6, pp.

1156–1158, 1997.

31. Mahmoud, A. M. A., B. Depoorter, N.

Piens, and F. H. Comhaire, ‘‘The Performance

of 10 Different Methods for the Estimation of

Sperm Concentration,’’ Fertility and Sterility,

vol. 68, No. 2, pp. 340–345, 1997.

32. Ziebe, S. and C. Y. Andersen, ‘‘Isolation

of Motile Spermatozoa: Comparison of

Percoll Centrifugation, SpermPrep Filtration

and Swim-Up Techniques,’’ Journal of

Assisted Reproduction and Genetics vol. 10,

No. 7, pp. 485–487, 1993.

33. Carrell, D.T. et al., ‘‘A Randomized,

Prospective Analysis of Five Sperm

Preparation Techniques Before Intrauterine

Insemination of Husband Sperm,’’ Fertility

and Sterility, vol. 69, No. 1, pp. 122–126,

1998.

34. Ozornek, M. H., P. Bielfeld, and R. S.

Jeyendran, ‘‘Increase Recovery of Viable

Spermatozoa Through Oscillating

Centrifugation,’’ Fertility and Sterility vol. 70,

No. 4, pp. 712–714, 1998.

35. King, K., ‘‘Antibiotics: Effect on

Cryopreserved-thawed Human Sperm

Motility In Vitro,’’ Fertility and Sterility, vol.

67, No. 6, pp. 1146–1151, 1997.

36. Cohen, J., A. Gilligan, W. Esposity, T.

Schimmel, and B. Dale, ‘‘Ambient Air and its

Potential Effects on Conception in Vitro,’’

Human Reproduction, vol. 12, No. 8, pp.

1742–1749, 1997.

37. Francis, M. M. et al., ‘‘Embryo toxicity

of three commercially available powderless

1548 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

surgical gloves,’’ Journal of Assisted

Reproduction and Genetics, vol. 9, No. 3, pp.

283–357, 1992.

38. Munne, S. et al., ‘‘Treatment-related

Chromosome Abnormalities in Human

Embryos,’’ Human Reproduction, vol. 12, No.

4, pp. 780–784, 1997.

39. Brinsden, P. R. and P. A. Rainsbury,

eds., A Textbook of In Vitro Fertilization and

Assisted Reproduction, Park Ridge, NJ: The

Parthenon Publishing Group, 1992.

40. Hammitt, D. G. et al., ‘‘Prediction of

Nuclear Maturity from Cumulus-coronal

Morphology: Influence of Embryologist

Experience,’’ Journal of Assisted

Reproduction and Genetics, vol. 9, No. 5, pp.

439–467, 1992.

41. Wilcox, L. S. and J. S. Marks,

‘‘Regulating assisted reproductive

technologies: public health, consumer

protection, and public resources,’’ Women’s

Health Issues, vol. 6, No. 3, pp. 175–180,

1996.

42. Pool, T. B. ‘‘Practices Contributing to

Quality Performance in the Embryo

Laboratory and the Status of Laboratory

Regulation in the U.S.,’’ Human

Reproduction, vol. 12, No. 12, pp. 2591–

2593, 1997.

43. Callahan, T. L., J. E. Hall, S. L. Ettner,

C. L. Christiansen, M. F. Greene, and W. F.

Crowley, ‘‘The Economic Impact of MultipleGestation Pregnancies and the Contribution

of Assisted Reproductive Techniques to

Their Incidence,’’ The New England Journal

of Medicine, vol. 331, No. 4, pp. 244–249,

1994.

44. Prottas, Jeffrey, ‘‘A Study of the Tissue

Procurement and Distribution System of the

United States,’’ Brandeis University, FDA/

HRSA Contract No. 240–090–0048, October

1995.

45. American Medical Association,

Socioeconomics Characteristics of Medical

Practice, table 47, p. 150, 1994.

46. Fee Schedule 1/98, Donor Semen 0.5cc

and Donor Semen 0.8cc-1.0cc, The Sperm

Bank of California, at

www.thespermbankofca.org/fees96.htm

X. The Paperwork Reduction Act of

1995

This proposed rule contains

information collection provisions that

are subject to review by OMB under the

Paperwork Reduction Act of 1995 (44

U.S.C. 350193520). A description of

these provisions is shown below with

an estimate of the annual reporting and

recordkeeping burden. Included in the

estimate is the time for reviewing the

instructions, searching existing data

sources, gathering and maintaining the

data needed, and completing and

reviewing each collection of

information.

FDA invites comments on: (1)

Whether the proposed collection of

information is necessary for the proper

performance of FDA’s functions,

including whether the information will

have practical utility; (2) the accuracy of

FDA’s estimate of the burden of the

proposed collection of information,

including the validity of the

methodology and assumptions used; (3)

ways to enhance the quality, utility, and

clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: Reporting and Recordkeeping

Requirements in Current Good Tissue

Practice.

Description: Under the authority of

section 361 of the PHS Act, FDA is

proposing new regulations to require

manufacturers of human cellular and

tissue-based products to follow CGTP,

which would include information

collection provisions such as the

establishment and maintenance of

SOP’s, recordkeeping, reporting, and

labeling of the products. The CGTP

information collection provisions would

provide: (1) additional measures for

preventing the introduction,

transmission, or spread of

communicable diseases; (2) step-by-step

consistency in the manufacturing of the

product; (3) necessary information to

FDA for the purpose of protecting

public health and safety; (4)

accountability in the manufacturing of

cellular and tissue-based products; (5)

information for meaningful FDA

inspections; (6) information facilitating

the tracking of a product back to its

original source or to a recipient; (7)

information to FDA of any adverse

reaction; and (8) information that would

aid in the investigation of any

introduction, transmission, or spread of

a communicable disease.

Table 11 lists provisions that would

require reporting or disclosure of

information to third parties, the Federal

government, or the public. Section

1271.155(a) would require the

submission of a request for FDA

approval of an exemption or an

alternative from any requirement in

subpart C or D of part 1271 of the

proposed rule. When documentation on

the determination of donor suitability is

translated into English, § 1271.270(c)

would require a statement of

authenticity by the translator. Section

1271.290(c) would require a unique

identifier be affixed to each cellular or

tissue-based product to relate the

product to the donor and all records

pertaining to the product. Whenever an

establishment initially distributes

product to a consignee, § 1271.290(f)

would require the establishment to

inform the consignee, in writing, of the

product tracking requirements and the

methods the establishment uses to fulfill

the requirements. Establishments

described in proposed § 1271.10 would

be required under proposed

§ 1271.350(a) and (b) to report to the

agency any adverse reaction or any error

or accident that may reasonably be

expected to lead to a reportable adverse

reaction as defined in proposed

§ 1271.3(ee). Section 1271.370(a)(2) and

(a)(3) would require establishments to

include specific information on the

product label and package insert.

Table 12 lists recordkeeping

provisions under the proposed rule,

establishments would be required to

prepare and maintain written SOP’s for

all significant steps performed in the

manufacturing and tracking of human

cellular and tissue-based products. As

calculated in table 12, the preparation of

the SOP’s would result in a one-time

impact on establishments rather than

the year to year maintenance of the

SOP’s because, once composed, SOP’s

would only be reviewed annually and

updated as necessary.

The SOP provisions proposed under

part 1271 in the combined maintenance

estimate include: (1) § 1271.160(b)(2)

(receiving, investigation, evaluating, and

documenting information received from

other sources); (2) § 1271.160(f) (quality

program); (3) § 1271.180 (all significant

steps performed in the manufacture of

human cellular and tissue-based

products); (4) § 1271.190(c)(3) (facility

cleaning and sanitization); (5)

§ 1271.195(a) (control and monitoring of

environmental conditions); (6)

§ 1271.200(b) (cleaning, sanitizing, and

maintenance of equipment); (7)

§ 1271.200(c) (calibration of equipment);

(8) § 1271.210(a) (receipt and

verification of supplies and reagents);

(9) § 1271.210(b) (validation and/or

verification of in-house reagents); (10)

§ 1271.220(b) (use and removal of

processing material); (11) § 1271.220(d)

(control of in-process product); (12)

§ 1271.225(a) (verification or validation

of changes to a process); (13)

§ 1271.230(d) (maintenance and control

of validated processes); (14) § 1271.250

(labeling of human cellular and tissuebased products); (15) § 1271.265(a) to (c)

(receipt, acceptance or rejection,

distribution, and destruction or other

disposition of human cellular or tissuebased products); (16) § 1271.265(f)

(suitable for return to inventory); (17)

§ 1271.270(b) (records management

system); (18) § 1271.290(b) (method of

product tracking); and, (19)

§ 1271.320(a) (review, evaluation, and

documentation of all complaints).

Proposed part 1271 would require the

following additional recordkeeping

provisions listed under table 12. Section

1271.155(f) would require an

establishment operating under the terms

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1549

of an exemption or alternative to

maintain documentation of the terms

and date of FDA approval. Section

1271.160(b)(3) would require

documentation of corrective actions

taken as a result of an audit of the

quality program. Section 1271.160(b)(7)

would require documentation of all

product deviations in manufacturing

cellular or tissue-based products.

Section 1271.160(d)(3) would require

documentation of the results of all

audits and reaudits of the quality

program. Section 1271.160(e) would

require documentation of computer

validation activities and results when

computers are used as part of the quality

program, as part of manufacturing, or for

maintaining data or records. Section

1271.170(d) would require the

maintenance of records of education,

experience, training, and retraining of

all personnel. Section 1271.190(c)(4)

would require documentation of all

significant facility cleaning and

sanitation. Section 1271.195(c) would

require documentation of environmental

control and monitoring activities.

Section 1271.200(e) would require

documentation of all equipment

maintenance, cleaning, sanitizing,

calibration, and other activities. Section

1271.210(c) would require

documentation of the receipt,

verification, and use of each supply or

reagent. Section 1271.220(b) and (d)

would require documentation of the

adequate removal of processing material

and the verification activities for inprocess product. Section 1271.225(b)

would require documentation of all

changes to established processes,

including rationale and the date of

implementation. Section 1271.230(a)

would require documentation of

validation activities when the results of

a process cannot be fully verified by

subsequent inspection and tests. Section

1271.230(b) would require

documentation of the validation of any

process-related claim. Section

1271.230(e) would require

documentation of the review and

evaluation of a process and revalidation

of the process, if necessary, when any

changes to or deviations from a

validated process occur. Section

1271.260(b)(3) and (d) would require

documentation of the storage

temperature of human cellular and

tissue-based products and any

corrective action taken when acceptable

storage conditions are not met. Section

1271.265(a) and (b) would require

documentation of the receipt,

acceptance or rejection, distribution,

and destruction or other disposition of

a human cellular or tissue-based

product. Section 1271.270(a) and (c)

would require documentation of each

significant step in manufacturing

required in subparts C and D of part

1271, the results and interpretation of

all testing and screening for relevant

communicable disease agents and

diseases, and the determination of

donor suitability.

Section 1271.180 would require the

retention of obsolete procedures for 10

years. Section 1271.270(e) would

require the retention of all records for a

period of 10 years after their creation.

Records pertaining to a particular

human cellular or tissue-based product

would be required to be retained at least

10 years after the date of implantation,

transplantation, infusion, or transfer of

the product. If the date of implantation,

transplantation, infusion, or transfer is

not known, then records would be

required to be retained at least 10 years

after the date of the product’s

distribution, disposition, or expiration,

whichever is latest. This retention time

is necessary because certain cellular and

tissue-based products have long storage

periods. In addition, advances in

medical technology have created

opportunities for diagnosis and therapy

for up to 10 years after recipient

exposure to a donor later determined to

be at risk for communicable disease

agents or diseases.

Section 1271.270(f) would require

documentation of any contract,

agreement, or other arrangement with

another establishment under which any

step in the manufacturing process is

performed by the other establishment.

Section 1271.290(e) would require

documentation of the disposition of

each of its human cellular or tissuebased product as part of its tracking

method. Section 1271.290(f) would

require an establishment to document

that a consignee agreed to participate in

its tracking method and will take all

necessary steps to ensure compliance

with the requirements of the regulation.

Section 1271.320(b) would require an

establishment to maintain a record of

each complaint that it receives,

including a review and evaluation.

Section 1271.350(c) would require the

documentation of adverse reaction

reports, errors and accidents in

manufacturing that may lead to product

deviation reports, and the investigation

of these reports.

Description of Respondents:

Manufacturers of cellular and tissuebased products.

FDA estimates the burden of this

collection of information as follows:

TABLE 11.—ESTIMATED ANNUAL REPORTING BURDEN 1

21 CFR Section No. of

Respondents

Annual Frequency

per Response

Total Annual

Responses Hours per Response Total Hours

1271.155(a) 1,065 1 1,065 3 3,195

1271.270(c) 1,065 1 1,065 1 1,065

1271.290(c) 791 250 198,215 0.08 15,857

1271.290(f) 1,065 1 1,065 1 1,065

1271.350(a) 1,065 6 6,390 0.5 3,195

1271.350(b) 1,065 2 2,130 0.5 1,065

1271.370(a)(2) and (a)(3) 633 207 131,005 0.25 32,751

Total 58,193

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

TABLE 12.—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1

21 CFR Section No. of

Recordkeepers

Annual

Frequency per

Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

One-time Burden (Creation of SOP’s 2) 1,065 9 9,585 16 153,360

One-time Burden (Review of existing SOP’s for

compliance) 1,065 19 20,235 5 101,175

1550 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

TABLE 12.—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1—Continued

21 CFR Section No. of

Recordkeepers

Annual

Frequency per

Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

SOP Maintenance (See previous list of 19 SOP’s) 1,065 19 20,235 1 20,235

1271.155(f) 1,065 1 1,065 0.25 266

1271.160(b)(3) 483 2 966 6 5,796

1271.160(b)(7) 597 15 8,955 0.5 4,478

1271.160(d)(3) 558 1 558 13 7,254

1271.160(e) 597 5 2,985 0.25 746

1271.170(d) 483 1 483 1 483

1271.180 483 1 483 120 57,960

1271.190(c)(4) 558 12 6,696 1 6,696

1271.195(c) 822 12 9,864 1 9,864

1271.200(e) 483 12 5,796 1 5,796

1271.210(c) 597 12 7,164 1 7,164

1271.220(b) and (d) 91 781 71,070 0.08 5,686

1271.225(b) 1,065 2 2,130 1 2,130

1271.230(a) 755 1 755 1 755

1271.230(b) 980 1 980 1 980

1271.230(e) 1,065 1 1,065 1 1,065

1271.260(b)(3) 597 356 212,532 0.08 17,003

1271.260(d) 747 12 8,964 0.25 2,241

1271.265(a) 597 360 214,920 0.08 17,194

1271.265(b) 822 407 334,554 0.08 26,764

1271.270(a) and (c) 597 360 214,920 0.1 21,492

1271.270(f) 755 2 1,510 0.25 378

1271.290(e) 641 306 196,146 0.3 58,844

1271.290(f) 1,065 57 60,705 0.35 21,247

1271.320(b) 830 5 4,150 1 4,150

1271.350(c) 726 6 4,356 0.5 2,178

Total 563,380

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

2Standard operating procedures.

Under this proposed rule, 19 SOP’s

would be required as previously

described. FDA is assuming that

approximately 1,065 manufacturers

would have to create up to 9 SOP’s for

a total of 9,585 records, and the agency

estimates that it would take 16 hours

per record to create 9 new SOP’s for a

total of 153,360 hours as a one-time

burden. The agency estimates that up to

19 SOP’s would already exist as a result

of complying with current applicable

regulations or following industry

organizational standards.

Approximately 1,065 manufacturers

would have to review these 19 SOP’s for

compliance with the regulations, which

would expend approximately 5 hours

per SOP as a one-time burden. Annual

SOP maintenance of existing SOP’s is

estimated to involve 1 hour annually

per SOP, totaling 19 hours annually per

recordkeeper.

In some cases, the estimated burden

may appear to be lower or higher than

the burden experienced by individual

establishments. The estimated burden in

these charts is an estimated average

burden, taking into account the range of

impact each proposed regulation may

have. In estimating the burden, FDA

compared the proposed regulations with

the current voluntary standards of a

number of industry organizations, such

as, AATB, EBAA, AABB, FAHCT, and

CAP, and the guidelines provided by

ASRM. In those cases where a voluntary

industry standard appears to be

equivalent to a proposed regulation,

FDA has assumed that any reporting or

recordkeeping burden is a customary

and usual business practice of

establishments who are members of

those organizations and no additional

burden is calculated here. In some cases

establishments affected by this proposed

rule may already be required to comply

with regulations for manufacturers of

human drugs or biological products,

e.g., parts 210, 211, 312, 314, and 606

(21 CFR parts 312, 314, and 606).

FDA has estimated the reporting

(table 11) and recordkeeping (table 12)

burdens based upon the agency’s

institutional experience with

comparable recordkeeping and reporting

provisions applicable to the human drug

and biological product industries, recent

information from trade organizations

related to the manufacturing of products

utilizing cells and tissues, and data

provided by the Eastern Research Group

(ERG), a consulting firm hired by FDA

to prepare an economic analysis of the

potential economic impact on sperm

banks and ART facilities.

The agency has estimated that there

are approximately 1,065 manufacturers

of cellular and tissue-based products

(approximately 110 manufacturers of

conventional tissue, 114 manufacturers

of eye tissue, 425 manufacturers of

peripheral and cord blood stem cells,

350 manufacturers of reproductive

tissue, and 66 manufacturers of cellular

or tissue-based licensed biological

products or devices). FDA obtained

these estimates of manufacturers

(including percentage of members and

nonmembers) from the various trade

organizations and the agency’s

registration systems for biological

product and device manufacturers. The

total number of respondents and

recordkeepers, 1,065, in the tables is

decreased for each provision by the

number of establishments that follow, as

usual and customary practice, the

applicable established trade

organizational standards comparable to

the CGTP requirements, i.e., AATB,

EBAA, FAHCT, AABB, or CAP. FDA

based the estimated numbers for

‘‘Number of Respondents’’ and

‘‘Number of Recordkeepers’’ on

information provided by the trade

organizations.

FDA based the estimated numbers for

‘‘Annual Frequency per Response,’’

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1551

‘‘Total Annual Responses,’’ ‘‘Annual

Frequency per Recordkeeping,’’ and

‘‘Total Annual Records’’ on information

received from the trade organizations,

institutional experience with similar

requirements (good manufacturing

practice), general information provided

to FDA during inspections of

manufacturers of human tissue intended

for transplantation, and information

gathered by ERG.

The estimates for ‘‘Hours per

Response’’ or ‘‘Hours per Recordkeeper’’

were calculated using comparable

burdens under drug GMP regulations,

part 211, and GMP for blood and blood

components, part 606, or by using the

information provided by ERG, e.g., time

spent on §§ 1271.190(c)(4)

(documentation of cleaning and

sanitation) and 1271.195(c)

(documentation of environmental

control and monitoring activities) was

an estimate provided by ERG.

In compliance with the Paperwork

Reduction Act of 1995 (44 U.S.C.

3507(d), the agency has submitted the

information collection provisions of this

proposed rule to OMB for review.

Interested persons are requested to send

comments regarding information

collection by February 7, 2001 to the

Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Wendy

Taylor, Desk Officer for FDA.

XI. Federalism

FDA has analyzed this proposed rule

in accordance with the principles set

forth in Executive Order 13132. FDA

has concluded that the proposed rule

raises Federalism implications because

it could preempt some States’ laws

regarding donated human cells and

tissues. FDA currently is seeking

comments from elected State and local

government officials under Executive

Order 13132 on: (1) The need for the

proposed good tissue practice rule to

prevent communicable disease

transmission through human cellular

and tissue-based products; (2)

alternatives that would limit the scope

of such national requirements or

otherwise preserve State prerogatives

and authority; (3) the proposed good

tissue practice provisions; and (4) any

other issues raised by this proposed rule

possibly affecting State laws and

authorities.

XII. Request For Comments

Interested persons may submit to the

Dockets Management Branch (address

above) written comments on this

proposal by May 8, 2001. Two copies of

any comments are to be submitted,

except that individuals may submit one

copy. Comments are to be identified

with the docket number found in

brackets in the heading of this

document. Received comments may be

seen in the Dockets Management Branch

between 9 a.m. and 4 p.m., Monday

through Friday. Comments received in

response to the proposed GTP rule

could support a change that will affect

language in previously published

proposed tissue rules. In the event that

any tissue rule becomes effective before

either or both of the remaining tissue

rules become effective, FDA intends to

make conforming amendments to those

final rules at the same time the

remaining tissue rules become effective.

List of Subjects in 21 CFR Part 1271

Human cellular and tissue-based

products, Communicable diseases, HIV/

AIDS, Reporting and recordkeeping

requirements.

Therefore, under the Public Health

Service Act, and under the authority

delegated to the commissioner of Food

and Drugs, it is proposed to amend 21

CFR Chapter I as follows:

Part 1271 as proposed in the Federal

Register of May 14, 1998 (63 FR 26744)

and September 30, 1999 (64 FR 52696)

is amended as follows:

PART 1271—HUMAN CELLULAR AND

TISSUE-BASED PRODUCTS

1. The authority citation for 21 CFR

part 1271 is revised to read as follows:

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

264, 271.

2. Section 1271.3 is amended by

adding paragraphs (ff) through (tt) to

read as follows:

§ 1271.3 Definitions.

* * * * *

(ff) Available for distribution means

that the human cellular or tissue-based

product has been determined to meet all

release specifications and to be suitable

for distribution.

(gg) Adverse reaction means a noxious

and unintended response to any human

cellular or tissue-based product for

which there is a reasonable possibility

that the response may have been caused

by the product (i.e., the relationship

cannot be ruled out).

(hh) Processing material means any

material or substance that is used in, or

to facilitate, processing, but which is not

intended by the manufacturer to be

included in the human cellular or

tissue-based product when it is made

available for distribution.

(ii) Complaint means any written,

oral, or electronic communication that

alleges:

(1) That a human cellular or tissuebased product has transmitted or may

have transmitted a communicable

disease to the recipient of the product;

(2) That the function or integrity of a

human cellular or tissue-based product

may have been impaired; or

(3) Any other problem with a human

cellular or tissue-based product that

could result from the failure to comply

with current good tissue practice.

(jj) Distribution means any

conveyance or shipment of human

cellular or tissue-based products

(including importation and exportation),

whether or not such conveyance or

shipment is entirely intrastate and

whether or not possession of the

product is taken.

(kk) Product deviation means an event

that represents a deviation from current

good tissue practice, applicable

standards, or established specifications;

or an unexpected or unforeseeable event

that may relate to the transmission or

potential transmission of a

communicable disease agent or disease

from a human cellular or tissue-based

product to a recipient, or may lead to

product contamination, or may

adversely affect the function or integrity

of the product.

(ll) Establish and maintain means

define, document (in writing or

electronically), and implement, then

follow, review, and as needed, revise on

an ongoing basis.

(mm) Processing means any activity

other than recovery, donor screening,

donor testing, storage, labeling,

packaging, or distribution performed on

a human cellular or tissue-based

product, including but not limited to

preparation, sterilization, steps to

inactivate and remove adventitious

agents, preservation for storage, and

removal from storage.

(nn) Quality audit means a

documented, independent inspection

and review of an establishment’s

activities, including manufacturing and

tracking, performed according to

procedures, to verify, by examination

and evaluation of objective evidence,

the degree of compliance with those

aspects of the quality program under

review.

(oo) Quality program means an

organization’s comprehensive system

for manufacturing and tracking human

cellular and tissue-based products. This

program includes preventing, detecting,

and correcting deficiencies that may

lead to circumstances that increase the

risk of introduction, transmission, or

spread of communicable disease.

(pp) Recovery means the process of

obtaining from a donor cells or tissues

that are intended for use in human

1552 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

implantation, transplantation, infusion,

or transfer.

(qq) Storage means holding human

cellular or tissue-based products for

future processing and/or distribution.

(rr) Validation means confirmation by

examination and provision of objective

evidence that particular requirements

can consistently be fulfilled. Validation

of a process, or process validation,

means establishing by objective

evidence that a process consistently

produces a result or product meeting its

predetermined specifications.

(ss) Verification means confirmation

by examination and provision of

objective evidence that specified

requirements have been fulfilled.

(tt) Importer of record means the

person, establishment, or its

representative responsible for making

entry of imported goods in accordance

with all laws affecting such importation.

3. Subpart D, consisting of

§§ 1271.150 through 1271.320, is added

to part 1271 to read as follows:

Subpart D—Current Good Tissue

Practice

Sec.

1271.150 Current good tissue practice:

general.

1271.155 Exemptions and alternatives.

1271.160 Establishment and maintenance of

a quality program.

1271.170 Organization and personnel.

1271.180 Procedures.

1271.190 Facilities.

1271.195 Environmental control and

monitoring.

1271.200 Equipment.

1271.210 Supplies and reagents.

1271.220 Process controls.

1271.225 Process changes.

1271.230 Process validation.

1271.250 Labeling controls.

1271.260 Storage.

1271.265 Receipt and distribution.

1271.270 Records.

1271.290 Tracking.

1271.320 Complaint file.

Subpart D—Current Good Tissue

Practice

§ 1271.150 Current good tissue practice:

general.

(a) General. Current good tissue

practice (CGTP) requirements are set

forth in this subpart and in subpart C of

this part. CGTP requirements govern the

methods used in, and the facilities and

controls used for, the manufacture of

human cellular and tissue-based

products, including but not limited to

all steps in recovery, donor screening,

donor testing, processing, storage,

labeling, packaging, and distribution.

The CGTP requirements are intended to

prevent the introduction, transmission,

and spread of communicable disease

through the use of human cellular and

tissue-based products by helping to

ensure that the products do not contain

communicable disease agents; that the

products do not become contaminated

during manufacturing; and that the

function and integrity of the products

are not impaired through improper

manufacturing. The CGTP provisions

specifically governing determinations of

donor suitability, including donor

screening and testing, are set out

separately in subpart C of this part.

(b) Compliance with applicable

requirements. (1) If an establishment

engages in only some operations subject

to the regulations in this subpart and

subpart C of this part, and not others,

that establishment need only comply

with those requirements applicable to

the operations in which it engages.

However, an establishment that engages

another establishment under a contract,

agreement, or other arrangement, to

perform any step in the manufacturing

process, is responsible for ensuring that

the work is performed in compliance

with the requirements in this subpart

and subpart C of this part.

(2) The establishment that determines

that a product meets release criteria and

makes the product available for

distribution, whether or not that

establishment is the actual distributor,

is responsible for ensuring that the

product has been manufactured in

compliance with the requirements of

subparts C and D of this part and any

other applicable requirements.

(c) Compliance with parts 210, 211,

and 820 of this chapter. With respect to

human cellular or tissue-based products

regulated as biological drugs or devices

under section 351 of the Public Health

Service Act and/or the Federal Food,

Drug, and Cosmetic Act, the procedures

contained in this subpart and in subpart

C of this part and the current good

manufacturing practice regulations in

parts 210 and 211 of this chapter and

the quality system regulations in part

820 of this chapter, shall be considered

to supplement, not supersede, each

other unless the regulations explicitly

provide otherwise. In the event that it is

impossible to comply with all

applicable regulations in these parts, the

regulations specifically applicable to the

biological drug or device in question

shall supersede any other requirements.

(d) Where appropriate. When a

requirement is qualified by ‘‘where

appropriate,’’ it is deemed to be

‘‘appropriate’’ unless the establishment

can document justification otherwise. A

requirement is ‘‘appropriate’’ if

nonimplementation could reasonably be

expected to result in the product’s not

meeting its specified requirements

related to prevention of introduction,

transmission, or spread of

communicable disease agents and

diseases, or in the establishment’s

inability to carry out any necessary

corrective action.

§ 1271.155 Exemptions and alternatives.

(a) General. An establishment may

request an exemption or alternative

from any requirement in subpart C or D

of this part regarding a human cellular

or tissue-based product.

(b) Request for exemption or

alternative. A request under this section

shall be submitted to the Director,

Center for Biologics Evaluation and

Research (the Director). The request

shall be accompanied by supporting

documentation, including all relevant

valid scientific data. A request for an

exemption shall contain information

justifying the exemption. A request for

an alternative shall contain a

description of an alternative that

satisfies the purpose of the requirement.

(c) Criteria for granting exemption or

alternative. The Director may grant an

exemption or alternative if he or she

finds that such action is consistent with

the goals of preventing the introduction,

transmission, and spread of

communicable disease and that:

(1) The information submitted

justifies an exemption; or

(2) The proposed alternative satisfies

the purpose of the requirement.

(d) Form of request. A request for an

exemption or alternative shall ordinarily

be made in writing or electronically.

However, in limited circumstances such

a request may be made orally, and an

exemption or alternative may be granted

orally by the Director. An oral request

and approval shall be followed by an

immediate written request and written

acknowledgment of approval.

(e) Operation under exemption or

alternative. An establishment shall not

begin operating under the terms of a

requested exemption or alternative until

the exemption or alternative has been

granted in writing. An establishment

may apply for an extension of an

exemption or alternative beyond its

expiration date, if any.

(f) Documentation. An establishment

operating under the terms of an

exemption or alternative shall maintain

documentation of:

(1) FDA’s granting of the exemption or

alternative, and

(2) The date on which it began

operating under the terms of the

exemption or alternative.

§ 1271.160 Establishment and

maintenance of a quality program.

(a) General. An establishment that

performs any step in the manufacture of

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1553

human cellular and tissue-based

products shall establish and maintain a

quality program that is appropriate for

the specific human cellular and tissuebased products manufactured and the

manufacturing steps performed and that

meets the requirements of this subpart.

(b) Functions. Functions of the quality

program shall include, but not be

limited to:

(1) Ensuring that appropriate

procedures are established and

maintained, and ensuring compliance

with the requirements of § 1271.180

with respect to procedures, including

review, approval, revision, and

archiving;

(2) Ensuring that procedures exist for

receiving, investigating, evaluating, and

documenting information received from

other sources and for sharing with

consignees and other establishments

that are known to have recovered cells

or tissue from the same donor any

information pertaining to the integrity

and function of a human cellular or

tissue-based product, possible

contamination of the product, or the

potential transmission of communicable

disease by the product. In the case of

information received after the product is

made available for distribution or

shipped to the consignee, procedures

shall include provisions for evaluating

the effect this information has on the

product and for the notification of all

entities to whom affected product was

distributed, the quarantine and recall of

the product, and/or reporting to FDA, as

necessary.

(3) Ensuring that appropriate

corrective actions, including reaudits of

deficiencies, are taken and documented,

as necessary. Corrective actions shall be

verified to ensure that such actions are

effective and do not adversely affect the

finished product. Where appropriate,

corrective actions shall include both

short-term action to address the

immediate problem and long-term

action to prevent the problem’s

recurrence. Documentation of corrective

actions shall include where appropriate:

(i) Identification of the human cellular

or tissue-based product affected and a

description of its disposition;

(ii) The nature of the problem

requiring corrective action;

(iii) A description of the corrective

action taken; and

(iv) The date(s) of the corrective

action.

(4) Ensuring the proper training and

education of personnel;

(5) Establishing and maintaining

appropriate monitoring systems as

necessary to comply with the

requirements of this subpart (e.g.,

environmental monitoring);

(6) Establishing and maintaining a

system for the maintenance of records in

compliance with § 1271.270;

(7) Investigating and documenting all

product deviations and making reports

if required under § 1271.350(b) or other

applicable regulations. Each

investigation shall include a review and

evaluation of the product deviation, the

efforts made to determine the cause, and

the implementation of corrective

action(s) designed to address the

product deviation and prevent

recurrence. Each establishment shall

also perform a periodic review and

analysis of all product deviations, at

least once each year, for the purpose of

identifying trends and adopting

appropriate preventive measures. This

analysis shall be available for review

upon inspection and for submission to

FDA upon request; and

(8) Conducting evaluations,

investigations, audits, and other actions

necessary to ensure compliance with the

requirements of this subpart.

(c) Authority over program. One or

more designated persons shall have

authority over and responsibility for

ensuring that the quality program is

effectively established and effectively

maintained. This person shall report to

management on the performance of the

quality program on no less than an

annual basis. If this person also

performs other tasks in the

establishment, he or she shall not have

final oversight over his or her own

work.

(d) Audits. (1) A comprehensive

quality audit, as defined in § 1271.3(nn),

shall be performed no less than once in

a 12-month period. Special audits shall

be performed as necessary. All audits

shall be conducted in accordance with

procedures to assure that the quality

program is operating effectively and to

identify trends or recurring problems.

(2) Quality audits shall be conducted

by individuals with sufficient

knowledge, training, and experience to

identify problems in the specific

processes under review, but who do not

have direct responsibility for the

processes being audited.

(3) A documented report of the results

of the audits and reaudits, where taken,

shall be retained. Such reports shall be

reviewed by management having

responsibility for the matters audited,

and this management review shall be

documented.

(e) Computers. If computers or

automated data processing systems are

used as part of the quality program, as

part of manufacture or tracking, or for

maintaining data or records related to

the manufacture or tracking of human

cellular or tissue-based products, the

establishment shall validate computer

software for its intended use according

to an established protocol. All software

changes shall be validated before

approval and issuance. These validation

activities and results shall be

documented.

(f) Procedures. Procedures shall be

established and maintained for a quality

program, including quality audits.

§ 1271.170 Organization and personnel.

(a) General. Each establishment shall

maintain an adequate organizational

structure and sufficient personnel to

ensure that the requirements of this part

are met.

(b) Competent performance of

functions. Each establishment shall

have sufficient personnel with the

necessary education and experience to

assure competent performance of their

assigned functions. Personnel shall

perform only those activities for which

they are qualified.

(c) Training. All personnel shall be

trained, and retrained as necessary, to

perform their assigned responsibilities

adequately. Personnel shall be made

aware of possible consequences of

improper performance of their duties;

e.g., the risk of transmission of

communicable disease agents and

diseases, and the hazards associated

with those disease agents and diseases,

and the risk of adversely affecting

function and integrity of human cellular

and tissue-based products.

(d) Records. A record of the

education, experience, training, and

retraining shall be maintained for all

personnel.

§ 1271.180 Procedures.

Each establishment shall establish

and maintain procedures for all

significant steps that it performs in the

manufacture of human cellular and

tissue-based products. These procedures

shall be designed to prevent

circumstances that increase the risk of

the introduction, transmission, and

spread of communicable disease

through the use of human cellular and

tissue-based products by ensuring that

the products do not contain relevant

communicable disease agents; that the

products do not become contaminated

during manufacturing; and that the

function and integrity of the products

are not impaired through improper

manufacturing. Procedures shall be

designed to ensure compliance with the

requirements of this part. Prior to

implementation, all procedures shall be

reviewed and approved by a responsible

person. At least once in a 12-month

period, all procedures shall be reviewed

and, if necessary, revised, and the

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review shall be documented. Procedures

shall be readily available to the

personnel in the area where the

operations to which they relate are

performed, unless this is impractical.

Any deviation from a procedure shall be

authorized in advance by a responsible

person, recorded, and justified. An

establishment may adopt current

standard procedures, such as those in a

technical manual prepared by another

organization, provided the procedures

are consistent with and at least as

stringent as the requirements of this part

and appropriate for the operations

conducted at the establishment.

Obsolete procedures shall be archived

for at least 10 years.

§ 1271.190 Facilities.

(a) General. Any facility used in the

manufacture of human cellular or

tissue-based products shall be of

suitable size, construction, and location

to facilitate cleaning, relevant

maintenance, and proper operations.

The facility shall be maintained in a

good state of repair. Adequate lighting,

ventilation, plumbing, drainage, and

washing and toilet facilities shall be

provided.

(b) Operations. A facility used in the

manufacture of human cellular or

tissue-based products shall be divided

into separate or defined areas of

adequate size for each operation that

takes place in the facility, or other

control systems shall be established and

maintained to prevent improper

labeling, mix-ups, contamination, crosscontamination, and accidental exposure

of human cellular and tissue-based

products to communicable disease

agents.

(c) Facility cleaning and sanitation.

(1) Any facility used in the manufacture

of human cellular and tissue-based

products shall be maintained in a clean,

sanitary, and orderly manner.

(2) Sewage, trash, and other refuse

shall be disposed of in a timely, safe,

and sanitary manner.

(3) Procedures for facility cleaning

and sanitation shall be established and

maintained. These procedures shall

assign responsibility for sanitation and

shall describe in sufficient detail the

cleaning methods to be used and the

schedule for cleaning the facility.

(4) All significant cleaning and

sanitation activities shall be

documented, and records shall be

maintained.

§ 1271.195 Environmental control and

monitoring.

(a) General. Where environmental

conditions could reasonably be

expected to have an adverse effect on

the function or integrity of human

cellular and tissue-based products, or to

cause contamination or crosscontamination of products or equipment

or accidental exposure of products to

communicable disease agents,

procedures shall be established and

maintained to adequately control and

monitor environmental conditions and

to provide proper conditions for

operations. Where appropriate, these

procedures shall provide for the

following control and monitoring

activities or systems:

(1) Temperature and humidity

controls;

(2) Ventilation and air filtration;

(3) Cleaning and disinfecting of rooms

and equipment to ensure aseptic

processing operations;

(4) Maintenance of equipment used to

control conditions necessary for aseptic

processing operations; and

(5) Environmental monitoring for

organisms.

(b) Inspections. Each environmental

control system shall be inspected

periodically to verify that the system,

including necessary equipment, is

adequate and functioning properly.

Appropriate corrective action shall be

taken as necessary.

(c) Records. Environmental control

and monitoring activities shall be

documented, and records shall be

maintained.

§ 1271.200 Equipment.

(a) General. Equipment used in the

manufacture of human cellular and

tissue-based products shall be of

appropriate design for its use, shall be

suitably located and installed to

facilitate operations, including cleaning

and maintenance, and shall not have

any adverse effect on the products. Any

automated, mechanical, electronic,

computer, or other equipment used for

inspection, measuring, and testing shall

be capable of producing valid results.

(b) Procedures and schedules.

Procedures shall be established and

maintained for cleaning, sanitizing, and

maintaining equipment to prevent

malfunctions, contamination or crosscontamination, accidental exposure of

human cellular and tissue-based

products to communicable disease

agents, and other events that could

reasonably be expected to have an

adverse effect on product function or

integrity. Cleaning, sanitizing, and

maintenance of equipment shall be

performed according to established

schedules.

(c) Calibration of equipment. All

automated, mechanical, electronic,

computer, or other equipment used for

inspection, measuring, and testing shall

be routinely calibrated according to

established procedures and schedules.

Calibration procedures shall include

specific directions and, where

applicable, shall include limits for

accuracy and precision. When accuracy

and precision limits are not met, there

shall be provisions for corrective action

to reestablish the limits and to evaluate

whether there were any adverse effects

on any human cellular or tissue-based

product.

(d) Inspections. Equipment shall be

routinely inspected for cleanliness,

sanitation, and calibration, and to assure

adherence to applicable equipment

maintenance schedules.

(e) Records. All maintenance,

cleaning, sanitizing, calibration, and

other activities performed in accordance

with this section shall be documented

and maintained. Records of recent

maintenance, cleaning, sanitizing,

calibration, and other activities shall be

available at each piece of equipment.

Records of the use of each piece of

equipment, which shall include the

identification of each human cellular or

tissue-based product manufactured with

that equipment, shall be maintained.

§ 1271.210 Supplies and reagents.

(a) Receipt and verification.

Procedures shall be established and

maintained for receiving supplies and

reagents used in the manufacture of

human cellular and tissue-based

products. Supplies and reagents shall be

verified to meet specifications designed

to prevent circumstances that increase

the risk of the introduction,

transmission, or spread of

communicable disease through product

contamination or the impairment of

product function or integrity, and shall

not be used until such verification is

completed. Verification may be

accomplished by the establishment that

uses the supply or reagent, or by the

vendor of the supply or reagent.

(b) Reagents. Reagents used in

processing and preservation of human

cellular and tissue-based products shall

be of appropriate grade for the intended

use and shall be sterile, if appropriate.

Procedures for production of in-house

reagents shall be validated and/or

verified.

(c) Records. The following records

pertaining to supplies and reagents shall

be maintained:

(1) Records of the receipt of each

supply or reagent, including the type,

manufacturer, lot number, date of

receipt, and expiration date;

(2) Records of the verification of each

supply or reagent, including test results

or, in the case of vendor verification, a

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certificate of analysis from the vendor;

and

(3) Records of the use of each supply

or reagent, which shall include the

identification of each human cellular or

tissue-based product manufactured with

the supply or reagent.

§ 1271.220 Process controls.

(a) General. Each establishment

engaged in the processing of human

cellular or tissue-based products shall

develop, conduct, control, and monitor

its manufacturing processes to ensure

that each human cellular or tissue-based

product conforms to specifications, is

not contaminated, maintains its

function and integrity, and is

manufactured so as to prevent

transmission of communicable disease

by the product.

(b) Processing material. Where a

processing material could reasonably be

expected to have an adverse effect on a

human cellular or tissue-based

product’s function or integrity, the

establishment shall establish and

maintain procedures for the use and

removal of such processing material to

ensure that it is removed or limited to

an amount that does not adversely affect

the product’s function or integrity. The

removal or reduction of such processing

material shall be documented.

(c) Pooling. Human cells or tissue

from two or more donors shall not be

pooled (placed in physical contact or

mixed in a single receptacle) during

manufacturing.

(d) In-process monitoring. Procedures

shall be established and maintained,

where appropriate, to ensure that

specified requirements of in-process

product are met. Such procedures shall

ensure that in-process product is

controlled until the required inspection

and tests or other verification activities

have been completed or necessary

approvals are received and documented.

Sampling of in-process products shall

be representative of the material to be

evaluated.

§ 1271.225 Process changes.

(a) Procedures. Procedures shall be

established and maintained for making

changes to a process. Any such change

shall be verified or validated, to ensure

that the change does not create an

adverse impact elsewhere in the

operation, and shall be approved before

implementation by a responsible person

with appropriate knowledge and

background.

(b) Change records. All changes to

established processes shall be

documented, including the rationale for

the change and the date of

implementation. Change records shall

include a description of the change,

identification of the affected documents,

the signature of the approving

individual(s), approval date, and when

the change becomes effective. Approved

changes shall be communicated to the

appropriate personnel in a timely

manner.

§ 1271.230 Process validation.

(a) General. Where the results of a

process cannot be fully verified by

subsequent inspection and tests, the

process shall be validated and approved

according to established procedures.

The validation activities and results,

including the date and signature of the

individual(s) approving the validation,

shall be documented.

(b) Claims. Any process-related claim

in labeling or promotional materials for

a human cellular or tissue-based

product, e.g., a claim for sterility or viral

inactivation, shall be based on a

validated process. Validation shall be

documented, and the documentation

shall be maintained at the establishment

and made available for review on

inspection.

(c) Dura mater. Dura mater shall be

processed using a validated procedure

that reduces transmissible spongiform

encephalopathy, while preserving the

clinical utility of the product.

(d) Procedures. Procedures shall be

established and maintained for

monitoring and control of validated

processes to ensure that the specified

requirements continue to be met.

(e) Changes and deviations. When

changes to or deviations from a

validated process occur, the

establishment shall review and evaluate

the process and perform revalidation

where appropriate. These activities shall

be documented.

§ 1271.250 Labeling controls.

Procedures shall be established and

maintained to control the labeling of

human cellular and tissue-based

products. These procedures shall be

designed to ensure proper product

identification and to prevent mix-ups.

Procedures shall include verification of

label accuracy, legibility, and integrity.

Procedures shall ensure that each

product is labeled in accordance with

all applicable labeling requirements,

including those in §§ 1271.55, 1271.65,

1271.75, 1271.90, 1271.290, and

1271.370, and that each product made

available for distribution is

accompanied by documentation of the

donor suitability determination as

required under § 1271.55.

§ 1271.260 Storage.

(a) Control of storage areas. Each

establishment shall control its storage

areas and stock rooms to prevent mixups, commingling, deterioration,

contamination, and crosscontamination, of human cellular and

tissue-based products and supplies, and

any other condition that may adversely

affect product function or integrity, and

to prevent improper release for

distribution.

(b) Temperature. (1) Each

establishment shall store human cellular

and tissue-based products at an

appropriate temperature and for no

longer than the maximum storage period

for the product.

(2) Acceptable temperature limits for

storage of human cellular and tissuebased products at each step of the

manufacturing process shall be

established to ensure product function

and integrity, to prevent product

deterioration, and to inhibit the growth

of infectious agents.

(3) Storage temperatures for human

cellular and tissue-based products shall

be maintained and recorded. Recorded

temperatures shall be reviewed

periodically to assure that temperatures

have not exceeded acceptable limits.

(c) Expiration date. Where

appropriate, an expiration date shall be

assigned to each human cellular or

tissue-based product based on the

following factors:

(1) Product type;

(2) Processing procedures, including

the method of preservation;

(3) Storage conditions; and

(4) Packaging.

(d) Corrective action. Corrective

action shall be taken and documented

whenever proper storage conditions are

not met.

§ 1271.265 Receipt and distribution.

(a) General. Procedures shall be

established and maintained for the

following activities: receipt, acceptance

or rejection, distribution, and

destruction or other disposition of

human cellular or tissue-based

products, and these activities shall be

documented. Documentation shall

include:

(1) Identification of the human

cellular or tissue-based product;

(2) Activities performed and the

results of such activities;

(3) Date(s) of activity;

(4) Quantity of human cellular or

tissue-based product subject to the

activity; and

(5) Disposition of the human cellular

or tissue-based product (e.g., identity of

consignee).

(b) Receiving activities. Procedures

shall be established and maintained for

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receiving and accepting or rejecting

human cellular or tissue-based products

for processing, distribution, or any other

step in the manufacturing process. The

status of each incoming human cellular

or tissue-based product (e.g., with

respect to quarantine, donor screening

and testing, and processing) shall be

determined and identified promptly

after receipt, and each product shall be

handled in a manner appropriate to its

status. Each incoming human cellular or

tissue-based product shall be inspected

according to established procedures for

damage, contamination, deterioration,

or other indications that the integrity of

the product has been impaired.

Acceptance or rejection of incoming

products shall be documented.

(c) Availability for distribution.

Procedures shall be established and

maintained for making human cellular

and tissue-based products available for

distribution. These procedures, which

shall include release criteria, shall be

designed to prevent the release of

products that are in quarantine, are

contaminated, have deteriorated, or

otherwise have been manufactured in

violation of current good tissue practice

and, except as provided under

§§ 1271.65 and 1271.90, products from

donors who have been determined to be

unsuitable or for whom a donorsuitability determination has not been

completed. Prior to making a human

cellular or tissue-based product

available for distribution, the

establishment shall verify and

document that the release criteria have

been met and shall review all records

pertaining to the product. The

determination that a human cellular or

tissue-based product is available for

distribution shall be documented and

dated by a responsible person.

(d) Packaging. Packaging and

shipping containers shall be designed,

validated, and constructed to ensure

product function and integrity and

protect the product from damage,

deterioration, contamination, or other

adverse effects during customary

conditions of processing, storage,

handling, and distribution.

(e) Shipping conditions. Appropriate

shipping conditions shall be defined for

each type of human cellular or tissuebased product to be maintained during

transit.

(f) Return to inventory. Procedures

shall be established and maintained to

determine if a product that is returned

to an establishment is suitable to be

returned to inventory.

§ 1271.270 Records.

(a) General. Records shall be

maintained concurrently with the

performance of each significant step

required in this subpart and subpart C

of this part. Any requirement in this

part that an action be documented

involves the creation of a record, which

record is subject to the requirements of

this section. All records shall be

accurate, indelible, and legible. The

records shall identify the person

performing the work, the dates of the

various entries, and shall be as detailed

as necessary to provide a complete

history of the work performed and to

relate the records to the particular

human cellular or tissue-based product

involved. Record security systems shall

be adequate to ensure the

confidentiality of donors and recipients

of human cellular and tissue-based

products.

(b) Records management system. A

records management system shall be

established and maintained. Under this

system, records pertaining to a

particular human cellular or tissuebased product manufactured shall be

maintained in such a way as to facilitate

review of the product’s history prior to

making it available for distribution and,

if necessary, subsequent to the product’s

release as part of a follow-up evaluation

or investigation. Records pertinent to

the manufacture of each type of human

cellular or tissue-based product (e.g.,

procedures, specifications, labeling and

packaging procedures, equipment logs)

shall also be maintained and organized

under the records management system.

If records are maintained in more than

one location, then the records

management system shall be designed to

ensure prompt identification, location,

and retrieval of all records.

(c) Other recordkeeping requirements.

Procedures shall be established and

maintained to ensure compliance with

the recordkeeping requirements in

§ 1271.55. Documentation of results and

interpretation of all testing for relevant

communicable disease agents in

compliance with §§ 1271.80 and

1271.85 shall be maintained, as well as

the name and address of the testing

laboratory or laboratories.

Documentation of the results and

interpretation of all donor screening for

relevant communicable disease in

compliance with § 1271.75 shall be

maintained in accordance with

§ 1271.270. Documentation of the

donor-suitability determination,

including the name of the responsible

person who made the determination and

the date of the determination, shall also

be maintained. Information on the

identity and relevant medical records of

the donor, as defined in § 1271.3(v),

shall be in English or, if in another

language, shall be translated to English

and accompanied by a statement of

authenticity by the translator that

specifically identifies the translated

document.

(d) Methods of retention. Records

required under this subpart may be

maintained electronically, as original

paper records, or as true copies such as

photocopies, microfiche, or microfilm,

in which case suitable reader and

photocopying equipment shall be

readily available. Records stored in

automated data processing systems shall

be backed up. Electronic records and

electronic signatures are subject to the

requirements in part 11 of this chapter.

(e) Length of retention. All records

shall be retained 10 years after their

creation. However, records pertaining to

a particular human cellular or tissuebased product shall be retained at least

10 years after the date of implantation,

transplantation, infusion, or transfer of

the product, or if the date of

implantation, transplantation, infusion ,

or transfer is not known, then records

shall be retained at least 10 years after

the date of the product’s distribution,

disposition, or expiration, whichever is

latest. Records for archived specimens

of dura mater shall be retained 10 years

after the appropriate disposition of the

specimens. The establishment shall

make provisions for all records to be

maintained for the required period in

the event that the establishment ceases

operation.

(f) Contracts and agreements. Each

establishment shall maintain records of

any contract, agreement, or other

arrangement with another establishment

under which any step in the

manufacturing process is performed by

the other establishment. These records

shall include the name and address of

the other establishment and the

responsibilities of each party to the

contract, agreement, or other

arrangement.

§ 1271.290 Tracking.

(a) General. Each establishment that

performs any step in the manufacture of

a human cellular or tissue-based

product shall track each such product in

accordance with this section.

(b) Method of product tracking. (1)

Each establishment shall establish and

maintain a method of product tracking

that enables the tracking of all human

cellular and tissue-based products from:

(i) The donor to the recipient or final

disposition; and

(ii) The recipient or final disposition

to the donor.

(2) Alternatively, an establishment

that performs some but not all of the

steps in the manufacture of a human

cellular or tissue-based product may

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1557

participate in a method of product

tracking that has been established and is

maintained by another establishment

responsible for other steps in the

manufacture of the same product,

provided that the tracking method

complies with all the requirements of

this section.

(c) Distinct identification code. As

part of its tracking method, an

establishment shall ensure that each

human cellular and tissue-based

product that it manufactures is assigned

and labeled with a distinct

identification code, e.g., alphanumeric,

that relates the product to the donor and

to all records pertaining to the product.

Except in the case of autologous or

directed donations, such a code must be

created specifically for tracking and may

not include an individual’s name, social

security or medical record number. An

establishment may adopt a distinct

identification code assigned by another

establishment engaged in the

manufacturing process, or may assign a

new code. An establishment that assigns

a new code to a product shall establish

and maintain procedures for relating the

new code to the old code.

(d) Product information. As part of its

tracking method, an establishment shall

ensure that the identifier and type of

each human cellular or tissue-based

product that is implanted, transplanted,

infused, or transferred into a recipient is

recorded in the recipient’s medical

records, or in other pertinent records, to

enable tracking from the recipient to the

donor.

(e) Recipient information. As part of

its tracking method, an establishment

shall document, and maintain records

of, the disposition of each of its human

cellular or tissue-based products, to

enable tracking from the donor to the

recipient or final disposition. The

information to be maintained shall

permit the prompt identification of the

recipient of the product, if any.

(f) Consignees. At or before the time

of distribution of a human cellular or

tissue-based product to a consignee, an

establishment shall inform the

consignee in writing of the requirements

in this section and of the tracking

method that the establishment has

established and is maintaining to

comply with these requirements. Upon

initial distribution of product to the

consignee, the establishment shall

document that the consignee agreed to

participate in its tracking method and to

take all necessary steps to ensure

compliance with the requirements of

this section.

(g) Requirements specific to dura

mater donors. Appropriate specimens

from each donor of dura mater shall be

archived, under appropriate storage

conditions, and for the appropriate

duration, to enable testing of the

archived material for evidence of

transmissible sponiform

encephalopathy, and appropriate

disposition of any affected dura mater

tissue, if necessary.

§ 1271.320 Complaint file.

(a) Procedures. Each establishment

shall establish and maintain procedures

for the prompt review, evaluation, and

documentation of all complaints, as

defined in § 1271.3(ii), and the

investigation of complaints as

appropriate.

(b) Complaint file. Each establishment

shall maintain a record of each

complaint that it receives in a file

designated for complaints. The

complaint file shall contain sufficient

information about each complaint for

proper review and evaluation of the

complaint, including the identifier of

the human cellular or tissue-based

product that is the subject of the

complaint. The complaint file shall be

made available for review and copying

upon request from an authorized

employee of the Food and Drug

Administration.

(c) Review and evaluation of

complaints. Each complaint shall be

reviewed and evaluated to determine if

the complaint is related to a product

deviation of a human cellular or tissuebased product or to an adverse reaction,

and to determine if a report under

§ 1271.350 or another applicable

regulation is required. Each complaint

that represents an event required to be

reported to FDA shall be promptly

reviewed, evaluated, and investigated. A

complaint that does not represent an

event required to be reported shall be

reviewed and evaluated to determine

whether investigation is necessary;

investigation may include referring a

copy of the complaint to another

establishment that performed

manufacturing steps pertinent to the

complaint. When no investigation is

made, the establishment shall maintain

a record that includes the reason no

investigation was made, and the name

of the individual responsible for the

decision not to investigate.

4. Subpart E, consisting of

§§ 1271.330 through 1271.370, is added

to part 1271 to read as follow:

Subpart E—Additional Requirements for

Establishments Described in § 1271.10

Sec.

1271.330 Applicability.

1271.350 Reporting.

1271.370 Labeling and claims.

Subpart E—Additional Requirements

for Establishments Described in

§ 1271.10

§ 1271.330 Applicability

The provisions set forth in this

subpart are applicable only to human

cellular and tissue-based products

described in § 1271.10 and regulated

solely under section 361 of the Public

Health Service Act (the PHS Act) and

the regulations in this part, and to the

establishments that manufacture those

products. Human cellular and tissuebased products described in § 1271.15

and regulated as drugs, devices, and/or

biological products under the act and/or

section 351 of the PHS Act, and the

establishments that manufacture those

products, are not subject to the

regulations set forth in this subpart.

§ 1271.350 Reporting.

(a) Adverse reaction reports. (1) Any

establishment that receives information

about an adverse reaction, regardless of

source, shall review the information to

determine whether the adverse reaction

is required to be reported. The

establishment shall report any adverse

reaction involving the transmission of a

communicable disease, product

contamination, or failure of the

product’s function or integrity if the

adverse reaction:

(i) Is fatal;

(ii) Is life-threatening;

(iii) Results in permanent impairment

of a body function or permanent damage

to body structure; or

(iv) Necessitates medical or surgical

intervention. Each report shall be

submitted on an FDA Form-3500A to

the address in paragraph (a)(4) of this

section within 15 calendar days of

initial receipt of the information.

(2) The establishment shall promptly

investigate all adverse reactions that are

subject of these 15-day reports and shall

submit follow-up reports within 15

calendar days of the receipt of new

information or as requested by FDA. If

additional information is not obtainable,

a follow-up report may be required that

describes briefly the steps taken to seek

additional information and the reasons

why it could not be obtained.

(3) Copies of the reporting form (FDA3500A) may be obtained from the Center

for Biologics Evaluation and Research

(see address in paragraph (a)(4) of this

section). Additional supplies of the form

may be obtained from the Consolidated

Forms and Publications Distribution

Center, 3222 Hubbard Rd., Landover,

MD 20785.

(4) The establishment shall submit

two copies of each report described in

this paragraph to the Center for

1558 Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules

Biologics Evaluation and Research

(HFM-210), Food and Drug

Administration, 1401 Rockville Pike,

suite 200N, Rockville, MD 20852–1448.

FDA may waive the requirement for the

second copy in appropriate

circumstances.

(b) Reports of product deviations. (1)

Any establishment that becomes aware

of a product deviation in the

manufacture of a distributed human

cellular or tissue-based product shall

immediately determine whether the

product deviation is of the type that

could reasonably be expected to lead to

a reportable adverse reaction and, if it

is, shall report the product deviation to

the address in paragraph (b)(3) of this

section as soon as possible.

(2) Each report shall contain a

description of the product deviation and

information on all corrective actions

that have been or will be taken in

response to the product deviation (e.g.,

recalls).

(3) Each report of a product deviation

shall be reported to the Director, Office

of Compliance and Biologics Quality,

Center for Biologics Evaluation and

Research (HFM-600), 1401 Rockville

Pike, suite 200N, Rockville, MD 20852–

1448.

(c) Records. Reports and

investigations required under this

section shall be documented and

records shall be maintained.

§ 1271.370 Labeling and claims.

(a) Label information and

accompanying materials. (1) Each

human cellular or tissue-based product

made available for distribution shall be

labeled clearly and accurately.

(2) The following information shall

appear on the product label:

(i) Name and address of the

establishment that determines that the

product meets release criteria and

makes the product available for

distribution;

(ii) Description of the type of product;

and

(iii) Expiration date, if any.

(3) The following information shall

appear either on the product label or

package insert:

(i) Storage temperature;

(ii) Warnings, where appropriate; and

(iii) Instructions for use.

(b) Claims. (1) All labeling,

advertising, and promotional materials

for a human cellular or tissue-based

product shall be clear, truthful, and

balanced in all respects, and may not be

false or misleading in any particular.

(2) A labeling claim or promotional

materials regarding the therapeutic or

clinical outcome of a human cellular or

tissue-based product (other than

reconstruction, replacement, repair, or

supplementation of cells or tissue) is

considered a claim for a use other than

a homologous use, as defined in

§ 1271.3(d), and the product, including

labeling, shall be regulated under

section 351 of the PHS Act and/or the

Federal Food, Drug, and Cosmetic Act.

5. Subpart F, consisting of

§§ 1271.390 through 1271.440, is added

to part 1271 to read as follows:

Subpart F—Inspection and Enforcement of

Establishments Described in § 1271.10

Sec.

1271.390 Applicability.

1271.400 Inspections.

1271.420 Human cellular and tissue-based

products offered for import.

1271.440 Orders of retention, recall,

destruction, and cessation of

manufacturing.

Subpart F—Inspection and

Enforcement of Establishments

Described in § 1271.10

§ 1271.390 Applicability.

The provisions set forth in this

subpart are applicable only to human

cellular and tissue-based products

described in § 1271.10 and regulated

solely under section 361 of the Public

Health Service Act (the PHS Act) and

the regulations in this part, and to the

establishments that manufacture those

products. Human cellular and tissuebased products described in § 1271.15

and regulated as drugs, devices, and/or

biological products under the act and/or

section 351 of the PHS Act, and the

establishments that manufacture those

products, are not subject to the

regulations set forth in this subpart.

§ 1271.400 Inspections.

(a) An establishment subject to this

part as described in § 1271.10, including

any location performing contract

services, shall permit an authorized

representative of the Food and Drug

Administration (FDA) to make at any

reasonable time and in a reasonable

manner such inspection of the

establishment, including but not limited

to its facilities, equipment, processes,

products, procedures, labeling, and

records, as may be necessary in the

judgment of such representative to

determine compliance with the

provisions of this part. Such inspection

may be made with or without notice and

will ordinarily be made during regular

business hours.

(b) The frequency of inspection will

be at the agency’s discretion.

(c) FDA’s representative will call

upon the most responsible person

available at the time of the inspection of

the establishment and may question the

personnel of the establishment as the

representative deems necessary.

(d) FDA’s representative may review

and copy any records required to be

kept under this part and may take

photographs or make videotapes.

(e) The public disclosure of records

containing the name or other positive

identification of donors or recipients of

human cellular or tissue-based products

will be handled in accordance with

FDA’s procedures on disclosure of

information as set forth in part 20 of this

chapter.

§ 1271.420 Human cellular and tissuebased products offered for import.

(a) When a human cellular or tissuebased product is offered for entry, the

importer of record shall notify the

director of the district of the Food and

Drug Administration (FDA) having

jurisdiction over the port of entry

through which the product is imported

or offered for import, or such officer of

the district as the director may designate

to act in his or her behalf in

administering and enforcing this part.

(b) A human cellular or tissue-based

product offered for import shall be held

intact, under conditions necessary to

maintain product function and integrity

and prevent transmission of

communicable disease, until it is

released by FDA.

§ 1271.440 Orders of retention, recall,

destruction, and cessation of

manufacturing.

(a) Upon an agency finding that a

human cellular or tissue-based product

or an establishment is in violation of the

regulations in this part, an authorized

Food and Drug Administration (FDA)

representative may take one or more of

the following actions:

(1) Serve upon the person who

distributed the human cellular or tissuebased product a written order that the

product be recalled and/or destroyed, as

appropriate, and upon persons in

possession of the product that the

product shall be retained until it is

recalled by the distributor, destroyed, or

disposed of as agreed by FDA, or the

safety of the product is confirmed;

(2) Take possession of and/or destroy

the violative human cellular or tissuebased product; or

(3) Serve upon the establishment an

order to cease manufacturing until

compliance with the regulations of this

part has been achieved.

(b) A written order issued under

paragraph (a) of this section will state

with particularity the facts that justify

the order.

(c)(1) A written order issued under

paragraph (a)(1) of this section will

Federal Register / Vol. 66, No. 5 / Monday, January 8, 2001 / Proposed Rules 1559

ordinarily provide that the human

cellular or tissue-based product be

recalled and/or destroyed within 5

working days from the date of receipt of

the order. After receipt of an order

issued under paragraph (a)(1) of this

section, the establishment in possession

of the human cellular or tissue-based

product shall not distribute or dispose

of the product in any manner except to

recall and/or destroy the product

consistent with the provisions of the

order, under the supervision of an

authorized FDA representative.

(2) In lieu of paragraph (c)(1) of this

section, other arrangements for assuring

the proper disposition of the human

cellular or tissue-based product may be

agreed upon by the person receiving the

written order and an authorized official

of FDA. Such arrangements may

include, among others, providing FDA

with records or other written

information that adequately assure that

the human cellular or tissue-based

product has been recovered, processed,

stored, and distributed in conformance

with this part, and that, except as

provided under §§ 1271.65 and 1271.90,

the donor of the cells or tissue for the

product has been determined to be

suitable.

(d) A written order issued under

paragraph (a)(3) of this section will

specify the regulations with which

compliance shall be achieved and will

ordinarily specify the particular

operations covered by the order. After

receipt of an order issued under

paragraph (a)(3) of this section, an

establishment shall not resume

operations without prior authorization

of an authorized official of FDA.

(e) Within 5 working days of receipt

of a written order for retention, recall,

destruction, and/or cessation (or within

5 working days of the agency’s

possession of a human cellular or tissuebased product under paragraph (a)(2) of

this section), the recipient of the written

order or prior possessor of such product

may request a hearing on the matter in

accordance with part 16 of this chapter.

An order of destruction will be held in

abeyance pending resolution of the

hearing request.

Dated: August 29, 2000.

Jane E. Henney,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 01–447 Filed 1–5–01; 8:45 am]

BILLING CODE 4160–01–F