[Federal Register Volume 72, Number 8 (Friday, January 12, 2007)]
[Proposed Rules]
[Pages 1581-1619]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-22329]



[[Page 1581]]

-----------------------------------------------------------------------

Part II





Department of Health and Human Services





-----------------------------------------------------------------------



Food and Drug Administration



-----------------------------------------------------------------------



21 CFR Parts 211, 226, 300, et al.



 Use of Materials Derived from Cattle in Medical Products Intended for 
Use in Humans and Drugs Intended for Use in Ruminants; Proposed Rule

Federal Register / Vol. 72, No. 8 / Friday, January 12, 2007 / 
Proposed Rules

[[Page 1582]]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 211, 226, 300, 500, 530, 600, 895, and 1271

[Docket No. 2005N-0373]
RIN 0910-AF54


Use of Materials Derived from Cattle in Medical Products Intended 
for Use in Humans and Drugs Intended for Use in Ruminants

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to 
prohibit the use of certain cattle material in, or in the manufacture 
(including processing) of, drugs, biologics, and medical devices 
intended for use in humans and human cells, tissues, and cellular and 
tissue-based products (HCT/Ps) (collectively, medical products for 
humans), and in drugs intended for use in ruminant animals (drugs for 
ruminants). FDA is also proposing new recordkeeping requirements for 
medical products for humans and drugs for ruminants that are 
manufactured from or otherwise contain material from cattle. FDA is 
proposing these actions as part of its continuing efforts to strengthen 
defenses against the potential risk of exposure to, and spread of, 
bovine spongiform encephalopathy (BSE) and related human disease in the 
United States.

DATES: Submit written or electronic comments on the proposed rule by 
March 13, 2007. Submit written comments on the information collection 
requirements by February 12, 2007. Requests for an informal hearing on 
the proposed ban related to medical devices must be submitted by 
February 12, 2007.

ADDRESSES: You may submit comments, identified by Docket No. 2005N-0373 
and RIN number 0910-AF54, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm, including any personal information provided. For detailed 
instructions on submitting comments and additional information on the 
rulemaking process, see section VII ``Effective Date and Opportunity 
for Public Comment'' in the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.
    Information Collection Provisions: To ensure that comments on the 
information collection are received, Office of Management and Budget 
(OMB) recommends that written comments be faxed to the Office of 
Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 
202-395-6974.

FOR FURTHER INFORMATION CONTACT:
    For information concerning products regulated by the Center for 
Drug Evaluation and Research: Vikki Kinsey, Center for Drug Evaluation 
and Research (HFD-006), Food and Drug Administration, 5515 Security 
Lane, rm. 5110, Rockville, MD 20852, 301-443-5578, e-mail: 
[email protected].
    For information concerning products regulated by the Center for 
Biologics Evaluation and Research: Stephen M. Ripley, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, rm 594N, Rockville, MD 20852-1448, 
301-827-6210, e-mail: [email protected].
    For information concerning products regulated by the Center for 
Devices and Radiological Health: Scott G. McNamee, Center for Devices 
and Radiological Health, Food and Drug Administration, 2094 Gaither 
Rd., rm. 230, Rockville, MD 20850, 240-276-0105, e-mail: 
[email protected].
    For information concerning products regulated by the Center for 
Veterinary Medicine: Michael J. Popek, Center for Veterinary Medicine 
(HFV-144), Food and Drug Administration, 7500 Standish Pl., Rockville, 
MD 20855, 301-827-6462, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Background
    A. Transmissible Spongiform Encephalopathies
    B. Bovine Spongiform Encephalopathy
    C. Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease
    D. BSE Risk Assessments
    1. Harvard-Tuskegee Study
    2. USDA Surveillance Program
    3. BSE Testing for Product Safety Purposes
    4. BSE Infectivity via Medical Products for Humans and Drugs for 
Ruminants
    E. Cattle Materials
    1. Specified Risk Material
    2. Small Intestine
    3. Mechanically Separated Beef
    4. Nonambulatory Disabled Cattle
    5. Cattle Not Inspected and Passed for Human Consumption
    6. Tallow and Tallow Derivatives
    7. Fetal Calf Serum
    8. Additional Requirements
    F. Medical Products for Humans and Drugs for Ruminants That May 
Contain Cattle Material
    1. Drugs for Humans
    2. Biologics for Humans
    3. HCT/Ps
    4. Medical Devices for Humans
    5. Drugs for Ruminants
III. USDA/FSIS IFR
IV. FDA Actions on BSE
    A. Regulations
    1. FDA 1997 Ruminant Feed Rule
    2. FDA/USDA Animal Feed ANPRM and FDA 2005 Animal Feed Proposed 
Rule
    3. Foods IFR
    4. Foods Recordkeeping/Access Final

[[Page 1583]]

Rule
    B. FDA Guidance
V. Description of Proposed Rule
    A. Definitions
    B. Proposed Requirements for Prohibited Cattle Materials and 
Permission for an Exception or Alternative to These Requirements
    C. Tallow and Tallow Derivatives
    D. Proposed Requirements Regarding Extralabel Drug Use in Animals
    E. Proposed Recordkeeping Requirements
    1. Types of Records
    2. Proposed Periods for Records Retention
    3. Location of Records
VI. Legal Authority
VII. Effective Date and Opportunity for Public Comment
VIII. Analysis of Impacts
    A. Need for the Proposed Rule
    B. Scope of the Proposed Rule
    C. Costs of the Proposed Rule
    1. Potential Market Adjustments
    2. Cost of Requests for Exception or Alternatives to the Limitation 
on the Use of Prohibited Cattle Material
    3. Cost of Substitutes
    4. Recordkeeping Requirements of the Proposed Rule
    5. Labeling Costs for Drugs Prohibited from Extralabel Use
    6. Summary of the Cost for the Proposed Rule
    D. Benefits of the Proposed Rule
    1. Reduced Risk of Exposure to BSE Infectivity
    2. Value of the Potential Reduction of Human Illness
    E. Summary of the Potential Costs and Benefits of the Proposed Rule
    F. Regulatory Options Considered
    G. Regulatory Flexibility Analysis
IX. Paperwork Reduction Act Analysis
X. Environmental Impact Analysis
XI. Federalism
XII. References

I. Introduction

    On January 26, 2004, the U.S. Department of Health and Human 
Services announced its plan to establish new safeguards to strengthen 
existing firewalls against transmission of BSE in the United States. 
Consumption of products contaminated with the agent that causes BSE has 
been linked to the human disease variant Creutzfeldt-Jakob disease 
(vCJD). Current protections against the spread of BSE in the United 
States include:
     FDA's ruminant feed regulation (the 1997 ruminant feed 
rule) (62 FR 30936, June 5, 1997) (see section V.A.8 of this document 
for definition of ruminant),
     U.S. Department of Agriculture's (USDA's) Food Safety and 
Inspection Service (FSIS) interim final rule banning specified risk 
materials (SRMs) and certain other cattle material in human food (the 
USDA/FSIS IFR) (69 FR 1862, January 12, 2004; as amended, 70 FR 53043, 
September 7, 2005),
     FDA's interim final rule banning the use of SRMs and 
certain other cattle material in human food, including dietary 
supplements, and cosmetics (the Foods IFR) (69 FR 42256, July 14, 2004; 
as amended, 70 FR 53063, September 7, 2005), and
     Import controls.
    FDA also has requirements for establishment and maintenance of 
records concerning use of materials derived from cattle in human food 
and cosmetics (the Foods Recordkeeping/Access final rule) (71 FR 59653, 
October 11, 2006). In addition, FDA, in conjunction with USDA, issued 
an advance notice of proposed rulemaking (ANPRM) to solicit comment on 
additional measures under consideration, including measures related to 
animal feeds (the joint ANPRM) (69 FR 42288, July 14, 2004). On October 
6, 2005 (70 FR 58570), we issued a proposed rule that would prohibit 
certain cattle materials from all animal feed (FDA 2005 Animal Feed 
proposed rule).
    In this medical products proposed rule, FDA is proposing to 
prohibit use of SRMs and certain other cattle material in, or in the 
manufacture (including processing) of, medical products for humans and 
drugs for ruminants because of the risk of transmission of BSE. FDA is 
also proposing recordkeeping requirements for medical products for 
humans and drugs for ruminants that are manufactured from or otherwise 
contain material from cattle to ensure compliance with the prohibitions 
in this proposed rule. The proposed requirements are consistent with 
the requirements in the USDA/FSIS IFR and the Foods IFR, as well as 
those in the Foods Recordkeeping/Access final rule. The proposed 
requirements in this medical products proposed rule only apply to 
medical products for humans and drugs for ruminants. They do not apply 
to any other product regulated by FDA.

II. Background

A. Transmissible Spongiform Encephalopathies

    Transmissible spongiform encephalopathies (TSEs) are fatal 
neurodegenerative disorders that have been identified in humans and a 
number of animal species (e.g., cattle, sheep, goats, elk, deer, cats, 
and mink), but primarily in ruminants (i.e., animals that have a 
stomach with four compartments, such as cattle and buffalo). A TSE is 
characterized by a long incubation period, followed by a shorter course 
of neurological symptoms, followed by death (Ref. 1). Postmortem 
histopathology of the brain tissue from humans and animals with TSEs is 
characterized by a sponge-like appearance of the brain and deposits of 
abnormal forms of certain cell-associated proteins (normal prion 
proteins) in the brain.
    TSEs in humans include CJD, vCJD, Gerstmann-Str[auml]ussler-
Scheinker syndrome, kuru, fatal familial insomnia, and sporadic fatal 
insomnia (Ref. 8). Nonhuman TSEs include BSE in cattle, scrapie in 
sheep and goats, transmissible mink encephalopathy (TME) in mink, 
feline spongiform encephalopathy (FSE) in cats, and chronic wasting 
disease (CWD) in deer and elk (Ref. 8). Scrapie and CWD occur, and TME 
has occurred, in the United States. On December 23, 2003, USDA 
diagnosed BSE in an adult cow in the United States that had been 
imported from Canada. Since then, USDA has confirmed two other cases of 
BSE in adult cows in the United States. One cow, which was diagnosed on 
June 24, 2005, was born and raised in Texas. The other cow, which was 
diagnosed on March 15, 2006, had been on a farm in Alabama for less 
than a year. The Texas cow was 12 years old and the Alabama cow was 
determined to be more than 10 years old. Therefore, both cows were born 
before the 1997 ruminant feed rule was in place. USDA determined that 
no part of the animals entered the human food or animal feed chains.
    The pathogenesis of TSEs is poorly understood. TSE agents resist 
complete inactivation by treatments that destroy conventional 
microorganisms, like bacteria and viruses. Thus, conventional 
microorganisms are not likely causes of TSEs (Ref. 9). The most widely 
accepted explanation for TSEs, the prion theory, suggests that the 
infectious agents of TSEs are abnormally folded forms of normal prion 
proteins (Refs. 10 and 11). Normal prion protein genes are found widely 
in nature. In mammals, normal prion proteins are primarily expressed in 
neurons, but also can be found in other tissues in lower 
concentrations, depending on the mammalian species (Ref. 12). It is not 
well understood how the abnormal folding of prion proteins occurs or 
why hosts cannot efficiently dispose of or develop immunity to these 
proteins.
    The current lack of an antemortem diagnostic test for TSEs in 
either humans or animals limits surveillance

[[Page 1584]]

for these diseases, studies of disease pathogenesis, and other research 
efforts. Diagnosis is confirmed by special postmortem examination of 
brain tissue by identification of abnormal prion proteins in advanced 
stages of the disease. At earlier stages of disease development, 
abnormal prion proteins are undetectable in brain tissue. Presently, 
there are no effective treatments for TSEs, and all TSEs are invariably 
fatal (Ref. 1).

B. Bovine Spongiform Encephalopathy

    BSE is a TSE of cattle with a long incubation period (up to 8 years 
or longer), most likely acquired following consumption of an animal 
product containing the BSE infectious agent (Refs. 13 and 14). The 
British Ministry of Agriculture, Fisheries and Food (now known as the 
Department for Environment, Food, and Rural Affairs) first recognized 
BSE as a distinct disease in November 1986. The clinical signs of BSE 
include behavioral, gait, and postural abnormalities. The disease 
usually presents in cattle as increased apprehension, increased 
reaction to sound and touch, and a swaying gait. These signs are 
accompanied by subtle changes in the normal behavior of the cow, such 
as separation from the herd while at pasture, disorientation, staring, 
and excessive licking of the nose or flanks. The disease progresses to 
stumbling and falling, and ends with seizures, coma, and death (Ref. 
15).
    Experiments indicate that the infectious dose for cattle is very 
low. One gram of homogenized brain from affected cattle caused BSE in 7 
out of 10 calves fed the brain sample. Six years after oral consumption 
of lower doses of brain material, 3 of 15 calves fed 0.1 gram, and 1 of 
15 calves fed 0.01 gram, and 1 of 15 calves fed 0.001 gram (1 mg) of 
brain sample had developed the disease. This experiment is ongoing 
(Ref. 16).
    Epidemiological studies have characterized the outbreak of BSE in 
the United Kingdom as a prolonged epidemic in which early cases were 
seen simultaneously at various locations, but with all occurrences 
presumably due to a common point source of infection (Ref. 17). 
Consistent with this observation, the subsequent spread of BSE was 
associated with the feeding of meat-and-bone-meal from rendered BSE-
infected cattle to non-infected cattle (Ref. 17). It appears likely 
that the BSE agent was transmitted among cattle at an increasing rate 
by ruminant-to-ruminant feeding until the United Kingdom ban on such 
practices went into effect in 1988 (Ref. 13). The United Kingdom 
instituted a ruminant-to-ruminant feed ban to stop the cycle of 
infection, restrict the geographic spread of the disease, and eliminate 
potential sources of new infections. Since BSE was first identified in 
the United Kingdom, approximately 185,000 cattle have been diagnosed 
with the disease there (Ref. 18). The precautionary slaughter of 
millions of British cows and increasingly stringent prohibitions on 
certain animal feeding practices appear to have slowed, but not 
eradicated, the BSE epidemic in the United Kingdom. In 1992 (the peak 
year of the epidemic), there were over 37,000 cases of BSE in the 
United Kingdom; in 2005, there were 225 cases (Ref. 18).
    The introduction of BSE into other countries presumably originated 
from their import of cattle, or animal feed made with cattle material, 
from the United Kingdom during the BSE epidemic (Ref. 13). In addition 
to the United Kingdom, BSE has been detected in indigenous cattle in 
Austria, Belgium, Canada, the Czech Republic, Denmark, Finland, France, 
Germany, Greece, Israel, Italy, Japan, Liechtenstein, Luxembourg, the 
Netherlands, Poland, Portugal, the Republic of Ireland, Slovakia, 
Slovenia, Spain, Sweden, Switzerland and the United States (Ref. 19).

C. Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease

    Creutzfeldt-Jakob Disease (CJD) is a sporadic disease of humans 
that exists throughout the world with an annual incidence of 
approximately one case per million population (Ref. 10). The highest 
death rates in the United States and the United Kingdom occur in 
individuals between the ages of 60 and 70 (Ref. 20). Death generally 
occurs after less than a year of progressive neurological deterioration 
(Ref. 10). Early symptoms typically include changes in sleeping and 
eating patterns, followed by inappropriate behavior and eventual 
dementia, lack of coordination, and myoclonic spasms. CJD is always 
fatal (Ref. 20). The cause of sporadic CJD is not fully understood, but 
genetic susceptibility may play a role (Ref. 10). CJD has been 
inadvertently transmitted between humans during medical treatment or 
diagnostic procedures via contaminated neurosurgical instruments, 
transplants of dura mater and corneas, and injection of pituitary 
extract (Ref. 10).
    In April 1996, British scientists reported a previously undetected 
new vCJD in young patients, with symptoms somewhat different from 
sporadic CJD (Refs. 21 and 22). All cases of vCJD had histopathologic 
evidence of spongiform changes in the brain, but also showed formation 
of ``florid'' plaques (a core of amyloid protein with surrounding halos 
of vacuoles) not typically seen in other forms of CJD (Ref. 10). 
Clinically, vCJD usually begins with a psychiatric presentation, such 
as depression, anxiety, nightmares, or hallucinations. These symptoms 
are followed by memory impairment, then dementia in the late stages. 
The clinical course generally ranges from 9 months to 3 years before 
death occurs (Ref. 23). The probable incubation period for vCJD in 
humans may range from 5 to more than 20 years (Ref. 39).
    Scientists have concluded that exposure to the BSE agent is the 
most plausible explanation for the occurrence of vCJD (Refs. 24 through 
27). Monkeys (genetically the closest animal model to humans) 
inoculated with samples of brain from BSE-infected cattle have been 
found to develop a TSE that is histopathologically similar to vCJD 
(Ref. 28), as have mice inoculated or fed with BSE-infected tissue 
(Ref. 29). Studies have shown that abnormal prion proteins from vCJD 
patients are molecularly similar to abnormal prion proteins from BSE-
infected cattle, but different from abnormal prion proteins from 
patients with CJD (Ref. 23). Although the exact route of exposure is 
not known, most scientists believe that vCJD in humans has been caused 
by consumption of cattle products contaminated with the agent that 
causes BSE (Refs. 20, 30, and 31). There is thought to be a 10- to 
10,000-fold increase in the amount of infectious material needed to 
cause illness in humans as compared with cattle because of the species 
barrier, although the European Commission's Scientific Steering 
Committee cautioned that this range is uncertain and in an unlikely, 
but worst case scenario, the species barrier may not exist (Ref. 40).
    As of August 2006, 162 probable and confirmed cases of vCJD have 
been reported in the United Kingdom (Ref. 32). In addition, there have 
been 15 vCJD cases in France, 3 in Ireland, 2 in the United States ,and 
1 each in Canada, Italy, the Netherlands, Portugal, Japan, Spain, and 
Saudi Arabia (Refs. 33 through 38 and 70). The two cases in the United 
States, one of the three from Ireland, and the single cases from Canada 
and Japan are likely due to the individual's exposure to BSE in the 
United Kingdom (Refs. 34, 36, and 70).
    The infectious dose for humans is not known. Despite widespread 
exposure in the United Kingdom to BSE-contaminated meat products, only 
a very small percentage of the exposed population has been diagnosed 
with vCJD to date. This may reflect a partial

[[Page 1585]]

species barrier to disease transmission from cattle to humans via the 
oral route of exposure (Ref. 40).

D. BSE Risk Assessments

1. Harvard-Tuskegee Study
    In 1998, USDA asked the Harvard Center for Risk Analysis (HCRA) and 
the Center for Computational Epidemiology at Tuskegee University to 
evaluate United States measures to prevent the spread of BSE to animals 
and humans if it were to occur in this country. The Harvard-Tuskegee 
risk assessment (the Harvard-Tuskegee study determined that the United 
States was highly resistant to any proliferation of BSE or a similar 
disease (Ref. 41). The risk assessment model also demonstrated that 
certain new control measures could reduce the small risk even further.
    The Harvard-Tuskegee study involved a probabilistic simulation 
model to determine the consequences of introducing BSE into the U.S. 
cattle population. This simulation indicated that, in a hypothetical 
situation in which 10 infected cattle were imported into the United 
States, on average only 4 new cases of BSE would arise, and the disease 
would be eliminated in 20 years. The Harvard-Tuskegee study determined 
that these new cases of BSE would most likely arise in the United 
States from incomplete compliance with the FDA 1997 ruminant feed rule 
(see section III.A.1 of this document), and also concluded that an 
epidemic of BSE in this country resulting from scrapie, CWD, or another 
TSE is unlikely.
    The Harvard-Tuskegee study estimated the number of cattle 
infectious doses that might be available for human exposure, but it did 
not estimate the likelihood of human disease from this exposure because 
the relationship between the two is not known. According to the study, 
the estimated total infectivity available for human exposure from the 
importation of 10 infected cattle is 39 cattle infectious doses over 20 
years. The Harvard-Tuskegee study determined that the greatest sources 
of infectivity to consumers from food are direct consumption of cattle 
brain and spinal cord and also meat that contains central nervous 
system tissue from advanced meat recovery systems. The Harvard-Tuskegee 
study did not address potential human exposure to the BSE agent through 
food, medical products for humans, or drugs for ruminants that contain 
ingredients of bovine origin, such as gelatin (from bovine bones and 
hides), heparin and surfactants (from bovine lung), insulin (from 
bovine pancreas), hormones (from bovine urine and serum), enzymes (from 
bovine intestine), or glycosphingolipids (from bovine brains).
    The Harvard-Tuskegee study identified three pathways that could 
lead to cattle or human exposure to the BSE agent through food or feed: 
(1) Noncompliance with the FDA 1997 ruminant feed rule prohibiting the 
use of certain proteins in feed for cattle and other ruminants; (2) 
rendering of animals that die on the farm and use (through illegal 
diversion or cross-contamination) of the rendered product in ruminant 
feed; and (3) the inclusion of high-risk tissues from cattle, such as 
brain and spinal cord, in products for human oral consumption. 
Evaluation of potential risk mitigation measures in the study found 
that a prohibition against rendering of animals that die on the farm 
would reduce the potential cases of BSE following hypothetical exposure 
by 82 percent. In addition, a ban on including SRMs (defined in the 
study as brain, spinal cord, gut, eyes, and advanced meat recovery 
products without reference to age of the animals at slaughter) in human 
and animal food would reduce potential BSE cases in cattle by 88 
percent and potential human exposure to BSE by 95 percent. The Harvard-
Tuskegee study also noted the value of ensuring that low-risk cattle 
tissues are not cross-contaminated with high-risk tissue.
    USDA recently released an updated version of the BSE risk 
assessment model and report, completed by HCRA (Ref. 42). USDA 
requested that HCRA utilize an updated risk assessment model to 
evaluate the impact of measures implemented after the discovery of a 
BSE-positive cow in Washington State in December 2003, and 
recommendations made by an international BSE panel. The updated risk 
assessment estimates that the measures adopted by USDA in January 2004 
will result in a 99.6 percent (at the mean) relative reduction in 
potential human exposure to the BSE agent through consumption of beef 
and beef products.
2. USDA Surveillance Program
    The USDA has led targeted BSE surveillance efforts since 1990. On 
June 1, 2004, in response to a recommendation from the international 
scientific review panel that assessed USDA's investigation into the 
discovery of a BSE positive cow in Washington State on December 23, 
2003, USDA began an enhanced BSE surveillance effort. This effort 
continued to focus on the targeted subpopulation of cattle, with a goal 
to obtain as many samples as possible from the targeted population, to 
help determine whether BSE is present in the United States. Targeted 
cattle are defined as nonambulatory cattle; cattle exhibiting signs of 
a central nervous system disorder; cattle exhibiting other signs that 
may be associated with BSE, such as emaciation or injury; or dead 
cattle. To date, USDA has sampled more than 700,000 targeted cattle, 
only two of which were positive for BSE (Ref. 43). A detailed analysis 
of surveillance data obtained through March 2006 concluded that the 
prevalence of BSE in the United States is less than one infected animal 
per million adult animals (Ref. 7).
3. BSE Testing for Product Safety Purposes
    No validated antemortem tests for BSE exist. The currently 
available postmortem tests, although useful for disease surveillance 
(i.e., determining the rate of disease in the population of cattle), 
are not appropriate as safety indicators for food, medical products for 
humans, or drugs for ruminants. This is due, in part, to limitations on 
the existing testing methods, which rely on the use of postmortem brain 
tissue. Experimental evidence demonstrates that, in cattle infected 
orally, certain potentially infective tissues (such as the distal ileum 
and tonsil) are the first tissues to accumulate infectivity in the 
incubation period and this infectivity occurs prior to any demonstrated 
infectivity in brain tissue (Refs. 3, 45, and 46). Therefore, tests 
conducted on brain tissue may not reflect accurately the potential 
infectivity in other tissues that develop infectivity earlier, such as 
the distal ileum. Development of effective safety indicators for food, 
medical products for humans, and drugs for ruminants will require 
improved understanding of the pathogenesis of the disease and improved 
laboratory methods.
4. BSE Infectivity via Medical Products for Humans and Drugs for 
Ruminants
    While BSE is usually a concern identified with food safety or 
animal health, medical products for humans or drugs for ruminants, 
because of the ways they are used or come into contact with the body, 
provide another route for human or ruminant exposure to the BSE 
infectious agent. Medical products for humans and drugs for ruminants 
may contain or be made using a variety of cattle-derived materials. 
Examples of materials that are sometimes derived from cattle and that 
are used in, or in the manufacture of, these products include gelatin, 
heparin, surfactants, hormones, enzymes,

[[Page 1586]]

glycosphingolipids, amino acids, glycerol, detergents, blood, collagen, 
fetal calf serum, bovine meat, and tallow and tallow derivatives.
    The route by which TSE-contaminated material is introduced into a 
host is an important determinant of TSE transmissibility. Animal 
studies have indicated that injection of a TSE agent directly into the 
brain or spinal cord is the most efficient route of transmission, 
followed by intravenous, intraperitoneal, and subcutaneous routes, and 
then by the oral route (Refs. 2 and 47 through 56). Topical 
administration on intact skin is unlikely to lead to disease 
transmission, but topical products presumably can cause disease if 
administered to skin with cuts, abrasions, or open wounds, or if 
administered to the eyes or other mucosal tissue (Refs. 57 through 59).
    Currently, no validated method for testing products for humans and 
ruminants for the agent that causes BSE is available; therefore, we do 
not have a means of distinguishing products that contain infectious 
material from products that do not. End users (e.g., consumers, 
physicians, farmers, veterinarians) also often are not able to 
determine which products contain prohibited cattle materials and which 
products do not because such information is generally not included in 
product labels or labeling. For example, rendered material including 
brain and spinal cord may become an ingredient in a medical product for 
humans or a drug for ruminants, although its presence may not be 
indicated on the label. Furthermore, end users have no way to determine 
whether cattle material in these products was sourced from 
nonambulatory disabled cattle or from cattle that were not inspected 
and passed for human consumption.
    Based on what is known about transmission of BSE, there is risk of 
occurrence of vCJD in humans and of TSE in ruminants from the use of 
high-risk cattle-derived materials in medical products for humans and 
drugs for animals. While the results from USDA's ongoing testing are 
reassuring and so far have identified only two additional BSE-infected 
cows in the United States, one cannot rule out the possibility of 
future discovery of additional positive animals in the United States or 
in a country allowed to export cattle material to the United States, or 
of a future introduction of BSE. To provide consistent protection 
across the range of FDA-regulated products, it is necessary to put in 
place measures to reduce further the risk of spread of BSE in cattle 
and the risk of vCJD in humans. These risks may be reduced by 
restricting the use of high-risk cattle materials in the manufacture of 
drugs for ruminants and medical products for humans, similar to 
existing restrictions for food and cosmetics.

E. Cattle Materials

    This proposed rule would apply to medical products for humans and 
drugs for ruminants that are manufactured from or otherwise contain 
certain cattle material. This section discusses the reasons for FDA's 
decision to propose to restrict the use of such material in medical 
products for humans and drugs for ruminants.
1. Specified Risk Materials
    This proposed rule would designate SRMs as prohibited cattle 
materials in medical products for humans and drugs for ruminants. 
Specified risk materials would be defined, consistent with the Foods 
IFR (69 FR 42256 at 42259 and 70 FR 53063 at 53064 through 53065; 
discussed in section IV.A.3 of this document) and the USDA/FSIS IFR (69 
FR 1862 and 70 FR 53043; discussed in section III of this document) as 
the brain, skull, eyes, trigeminal ganglia (clusters of nerve cells 
connected to the brain that lie close to the exterior of the skull), 
spinal cord, vertebral column (excluding the vertebrae of the tail, the 
transverse processes of the thoracic and lumbar vertebrae, and the 
wings of the sacrum), and dorsal root ganglia (clusters of nerve cells 
attached to the spinal cord that are contained within the bones of the 
vertebral column) of cattle 30 months and older, and the tonsils and 
distal ileum of the small intestine of all cattle.
    In a pathogenesis study in which cattle were orally inoculated with 
BSE and then one to three animals were killed and tested at sequential 
4- to 6-month intervals, Wells et al. found infectivity using a mouse 
bioassay at 32 months postinoculation in brain, spinal cord, dorsal 
root ganglia, and trigeminal ganglia (Ref. 3). Unequivocal clinical 
disease was first observed at 38 months postinoculation. It is not 
known how representative these results are, given the extremely small 
number of cattle tested and the limitations inherent in the mouse 
bioassay. It also should be noted that only one animal was tested at 26 
months postinoculation and no testing was performed again until 32 
months postinoculation. Thus, no conclusion can be drawn as to when, in 
the period between 26 and 32 months postinoculation, infectivity 
appeared in the tested tissues. The studies will continue for several 
more years, using a more sensitive cattle assay, to determine if any of 
the tissues that initially did not appear to be infective actually 
contain low levels of infection (Refs. 2 through 6 and 60). Infectivity 
has also been found at 6 months postinoculation in distal ileum and at 
10 months postinoculation in tonsils (Refs. 4 and 60).
    In cattle infected with BSE under field conditions (i.e., not 
intentionally exposed to BSE as part of an experiment), infectivity has 
been found in the brain, spinal cord, and retina of the eye in animals 
with clinical disease (Ref. 60). The Scientific Steering Committee of 
the European Union (Ref. 31) has reported on the proportion of total 
infectivity in various tissues. They estimate that in an animal with 
clinical disease, approximately 64 percent of the infectivity is in the 
brain, 26 percent is in the spinal cord, 4 percent is in the dorsal 
root ganglia, 2.5 percent is in the trigeminal ganglia, and 3 percent 
is in the distal ileum. The eyes are estimated to contain less than 1 
percent of the infectivity. In 2003, P. J. Comer and P. J. Huntly 
reported generally similar estimates of infectivity (i.e., 60.2 percent 
in brain, 24.1 percent in the spinal cord, 3.6 percent in the dorsal 
root ganglia, 2.4 percent in the trigeminal ganglia and 9.6 percent in 
the distal ileum) (Ref. 44).
    Clinical cases of BSE in cattle under 30 months old are rare. For 
example, according to the United Kingdom's Department of Environment, 
Food and Rural Affairs, among the birth cohort of cattle in the United 
Kingdom that had the highest incidence of BSE (those born in 1987-88), 
cattle under 3 years old represented less than 0.16 percent of cattle 
with BSE (61 out of 39,140 cattle with BSE) (Ref. 61). Another report, 
looking at selected herds whose ages were known, found that in the 
first 6 months of 1989 and 1990, the BSE incidence in 2-year-old cattle 
(0.04 percent in 1989 and 0.05 percent in 1990) was approximately 15-
fold lower than that in 3-year-old cattle (0.56 percent in 1989 and 
0.86 percent in 1990), and was 45- to 75-fold lower than the incidence 
in 4-year-old cattle (2.83 percent in 1989 and 2.76 percent in 1990) 
(Ref. 62). Two-year-old cattle represented only about one-half of 1 
percent of the total BSE cases in the selected herds in those 6-month 
periods. The incidence in 2-year-old cattle (0.01 percent) decreased 
considerably in 1991, presumably reflecting the fact that they were 
born after July 1988, when the United Kingdom instituted measures 
prohibiting the use of meat and bone meal in cattle feed.
    We recognize that certain tissue from infected animals will be 
infectious a number of months before the animals exhibit clinical 
symptoms. However, in

[[Page 1587]]

BSE, as in other TSEs, the total amount of infectivity in an animal 
increases throughout the incubation period reaching the highest load 
when an animal begins to demonstrate clinical signs (Ref. 44). Because 
of this evidence combined with the very low incidence of clinical BSE 
in cattle younger than 30 months, we are proposing, consistent with the 
Foods IFR (69 FR 42256 at 42259) and the USDA/FSIS IFR (69 FR 1862), 
that brain, skull, eyes, trigeminal ganglia, spinal cord, vertebral 
column (excluding the vertebrae of the tail, the transverse processes 
of the thoracic and lumbar vertebrae, and the wings of the sacrum), and 
dorsal root ganglia should be considered SRMs only in cattle 30 months 
and older. We include the skull and the vertebral column in the list of 
SRMs because, even though they have not been shown to harbor BSE 
infectivity, they contain tissues (i.e., brain and spinal cord) that 
have been shown to be infectious. We did not include, consistent with 
the Foods IFR (69 FR 42256 at 42259) and the USDA/FSIS IFR (69 FR 1862 
at 1868), the vertebrae of the tail, the transverse processes of the 
thoracic and lumbar vertebrae, and the wings of the sacrum as SRMs with 
the rest of the vertebral column because they do not contain spinal 
cord or dorsal root ganglia. As the science and epidemiology on this 
issue develop, FDA may find it necessary through future rulemaking to 
modify the tissues classified as SRMs and the age at which these 
tissues are classified as SRMs.
    Based on the previously mentioned experimental evidence indicating 
that tonsils become infective by 10 months postinoculation and distal 
ileum by 6 months postinoculation (Refs. 3 and 4), we are proposing, 
consistent with the Foods IFR (69 FR 42256 at 42259 and 70 FR 53063 at 
53064 through 53065) and USDA/FSIS IFR (69 FR 1862 and 70 FR 53043), 
that the tonsil and distal ileum of the small intestine of all cattle 
be considered SRMs.
2. Small Intestine
    The small intestine is not considered prohibited cattle material if 
the distal ileum is removed by a procedure that removes at least 80 
inches of the uncoiled and trimmed small intestine as measured from the 
caeco-colic junction and progressing proximally towards the jejunum or 
by a procedure that the establishment can demonstrate is equally 
effective in ensuring complete removal of the distal ileum. In this 
medical products proposed rule, we are proposing to prohibit the use of 
small intestine of all cattle in medical products for humans and drugs 
for ruminants if procedures that completely remove the distal ileum are 
not used. This provision is consistent with USDA (70 FR 53043) and FDA 
(70 FR 53063) requirements. .
3. Mechanically Separated Beef
    Mechanically Separated (Species) is a standardized food defined by 
USDA in 9 CFR 319.5 (see section V.A of this document for the proposed 
definition of mechanically separated beef). The standard does not limit 
the amount of spinal cord and dorsal root ganglia allowed in vertebral 
column used to produce the product. Consequently, mechanically 
separated beef may contain concentrated amounts of such tissues. 
Because we are proposing that spinal cord, dorsal root ganglia and 
vertebral column be considered SRMs, we are also proposing, consistent 
with the USDA/FSIS and Foods IFRs (69 FR 1862 at 1866 through 1867 and 
69 FR 42256 at 42259), to include mechanically separated beef as a 
prohibited cattle material.
4. Nonambulatory Disabled Cattle
    Experience has shown that nonambulatory disabled cattle (see 
section V.A of this document for the proposed definition) are the 
population at greatest risk for harboring BSE. Surveillance data in the 
European Union in 2002 showed that there were 29 positive/10,000 tests 
for BSE among healthy-appearing cattle of all ages and 148 positive/
10,000 tests for BSE among nonambulatory animals of all ages (Ref. 63). 
In Switzerland, sampling of particular populations of cattle revealed 
that BSE-positive animals were 49 to 58 times more likely to be found 
in the nonambulatory population than in the population selected for 
passive surveillance (Ref. 64). The Harvard-Tuskegee study estimated 
that, following importation of 10 infected cattle, a prohibition 
against rendering animals that die on the farm (these animals could be 
nonambulatory disabled) would decrease the number of new cases of BSE 
by 82 percent.
    Because typical clinical signs of BSE cannot always be observed in 
nonambulatory disabled cattle, and because evidence has indicated these 
cattle are more likely to have BSE than apparently healthy cattle, FDA 
is proposing, consistent with the Foods IFR (69 FR 42256 at 42259), to 
include material from nonambulatory disabled cattle as prohibited 
cattle materials. This proposal is also consistent with USDA's 
requirement that all nonambulatory disabled cattle presented for 
slaughter be condemned (69 FR 1862 at 1870 and 1871).
5. Cattle Not Inspected and Passed for Human Consumption
    Cattle that have not been inspected (see section V.A of this 
document for the proposed definition) are at higher risk of having BSE, 
as well as other diseases, because they will not have been examined by 
USDA for their disease status in general and potential for harboring 
BSE in particular. In addition, such cattle are likely to have died on 
the farm or en route to slaughter, and these animals are not eligible 
for inspection by USDA. For cattle that are inspected but not passed, a 
regulatory authority (USDA or other) has made a determination that they 
are not appropriate for use in human food (69 FR 42256 at 42259). Such 
a determination may be based, among other things, on evidence of a 
neurological disorder associated with a higher risk of BSE. Moreover, 
material from cattle not inspected or inspected and not passed for 
human consumption is prohibited from human food (69 FR 42256 at 42259). 
In this rulemaking, FDA is proposing to extend this prohibition to 
medical products for humans and drugs for ruminants. By requiring that 
material from cattle for use in medical products for humans and drugs 
for ruminants be inspected and passed for human consumption, we would 
minimize the risk to humans and ruminants of exposure to the agent that 
causes BSE.
6. Tallow and Tallow Derivatives
    Tallow is an animal-derived hard fat that has been heat processed; 
most tallow is derived from cattle. In this proposed rule, we use the 
term tallow to refer only to tallow derived from cattle. Any risk of 
BSE transmission from tallow is a result of protein that is present as 
an impurity in the tallow. Taylor et al. (Refs. 65 and 66) found in 
rendering studies with abnormal prion protein that the prion protein 
did not preferentially migrate into the fat fraction, but remained with 
the protein fraction. Therefore, there is no reason to believe that 
tallow is likely to contain unusually high amounts of prion protein as 
a constituent of the insoluble impurities fraction that remains in 
tallow after rendering. Taylor et al. (Refs. 65 and 66) also reported 
that the various rendering processes used for tallow production in the 
United Kingdom were sufficient to produce tallow that did not result in 
infection when injected into the brains of mice, even though the 
starting material was highly spiked with the scrapie agent. Wilesmith 
et al. (Ref. 67) noted that the geographical variation in the incidence

[[Page 1588]]

of BSE in the United Kingdom was not consistent with the use of tallow 
in cattle feed and concluded that the most likely source of infection 
in cattle was BSE-contaminated meat and bone meal.
    The World Organisation for Animal Health (OIE) (formerly the Office 
International des Epizooties), the international animal health standard 
setting body, categorizes tallow with insoluble impurities of no more 
than 0.15 percent as protein-free tallow and indicates that tallow that 
meets this standard can be safely consumed by animals, regardless of 
the starting materials (Ref. 68). FDA's Transmissible Spongiform 
Encephalopathies Advisory Committee (TSEAC) considered the safety of 
tallow in 1998 (Ref. 69). Although members of the TSEAC indicated that 
tallow is a food with extremely low risk of transmitting BSE to humans 
or animals, they did not see a need to change FDA's recommendation that 
tallow not be sourced from cattle born, raised, or slaughtered in 
countries where BSE is known to exist.
    Based on the research and the opinions noted previously that show 
that tallow is inherently a low risk material because of the procedures 
by which it is manufactured, we are proposing to permit tallow from any 
country to be used in medical products for humans and drugs for 
ruminants, as we have for human food and cosmetics (69 FR 42256 at 
42260 and 42261), if it contains no more than 0.15 percent insoluble 
impurities regardless of the starting materials or if it otherwise 
complies with these regulations (e.g., made without the use of any 
prohibited cattle materials). We recognize that the TSEAC did not see a 
need to change FDA's tallow import policy, which recommended against 
use of tallow from cattle born, raised, or slaughtered in countries 
where BSE is known to exist. However, the TSEAC was not asked to 
provide recommendations regarding import of tallow that met our 
proposed requirements. We believe we are proposing a tallow standard 
for medical products for humans and drugs for ruminants that is 
consistent with statutory safety standards and the recommendations by 
OIE with respect to bovine-derived tallow to prevent BSE in cattle and 
vCJD in humans.
    Distinct from tallow are tallow derivatives. These derivatives are 
produced by subjecting tallow to chemical processes (hydrolysis, trans-
esterification, or saponification) that involve high temperature and 
pressure. The TSEAC considered tallow derivatives in 1998 (Ref. 69) and 
determined that the rigorous conditions of manufacture are sufficient 
to further reduce the BSE risk in tallow derivatives. In addition, the 
OIE also recommends that derivatives of protein-free tallow be freely 
traded among countries because they pose an insignificant BSE risk to 
animals (Ref. 68). Because we believe that tallow has negligible risk 
of transmitting BSE, and tallow derivatives undergo additional 
processing, we do not believe that tallow derivatives pose a risk of 
transmitting the agent that causes BSE to humans. Therefore, we are 
proposing, consistent with the Foods IFR (69 FR 42256 at 42261), that 
tallow derivatives not be considered a prohibited cattle material. FDA 
proposes to clarify, as in the amendments to the Foods IFR (70 FR 
53063), that the ``no more than 0.15 percent insoluble impurities'' 
restriction for tallow does not apply to tallow derivatives.
7. Fetal Calf Serum
    Current evidence suggests that cow-to-calf transmission of BSE is 
unlikely to occur (Refs. 14 and 46). Therefore, the serum of fetal 
calves is unlikely to contain any BSE infectious material, irrespective 
of the age of the mother. However, because fetal calf serum (FCS) is 
generally collected from fetuses of dairy cows culled for low milk 
production or for health reasons, these cows are often considerably 
older than 30 months. FDA believes that manufacturers commonly take 
appropriate steps to prevent contamination of the FCS with specified 
risk materials from the mother. These steps include the normal dressing 
procedures used in slaughter houses, consisting of removing the uterus 
completely from the carcass and other viscera of cows that were 
inspected and passed, taking it to a separate space free of prohibited 
cattle materials for cardiac puncture, and collecting the fetal blood 
in a closed collection system using aseptic technique. Other procedures 
could also be used to provide adequate assurance that contamination has 
been prevented.
8. Additional Requirements
    If the agency finds that additional protections are needed for 
specific products or classes of products covered by applications (e.g., 
products with direct routes of exposure into the bloodstream or neural 
tissue such as injectable, ophthalmic, intranasal, or implanted FDA-
regulated products), it intends to provide those protections through 
the application review process or through other means, such as special 
controls for Class II devices. The agency believes it is possible that 
injectable, ophthalmic, intranasal, or implanted FDA-regulated products 
that contain cattle material other than prohibited cattle materials and 
that do not have an FDA approval covering use of that material may 
appear to be adulterated or misbranded under certain circumstances. If 
the agency finds that classes of such products or specific products do 
not meet the applicable statutory standards, it may take action even if 
the products comply with the requirements in this proposed regulation.

F. Medical Products for Humans and Drugs for Ruminants That May Contain 
Cattle Material

1. Drugs for Humans
    Under this proposed rule, drugs for humans cannot be manufactured 
from or otherwise contain prohibited cattle materials without written 
permission from FDA. For drugs subject to applications, the agency may 
provide additional protections through the application review process 
on a case-by-case basis to ensure that the products are safe and 
effective for their intended uses under section 505 of the Federal 
Food, Drug and Cosmetic Act (the act) (21 U.S.C. 355) and safe, pure, 
and potent under section 351 of the Public Health Service Act (the PHS 
Act) (42 U.S.C. 262). For drugs not subject to applications, if the 
agency finds that specific products or product classes do not meet the 
applicable statutory standards regarding adulteration and misbranding, 
it may take action even if the products comply with the requirements in 
this proposed rule.
    Many approved human drugs, as well as investigational human drugs, 
contain ingredients that are derived from cattle. Over the last 10 
years, FDA has maintained a database that identifies these drugs and 
their cattle-derived ingredients. Based on the information in this 
database, we are aware of no approved drugs and no investigational 
drugs that are manufactured with cattle material that would be 
prohibited under this proposed rule based on the type of cattle tissue 
used.\1\
---------------------------------------------------------------------------

    \1\All manufacturers would have to ensure that any cattle 
material they use comes from cattle that are inspected and passed 
and otherwise complies with the other requirements proposed in this 
rule.
---------------------------------------------------------------------------

    In addition to human drugs with approved applications, a number of 
human drugs are marketed without an approved application and, 
therefore, have not been subject to the new drug application (NDA) 
review process (e.g., products marketed under FDA's over-the-counter 
(OTC) monograph system, Active Pharmaceutical Ingredients,

[[Page 1589]]

homeopathic preparations, or products that purport to be 
``grandfathered''). Although FDA's database of these products is 
incomplete, some of them may contain cattle materials that would be 
prohibited under this proposed rule. The requirements proposed in this 
rulemaking apply to all drugs for humans, including those marketed 
without an approved application.
2. Biologics for Humans
    Many biological products are manufactured with, or otherwise use, 
cattle-derived material because this material can provide necessary 
nutrients for cell growth. For example, microorganisms used for vaccine 
manufacture are typically grown under controlled conditions in media 
that may contain cattle materials. Animal-derived products used in 
vaccine manufacture include amino acids, glycerol, detergents, gelatin, 
enzymes, and blood. Cattle skeletal muscle is used to prepare broths 
used in certain complex media.
    Many microorganisms that are difficult to grow and cells that are 
used to propagate viruses require serum in the growth media, which is 
typically derived from cattle blood. Cattle-derived materials (e.g., 
fetal calf serum, insulin, aprotinin, enzymes) are often used in cell 
culture techniques to manufacture hematological, cell, and gene-therapy 
products.
    Manufacturers of licensed products and sponsors of investigational 
new drug products are currently requested to provide, in their 
biologics license application (BLA) or investigational new drug 
application (IND), information regarding the source of all bovine-
derived materials used in the manufacture of their product. This 
information is reviewed by FDA along with other information provided in 
the application. SRMs are not ordinarily used in the manufacture of 
biological products. Biological products that are not intended for use 
in or on the body (e.g., in vitro diagnostics) would not be subject to 
the provisions of this proposed rule.
3. HCT/Ps
    This proposed rule would affect all HCT/Ps. HCT/Ps are defined in 
part 1271 (21 CFR part 1271) as ``articles containing or consisting of 
human cells or tissues that are intended for implantation, 
transplantation, infusion, or transfer into a human recipient. Examples 
of HCT/Ps include, but are not limited to, bone, ligament, skin, dura 
mater, heart valve, cornea, hematopoietic stem/progenitor cells derived 
from peripheral and cord blood, manipulated autologous chondrocytes, 
epithelial cells on a synthetic matrix, and semen or other reproductive 
tissue'' (Sec.  1271.3(d)). Certain exceptions apply (Sec.  
1271.3(d)(1) through (d)(7)).
    HCT/Ps are regulated according to a tiered, risk-based framework. 
HCT/Ps meeting the criteria listed in Sec.  1271.10 (e.g., minimally 
manipulated, intended for homologous use only (i.e., perform the same 
basic function(s) in the recipient as in the donor), not combined with 
a drug or device, and not having a systemic effect) are regulated 
solely under the authority of section 361 of the PHS Act (42 U.S.C. 
264). These ``361'' HCT/Ps are required to comply only with the 
applicable requirements in part 1271. Premarket review is not required 
for such products; therefore, FDA does not review any information 
regarding cattle-derived material that might be used in such products. 
This proposed rule would ban the use of prohibited cattle material in 
these products, which we believe would help reduce any possible BSE 
transmission through the use of ``361'' HCT/Ps manufactured using 
cattle-derived material.
    HCT/Ps that do not meet the criteria in Sec.  1271.10 are regulated 
as drugs and devices under the act, and/or biological products under 
section 351 of the PHS Act and the act. Establishments that manufacture 
such HCT/Ps must comply with the requirements in subparts C and D of 
part 1271 in addition to all other applicable regulations, including 
submission of the appropriate premarketing applications, and are 
included in this proposed rule. Information regarding the use of 
cattle-derived material in the manufacture of such HCT/Ps would be 
submitted as part of the premarket review, giving us the opportunity to 
evaluate any potential for risk of BSE transmission.
4. Medical Devices for Humans
    The Center for Devices and Radiological Health (CDRH) has an 
administrative database that FDA reviewers use to record PMA and 510(k) 
submissions. In 2002, FDA added an ``animal tissue flag'' to the CDRH 
administrative database. This ``flag'' indicates that the device 
contains or is manufactured with animal tissue of some kind; the 
species of animal tissue is not identified. The animal tissue flag has 
been recorded for 68 PMAs and 2,164 510(k)s. These numbers represent 
only devices for which PMAs or 510(k)s were filed since the animal 
tissue flag was added in 2002. They do not account for devices cleared 
or approved for marketing before that time that may contain or that may 
be manufactured with animal tissue.
    Examples of cattle material used in devices range from high risk 
tissues (such as bovine pituitary extract used as a component of growth 
media) used in a low risk clinical setting (such as a topical 
application), to low risk cattle tissues (such as collagen from cattle 
hide or muscle) used in a high risk clinical setting (such as direct 
application to the central nervous system).
    Premarket submissions for devices do not always include complete 
information about the source of animal components. In addition, not all 
devices are subject to premarket review, either because they are exempt 
from such review or because they have already been cleared or approved. 
FDA believes that it is important to help ensure that all devices that 
are intended for use in or on the body do not contain prohibited cattle 
materials. Examples of devices intended for use in or on the body 
include, but are not limited to, vascular grafts, bone fillers, 
lacrimal plugs, sutures, wound dressings, and heart valves (other than 
human heart valve allografts regulated solely under section 361 of the 
PHS Act). FDA has determined that the banning and recordkeeping 
provisions of this proposed rule are necessary to help ensure the 
safety of devices intended for use in or on the body. Medical devices 
that are not intended for use in or on the body (e.g., in vitro 
diagnostics, x-ray machines) would not be subject to the provisions of 
this proposed rule. FDA is not aware of any currently marketed device 
that is manufactured with cattle material that would be prohibited 
under this proposed rule.
5. Drugs for Ruminants
    The requirements proposed in this rulemaking would cover new animal 
drugs for ruminants. Ruminants present the highest risk of any animals 
for contracting BSE from prohibited cattle materials. Because FDA has 
other mechanisms to restrict the extralabel use of approved human and 
animal drugs that contain prohibited cattle materials in ruminants (see 
section V.D of this document), this proposed rule would only prohibit 
the use of certain cattle material in drugs intended for use in 
ruminants.
    Some drugs for ruminants may contain or be manufactured with 
cattle-derived materials. We are not aware of any drugs for ruminants 
that contain, as a component of the drug, cattle material that would be 
prohibited by the proposed rule. However, although the FDA animal drug 
database lists materials contained in drugs for animals, it does not 
identify materials

[[Page 1590]]

that are used in the manufacture of drugs for animals but that are not 
intended to be components of the drug (e.g., materials used in 
fermentation or cell culture production of drugs for animals). Because 
the FDA database does not contain information on materials used in the 
manufacture of drugs for animals, we cannot definitively conclude that 
no drugs for ruminants are manufactured with the use of cattle material 
that would be prohibited by this proposed rule. However, based on our 
knowledge of the processes and materials used in manufacture of drugs 
for ruminants, as well as the fact that very little cattle material is 
prohibited if sourced from cattle that were inspected and passed and 
were younger than 30 months old when slaughtered, we do not believe 
that prohibited cattle material is needed in the manufacture (through 
fermentation, cell culture or otherwise) of drugs for ruminants.

III. USDA/FSIS IFR

    On January 12, 2004, in response to the diagnosis of BSE in a cow 
in the United States, USDA published a series of interim final rules, 
including ``Prohibition of the Use of Specified Risk Materials for 
Human Food and Requirements for the Disposition of Non-Ambulatory 
Disabled Cattle'' (69 FR 1862). The USDA/FSIS IFR declared that SRMs 
were inedible and unfit for food and prohibited their use as human 
food. It also prohibited the use of the entire small intestine of all 
cattle in human food. In 2005, the USDA/FSIS IFR was amended, in part, 
to permit use of the small intestine of all cattle in human food if 
appropriate procedures are used to completely remove the distal ileum 
(70 FR 53043). In the Foods IFR, FDA extended similar protections to 
FDA-regulated human food and cosmetics. (See section IV.A.3 of this 
document for a discussion of the Foods IFR.)
    The USDA/FSIS and Foods IFRs will reduce but will not, by 
themselves, eliminate the use of prohibited cattle materials in 
domestic and imported FDA-regulated medical products for humans and 
drugs for ruminants. Even when excluded from human food produced in 
USDA-inspected establishments, prohibited cattle materials that have 
been denatured may leave the establishments for rendering or 
destruction. These materials, which previously have not been explicitly 
prohibited in medical products for humans and drugs for ruminants by 
FDA, might then be used in FDA-regulated medical products for humans 
and drugs for ruminants.
    Under the USDA/FSIS IFR, SRMs and carcasses of nonambulatory 
disabled cattle are designated as inedible. However, certain products, 
such as gelatin and collagen (which are both covered by the provisions 
of this medical products proposed rule) used in FDA-regulated medical 
products for humans and drugs for ruminants, have traditionally been 
produced from cattle material deemed inedible by the USDA. Therefore, 
such a designation by the USDA may not be enough to preclude use of 
prohibited cattle materials in FDA-regulated products without 
additional regulation by FDA. Furthermore, some cattle are not 
slaughtered under continuous USDA inspection (e.g., some are sent 
directly to rendering without first passing inspection). Cattle 
material from these animals, such as brains or bones, which include 
SRMs, could end up as starting material for medical products for humans 
and drugs for ruminants. If prohibited cattle materials were unlawfully 
used in FDA-regulated medical products for humans and drugs for 
ruminants, this proposed rule if finalized would facilitate FDA's 
ability to use the enforcement mechanisms of the act that apply to 
adulterated products (e.g., seizure) to prevent human or ruminant 
exposure to the prohibited cattle materials.
    Imported products also may contain the types of materials 
prohibited by the USDA, but would not fall within the scope of the 
USDA's import regulations either because of the nature of the products 
or their country of origin. Specifically, although both FSIS and USDA's 
Animal and Plant Health Inspection Service (APHIS) impose BSE-related 
prohibitions, these prohibitions collectively do not cover all FDA-
regulated medical products for humans and drugs for ruminants. For 
example, APHIS' BSE-related restrictions on imports do not cover 
gelatin for human use (beyond requiring a permit) and apply only to a 
limited number of countries (9 CFR 94.18).

IV. FDA Actions on BSE

A. Regulations

1. FDA 1997 Ruminant Feed Rule
    In the Federal Register of June 5, 1997 (62 FR 30936), FDA 
published a regulation that prohibits, with some exceptions, the use of 
protein derived from mammalian tissue in feed for cattle and other 
ruminant animals (21 CFR 589.2000). The agency published the FDA 1997 
ruminant feed rule to prevent the establishment and amplification of 
BSE in the United States and thereby minimize any risk to animals and 
humans. FDA recently proposed changes to these requirements to further 
strengthen the rule (see section IV.A.2 of this document).
2. FDA/USDA Animal Feed ANPRM and FDA 2005 Animal Feed Proposed Rule
    Following detection of BSE in an imported dairy cow in Washington 
State in December 2003, the Secretaries of the U.S. Departments of 
Agriculture and Health and Human Services announced a series of 
regulatory actions and policy changes to strengthen protections against 
the spread of BSE in U.S. cattle and against human exposure to the BSE 
agent. The Secretary of Agriculture also convened an international 
panel of experts on BSE to review the U.S. response to the Washington 
case and make recommendations that could provide meaningful additional 
public or animal health benefits.
    In the Federal Register of July 14, 2004 (69 FR 42287), FDA and 
USDA's FSIS and APHIS jointly published an ANPRM to solicit comment on 
additional measures under consideration based on those recommendations 
and other factors. FDA has since received comments on the joint ANPRM, 
and in the Federal Register of October 6, 2005 (70 FR 58570), published 
the FDA 2005 Animal Feed proposed rule to prohibit certain material 
from all animal food or feed.
3. Foods IFR
    In the Federal Register of July 14, 2004 (69 FR 42256), FDA 
published an IFR prohibiting the use of certain cattle material to 
address the potential risk of BSE in human food, including dietary 
supplements, and cosmetics. This rule took effect immediately upon 
publication. On September 7, 2005, FDA amended the Foods IFR to revise 
or clarify provisions with regard to: (1) Use of small intestine (see 
section II.E.2 of this document) (2) use of hide and hide-derived 
products (see section V.A of this document), (3) use of milk and milk 
products (see section V.A of this document), (4) source tallow for 
tallow derivatives (see section II.E.6 of this document), and (5) 
testing method cited for determining the level of insoluble impurities 
in tallow (see section V.C of this document). As a result, cattle 
materials prohibited in human food and cosmetics include SRMs, small 
intestine of all cattle if procedures that completely remove the distal 
ileum are not used, material from nonambulatory disabled cattle, 
material from cattle not inspected and passed for human consumption, 
and mechanically separated beef. SRMs include the brain,

[[Page 1591]]

skull, eyes, trigeminal ganglia, spinal cord, vertebral column 
(excluding the vertebrae of the tail, the transverse processes of the 
thoracic and lumbar vertebrae, and the wings of the sacrum), and dorsal 
root ganglia of cattle 30 months and older; and the tonsils and distal 
ileum of the small intestine of all cattle. Prohibited cattle materials 
do not include tallow that contains no more than 0.15 percent insoluble 
impurities, tallow derivatives, hides and hide-derived products, and 
milk and milk products. This action was taken to minimize human 
exposure to materials that are highly likely to contain the BSE agent 
in cattle infected with the disease.
4. Foods Recordkeeping/Access Final Rule
    In the Federal Register of October 11, 2006 (71 FR 59653), FDA also 
published a final rule to require that manufacturers and processors of 
human food and cosmetics that are manufactured from, processed with, or 
otherwise contain, material from cattle establish and maintain records 
sufficient to demonstrate that the food and cosmetics are in compliance 
with the Foods IFR. FDA believes that records documenting the absence 
of prohibited cattle materials in human food and cosmetics are critical 
for manufacturers, processors, and FDA to ensure compliance with the 
ban on the use of prohibited cattle materials in the Foods IFR. FDA 
solicited comment on the types of records that may already be available 
to document the absence of prohibited cattle materials in human food 
and cosmetics and the types of records that could be established to 
document the absence of prohibited cattle materials in these FDA-
regulated products. The effective date of the Foods Recordkeeping/
Access final rule is January 9, 2007. Until the Foods Recordkeeping/
Access final rule is effective, FDA is ensuring that it can enforce the 
new prohibitions in the Foods IFR through the provisions in that rule 
requiring that FDA be given access to any existing records relevant to 
compliance with the ban on prohibited cattle materials.
    This proposed rule for medical products for humans and drugs for 
ruminants is a companion to the Foods IFR and responds to the same 
public health concerns. This proposed rule serves as an additional 
safeguard to reduce human exposure to the agent that causes BSE that 
may be present in cattle-derived medical products for humans and drugs 
for ruminants that are from domestic and imported sources.

B. FDA Guidance

    During the past decade, we have communicated with the public and 
manufacturers, applicants, importers, and processors of FDA-regulated 
human and animal products regarding appropriate steps to increase 
product safety and minimize the risk of products being contaminated 
with the BSE agent. Most of our communications have been in the form of 
letters and guidance to industry and import alerts.
     November 1992--We wrote to manufacturers of dietary 
supplements to alert them to the developing concern about TSEs in 
animals and CJD in humans and recommended that they investigate the 
geographic sources of any bovine and ovine material used in their 
products.
     December 1993--We wrote to manufacturers of drugs, 
biologics, and medical devices and recommended against the use of 
bovine-derived materials from cattle that have resided in, or 
originated from, BSE countries.
     August 1994--We published a notice in the Federal Register 
(59 FR 44592, August 29, 1994) entitled ``Bovine-Derived Materials; 
Agency Letters to Manufacturers of FDA-Regulated Products.'' In the 
notice, we published the text of the November 1992 and December 1993 
letters previously described and, in addition, the text of letters to 
manufacturers of FDA-regulated products for animals (August 17, 1994), 
and manufacturers and importers of dietary supplements and cosmetics 
(August 17, 1994).
     October 1994--We issued Import Alert 17-04, which allowed 
for the detention, without physical examination, of bulk shipments of 
high-risk bovine tissues and tissue-derived ingredients from BSE 
countries. We have updated this alert whenever APHIS has revised the 
list of countries in 9 CFR 94.18.
     October 1997--We published a notice of availability (62 FR 
52345, October 7, 1997) of a guidance for industry entitled ``The 
Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed 
by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for 
Human Use.''
    The rule, if finalized, will supersede prior communications that 
address the same issues, including the communications identified 
previously.

V. Description of Proposed Rule

A. Definitions

    For the purposes of this regulation, we are proposing to define the 
terms ``prohibited cattle materials,'' ``inspected and passed,'' 
``mechanically separated beef,'' ``nonambulatory disabled cattle,'' 
``specified risk materials,'' ``tallow,'' ``tallow derivative,'' and 
``ruminant'' (proposed Sec. Sec.  300.200(a), 500.200(a), 600.16(a), 
895.102(a) and 1271.470(a)). The proposed terms and definitions are the 
same as those used in the Foods IFR (69 FR 42256 and 70 FR 53063), 
except that we are now including in proposed Sec.  500.200(a) a 
definition for ruminant and we have revised the definition of 
prohibited cattle materials as it relates to fetal calf material. We 
have also made minor editorial revisions to the definition of inspected 
and passed. The proposed definitions are consistent with definitions 
used by the USDA (69 FR 1862 and 70 FR 53043).
    1. Prohibited cattle materials means specified risk materials, 
small intestine of all cattle if procedures that completely remove the 
distal ileum are not used, material from nonambulatory disabled cattle, 
material from cattle not inspected and passed, or mechanically 
separated beef. Prohibited cattle materials do not include tallow that 
contains no more than 0.15 percent insoluble impurities, tallow 
derivatives, hides and hide-derived products, and milk and milk 
products. Prohibited cattle materials also do not include materials 
obtained from fetal calves of cows that were inspected and passed as 
long as the materials were obtained by procedures adequate to prevent 
contamination with specified risk materials.
    With regard to hides and hide-derived products, we are proposing 
that these products not be included in the definition of ``prohibited 
cattle materials.'' We are proposing this exemption because cattle hide 
has been determined to be a tissue with negligible risk of transmitting 
the agent that causes BSE; the OIE recommends that it be freely traded 
regardless of the BSE risk status of the exporting countries. Even 
though we are proposing to exempt hides and hide-derived products from 
the provisions of this proposed rule, applicants and manufacturers 
would be required to take precautions to avoid cross contamination of 
hides and other nonprohibited cattle material with prohibited cattle 
material during slaughter and processing.
    With regard to milk and milk products, we are proposing that these 
products also not be included in the definition of ``prohibited cattle 
materials.'' We recognize that milk and milk products present a 
negligible risk of transmitting the agent that causes BSE. The OIE 
recommends that milk and milk products be freely traded

[[Page 1592]]

among countries, regardless of the BSE risk status of the exporting 
country. In addition, the prohibitions for medical products for humans 
and drugs for ruminants applies to materials from cattle slaughtered on 
or after the effective date of the rule and is not meant to apply to 
milk and milk products, which come from live cattle.
    2. Inspected and passed means that the material is from an animal 
that has been inspected and passed for human consumption by the 
appropriate regulatory authority, and at the time the animal was 
inspected and passed, it was found to be not adulterated.
    3. Mechanically separated beef means a meat food product that is 
finely comminuted, resulting from the mechanical separation and removal 
of most of the bone from attached skeletal muscle of cattle carcasses 
and parts of carcasses, that meets the specifications contained in 9 
CFR 319.5, USDA's regulation that prescribes the standard of identity 
for Mechanically Separated (Species).
    4. Nonambulatory disabled cattle means cattle that cannot rise from 
a recumbent position or that cannot walk, including, but not limited 
to, those with broken appendages, severed tendons or ligaments, nerve 
paralysis, fractured vertebral column, or metabolic conditions.
    5. Specified risk material means the brain, skull, eyes, trigeminal 
ganglia, spinal cord, vertebral column (excluding the vertebrae of the 
tail, the transverse processes of the thoracic and lumbar vertebrae, 
and the wings of the sacrum), and dorsal root ganglia of cattle 30 
months and older, and the tonsils and distal ileum of the small 
intestine of all cattle.
    6. Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain not more than 0.15 percent insoluble 
impurities as determined by the method entitled ``Insoluble 
Impurities'' (AOCS Official Method Ca 3a-46), American Oil Chemists' 
Society (AOCS), 5th Edition, 1997, incorporated by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51, or another method 
equivalent in accuracy, precision, and sensitivity to AOCS Official 
Method Ca 3a-46. You may obtain copies of the method from AOCS (http://www.aocs.org) 2211 W. Bradley Ave., Champaign, IL 61821. Copies may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
5100 Paint Branch Pkwy., College Park, MD 20740, or at the National 
Archives and Records Administration (NARA). For information on the 
availability of this material at NARA, call 202-741-6030, or go to: 
http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
    7. Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or 
trans-esterification may be applied to obtain the desired product.
    8. Ruminant means any member of the suborder of animals that has a 
stomach with four compartments (rumen, reticulum, omasum, and abomasum) 
through which feed passes in digestion. The suborder includes, but is 
not limited to, cattle, buffalo, sheep, goats, deer, elk, and 
antelopes.

B. Proposed Requirements for Prohibited Cattle Materials and Permission 
for an Exception or Alternative to These Requirements

    USDA and FDA prohibit the use of SRMs, and mechanically separated 
beef in human food (69 FR 1862; 69 FR 42256). USDA also requires that 
all nonambulatory disabled cattle presented for slaughter be condemned 
(69 FR 1862), while FDA prohibits use of such cattle in human food (69 
FR 42256). USDA and FDA permit use of the small intestine of all cattle 
in human food if appropriate procedures are used to completely remove 
the distal ileum (70 FR 53043; 70 FR 53063).
    FDA imposes these prohibitions for cosmetics as well, and also 
prohibits material from cattle not inspected and passed in both human 
food and cosmetics (69 FR 42256; 70 FR 53063). To ensure that the same 
materials are not incorporated into other FDA-regulated products, we 
are now proposing to prohibit the use of these materials in, or in the 
manufacture of, medical products for humans and drugs for ruminants. As 
with human food and cosmetics, we are proposing the following five 
categories of material as prohibited cattle materials: (1) The small 
intestine from all cattle if procedures that would completely remove 
the distal ileum are not used, (2) SRMs, (3) mechanically separated 
beef, (4) material from nonambulatory disabled animals, and (5) 
material from cattle not inspected and passed.
    Scientists believe that the human disease vCJD is likely caused by 
the consumption of products contaminated with the agent that causes 
BSE. The relationship between the agent that causes BSE and human cases 
of vCJD has been described previously in section II.C of this document. 
Consumption of contaminated material is thought to cause illness in 
humans, although scientific research has not determined the infectious 
dose (see section II.C of this document), and there is not a test that 
would allow screening of cattle materials or derivative products for 
infectious material (see section II.D of this document). Therefore, we 
are proposing in Sec.  300.200(b)(1) that, except as provided in 
proposed Sec.  300.200(b)(2), no human drug be manufactured from or 
otherwise contain prohibited cattle materials obtained from cattle 
slaughtered on or after the effective date of the final rule based on 
this proposal. We are proposing similar limitations for other products: 
drugs for ruminants, human biological products (including blood 
products) and medical devices that are intended for use in or on the 
body, and HCT/Ps (defined at 21 CFR 1271.3(d)) (proposed Sec. Sec.  
500.200(b), 600.16(b), 895.102(b), and 1271.470(b)). With regard to 
HCT/Ps, this proposed prohibition (proposed Sec.  1271.470(b)) applies 
to use of prohibited cattle materials in the manufacture of the HCT/P 
rather than the manufacture of the HCT/P from prohibited cattle 
materials because HCT/Ps exclude animal tissues (Sec.  
1271.3(d)(2)(vi)).
    FDA is proposing to apply the requirements of this proposed rule to 
all products or components of products manufactured for use in the 
United States or imported into the United States. This proposed rule 
contains the basic requirements needed to provide further protection of 
humans and ruminants from the potential risks of BSE posed by the use 
of cattle material in the manufacture of these products. Additional 
measures that FDA determines are needed for individual products would 
be addressed on a case-by-case basis through the application review 
process. For non-application products, if the agency finds that 
specific products or product classes do not meet the applicable 
statutory standards regarding adulteration and misbranding, it may take 
action even if the products comply with the requirements in this 
proposed rule.
    The provisions in this proposed rule would apply to medical 
products for humans and drugs for ruminants that are manufactured from 
or that otherwise contain material from cattle slaughtered on or after 
the effective date of any final rule. The restrictions would not apply 
to such products (including cell lines used in the manufacture of 
products) that use or contain materials from cattle

[[Page 1593]]

slaughtered before the effective date of any final rule.
    The proposed rule would provide applicants and manufacturers a 
mechanism for requesting FDA to grant written permission for an 
exception or alternative to the limitations on the use of prohibited 
cattle materials in medical products for humans or drugs for ruminants 
(proposed Sec. Sec.  300.200(b)(2), 500.200(b)(2), 600.16(b)(2), 
895.102(b)(2), and 1271.470(b)(2)). Applicants and manufacturers that 
choose to request such permission would be required to submit the 
request in writing to the applicable FDA Center with the requisite 
information as detailed below. For products subject to an application 
or premarket notification, this written request would be required to 
reference the product's application number. The Center Director may 
permit an exception or alternative to this proposed rule's limitation 
on the use of prohibited cattle materials upon the submitter's request 
or on his or her own initiative. Including the application number of 
the product in a written request for products subject to applications 
or premarket notifications would ensure that existing applications and 
clearances reflect when an exception or alternative to these proposed 
requirements has been submitted and when an exception or alternative 
has been approved.
    FDA expects that applicants or manufacturers may submit a request 
for an exception or alternative when filing a new application or 
premarket notification for a product containing cattle material that 
would be prohibited under this proposed rule. Applicants or 
manufacturers may also submit a request for an exception or alternative 
if an existing product contains prohibited cattle materials under this 
proposal. Although FDA believes it is unlikely that applicants or 
manufacturers who currently are not using prohibited cattle materials 
in their products will reformulate their products to include prohibited 
cattle materials, proposing to do so would require not only a request 
for an exception or alternative but also a supplement to the approved 
application or a new premarket notification, consistent with existing 
regulations.
    A request for an exception or alternative to the requirements would 
include: (1) The reasons why an exception or alternative to the 
requirements is needed, (2) a description of the product, including the 
type of prohibited cattle materials used in its manufacturing, its 
manufacturing and purification processes, and its route of 
administration, (3) a description of the source of the prohibited 
cattle materials, including information on the location where the 
cattle were born, raised, and slaughtered and any other information 
relevant to the likelihood of the cattle having ingested material 
prohibited under Sec.  589.2000, and (4) any other relevant information 
(paragraphs (b)(2)(ii)(A) through ((b)(2)(ii)(C) and (b)(2)(ii)(E) of 
proposed Sec. Sec.  300.200, 500.200, 600.16, 895.102, and 1271.470). 
For medical products for humans, the request would be required to 
include a description of how the requirement is not necessary based on 
the risks of the prohibited cattle materials in the product and the 
benefits of the product or how such restrictions are not necessary to 
ensure the safety of the product (paragraph (b)(2)(ii)(D) of proposed 
Sec. Sec.  300.200, 600.16, 895.102, and 1271.470). For drugs for 
ruminants, the request would be required to include either: (1) A 
description of how the requirements are not necessary: (i) Based on the 
risks of the prohibited cattle materials in the product to the target 
animal and the benefits of the product to the target animal and (ii) to 
ensure a reasonable certainty of no harm to humans from any food 
derived from the target animal to which the product was administered, 
or (2) a description of how the requirements are not necessary to 
ensure the safety of the product with respect to both the target animal 
and any food derived from the target animal to which the product is 
administered (proposed Sec.  500.200(b)(2)(ii)(D)). FDA would respond 
to all requests in writing and could impose conditions in granting a 
request. FDA could also grant permission for an exception or 
alternative to the requirements on its own initiative based on an 
evaluation of the criteria described previously. A record of any 
exception or alternative to the requirements in paragraph (b)(1) of 
proposed Sec. Sec.  300.200, 500.200, 600.16, 895.102, and 1271.470 
that is granted by FDA would be required to be maintained by the 
applicant or manufacturer under the proposed recordkeeping requirements 
discussed in section V.E of this document.
    Although FDA believes that exceptions or alternatives to the 
requirements of this proposed rule would be rare, the proposal would 
allow medical products for humans and drugs for ruminants to be 
manufactured from or otherwise contain prohibited cattle materials if 
the agency determines that the risk posed by the use of prohibited 
cattle materials in the product would be outweighed by the benefits of 
the particular product or if the agency determines that prohibiting the 
use of these materials would be otherwise unnecessary to ensure the 
safety of the product. In the case of drugs intended for use in food-
producing ruminant species, the benefits of the product relate 
primarily to the target animal species (ruminants), whereas the risks 
relate to both the health of the target animal as well as the safety of 
the food derived from the target animal. However, the agency does not 
weigh the benefits of a drug to an animal against the risks of the drug 
to human health, but rather considers whether there is a reasonable 
certainty of no harm to humans from the use of the drug in animals. 
Therefore, the reasonable certainty of no harm standard would be 
applied when considering requests for exceptions or alternatives to the 
proposed requirements for drugs intended for use in food-producing 
ruminant species. In all cases, FDA intends to apply existing statutory 
safety standards in determining whether to grant a written request for 
an exception or alternative to the proposed limitations on the use of 
prohibited cattle materials. (See section V.E of this document for 
discussion.)
    In the joint ANPRM, USDA's FSIS sought comment on the issue of 
equivalence and BSE requirements (whether the agency should consider a 
country's BSE risk when determining whether a country has implemented 
equivalent sanitary measures to those required by the United States to 
prevent human exposure to the BSE agent) (69 FR 42287 at 42299 and 
42300). In the Foods IFR, FDA sought comment on the standards that 
should be applied when determining another country's BSE status, 
providing an exemption for ``BSE-free'' countries, and how to determine 
that countries meet any standards that might be developed (69 FR 42256 
at 42263). FDA here again requests comment on whether and, if so, on 
what basis to exempt products and components of products from ``BSE-
free'' countries from our respective requirements related to BSE, 
including those issued by this proposed rule.
    Proposed Sec. Sec.  211.116 and 226.60, which would be part of 
FDA's current good manufacturing practice (CGMP) requirements for 
finished pharmaceuticals for humans and ruminants and for type A 
medicated articles for ruminants would prohibit use of certain cattle 
materials, as described in proposed Sec. Sec.  300.200, 500.200 and 
600.16. The CGMP requirements contain the minimum methods that must be 
used for the manufacture, processing, packing, or holding of a drug to 
ensure that the drug

[[Page 1594]]

meets the quality and purity characteristics that it purports or is 
represented to possess. The CGMP requirements contained in part 211 (21 
CFR part 211) apply to finished pharmaceuticals and components of 
finished pharmaceuticals for both humans and animals.
    The CGMP requirements contained in part 226 (21 CFR part 226) apply 
to Type A medicated articles. Type A medicated products are intended 
solely for use in the manufacture of another Type A medicated article 
or a Type B or Type C medicated feed. A Type A medicated article 
consists of a new animal drug(s), with or without carrier, with or 
without inactive ingredients. Type A medicated articles are new animal 
drugs, and the manufacture of a Type A medicated article requires an 
approved new animal drug application (21 CFR part 514).

C. Tallow and Tallow Derivatives

    Tallow would be defined as ``the rendered fat of cattle obtained by 
pressing or by applying any other extraction process to tissues derived 
directly from discrete adipose tissue masses or to other carcass parts 
and tissues'' (proposed Sec. Sec.  300.200(a)(6), 500.200(a)(6), 
600.16(a)(6), 895.102(a)(6) and 1271.470(a)(6)). Tallow derivatives 
would be defined as any chemical obtained through initial hydrolysis, 
saponification, or trans-esterification of tallow; chemical conversion 
of material obtained by hydrolysis, saponification, or trans-
esterification may be applied to obtain the desired product (proposed 
Sec. Sec.  300.200(a)(7), 500.200(a)(7), 600.16(a)(7), 895.102(a)(7) 
and 1271.470(a)(7)). For the reason described in section II.K of this 
document, we are proposing that tallow with no more than 0.15 percent 
insoluble impurities and tallow derivatives would not be defined as 
prohibited cattle materials under this rule even when manufactured with 
prohibited materials (proposed Sec. Sec.  300.200(a)(1), 500.200(a)(1), 
600.16(a)(1), 895.102(a)(1) and 1271.470(a)(1)). (Tallow made without 
using prohibited cattle materials would not be subject to this purity 
requirement.) We are proposing that the insoluble impurities in tallow 
be measured by the method entitled ``Insoluble Impurities'' (AOCS 
Official Method Ca 3a-46), American Oil Chemists' Society (AOCS), 5th 
Edition, 1997, incorporated by reference in accordance with 5 U.S.C. 
552(a) and 1 CFR part 51, or another method equivalent in accuracy, 
precision, and sensitivity to the AOCS Official Method Ca 3a-46 
(proposed Sec. Sec.  300.200(a)(6), 500.200(a)(6), 600.16(a)(6), 
895.102(a)(6) and 1271.470(a)(6)). The AOCS Official Method Ca 3a-46 is 
currently used by the domestic tallow industry. Reference to the AOCS 
Official Method Ca 3a-46 in this proposed definition does not exclude 
use of another method. Any testing method may be used that is 
equivalent to the AOCS Official Method Ca 3a-46 in accuracy, precision, 
and sensitivity. Those wishing to use an alternate test would be 
responsible for determining that it is equivalent to the AOCS Official 
Method Ca 3a-46; it would not be necessary for FDA to approve the use 
of an alternate test.
    Tallow that contains more than 0.15 percent insoluble impurities 
could be used if it complies with the proposed requirements for cattle 
materials in proposed Sec.  300.200 for drugs for humans, proposed 
Sec.  500.200 for drugs for ruminants, proposed Sec.  600.16 for 
biological products, proposed Sec.  895.102 for medical devices for 
humans that are intended for use in or on the body, and proposed Sec.  
1271.470 for HCT/Ps (e.g., made without the use of any prohibited 
cattle materials).
    We note that, regardless of its purity level, tallow to be used in 
medical products for humans and drugs for ruminants would be subject to 
the other provisions of the act and would be adulterated if, for 
example, it has been prepared, packed, or held under insanitary 
conditions whereby it may have become contaminated with filth (section 
501(a)(2)(A) of the act)(21 U.S.C. 351(a)(2)(A)).

D. Proposed Requirements Regarding Extralabel Drug Use in Animals

    In 1994, Congress enacted the Animal Medicinal Drug Use 
Clarification Act (AMDUCA)(Public Law 103-396). This act authorizes the 
extralabel use of approved animal and human drugs in animals. The act, 
as well as FDA regulations in part 530 (21 CFR part 530), sets out 
certain conditions for extralabel use and authorizes FDA to prohibit 
the extralabel use of approved animal or human drugs in animals. 
Because FDA, elsewhere in this proposed rule, would prohibit the use of 
certain cattle materials in drugs for ruminants only, the agency is 
concerned that ruminants could still be exposed to prohibited cattle 
materials through the extralabel use in ruminants of a drug that was 
approved for a nonruminant species. Also, the agency is concerned about 
the extralabel use in ruminants of a drug that was approved for humans 
to the extent an exception or alternative to these proposed 
requirements has been granted. Therefore, in order to prevent the 
intentional or unintentional use of a drug containing prohibited cattle 
materials in ruminants, FDA is proposing to revise Sec.  530.41 to 
prohibit in ruminants the extralabel use of drugs containing prohibited 
cattle material and approved for use in other animals (nonruminants) or 
for humans (proposed Sec.  530.41(c)).
    FDA is also proposing to add new Sec.  530.42 that would require 
labels for drugs prohibited from extralabel use in ruminants and 
described under proposed Sec.  530.41(c) to bear or be accompanied by 
labeling information to communicate to the user that extralabel use in 
ruminants is prohibited. The proposed regulation would require label 
information to include the statement ``Federal law prohibits the 
extralabel use of this product in ruminants.'' AMDUCA and the 
implementing regulation at Sec.  530.11, however, prohibit the 
extralabel use of an approved new animal drug or human drug in or on 
animal feed. Since the extralabel use of all drugs in or on animal feed 
is excluded from the extralabel use provisions of AMDUCA, FDA believes 
it is unnecessary and potentially confusing to include the previous 
statement only on those feed products that contain drugs described in 
proposed Sec.  530.41(c). Therefore, the labeling requirement under 
proposed Sec.  530.42 would apply to all products that contain drugs 
described in proposed Sec.  530.41(c) except those products used in or 
on an animal feed. FDA intends for sponsors of approved products that 
would be subject to proposed Sec.  530.42 to revise their labeling by 
the effective date of the final rule based on this proposal. If 
necessary, FDA also would have the ability under proposed Sec.  
300.200(b)(2)(iii) to impose a labeling condition on a human drug 
regarding the extralabel use in ruminants of that human drug if an 
exception or alternative is granted.

E. Proposed Recordkeeping Requirements

    We are proposing that applicants and manufacturers of medical 
products for humans and drugs for ruminants that are manufactured from 
or otherwise contain material from cattle be required to establish and 
maintain records that demonstrate that the material from cattle meets 
the requirements of this proposed rule (proposed Sec. Sec.  
300.200(c)(1), 500.200(c)(1), 600.16(c)(1), 895.102(c)(1) and 
1271.470(c)(1)). Because at this time there is no way to screen 
reliably for the presence of the BSE agent or for the presence of 
prohibited cattle materials, applicants and manufacturers of medical 
products for humans and drugs

[[Page 1595]]

for ruminants must depend on records from the suppliers of cattle 
material to demonstrate that their source material is free from 
prohibited cattle materials. Similarly, without adequate records, FDA 
may not know whether applicants and manufacturers of medical products 
for humans and drugs for ruminants have complied with the prohibitions 
against use of prohibited cattle materials. Therefore, under proposed 
Sec. Sec.  300.200(c)(1), 500.200(c)(1), 600.16(c)(1), 895.102(c)(1) 
and 1271.470(c)(1), applicants and manufacturers of medical products 
for humans and drugs for ruminants that are manufactured from or 
otherwise contain material from cattle would be required to establish 
and maintain records sufficient to demonstrate that the medical 
products for humans and drugs for ruminants do not contain prohibited 
cattle materials.
1. Types of Records
    For example, to satisfy the requirement in proposed Sec. Sec.  
300.200(c)(1), 500.200(c)(1), 600.16(c)(1), 895.102(c)(1), and 
1271.470(c)(1) that records show the absence of prohibited cattle 
materials, applicants and manufacturers of medical products for humans 
and drugs for ruminants that are manufactured from or otherwise contain 
brain from cattle would have to establish and maintain records to 
demonstrate, among other things, that the cattle brain used is not from 
cattle over 30 months of age.
    In general, we would expect that having the following types of 
records on FDA-regulated medical products for humans or drugs for 
ruminants containing cattle material would be sufficient to demonstrate 
that the product is not manufactured from and does not otherwise 
contain prohibited cattle materials:
     A signed and dated affirmation (with contact information) 
by a slaughter establishment that cattle material supplied by that 
establishment in a particular shipment does not contain prohibited 
cattle materials. If two or more lots of cattle material from different 
slaughter establishments are pooled into a final product, then having 
records from each slaughter establishment should be sufficient.
     For products containing tallow, records from a slaughter 
establishment affirming that the tallow was produced from material 
containing no prohibited cattle materials or records (i.e., signed, 
dated, with contact information) from the tallow supplier affirming 
that the tallow contains no more than 0.15 percent insoluble impurities 
(e.g., a certificate of analyses).
     For products containing fetal calf materials, records from 
a slaughter establishment affirming that the fetal calf material was 
obtained: (1) From cows that were inspected and passed and (2) using 
procedures that ensure that the fetal material was not contaminated 
with prohibited cattle materials during slaughter or processing.
    Consistent with CGMP recordkeeping requirements, applicants and 
manufacturers who maintain documentation of compliance should maintain 
that information on a lot-by-lot basis. The lot-by-lot records would 
ensure that each time a shipment of cattle material is sent or 
received, there is documentation that a management official confirmed 
that the shipment was free of any prohibited cattle material.
    We request comments on alternative recordkeeping requirements that 
would ensure the requirements of the proposed rule would be met. We 
also request comments on whether existing recordkeeping practices 
include the required information and, if not, what changes the proposal 
would necessitate. In addition, we request comment on whether the rule 
should specifically require certain types of records.
2. Proposed Periods for Records Retention
    The following record retention time periods would be required by 
this proposal:
     For drugs for humans, we are proposing, consistent with 
our CGMP regulations for these products (Sec.  211.180), to require 
that records be retained for at least 1 year after the expiration date 
of the drug (proposed Sec.  300.200(c)(2)).
     For drugs for humans lacking an expiration date, we are 
proposing, consistent with our CGMP regulations for these products 
(Sec.  211.180), to require that records be retained for at least 3 
years after distribution of the last lot of the drug (proposed Sec.  
300.200(c)(2)).
     For drugs for ruminants other than Type A medicated 
articles, we are proposing, consistent with our CGMP regulations for 
these products (Sec.  211.180), to require that records be retained for 
at least 1 year after the expiration date of the product (proposed 
Sec.  500.200(c)(2)(ii)). Because all new animal drugs are required to 
have an expiration date, only the proposed 1-year records retention 
period would apply to all drugs for ruminants.
     For Type A medicated articles intended for use in 
ruminants, records would be retained, consistent with our CGMP 
regulations for these products (Sec.  226.110), for at least 2 years 
after distribution by the manufacturer (proposed Sec.  
500.200(c)(2)(i)).
     For human biological products, we reference 21 CFR 
600.12(b) for consistency with established recordkeeping periods. 
Records would be retained for no less than 5 years after the records of 
manufacture have been completed or 6 months after the latest expiration 
date for the individual product, whichever represents a later date 
(proposed Sec.  600.16(c)(2)).
     For medical devices that are intended for use in or on the 
body, we reference 21 CFR 820.180(b) for consistency with established 
recordkeeping periods. Records would be retained for a period of time 
equivalent to the design and expected life of the device, but in no 
case less than 2 years from the date of release for commercial 
distribution by the manufacturer (proposed Sec.  895.102(c)(2)).
     For HCT/Ps, we reference Sec.  1271.270(d) for consistency 
with established recordkeeping periods. Records would be retained for 
10 years after their creation unless otherwise stated in part 1271 
(proposed Sec.  1271.470(c)(2)).
    As discussed previously, records documenting the absence of 
prohibited cattle materials in medical products for humans and drugs 
for ruminants are needed to help applicants and manufacturers ensure 
that they meet the proposed requirements of this rulemaking and to help 
FDA monitor compliance. It is important for recall purposes that 
records be retained for the likely period of time during which the 
product might be used, so that FDA can assess compliance with the 
requirements for cause or otherwise. The proposed timeframes for 
retaining records reflect the likely period of time during which 
medical products for humans and drugs for ruminants covered by this 
proposed rule might be used. The proposed timeframes for retaining 
records are consistent with the relevant CGMP requirements in current 
rules. Because of the lengthy incubation period of BSE (see section 
II.C of this document), we are requesting comment on whether records 
should be required for a longer period of time than proposed in this 
rulemaking. This may assist with traceback and may assist applicants 
and manufacturers in proving that their products are not the source of 
BSE infection.
    In the Foods Recordkeeping/Access final rule, we require that 
records for FDA-regulated human food and cosmetics be retained for 2 
years after the date the records were created (21 CFR 189.5(c)(2) and 
21 CFR 700.27(c)(2)). FDA is requiring this

[[Page 1596]]

timeframe for these products so that the records will be available 
during the entire shelf life of the products covered by that rule.
3. Location of Records
    We are proposing that records be maintained at the applicant's or 
manufacturer's establishment or at a reasonably accessible location. 
Records would be considered to be reasonably accessible if they are 
accessible from an onsite location (proposed Sec. Sec.  300.200(c)(3), 
500.200(c)(3), 600.16(c)(3), 895.102(c)(3) and 1271.470(c)(3)). 
Electronic recordkeeping requirements for all types of FDA required 
recordkeeping are addressed under part 11 (21 CFR part 11). These 
requirements would pertain to any records that would be required by 
this proposed rule.
    Proposed Sec. Sec.  300.200(c)(4), 500.200(c)(4), 600.16(c)(4), 
895.102(c)(4) and 1271.470(c)(4) provide that records required by this 
subpart must be readily available to FDA for inspection and copying. 
All the records would be required to be in English.
    Because of inherent difficulties in accessing records maintained at 
foreign establishments, we are proposing requirements for importers of 
record of medical products for humans and drugs for ruminants (proposed 
Sec. Sec.  300.200(c)(5), 500.200(c)(5), 600.16(c)(5), 895.102(c)(5) 
and 1271.470(c)(5)). When filing entry with the U.S. Customs and Border 
Protection, importers of record of a product manufactured from or 
otherwise containing cattle material would be required to affirm that 
the product for import was manufactured from or otherwise contains 
cattle material and affirm that the product was manufactured in 
accordance with proposed Sec. Sec.  300.200(b), 500.200(b), 600.16(b), 
895.102(b) and 1271.470(b), as applicable. If the product was 
manufactured from or otherwise contains cattle material, then the 
importer of record would be required, if requested, to provide to FDA 
within 5 days records that would be sufficient to demonstrate that the 
product was not manufactured from and does not contain prohibited 
cattle material. FDA expects that the content of these records would be 
the same as that described as being sufficient for domestic products.
    FDA believes 5 days is a reasonable amount of time for the importer 
of record to respond while still allowing FDA sufficient time to review 
the documents to make an initial admissibility decision before the 
conditional release period for the product expires. If the importer of 
record fails to provide FDA with the records within 5 days, the product 
would be subject to detention because it would appear to be 
adulterated, and the owner or consignee would be afforded notice and an 
opportunity for hearing in accordance with section 801(a) of the act 
(21 U.S.C. 381).

VI. Legal Authority

    FDA has the authority to take the actions proposed in this rule 
under various statutory provisions. These provisions include sections 
201, 301, 501, 502, 505, 512, 516, 519, 701, 704, and 801(a) of the act 
(21 U.S.C. 321, 331, 351, 352, 355, 360b, 360f, 360i, 371, 374, and 
381(a)) and sections 351, 361, and 368 of the PHS Act (42 U.S.C. 262, 
264, and 271).
    With respect to drugs for humans, including drugs that are 
biological products, FDA is proposing these regulations under the 
adulteration provision in section 501(a)(2)(B) of the act, and under 
sections 201, 505, 701(a) and (b), 704, and 801(a) of the act.
    Under section 501(a)(2)(B) of the act, FDA has the authority to 
impose requirements necessary to ensure that drugs meet the 
requirements of the act with respect to identity, strength, quality, 
and purity. Under section 501(a)(2)(B) of the act, a drug is 
adulterated if: ``the methods used in, or the facilities and controls 
used for, its manufacture, processing, packing, or holding do not 
conform to or are not operated or administered in conformity with 
current good manufacturing practice to assure that such drug meets the 
requirements of this Act as to safety and has the identity and 
strength, and meets the quality and purity characteristics, which it 
purports or is represented to possess.''
    FDA is proposing to amend its CGMP regulations (proposed Sec.  
211.116) to prohibit the use of certain cattle materials in human drug 
products and components, including biological products, as provided by 
proposed Sec. Sec.  300.200 and 600.16. Proposed Sec. Sec.  300.200 and 
600.16 would require that no drug or biological product ``be 
manufactured from or otherwise contain prohibited cattle materials'' 
unless FDA has granted a request for an exception or alternative to the 
requirements. Proposed Sec.  211.116 would apply to drugs, including 
biological products, that are directly subject to the CGMP regulations. 
For drugs not directly subject to the CGMP regulations, such as active 
pharmaceutical ingredients and source materials, section 501(a)(2)(B) 
of the act supports the proposed requirements in Sec. Sec.  300.200 and 
600.16.
    As provided in proposed Sec. Sec.  300.200(d) and 600.16(d), a drug 
or biological product that fails to comply with the requirements of 
Sec. Sec.  300.200(b) and 600.16(b), respectively, would be adulterated 
under section 501(a)(2)(B) of the act. Because of the possibility of 
disease transmission to humans from exposure to prohibited cattle 
materials, prohibiting such cattle materials in drugs and biological 
products will help ensure that they meet the requirements of the act 
with respect to safety and have the identity, and meet the quality and 
purity characteristics they are purported or represented to possess.
    Section 201(p) of the act defines a new drug to include ``[a]ny 
drug *** the composition of which is such that such drug is not 
generally recognized, among experts qualified by scientific training 
and experience to evaluate the safety and effectiveness of drugs, as 
safe and effective for use under the conditions prescribed, 
recommended, or suggested in the labeling thereof ***.'' Based on the 
scientific data and information available to FDA regarding the 
possibility of disease transmission to humans from exposure to 
prohibited cattle materials, under this proposed rule any human drug 
manufactured from, or otherwise containing, prohibited cattle materials 
is not generally recognized as safe and effective (GRAS/GRAE), and 
therefore is a new drug under section 201(p) of the act.
    Section 505(a) of the act requires that ``[n]o person shall 
introduce or deliver for introduction into interstate commerce any new 
drug, unless an approval of an application filed pursuant to subsection 
(b) or (j) [of section 505] is effective with respect to such drug.'' 
Under section 505 of the act, new drug applications must demonstrate 
that a drug is safe and effective for its intended use(s). Because of 
the possibility of disease transmission to humans from exposure to 
prohibited cattle materials, prohibiting such cattle materials in drugs 
will help ensure that drugs are safe for their intended use(s). Based 
on the scientific data and information available to FDA regarding the 
possibility of disease transmission to humans from exposure to 
prohibited cattle materials, under this proposed rule FDA would not 
approve an application or supplement for a drug containing prohibited 
cattle materials unless an exception or alternative has been granted 
based upon the Center Director's determination that the safety standard 
in section 505 of the act would still be met. In addition, under the 
proposed rule, a drug containing prohibited cattle materials that is

[[Page 1597]]

already subject to an approval would no longer be shown to be safe 
based on the presence of prohibited cattle materials, and would be in 
violation of section 505 of the act unless an exception or alternative 
for use of the prohibited cattle materials has been granted. Section 
505 of the act also allows FDA to impose additional conditions on an 
application product on a case-by-case basis, should such conditions be 
necessary to ensure that the product meets the standard for approval 
set forth in section 505 of the act.
    Under section 701(a) of the act, FDA is authorized to issue 
regulations for the act's efficient enforcement. The proposed 
regulations would require measures to ensure that drugs for humans, 
including biologics, are being manufactured, processed, packed, or held 
in conformity with CGMP, and to ensure that new drugs comply with 
section 505 of the act, which would allow for efficient enforcement of 
the act. Under the proposed regulations, applicants and manufacturers 
of drugs for humans that are manufactured from or otherwise contain 
material from cattle also would be required to establish and maintain 
records that document the absence of prohibited cattle materials in 
such products and have such records readily available to FDA for 
inspection and copying. These proposed recordkeeping requirements are 
also authorized under sections 501(a)(2)(B) and 505(k) of the act.
    Once material is removed from cattle, we may not be able to obtain 
the information necessary to determine whether it is prohibited cattle 
material. For example, we would not know from examination of a spinal 
cord whether the source animal was 30 months of age or over at the time 
of slaughter, or whether it was inspected and passed. Because at this 
time there is no way to test reliably for the presence of the BSE agent 
or the presence of the cattle materials prohibited in proposed Sec.  
300.200, applicants and manufacturers of drugs for humans would have to 
depend on records from their suppliers of cattle materials to ensure 
that their source material does not contain any cattle materials 
prohibited under proposed Sec.  300.200. Without adequate records, FDA 
cannot know whether applicants and manufacturers of drugs for humans 
have complied with the prohibitions against certain cattle materials 
under proposed Sec.  300.200. Therefore, the proposed recordkeeping 
requirements are necessary for the efficient enforcement of these rules 
and authorized under section 701(a) of the act. Under proposed Sec.  
300.200(e) and 600.16(e), the failure of an applicant or manufacturer 
to comply with the requirements of Sec. Sec.  300.200(c) and 600.16(c), 
respectively, would render a drug or biological product adulterated.
    We are also proposing provisions relating to records regarding 
imported drugs for humans under sections 801(a) and 701(b) of the act. 
Importers of record of such a drug product manufactured from or 
otherwise containing cattle material would be required to affirm that 
such a drug product for import was manufactured from or contains cattle 
material, and affirm that it was manufactured in compliance with the 
proposed rule. If such a drug was manufactured from or otherwise 
contains cattle material, then importers of record would also be 
required, if requested, to provide records to FDA within 5 days 
sufficient to demonstrate compliance. Under proposed Sec. Sec.  
300.200(f) and 600.16(f), failure of an importer of record to comply 
with those requirements causes a drug for humans to appear to be 
adulterated.
    Section 801(a) of the act provides requirements with regard to 
imported drugs and provides for refusal of admission into the United 
States of drugs for humans that appear to be adulterated. Section 
701(b) of the act authorizes the Secretaries of Treasury\2\ and Health 
and Human Services to jointly prescribe regulations for the efficient 
enforcement of section 801 of the act.
---------------------------------------------------------------------------

    \2\Under the Homeland Security Act of 2002 (Public Law 107-296), 
the Secretary of the Treasury has delegated all relevant Customs 
revenue authorities to the Secretary of Homeland Security, who has, 
in turn, delegated them to the Commissioner of Customs and Border 
Protection (CBP or Customs). If finalized, we will issue this rule 
jointly with the Department of Homeland Security.
---------------------------------------------------------------------------

    Because most biological products, including blood, are also drugs, 
the sections of the act discussed previously provide legal authority 
for issuing a regulation limiting the use of prohibited cattle 
materials in such biological products. There is, however, additional 
legal authority for the proposed rule's requirements with respect to 
biological products generally. Section 351(a)(2)(A) of the PHS Act (42 
U.S.C. 262(a)(2)(A)) requires that FDA ``establish, by regulation, 
requirements for the approval, suspension, and revocation of biologics 
licenses.'' Approval of a biologics license application (BLA) must be 
based on a demonstration that the biological product is ``safe, pure, 
and potent'' (section 351(a)(2)(C)(i)(I) of the PHS Act). Limiting the 
use of prohibited cattle materials in biological products is designed 
to ensure the safety, purity, and potency of such licensed biological 
products. Based on the scientific data and information available to FDA 
regarding the possibility of disease transmission to humans from 
exposure to prohibited cattle materials, under the proposed rule FDA 
would not approve a BLA or supplement for a biological product 
containing prohibited cattle materials unless an exception or 
alternative has been granted based upon the Center Director's 
determination that the safety standard in section 351(a)(2)(C) of the 
PHS Act would still be met. In addition, under the proposed rule, a 
biological product containing prohibited cattle materials that is 
already licensed would no longer be demonstrated to be safe based on 
the presence of prohibited cattle materials, and would be in violation 
of section 351(a)(1) of the PHS Act and section 505 of the act, unless 
an exception or alternative for use of the prohibited cattle materials 
has been granted. Accordingly, FDA is proposing to amend its biological 
product regulations to prohibit the use of certain cattle materials in 
biological products as provided by proposed Sec.  600.16.
    With respect to devices, FDA is proposing to issue these 
regulations under the adulteration provision in section 501(g) of the 
act, under the misbranding provision in section 502(t) of the act, and 
under sections 516, 519(a), 701(a) and (b), and 801 of the act.
    Under section 516 of the act, FDA may issue a regulation making a 
device a banned device if the agency determines, on the basis of all 
available data and information, that a device presents an unreasonable 
and substantial risk of illness or injury that can not be corrected or 
eliminated by labeling. A banned device is deemed adulterated under 
section 501(g) of the act. There are several routes through which 
devices intended for use in or on the body have the potential to 
introduce the BSE agent into humans if the devices contain prohibited 
cattle materials. It is well documented that central nervous system 
tissue, including the optic nerve, carries infectivity in animals with 
TSEs and humans with vCJD. Infectivity has also been transmitted to 
animals via mucosal tissue. Finally, although transmission through 
intact skin is not likely, the BSE agent has the potential to be 
introduced into the body through cut or abraded skin. FDA has 
concluded, therefore, that devices intended for use in or on the body 
that contain prohibited cattle materials have the potential to expose 
recipients of those devices if the originating cattle had BSE. Although 
the

[[Page 1598]]

over all risk of exposure is low given the low rate of BSE in U.S. 
cattle, this risk is deemed unacceptable given the fatal nature of 
vCJD. The agency is not aware of any device that can be manufactured 
only with prohibited cattle materials; thus, there should be no benefit 
to the public health from the continued marketing of devices containing 
these materials. FDA has determined, therefore, that devices intended 
for use in or on the body that contain prohibited cattle materials 
present an unreasonable risk to health in relation to the benefit to 
the public health from their continued marketing. Moreover, because 
there is no safe way to use these devices, the risk of disease cannot 
be corrected or eliminated by labeling.
    It is clear, based on all available data and information, that the 
risk of BSE exposure may be significantly reduced by banning devices 
intended for use in or on the body that contain prohibited cattle 
materials. The agency is proposing to ban such devices, therefore, in 
accordance with section 516 of the act. Devices already in commercial 
distribution or already sold to the ultimate user are not subject to 
this ban because FDA is not aware of any currently marketed device that 
contains prohibited cattle materials. Manufacturers currently are not 
required to maintain records that contain information about bovine 
materials that would be needed to identify devices that might contain 
such materials. In accordance with section 516 of the act and 21 CFR 
part 895, interested persons may request an informal hearing on the 
provisions of the proposed regulation with respect to medical devices 
within 30 days. If a request for an informal hearing is granted, the 
hearing will be conducted as a regulatory hearing under 21 CFR part 16.
    The proposed recordkeeping requirements for devices in this 
proposed rule are authorized under section 519(a) of the act. Under 
section 519(a), the agency may, by regulation, require that 
manufacturers and importers establish and maintain records, make 
reports, and provide information that the agency determines is 
necessary to ensure that devices are not adulterated or misbranded and 
to otherwise ensure their safety and effectiveness. FDA has determined 
that the recordkeeping requirements in this proposed rule are necessary 
to ensure that devices intended for use in or on the body do not 
contain prohibited cattle materials and, thus, are not adulterated 
under section 501(g) of the act. A device for which there is a failure 
or refusal to furnish any material or information required under this 
proposed regulation would be deemed misbranded under section 502(t) of 
the act.
    The proposed recordkeeping requirements are also authorized under 
sections 701(a) and (b) and 801(a) of the act. Because at this time 
there is no way to screen reliably for the presence of the BSE agent or 
the presence of the cattle materials prohibited under this proposed 
rule, applicants and manufacturers of medical devices would have to 
depend on records from their suppliers of cattle materials to ensure 
that their source material does not contain any prohibited cattle 
materials. The proposed requirements also would allow the agency to 
monitor compliance with the proposed ban and, therefore, are necessary 
for the efficient enforcement of the act, in accordance with section 
701(a) of the act. Section 801(a) of the act contains requirements with 
regard to imported devices and provides for refusal of admission into 
the United States of devices that appear to be adulterated or 
misbranded. Section 701(b) of the act authorizes the Secretaries of the 
Treasury and Health and Human Services to jointly prescribe regulations 
for the efficient enforcement of section 801 of the act.
    With respect to new animal drugs, FDA is proposing to issue these 
regulations under the adulteration provision in section 501(a)(2)(B) of 
the act and sections 512, 701(a) and (b) and 801(a) of the act. The 
adulteration provision in section 501(a)(2)(B) of the act provides FDA 
the same authority for new animal drugs as described for drugs for 
humans previously in this document.
    FDA is proposing to amend its CGMP regulations to prohibit the use 
of certain cattle materials in drug products and components intended 
for use in ruminant animals (proposed Sec.  211.116). Proposed Sec.  
500.200 would require that no drug product or component intended for 
use in ruminants ``be manufactured from or otherwise contain prohibited 
cattle materials.'' Proposed Sec.  211.116 would apply to drugs that 
are directly subject to the CGMP regulations. For drugs for ruminants 
that are not directly subject to the CGMP regulations, section 
501(a)(2)(B) of the act supports the proposed requirements in proposed 
Sec.  500.200.
    As provided in proposed Sec.  500.200(d), a drug that fails to 
comply with the requirements of Sec.  500.200(b) would be adulterated 
under section 501(a)(2)(B) of the act. Because of the possibility of 
disease transmission to ruminants from exposure to prohibited cattle 
materials and to humans from consuming food from animals exposed to 
prohibited cattle material, prohibiting such cattle materials in drugs 
for ruminants would help ensure that new animal drugs for ruminants 
meet the requirements of the act with respect to safety, and have the 
identity, and meet the quality and purity characteristics they are 
purported or represented to possess.
    Section 201(v) of the act defines a new animal drug to include 
``[a]ny drug intended for use for animals other than man *** the 
composition of which is such that such drug is not generally 
recognized, among experts qualified by scientific training and 
experience to evaluate the safety and effectiveness of animal drugs, as 
safe and effective for use under the conditions prescribed, 
recommended, or suggested in the labeling thereof ***.'' Based on the 
scientific data and information available to FDA regarding the 
possibility of disease transmission to ruminants from exposure to 
prohibited cattle materials, under this proposed rule any drug for 
ruminants manufactured from or otherwise containing prohibited cattle 
materials is not GRAS/GRAE, and therefore is a new animal drug under 
section 201(v) of the act.
    Section 512 of the act provides that a new animal drug is unsafe 
for purposes of the adulteration provisions in section 501(a)(5) and 
section 402(a)(2)(C)(ii) of the act (21 U.S.C. 342(a)(2)(c)(ii)) unless 
there is an approval of that new animal drug application in effect. For 
a new animal drug application to be approved, the drug must be safe and 
effective for its intended use(s). Based on the scientific data and 
information available to FDA regarding the possibility of disease 
transmission to humans from exposure to prohibited cattle materials, 
under the proposed rule FDA would not approve an application or 
supplement for a drug for ruminants containing prohibited cattle 
materials unless an exception or alternative has been granted based 
upon the Center Director's determination that the safety standard in 
section 512 of the act would still be met. In addition, under the 
proposed rule, a drug for ruminants containing prohibited cattle 
materials that is already subject to an approval would no longer be 
shown to be safe based on the presence of prohibited cattle materials, 
and would be in violation of section 512 of the act unless an exception 
or alternative for use of the prohibited cattle materials has been 
granted.
    Under section 512(a)(4) and section (a)(5) of the act, extralabel 
use of an approved animal drug or human drug in animals is authorized 
if done under certain conditions set out in FDA

[[Page 1599]]

regulations. However, section 512(a)(4)(A) of the act also allows FDA 
to prohibit particular extralabel uses of an approved new animal drug. 
Thus, for example, a drug approved for use in treating an animal of a 
nonruminant species could legally be used extralabelly to treat a 
ruminant animal, if it meets required conditions, unless specifically 
prohibited. Such drugs for nonruminant animals are allowed to contain 
cattle materials prohibited from use in drugs for ruminants. Absent a 
special prohibition, these drugs also could be used in ruminants, 
through extralabel use, thereby providing an avenue through which 
ruminants could be exposed to prohibited cattle material. Any human 
drug for which an exception or alternative is granted could also be 
used extralabelly in ruminants, which could also provide another avenue 
through which ruminants could be exposed to prohibited cattle 
materials. Therefore, under section 512(a)(4)(A) of the act (for drugs 
for animals) and section 512(a)(5) of the act (for drugs for humans), 
FDA is proposing to prohibit such extralabel use in ruminants of drugs 
for nonruminants or for humans containing the prohibited material.
    FDA is issuing the proposed labeling requirement under sections 
502(a) and 201(n) of the act (21 U.S.C. 352(a) and 321(n)). Section 
502(a) provides that a drug is deemed misbranded if its labeling is 
false or misleading in any particular. Section 201(n) provides that 
``*** in determining whether the labeling *** is misleading, there 
shall be taken into account (among other things) not only 
representations made or suggested by statement, word, design, device, 
or any combination thereof, but also the extent to which the labeling 
*** fails to reveal facts material in the light of such representations 
or material with respect to consequences which may result from the use 
of the article to which the labeling *** relates under the conditions 
of use *** as are customary or usual.'' The proposed rule would require 
drugs for non-ruminants that contain prohibited materials that are 
prohibited from extralabel use in ruminants to be labeled ``Federal law 
prohibits the extralabel use of this product in ruminants.'' We believe 
this statement is material with respect to the consequences that may 
result from the extralabel use of nonruminant drugs with prohibited 
materials in ruminants. As discussed in other sections of this 
preamble, the use of materials prohibited in drugs for ruminants 
presents a risk of BSE. Therefore, under this proposed rule, the 
failure to include the labeling statement on drugs for nonruminants 
which contain prohibited materials would render the drugs misbranded 
under section 502(a) of the act. Under section 701(a) of the act, FDA 
is authorized to issue regulations for the act's efficient enforcement. 
Regulations that propose measures to ensure that drugs for animals are 
being manufactured, processed, packed, or held in conformity with CGMP, 
and to ensure that they comply with section 512 of the act, allow for 
efficient enforcement of the act. These proposed regulations would 
require applicants and manufacturers of drugs for ruminants that are 
manufactured from or otherwise contain material from cattle to 
establish and maintain records that document the absence of prohibited 
cattle materials in such products and make such records readily 
available to FDA for inspection and copying. These proposed 
recordkeeping requirements are also authorized under sections 
501(a)(2)(B) and 512(l) of the act.
    Once material is removed from cattle, we may not be able to obtain 
the information necessary to determine whether it is prohibited cattle 
material. As noted previously, we would not know from examination of a 
spinal cord whether the source animal was over 30 months of age at the 
time of slaughter or whether it was inspected and passed. Because at 
this time there is no way to test reliably for the presence of the BSE 
agent or the presence of the cattle materials prohibited in proposed 
Sec.  500.200, applicants and manufacturers of drugs for ruminants must 
depend on records from their suppliers of cattle materials to ensure 
that their source material does not contain any cattle materials 
prohibited under proposed Sec.  500.200. Therefore, the proposed 
recordkeeping requirements are necessary for the efficient enforcement 
of the proposed rule. Under proposed Sec.  500.200(e), the failure of 
an applicant or manufacturer to comply with the requirements of Sec.  
500.200(c) would render a drug for ruminants adulterated.
    We are also proposing provisions relating to records regarding 
imported drugs for ruminants under sections 801(a) and 701(b) of the 
act. Importers of record of a drug for ruminants that was manufactured 
from or otherwise contains cattle material would be required to affirm 
that the drug product for import was manufactured from or contains 
cattle material, and affirm that it was manufactured in compliance with 
the proposed rule. If a drug was manufactured from or otherwise 
contains cattle material, then importers of record would also be 
required, if requested, to provide records to FDA within 5 days 
sufficient to demonstrate compliance. Under proposed Sec.  500.200(f), 
failure of an importer of record to comply with these requirements 
causes a drug to appear to be adulterated. Section 801(a) of the act 
provides requirements with regard to imported drugs and provides for 
refusal of admission into the United States of drugs for ruminants that 
appear to be adulterated. Section 701(b) of the act authorizes the 
Secretaries of Treasury\3\ and Health and Human Services to jointly 
prescribe regulations for the efficient enforcement of section 801 of 
the act.
---------------------------------------------------------------------------

    \3\Under the Homeland Security Act of 2002 (Public Law 107-296), 
the Secretary of the Treasury has delegated all relevant Customs 
revenue authorities to the Secretary of Homeland Security, who has, 
in turn, delegated them to the Commissioner of Customs and Border 
Protection (CBP or Customs). If finalized, we will issue this rule 
jointly with the Department of Homeland Security.
---------------------------------------------------------------------------

    FDA has invoked section 361 of the PHS Act (42 U.S.C. 264) to 
prevent the transmission of numerous communicable diseases, including 
diseases spread through certain shellfish, turtles, birds, and human 
tissue intended for transplantation (see 21 CFR 1240.60 (molluscan 
shellfish), 1240.62 (turtles), 1240.65 (parrots and other psittacine 
birds), and parts 1270 and 1271 (human tissue)). Recently, FDA also 
issued under section 361 of the PHS Act regulations designed to prevent 
the spread of monkeypox from African rodents to humans (21 CFR 
1240.63).
    Section 361 of the PHS Act provides legal authority for FDA to 
limit the use of prohibited cattle materials in drugs, biological 
products, devices, new animal drugs for ruminants, and HCT/Ps and to 
inspect and copy pertinent manufacturing records to ensure compliance. 
Section 361(a) of the PHS Act authorizes issuance and enforcement of 
regulations necessary to prevent the introduction, transmission, or 
spread of communicable diseases from foreign countries or between 
states. Section 361(a) of the PHS Act also provides for such inspection 
and destruction of articles found to be so infected or contaminated as 
to be ``sources of dangerous infection to human beings,'' as well as 
other measures that may be necessary to prevent the introduction, 
transmission, or spread of communicable diseases from a foreign country 
into a State, or from one State to another State.
    Because the use of prohibited cattle materials in medical products 
for humans and drugs for ruminants increases the risk that the agent 
that

[[Page 1600]]

causes BSE could be transmitted to humans, limiting the use of 
prohibited cattle materials in medical products for humans and drugs 
for ruminants is a needed component of our efforts to prevent the 
transmission and spread of TSEs including vCJD, in humans. Scientists 
have concluded that exposure to the BSE agent is the most plausible 
explanation for the occurrence of vCJD (Refs. 24 through 27). For 
medical products for humans, by prohibiting use of certain cattle 
materials, the proposed rule would reduce the risk that the BSE agent 
would be transmitted directly into any person through exposure to an 
infectious medical product. For drugs for ruminants, by prohibiting use 
of certain cattle materials, the proposed rule would reduce the risk 
that the BSE agent would be transmitted directly into any ruminant. By 
protecting ruminants from exposure to the BSE agent through animal 
drugs, the proposed rule would also prevent transmission of the BSE 
agent to humans who may be exposed to products containing any ruminant 
materials. Consistent with the authority granted by section 361 of the 
PHS Act to issue and enforce such regulations as are necessary to 
prevent communicable disease transmission from foreign countries into 
the United States and from one State or possession into another, this 
proposed rule would provide for FDA to be able to inspect and copy 
pertinent manufacturing records. Because at this time there is no way 
to screen reliably for the presence of the BSE agent or the presence of 
the cattle materials prohibited under this proposed rule, the 
requirements with respect to the maintenance, inspection, and copying 
of manufacturing records are directly necessary to permit FDA to 
enforce the other measures designed to prevent transmission of BSE.
    The proposed rule contains a procedure under which FDA could permit 
a manufacturer an exception or alternative to the restrictions on the 
use of prohibited cattle materials under limited circumstances. 
Specifically, a manufacturer would submit a written request for an 
exception or alternative to the requirements by describing: (1) Why an 
exception or alternative is needed; (2) the implicated product, 
including the type of prohibited cattle material, its manufacturing and 
purification processes, and its route of administration; (3) the source 
of the prohibited cattle material including information on the location 
where the cattle was born, raised, and slaughtered; and (4) any other 
information relevant to the likelihood of the cattle having ingested 
material prohibited under Sec.  589.2000. For medical products for 
humans, the written request also would include: (1) How the limitations 
are not necessary based on the risks of the prohibited cattle materials 
in the product and the benefits of the product or (2) how such 
restrictions are not necessary to ensure the safety of the product. For 
drugs for ruminants, the written request would also include: (1) How 
the requirement is not necessary: (i) Based on the risks of the 
prohibited cattle materials in the product to the target animal and the 
benefits of the product to the target animal and (ii) to ensure a 
reasonable certainty of no harm to humans from any food derived from 
the target animal to which the product is administered, or (2) how the 
requirement is not necessary to ensure the safety of the product with 
respect to both the target animal and any food derived from the target 
animal to which the product is administered. The relevant Center 
Director could also grant written permission for an exception or 
alternative to the proposed requirements on his own initiative, based 
on these same criteria.
    As discussed previously, under this proposal, FDA expects that 
applicants or manufacturers may submit a request for an exception or 
alternative when filing a new application or premarket notification for 
a product containing prohibited cattle materials, or if an existing 
product contains prohibited cattle materials. Although FDA believes it 
is unlikely that applicants or manufacturers who currently are not 
using prohibited cattle materials in their products will reformulate 
their products to include prohibited cattle materials, proposing to do 
so would require not only a request for an exception or alternative but 
also a supplement to the approved application or a new premarket 
notification, consistent with existing regulations.
    In considering whether an exception or alternative to requirements 
of this proposed rule would meet the criteria described previously and 
therefore be appropriate, FDA would be required to ensure that the 
statutory safety standards would still be met if the exception or 
alternative were permitted. For drugs for humans, FDA intends to apply 
the safety standards set forth in sections 501(a)(2)(B) and 505 of the 
act. Specifically, FDA would only approve a request for an exception or 
alternative to the proposed limitations on prohibited cattle material 
if, notwithstanding the exception or alternative: (1) The drug and the 
methods used in, or the facilities or controls used for, its 
manufacturing, processing, packing, or holding conform to or are 
operated or administered in conformity with CGMP to ensure that such 
drug meets the requirements of the act as to safety and (2) the drug is 
safe for its intended use(s).
    For biological products, FDA intends to apply the safety standard 
provided in section 351 of the PHS Act. Specifically, FDA would only 
approve a request for an exception or alternative to the proposed 
limitations on prohibited cattle material if, notwithstanding the 
exception or alternative: (1) The biological product that is the 
subject of the application is safe and (2) the facility in which the 
biological product is manufactured, processed, packed, or held meets 
standards designed to ensure that the biological product continues to 
be safe.
    For human cells, tissues, and cellular and tissue-based products 
and other products regulated under the authority of section 361 of the 
PHS Act, FDA would only approve a request for an exception or 
alternative to the proposed limitations on prohibited cattle material 
if such limitations are not necessary to prevent the introduction, 
transmission, or spread of TSE.
    For devices, FDA intends to apply the standard in section 516 of 
the act. Specifically, FDA would approve a request for an exception or 
alternative to the proposed ban on prohibited cattle materials only if, 
notwithstanding the exception or alternative, the device does not 
present an unreasonable and substantial risk of illness or injury.
    For new animal drugs, FDA intends to apply the safety standards set 
forth in section 512 and 501(a)(2)(B) of the act. Specifically, FDA 
would approve a request for an exception or alternative to the proposed 
limitations on prohibited cattle material only if, notwithstanding the 
exception or alternative: (1) The drug and the methods used in, or the 
facilities or controls used for, its manufacturing, processing, 
packing, or holding conform to or are operated or administered in 
conformity with CGMP to ensure that such drug meets the requirements of 
the act as to safety and (2) the drug is safe for its intended use(s).

VII. Effective Date and Opportunity for Public Comment

    We are proposing that any final rule based on this proposal be 
effective 30 days after its issuance in the Federal Register.
    Requests for an informal hearing on the proposed ban related to 
medical devices must be submitted by (see DATES).
    FDA invites public comment on this proposed rule, including the 
proposed

[[Page 1601]]

effective date for any final rule issued as a result of this proposal. 
The comment period on this proposed rule will be 60 days. The agency 
will consider modifications to this proposed rule based on comments 
made during the comment period. Interested persons may submit to the 
Division of Dockets Management (see ADDRESSES) written or electronic 
comments regarding this proposed rule. Submit a single copy of 
electronic comments or two paper copies of any mailed comments, except 
that individuals may submit one paper 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 Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

VIII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is not an economically significant regulatory action 
as defined by the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because FDA has taken regulatory action to reduce 
the risk of exposure to BSE in the United States and kept affected 
entities informed on best practices, FDA believes the proposed rule 
would codify current practices of most affected entities and ensure 
regulatory consistency across FDA-regulated products. Few entities will 
need to reformulate with alternative ingredients, submit a request for 
exception or alternative to the limitation on the use of prohibited 
cattle material, or cease marketing. The FDA believes most market 
adjustments have taken place and this rule will not have a significant 
economic impact on a substantial number of small entities. A few 
manufacturers of certain drugs prohibited from extralabel use in 
ruminants would incur one-time costs to add a warning statement to the 
product labeling. In addition, all manufacturers that use cattle 
material would incur minor annual incremental recordkeeping costs. Over 
10 years, the annualized costs of the proposed rule range from about 
$235,000 to $922,000 (at a 3 percent discount rate) and from about 
$235,000 to $923,000 (at a 7 percent discount rate).
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $122 million, using the most current (2005) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
rule to result in any 1-year expenditure that would meet or exceed this 
amount.

A. Need for the Proposed Rule

    The need for this rule stems from inadequate information. 
Consumers, physicians, farmers, and veterinarians lack the information 
necessary to determine whether medical products for humans or drugs for 
ruminants have the potential to contain materials contaminated with the 
agent that causes BSE.
    Currently, no validated method exists for testing medical products 
for humans and drugs for ruminants for the agent that causes BSE; 
therefore, we do not have a means of distinguishing products that 
contain infectious material from products that do not. For example, 
rendered material including brain and spinal cord may become an 
ingredient in medical products for humans or drugs for ruminants even 
though its presence may not be indicated as such on the label. 
Furthermore, end users have no way to determine whether cattle material 
in these products was sourced from nonambulatory disabled cattle or 
from cattle that were not inspected and passed for human consumption.
    Based on what is known about the transmission of BSE, there is some 
risk of occurrence of vCJD in humans or of BSE in ruminants from the 
use of certain cattle-derived materials in medical products for humans 
and drugs for ruminants, respectively. While the results from USDA's 
ongoing testing\4\ are reassuring, one cannot rule out the possible 
future discovery of other positive animals in the United States or in a 
country allowed to export cattle material to the United States, or of a 
future introduction of BSE. To provide consistent protection across the 
range of FDA-regulated products, it is necessary to put in place 
measures to reduce further the risk of spread of BSE in cattle and the 
risk of vCJD in humans. This risk may be reduced by restricting the use 
of high-risk cattle materials in the manufacture of drugs for ruminants 
and medical products for humans, similar to existing restrictions for 
food and cosmetics.
---------------------------------------------------------------------------

    \4\USDA began a BSE testing program for cattle on June 1, 2004, 
after discovery of a case of BSE in a cow in Washington State on 
December 23, 2003.
---------------------------------------------------------------------------

    As discussed in section IV of this document, for over a decade the 
FDA has taken various actions to reduce the risk of exposure to BSE in 
agency-regulated medical products for humans and drugs for ruminants, 
including: (1) Providing information (through letters to 
manufacturers), import alerts, and guidances to industry related to 
bovine materials, (2) convening TSE advisory committee meetings to 
provide guidance on the sourcing of certain bovine products, including 
gelatin, (3) encouraging companies to be aware of and to document 
sourcing of bovine material through letters to manufacturers of drugs, 
biologics, and medical devices, and through the product approval 
processes, and (4) recommending that manufacturers develop plans to 
ensure, with a high degree of certainty, that bovine and ovine 
materials used in their products were not from countries where BSE 
exists (``BSE countries'' specified by USDA's APHIS in 9 CFR 94.18) or 
from sheep flocks (foreign or domestic) infected with scrapie. 
Moreover, manufacturers who also operate in Europe have taken steps to 
comply with European Union TSE regulations and guidances. The agency 
has also taken regulatory action to decrease the likelihood of human 
and ruminant exposure to BSE (e.g., FDA 1997 ruminant feed rule, FDA/
USDA Animal Feed ANPRM, FDA 2005 Animal Feed proposed rule, Foods IFR, 
and Foods Recordkeeping/Access final rule).
    The agency is proposing additional regulatory action with this rule 
for medical products for humans and drugs for ruminants that contain 
certain cattle material. Existing regulations do not explicitly bar the 
use of prohibited cattle material for these products. By requiring that 
no medical product for humans or drug for ruminants be manufactured 
from or otherwise contain prohibited cattle materials, this proposed 
rule adds another safeguard to minimize human and ruminant

[[Page 1602]]

exposure to cattle material that scientific studies have demonstrated 
could contain the BSE agent. This proposed rule is consistent with 
interim final rules issued by the USDA (USDA/FSIS IFR) and FDA (Foods 
IFR) that exclude certain cattle material from human food, including 
dietary supplements, and cosmetics.

B. Scope of the Proposed Rule

    Both the USDA/FSIS and Foods IFRs define SRMs as: (1) Brain, skull, 
eyes, trigeminal ganglia, spinal cord, vertebral column (excluding the 
vertebrae of the tail, the transverse process of the thoracic and 
lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia 
of cattle 30 months and older, and (2) the tonsils and distal ileum of 
the small intestine of all cattle. The USDA/FSIS IFR: (1) Declares 
SRMs, mechanically separated beef, and the carcasses and parts of 
nonambulatory disabled cattle to be inedible and unfit for human food, 
and prohibits their use in human food and (2) requires that the entire 
small intestine of all cattle be removed and disposed of as inedible if 
procedures that completely remove the distal ileum are not used. The 
Foods IFR limits the use of prohibited cattle materials in FDA-
regulated human food, including dietary supplements, and cosmetics. 
Prohibited cattle material includes: (1) All materials declared 
inedible by the USDA/FSIS IFR and (2) material from cattle not 
inspected and passed for human consumption. However, prohibited cattle 
materials do not include tallow that contains no more than 0.15 percent 
insoluble impurities, tallow derivatives, hides and hide-derived 
products, and milk and milk products.
    This proposed rule would define SRMs consistent with both the USDA/
FSIS and Foods IFRs and would define prohibited cattle materials 
consistent with the Foods IFR. The proposed rule would also clarify for 
medical products for humans and drugs for ruminants that prohibited 
cattle materials do not include materials obtained from fetal calves of 
cows that were inspected and passed, as long as the materials were 
obtained from suppliers who follow procedures adequate to prevent 
contamination with SRMs.
    Current industry practices and full compliance with the USDA/FSIS 
and Foods IFRs serve as the baseline for this proposed rule. As 
discussed in section IV of this document, the agency has taken various 
actions over 10 years to reduce the risk of exposure to the agent that 
causes BSE in FDA-regulated products. We believe that most affected 
manufacturers have taken steps to address FDA's existing 
recommendations regarding the use of cattle material in FDA-regulated 
products. Because medical products for humans and drugs for ruminants 
normally use edible cattle material, we assume that the prohibited 
materials are not widely used in the manufacture and processing of 
these FDA-regulated products. By determining that medical products for 
humans and drugs for ruminants manufactured from, or otherwise 
containing, prohibited cattle materials violate the act and the PHS 
act, this proposed rule would clarify FDA's ability to bar the use of 
prohibited cattle materials in medical products for humans and drugs 
for ruminants that would be outside the scope of other BSE regulations.

C. Costs of the Proposed Rule

    We assume that the recent USDA/FSIS and Foods IFRs have already led 
to most market adjustments regarding prohibited cattle materials. The 
manufacturers of products currently using materials from the brain, 
skull, eyes, trigeminal ganglia, spinal cord, vertebral column 
(excluding the vertebrae of the tail, the transverse process of the 
thoracic and lumbar vertebrae, and the wings of the sacrum), and dorsal 
root ganglia of cattle would presumably be able to continue to use 
these ingredients, but exclusively from cattle younger than 30 months 
of age. However, if manufacturers use cattle tonsils, the distal ileum 
of small intestine of cattle, or mechanically separated beef in the 
manufacture of medical products for humans or drugs for ruminants, they 
would need to reformulate with alternative ingredients, submit a 
request for exception or alternative to the requirements of the 
proposed rule, or cease marketing the products.
1. Potential Market Adjustments
    To the best of our knowledge, there are only a small number of 
manufacturers with drugs that do not have FDA approval (such as 
homeopathic drugs) that may be using prohibited cattle material. We 
believe the recent USDA/FSIS and Foods IFRs may have led any existing 
manufacturers to find substitutes for prohibited materials. The agency 
requests information about the impact of the proposed rule on 
manufacturers or importers of record of drugs that are marketed without 
an approved application for any reason.
2. Cost of Requests for Exceptions or Alternatives to the Limitation on 
the Use of Prohibited Cattle Material
    We estimate that very few firms would submit requests for 
exceptions or alternatives to the proposed rule's requirements. We 
estimate that those that do would spend between 60 hours and 120 hours 
to prepare and submit requests for exceptions or alternatives to the 
limitation on the use of prohibited cattle material. With an average 
loaded wage of $41.50, including 33 percent for benefits ($31.16 x 
1.33), each request would cost from $2,500 to $5,000 (source: Bureau of 
Labor Statistics (BLS) National Compensation Survey: Occupational Wages 
in the United States, July 2002, for executive, administrative, and 
managerial employees). Under this proposed rule, we estimate industry 
would submit three requests in the first year. Depending on the time 
needed to prepare and submit the request, first-year costs could range 
from $7,500 to $15,000. Moreover, as markets adjust further, we expect 
manufacturers would seek and obtain alternatives to prohibited cattle 
material, eliminating the need for future requests for exceptions or 
alternatives to the requirements of the proposed rule.
3. Cost of Substitutes
    Since the USDA/FSIS and Foods IFRs bar prohibited cattle material 
from edible rendering (i.e., processing of edible cattle waste material 
into marketable products such as gelatin or tallow), manufacturers of 
FDA-regulated human medical products for humans and drugs for ruminants 
using rendered material could continue to use edible rendered products.
    Some companies may need to find substitutes for other prohibited 
cattle material used in the manufacture of medical products for humans 
or drugs for ruminants. Agency records suggest that, because adequate 
substitutes exist, it is unlikely that the proposed rule would 
adversely affect markets. Nevertheless, we request comment from 
affected manufacturers about the costs and extent of substitution.
4. Recordkeeping Requirements of the Proposed Rule
    The USDA/FSIS IFR and the Foods IFR may affect the availability of 
prohibited cattle materials, but would not ensure that FDA-regulated 
medical products for humans or drugs for ruminants are free of 
prohibited cattle materials. Because at this time there is no way to 
screen reliably for the presence of the BSE agent or for the

[[Page 1603]]

presence of cattle materials prohibited under this proposed rule, 
applicants and manufacturers would have to depend on records from their 
suppliers of cattle materials to ensure that their source material does 
not contain any cattle materials prohibited under this proposal. In 
addition, the agency must be able to determine whether prohibited 
cattle materials are used in the products it regulates. Without 
records, FDA may not be able to determine the inspectional status or 
age of the source animal once cattle material is separated from its 
source. The proposed rule would require that applicants and 
manufacturers using cattle material establish and maintain records. 
Records must be kept at the manufacturing or processing establishment 
or another reasonably accessible location, and the agency's inspectors 
must have access to these records.
    The agency also proposes that importers of record of a medical 
product for humans or drug for ruminants that was manufactured from or 
otherwise contains cattle material affirm that the product was 
manufactured from or otherwise contained cattle material and affirm 
that the product was manufactured in accordance with the requirements 
in this proposed rule. Upon agency request, importers of record of 
affected products would provide to FDA within 5 days records that are 
sufficient to demonstrate compliance.
    a. Number of affected establishments. The proposed rule is expected 
to affect all establishments with medical products for humans or drugs 
for ruminants that are manufactured from, or otherwise contain cattle 
materials. According to 2002 Economic Census data, up to 6,195 
establishments manufactured affected products. In addition, for the 
current good tissue practice (CGTP) final rule, the agency estimated 
there are about 1,300 HCT/P establishments, most of which would be 
considered small (69 FR 68612 at 68654 and 68674).
    FDA has developed an automated system, the Operational and 
Administrative System for Import Support (OASIS), to process shipments 
of foreign products. According to a preliminary examination of OASIS 
data from fiscal year 2005, approximately 3,800 unique filers requested 
entry of FDA-regulated products into the United States. We believe, 
however, that the actual number of affected filers would be less than 
this number because some companies may specialize in imports of 
products such as food, dietary supplements or cosmetics that are 
outside the scope of this proposed rule. Nevertheless, for this 
analysis we assume that all filers identified by OASIS could be 
affected by the proposed requirements for importers of record.
    As shown in table 1 of this document, about 1,280 manufacturing 
establishments and 3,800 importers of record could be affected by the 
recordkeeping requirements. The agency seeks comment on these estimates 
from affected entities. In addition, although we believe the Foods 
Recordkeeping/Access final rule accounts for the recordkeeping burden 
to domestic and foreign suppliers, the agency requests comment from 
firms supplying cattle material to manufacturers of medical products 
for humans or drugs for ruminants about any additional burden that may 
be imposed by the recordkeeping requirements of this proposed rule.

                                                  Table 1.--Estimated Number of Affected Establishments
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Estimated Percentage of
  North American Industry Classification Scheme      Total Number of      Establishments Using   Estimated Number of Affected  Percent of Establishments
                  (NAICS) Code                      Establishments\1\      Cattle Material\2\           Establishments            Considered Small\3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
325411--medicinal & botanical manufacturing                        367                       75                           275                         98
--------------------------------------------------------------------------------------------------------------------------------------------------------
325412--pharmaceutical preparation                                 901                       75                           674                         91
 manufacturing\4\
--------------------------------------------------------------------------------------------------------------------------------------------------------
325414--biological product manufacturing\5\                        296                       85                           253                         96
--------------------------------------------------------------------------------------------------------------------------------------------------------
339112, 339113, 339114, 339115--medical devices                  4,631                     0.25                            12                         98
--------------------------------------------------------------------------------------------------------------------------------------------------------
621991--HCT/P\6\                                                 1,302                        5                            65                         66
--------------------------------------------------------------------------------------------------------------------------------------------------------
Subtotal                                                         7,497                       --                         1,278                         92
--------------------------------------------------------------------------------------------------------------------------------------------------------
Importers of record\7\                                           3,787                  unknown                         3,787                    unknown
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                           11,284  .......................                         5,065  .........................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Source: NAICS 325411, 325412, 325414, 339112, 339113, 339114, and 339115, table 4 of the 2002 Economic Census, Manufacturing, Industry Series; NAICS
  621991, table 3 in 69 FR 68612 at 68654. Number of importers of record estimated from FDA's OASIS data for FY 2005.
\2\Percentages are based on FDA's knowledge of products containing cattle material. We assume equal distribution of affected products across all
  establishments.
\3\ The SBA considers entities small if they have less than: (1) 750 employees for NAICS 325411 and 325412, (2) 500 employees for NAICS 32514, 339112,
  339113, 339114, and 339115, or (3) $9.0 million in revenues or receipts for NAICS 621991. Because the Economic Census uses different size categories
  than SBA, this analysis treats establishments in NAICS 325411 and 325412 with less than 999 employees as small. The agency previously estimated that
  about 66 percent of establishments in NAICS 621991 are small (table 14 in 69 FR 68612 at 68674).
\4\ We assume that cattle materials are used by 70 percent of establishments primarily manufacturing products for veterinary use and 75 percent of
  establishments primarily manufacturing products for human use. Source for the total number of establishments and the number of establishments
  manufacturing each primary product class: Tables 4 and 5 of the 2002 Economic Census, Manufacturing, Industry Series, EC02-311-325412.

[[Page 1604]]

 
\5\ We assume that cattle materials are used by 70 percent of establishments primarily manufacturing products for veterinary use and 90 percent of
  establishments primarily manufacturing products for human use. Source for the total number of establishments and the number of establishments
  manufacturing each primary product class: Tables 4 and 5 of the 2002 Economic Census, Manufacturing, Industry Series, EC02-311-325412.
\6\ We assume that from 1 to 5 percent of establishments use cattle materials.
\7\ Based on FY 2005 data in OASIS; equals the total number of unique filers for all FDA-regulated products.

    b. Recordkeeping costs. Manufacturers of medical products for 
humans and drugs for ruminants would need to establish and maintain 
appropriate records that document the absence of prohibited cattle 
materials in their products. This would require that manufacturers 
verify and maintain records from suppliers of any material derived from 
cattle. In addition, when filing an entry with the U.S. Customs and 
Border Protection, importers of record of affected products would be 
required to affirm that the product was manufactured from or otherwise 
contains cattle material and affirm that the product was manufactured 
in accordance with the proposed provisions. If a product was 
manufactured from, or otherwise contains, cattle material, then 
importers of record would also be required, if requested, to provide 
within 5 days records sufficient to demonstrate that the product was 
not manufactured from and does not contain prohibited cattle material.
    As noted previously, we believe that most entities have taken steps 
to address the sources of cattle materials. Moreover, the CGMP and CGTP 
regulations covering medical products for humans and drugs for 
ruminants require that procedures be in place for purchasing controls. 
We believe, however, that some affected manufacturers currently may not 
keep adequate records and might incur minor incremental recordkeeping 
costs. For this analysis, therefore, we assume that, on average, all 
affected small manufacturers may spend slightly more than 1 hour 
annually to maintain records. Similarly, we assume that, on average, 
all affected large manufacturers may spend slightly less than 3 hours 
annually to maintain records. With a loaded wage rate of $33.00 
(source: Bureau of Labor Statistics (BLS) National Compensation Survey: 
Occupational Wages in the United States, July 2002, adding 33 percent 
overhead for a computer programmer), small and large manufacturers 
might incur about $45 and $90, respectively, to ensure full compliance 
with the requirements to establish and maintain records.
    This rule would require importers of record of affected products to 
affirm that the product was manufactured from or otherwise contains 
cattle material and affirm that the product was manufactured in 
accordance with the proposed provisions. Although the marginal burden 
of each affirmation would be negligible, we believe the cumulative 
burden might cause smaller importers to spend about the same level of 
effort as small manufacturers (i.e., $45 annually). In contrast, we 
assume that larger importers might spend about 5 times the level of 
effort as small importers (i.e., $225 annually). Because the agency 
lacks information about importer size, we include a range of possible 
recordkeeping costs for this analysis. Table 2 shows the estimated 
recurring recordkeeping costs for this proposed rule. However, because 
there is some uncertainty about the new burden that might be imposed 
and the number of firms that might be affected by this proposed rule, 
the agency requests comment from affected manufacturers and importers 
of record on this estimated recordkeeping burden.

                                  Table 2.--Estimated Annual Recordkeeping Burden by Industry and Establishment Size\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                               Small                                       Large
         NAICS or Type of Industry         ----------------------------------------------------------------------------------------    Total Cost ($)
                                               Number Affected          Cost ($)           Number Affected          Cost ($)
--------------------------------------------------------------------------------------------------------------------------------------------------------
325411                                                       269                12,100                     7                   600                12,700
--------------------------------------------------------------------------------------------------------------------------------------------------------
325412                                                       615                27,700                    58                 5,200                32,900
--------------------------------------------------------------------------------------------------------------------------------------------------------
325414                                                       243                11,000                     9                   800                11,800
--------------------------------------------------------------------------------------------------------------------------------------------------------
339112, 339113, 339114, 339115                                11                   500                     0                     0                   500
--------------------------------------------------------------------------------------------------------------------------------------------------------
621991 (HCT/P)                                                43                 1,900                    22                 2,000                 3,900
--------------------------------------------------------------------------------------------------------------------------------------------------------
Subtotal                                                   1,182                53,200                    96                 8,600                61,800
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                            Lower Bound (i.e., 3,787 small importers)
                                            Upper Bound (i.e., 3,787 large importers)   ....................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Importers of record \2\                     ....................               170,400  ....................               852,100    170,400 to 852,100
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Total                                                                                                                             232,200 to 913,900
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Totals may not multiply or sum due to rounding.
\2\ Because we lack data on the size of affected importers of record, we calculate the lower and upper bounds for these costs, assuming that either all
  firms are small or all firms are large.


[[Page 1605]]

5. Labeling Costs for New Animal Drugs Prohibited from Extralabel Use
    Manufacturers of new animal drugs prohibited from extralabel use in 
ruminants would need to add a warning statement to the product 
labeling. We estimate manufacturers of about eight animal products 
would spend from $1,600 to $6,400 to change the product labeling and 
file a labeling supplement for each affected product. Costs are based 
on discussions with experts in the Center for Veterinary Medicine and 
are presented in table 3 of this document.

   Table 3.--Estimated One-Time Costs of Labeling Changes and Filing a
                               Supplement
------------------------------------------------------------------------
                                                          Total Cost \1\
        Cost Component           Hours/  Establishment         ($)
------------------------------------------------------------------------
Regulatory review and approval  3 to 12                  1,000 to 3,980
------------------------------------------------------------------------
Artwork \2\                     -                        4,000
------------------------------------------------------------------------
Manufacturing                   4 to 12                  570 to 1,710
------------------------------------------------------------------------
Inventory Loss \3\              -                        6,640 to 40,000
------------------------------------------------------------------------
Supplement preparation and      2 to 5                   660 to 1,660
 Submission
------------------------------------------------------------------------
Total Cost\4\                   .......................  12,870 to
                                                          51,350
------------------------------------------------------------------------
\1\ We calculated using a loaded wage rate for regulatory review and
  filing a supplement of $41.50, for manufacturing changes $17.80.
  Source: BLS National Compensation Survey: Occupational Wages in the
  United States, July 2002, adding 33 percent for benefits.
\2\ We assume the unit costs for artwork are $500 per product.
\3\ We assume the unit costs for inventory loss range from $830 to
  $5,000 per product.
\4\ Totals may not add or multiply due to rounding.

6. Summary of the Costs for the Proposed Rule
    Few firms will incur one-time costs for requests for exceptions or 
alternatives to the limitation on the use of prohibited cattle 
material. In addition, manufacturers of about eight animal products 
prohibited from extralabel use in ruminants would incur one-time costs 
to add a warning statement to the product labeling. All firms that use 
cattle material or import products that do would incur annual 
incremental costs for additional recordkeeping. The total one-time 
costs range from $20,400 to $66,300; annual costs range from $232,200 
to $913,900. The total annualized costs of this option range from 
$234,600 to $921,700 (at a 3 percent discount rate) and from $235,100 
to $923,300 (at a 7 percent discount rate) over 10 years. These costs 
are summarized in table 4 of this document.

             Table 4.--Summary of Total Compliance Costs \1\
------------------------------------------------------------------------
          One-Time Cost             Lower Bound ($)     Upper Bound ($)
------------------------------------------------------------------------
Requests for exception or         7,500               15,000
 alternative
------------------------------------------------------------------------
Change labeling and file a        12,900              51,300
 supplement
------------------------------------------------------------------------
Total one-time cost               20,400              66,300
------------------------------------------------------------------------
Annual recordkeeping cost         232,200             913,900
------------------------------------------------------------------------
Total annualized cost at 3        234,600             921,700
 percent
------------------------------------------------------------------------
Total annualized cost at 7        235,100             923,300
 percent
------------------------------------------------------------------------
\1\Numbers may not add due to rounding.

D. Benefits of the Proposed Rule

1. Reduced Risk of Exposure to BSE Infectivity
    USDA analyses to date have found the United States is highly 
resistant to the introduction or establishment of BSE and predict that 
even if BSE were introduced into the United States, only a small amount 
of potentially BSE-contaminated tissues would reach the human food 
supply and be available for consumption (Ref. 41). Moreover, their 
models predict that implementation of a ban on specified risk materials 
(e.g., spinal cords, brains, vertebral columns) from both human food 
and animal feed would reduce substantially the very low risk of 
additional BSE cases in cattle and the potential human exposure to 
infectivity from meat and meat products.
    None of these risk assessments considered the potential exposure to 
BSE infectivity from certain FDA-regulated products containing bovine 
material. The risks of exposure to BSE infectivity from medical 
products for humans and drugs for ruminants are unknown, but the risk 
of transmission could be higher than for foods and cosmetics assuming 
the presence of BSE infectivity. For example, the routes of 
administration for some of these products (such as from injectable and 
implantable products) are associated with higher risk than oral or 
topical exposure associated with foods and cosmetics. This proposed 
rule covers products not included in the recent USDA or Foods IFRs and 
would ensure that medical products for humans and drugs for ruminants 
containing cattle material meet specific requirements designed to 
reduce the risk of human exposure to BSE-infective materials.
    The proposed rule would decrease the likelihood of human and 
ruminant exposure to BSE in several ways. First, this rule would 
provide additional regulatory protection, beyond existing rules, by 
making clear that prohibited cattle material cannot be used in FDA-
regulated medical products for humans or drugs for ruminants. Second, 
because affected products manufactured from or otherwise containing 
prohibited cattle materials would be adulterated and the failure of an 
importer of record to comply with applicable reporting requirements 
creates the appearance of adulteration under section 801, the proposed 
rule would clarify FDA's ability to bar importation of medical products 
for humans or drugs for ruminants that contain prohibited cattle 
materials. For example, imported products may contain the types of 
materials prohibited by FDA, but may not fall under the scope of USDA's 
import restrictions.
2. Value of the Potential Reduction of Human Illness
    The public health benefit of this proposed rule is the value of the 
reduction in the risk of the human illness associated with exposure to 
the agent that causes BSE. If we define the baseline risk as the 
expected annual number of cases of vCJD per year, then the annual 
benefits of barring prohibited cattle materials from use in affected 
products would be: (baseline annual cases of vCJD--annual cases of vCJD 
under FDA PR) x (value of preventing a case of vCJD).
    We do not know the baseline expected annual number of cases, but 
based on the epidemiology of vCJD in the United Kingdom, we anticipate 
much less than one case of vCJD per year in the United States. Because 
the proposed rule would reduce rather than eliminate risk of exposure 
to BSE infectious materials, the reduction in the number of cases would 
be some fraction of the expected number. FDA uses the concept of the 
Value of a Statistical Life (VSL) in order to describe the value of 
preventing a case

[[Page 1606]]

of vCJD. This term refers to the sum of risk reductions expected in a 
population exposed to small changes in risk. It has no application to 
identifiable individuals or large reductions in risk. Most recent 
studies suggest values ranging from about $1 million to $10 million. In 
recent rulemakings, we have used $5 million and $6.5 million as the 
value of a statistical life, and we believe it is reasonable to use a 
similar VSL to value the cases of vCJD avoided.

E. Summary of the Potential Costs and Benefits of the Proposed Rule

    The total annualized costs of this proposed rule range from 
$234,600 to $921,700 (at a 3 percent discount rate) and from $235,100 
to $923,300 (at a 7 percent discount rate) over 10 years. By reducing 
exposure to potentially infectious materials, the requirements of the 
proposed rule would provide an additional safeguard against a case of 
vCJD occurring in humans if cattle infected with BSE were used in the 
manufacture or processing of medical products for humans and drugs for 
ruminants. We are unable to estimate the value of this potential 
reduction in the risk of cases of vCJD, even though we estimate the 
value of avoiding one death at $5.8 million. Nonetheless, we believe 
the potential benefits of the proposed rule justify the small costs of 
the rule.

F. Regulatory Options Considered

    For this proposed rule, FDA considered three regulatory options:
    (1) No new regulation. By definition, no costs and benefits are 
associated with the baseline. As noted previously, USDA and FDA actions 
to date would reduce, but not eliminate, the availability and use of 
prohibited cattle materials in domestic and imported FDA-regulated 
medical products for humans and drugs for ruminants. Without 
regulation, FDA would not be explicitly barring the use of prohibited 
cattle materials that could potentially contain the BSE infectious 
agent.
    (2) Propose a rule that (i) bars the use of prohibited cattle 
materials in medical products for humans and drugs for ruminants, 
unless a request for exception or alternative to the limitation of the 
use of prohibited cattle material has been granted, and (ii) requires 
establishment, maintenance, and access to records demonstrating that no 
medical products for humans or drugs for ruminants are manufactured 
from or otherwise contain prohibited cattle material. These would be 
the minimum basic requirements, and would not preclude the imposition 
of additional measures through the application review process or other 
means if FDA determined that they were necessary for ensuring the 
safety of individual products on a case-by-case basis.
    This is the regulatory option selected. The agency believes that 
this is the best option to meet its goal of minimizing human and 
ruminant exposure to materials that scientific studies have 
demonstrated are likely to contain the BSE agent in cattle infected 
with the disease. The ban on use of prohibited materials would 
eliminate exposure to the highest risk animals and the majority of the 
infectivity in an animal infected with the BSE agent. This option would 
provide reasonable balance by explicitly barring from medical products 
for humans and drugs for ruminants the use of potentially infectious 
materials already deemed unfit for foods by USDA and FDA and by 
imposing minimal regulatory burden. The agency must be able to 
determine that the products it regulates contain no prohibited cattle 
materials. Applicants and manufacturers must depend on records to 
ensure that affected products do not contain any cattle materials 
prohibited under the proposal. Without recordkeeping requirements, FDA 
may not be able to determine the source or age of cattle material once 
it is separated from the animal. In addition, records would allow the 
agency to determine the inspectional status of the source animals.
    (3) Propose a rule that, in addition to the requirements listed in 
option (2), bars the use in medical products for humans and drugs for 
ruminants of all neural material from cattle from countries with a high 
or medium risk of BSE if the cattle were slaughtered when over 6 months 
old, unless a request for exception or alternative to the requirements 
has been granted. This approach would be more consistent with 
recommendations of OIE and would add an additional layer of protection 
to that provided by option (2). This alternative would put an 
additional burden on those parts of the affected industries that source 
cattle materials from such countries and do not already have procedures 
in place ensuring and documenting compliance with the requirement.
    Compared to the preferred option (2), we believe this alternative 
would impose higher costs on, at most, a small segment of the affected 
industries. In fact, we know of no manufacturers of U.S. licensed or 
approved medical products for humans and drugs for ruminants for which 
this alternative would impose any additional burdens beyond those 
imposed under option (2), because they do not source such materials 
from such countries. However, we also believe it would not provide 
significant additional risk reduction because so few animals diagnosed 
with BSE are younger than 3 years old. For example, cattle born in 
1987/1988 in the United Kingdom had the highest incidence of BSE, with 
over 39,000 cattle diagnosed with BSE. Among those animals, cattle 
under 3 years old represented only 0.16 percent of cattle with BSE (61 
cattle). Once controls were put in place, that number decreased, so 
that of animals born after 1996, all cattle diagnosed with BSE have 
been 3 years old or older.

G. Regulatory Flexibility Analysis

    FDA has examined the economic implications of this proposed rule as 
required by the Regulatory Flexibility Act (5 U.S.C. 601-612). If a 
rule has a significant economic impact on a substantial number of small 
entities, the Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would lessen the economic effect of the rule on 
small entities. The FDA believes this proposed rule will not have a 
significant economic impact on a substantial number of small entities 
and requests comment.
    The proposed rule may affect entities classified in several 
industries including Medicinal & Botanical Manufacturing (NAICS 
325411), Pharmaceutical Preparation Manufacturing (NAICS 325412), 
Biological Product (Except Diagnostic) Manufacturing (NAICS 325414), 
Surgical and Medical Instrument Manufacturing (NAICS 339112), Surgical 
Appliance and Supplies Manufacturing (NAICS 339113), Dental Equipment 
and Supplies Manufacturing (NAICS 339114), Ophthalmic Goods 
Manufacturing (NAICS 339115), and Blood and Organ Banks (NAICS 621991). 
The Small Business Administration (SBA) regards an entity as small 
based on the number of employees or the average annual receipts. The 
size standards are: (1) 750 employees for NAICS categories 325411 and 
325412, (2) 500 employees for NAICS categories 325414, 339112, 339113, 
339114 and 339115, and (3) $9.0 million average annual receipts for 
NAICS 621991. The U.S. Census gathers employment data for 
establishments by NAICS and uses size categories that differ from those 
of the SBA for NAICS 325411 and 325412. For this regulatory flexibility 
analysis, therefore, we consider entities in these NAICS categories 
with less than 999 employees to be small. Using these size standards, 
2002 Census data, and the CGTP final rule (69 FR 68612 at 68654 and 
68674),

[[Page 1607]]

over 90 percent of these establishments would be considered small (see 
tables 1 and 2 of this document). However, the agency lacks information 
on the types of importers of record that might be affected by the 
proposed rule. Agency data on filers that import FDA-regulated products 
into the United States does not include the size of the importer of 
record. Therefore, for the initial regulatory flexibility analysis, we 
assume that all affected importers of record would be classified as 
small. The agency requests comment on this assumption.
    We believe requirements in this proposed rule must apply to all 
entities, regardless of size. No new skills are needed. To meet the 
proposed requirements, those applicants and manufacturers of medical 
products for humans or drugs for ruminants manufactured from or 
otherwise containing cattle tonsils, the distal ileum of the small 
intestine of cattle, or mechanically separated beef might need to 
switch to an alternative source material, submit a request for 
exception or alternative to the limitation on prohibited cattle 
material in this proposed rule, or cease marketing the products. We 
expect that other affected manufacturers would continue to use age-
specific cattle material from animals under 30 months of age. A few 
small entities could incur from $2,500 to $5,000 for each request 
submitted unless a request for exception or alternative to requirements 
of the proposed rule has already been granted. In addition, 
manufacturers of about eight animal products prohibited from extralabel 
use in ruminants would incur costs of between $1,600 and $6,400 per 
product to add a warning statement to the product labeling and file a 
labeling supplement. Although it is uncertain if any small entities 
will incur these costs, Table 5 shows that for very small 
establishments with less than 10 employees these one-time costs would 
equal less than 1.6 percent of the average annual value of shipments. 
Moreover, for all small establishments in each of the affected 
industries, the one-time costs to revise labeling or prepare a request 
for exception or alternative to requirements of the proposed rule would 
equal no more than 0.15 percent of the average annual value of 
shipments.

 Table 5. Potential direct compliance costs of the proposed rule as a percentage of average annual shipments for affected establishments with less than
                                                                    10 employees.\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                    Compliance Costs as a Percentage of Average Annual Shipments \2\
                                                           Average Annual     --------------------------------------------------------------------------
                   NAICS Category                          Shipments Per                                                          Request for Exception
                                                         Establishment ($)      Recordkeeping ($45 Per     Labeling Revision      or Alternative ($5,000
                                                                                    Establishment)        ($6,500 Per Product)         Per Request)
--------------------------------------------------------------------------------------------------------------------------------------------------------
325411, Medicinal and botanical manufacturing                       1,059,245                   0.004%                     0.6%                     0.5%
--------------------------------------------------------------------------------------------------------------------------------------------------------
325412, Pharmaceutical preparation manufacturing                    1,656,743                   0.003%                     0.4%                     0.3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
325414, Biological product (except diagnostic)                      1,057,862                   0.004%                     0.6%                     0.5%
 manufacturing
--------------------------------------------------------------------------------------------------------------------------------------------------------
339112, Surgical and medical instrument                               610,138                   0.007%                     1.0%                     0.8%
 manufacturing
--------------------------------------------------------------------------------------------------------------------------------------------------------
339113, Surgical appliance and supplies                               618,207                   0.007%                     1.0%                     0.8%
 manufacturing
--------------------------------------------------------------------------------------------------------------------------------------------------------
339114, Dental equipment and supplies manufacturing                   396,666                   0.011%                     1.6%                     1.3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
339115, Ophthalmic goods manufacturing \3\                          1,121,083                   0.004%                     0.6%                     0.4%
--------------------------------------------------------------------------------------------------------------------------------------------------------
621991 Blood and organ banks                                        4,281,172                   0.001%                     0.1%                     0.1%
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Source: Table 4 of 2002 Economic Census for NAICS 325411, 325412, 325414, 339112, 339113, 339114, 339115, and 621991.
\2\ Averages based on the sum of data for establishments with 1 to 4 employees and 5 to 9 employees. For establishments with 1 to 4 employees,
  recordkeeping costs equal less than 0.02 percent of average annual shipments for all NAICS categories. It is unlikely that entities with 1 to 4
  employees would incur compliance costs for a labeling revision or a request for exception or alternative to requirements of the proposed rule.
  Nevertheless, for these smallest entities, as a percentage of average annual shipments, a labeling revision equals less than 2.6 percent and a request
  for exemption or alternative equals less than 2.0 percent for all NAICS categories.
\3\ No information for establishments with 1 to 4 employees.

    Besides the one-time compliance burden that a few small entities 
might incur, most affected small manufacturers would incur minor new 
compliance costs for recordkeeping. For small manufacturers and small 
importers of record, these annual costs would equal about $45, a 
negligible amount for even the smallest entities. Table 5 shows that 
these incremental recordkeeping costs for establishments with less than 
10 employees would equal less than 0.02 percent of their average annual 
value of shipments.
    FDA lacks the data required to estimate the number of requests, the 
distribution of one-time labeling costs, and the new annual 
recordkeeping burden on small entities. We anticipate, however, that 
the potential costs might represent a very small percentage of their 
annual revenues and would not be a significant economic impact on 
affected small entities. Nevertheless, the agency requests detailed 
data on small business impacts from affected firms.
    As discussed in section VIII. F. of this document, FDA considered 
other regulatory options. The proposed rule is the least burdensome 
option that meets FDA's goal of minimizing human and ruminant exposure 
to materials that scientific studies have demonstrated are

[[Page 1608]]

likely to contain the BSE agent in cattle infected with the disease.

IX. Paperwork Reduction Act Analysis

    This proposed rule contains information collection requirements 
that are subject to review by OMB under the Paperwork Reduction Act of 
1995 (the PRA) (44 U.S.C. 3501 3520). A description of these provisions 
is given below with an estimate of the annual reporting and 
recordkeeping burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    FDA invites comments on the following topics: (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: Use of Materials Derived from Cattle in Medical Products 
Intended for Use in Humans and Drugs Intended for Use in Ruminants

    Description: As discussed previously in this document, we are 
proposing to prohibit the use of certain cattle material in medical 
products for humans and drugs for ruminants because of the risk of BSE 
and related human disease. The rulemaking contains reporting and 
recordkeeping requirements that are subject to review by OMB.
    Reporting. Under proposed Sec. Sec.  300.200(b)(2)(i) and 
(b)(2)(ii) for drugs for humans, 500.200(b)(2)(i) and (b)(2)(ii) for 
drugs for ruminants, 600.16(b)(2)(i) and (b)(2)(ii) for biological 
products, 895.102(b)(2)(i) and (b)(2)(ii) for human medical devices 
that are intended for use in or on the body, and 1271.470(b)(2)(i) and 
(b)(2)(ii) for HCT/Ps, applicants and manufacturers could request 
permission for an exception or alternative to the requirements in 
proposed Sec. Sec.  300.200(b)(1), 500.200(b)(1), 600.16(b)(1), 
895.102(b)(1), and 1271.470(b)(1) that no medical product for humans or 
drug for ruminants be manufactured from or otherwise contain prohibited 
cattle materials obtained from cattle slaughtered on or after the 
effective date of the regulation. To obtain written permission from FDA 
for an exception or alternative to the requirements, applicants and 
manufacturers would send a written request to the director of the 
Center having jurisdiction over the relevant product. Any request would 
contain the following:
     A statement of the reasons why an exception or alternative 
is needed;
     A description of the product, including the type of 
prohibited cattle materials used in its manufacturing, its 
manufacturing and purification processes, and its route of 
administration;
     A description of the source of the prohibited cattle 
materials, including information on the location where the cattle were 
born, raised, and slaughtered, and any other information relevant to 
the likelihood of the cattle having ingested material prohibited under 
? 589.2000;
     A description, if applicable, of how the requirements that 
pertain to their product in proposed Sec. Sec.  300.200(b)(1), 
600.16(b)(1), 895.102(b)(1), or 1271.470(b)(1) are not necessary based 
on the risks of the prohibited cattle materials in the product and the 
benefits of the product, or how such restrictions are not necessary to 
ensure the safety of the product;
     A description, if applicable, of: (1) How the requirements 
that pertain to their product in proposed Sec.  500.200(b)(1) are not 
necessary: (i) Based on the risks of the prohibited cattle materials in 
the product to the target animal and the benefits of the product to the 
target animal and (ii) to ensure a reasonable certainty of no harm to 
humans from any food derived from the target animal to which the 
product was administered, or (2) how such restrictions are not 
necessary to ensure the safety of the product with respect to both the 
target animal and any food derived from the target animal to which the 
product is administered; and
     Any other relevant information.
    As discussed in the Analysis of Impacts (see section VIII of this 
document), we estimate that a request for an exception or alternative 
to the requirements would take between 60 and 120 hours to complete and 
submit to FDA. For purposes of this information collection analysis, we 
estimate, as indicated in table 6 of this document, that each request 
would take approximately 120 hours. We estimate that only three 
requests would be submitted to FDA in the first year by applicants and 
manufacturers of medical products for humans and drugs for ruminants 
because only a small number of such products are currently manufactured 
with cattle materials that would be prohibited under this rule. We 
expect that applicants and manufacturers would seek, and obtain, 
alternatives to prohibited cattle materials, eliminating the need for 
future requests for an exception or alternative to the requirements of 
the proposed rule. We request comments on our estimates of the number 
of exception/alternative requests, the time for preparation and 
submission of the request, and the likelihood of requests beyond the 
first year after the rule would be in effect.
    Under proposed Sec. Sec.  300.200(c)(5), 500.200(c)(5), 
600.16(c)(5), 895.102(c)(5), and 1271.470(c)(5), when filing entry with 
the U.S. Customs and Border Protection, importers of record of a 
medical product for humans or a drug for ruminants that was 
manufactured from, or otherwise contains, cattle material would be 
required to affirm that the product was manufactured from or otherwise 
contained cattle material and affirm that the product was manufactured 
in accordance with the requirements in this proposed rule. If a product 
was manufactured from, or otherwise contains, cattle material, then 
importers of record would also, if requested, have to provide to FDA 
within 5 days records that would be sufficient to demonstrate that the 
product was not manufactured from, and does not contain, prohibited 
cattle material. As discussed in the Analysis of Impacts (see section 
VIII of this document), we estimate that 3,787 importers of record 
would be subject to this affirmation and potential record submission 
and that it would take each of them between 1 and 5 hours annually to 
process. For purposes of this information collection analysis, we 
estimate, as indicated in table 6 of this document, that this proposed 
provision would take each importer of record approximately 2.5 hours 
annually to process.
    Under proposed Sec.  530.42, FDA would require that labels for 
drugs prohibited from extralabel use in ruminants by proposed Sec.  
530.41(c) bear or be accompanied by the statement ``Federal law 
prohibits the extralabel use of this product in ruminants.'' This 
labeling statement is not subject to review by OMB because it is 
``originally supplied by the Federal Government to the recipient for 
the purpose of disclosure to the public'' (5 CFR 1320.3(c)(2)) and, 
therefore, does not constitute a ``collection of information'' under 
the PRA.

[[Page 1609]]

    Recordkeeping. Under proposed Sec. Sec.  300.200(c), 500.200(c), 
600.16(c), 895.102(c), and 1271.470(c), applicants and manufacturers of 
medical products for humans and drugs for ruminants that are 
manufactured from, or otherwise contain, material from cattle would be 
required to establish and maintain records demonstrating that their 
products have not been manufactured from and do not otherwise contain, 
prohibited cattle materials and make such records available to FDA for 
inspection and copying. These proposed requirements are necessary 
because, once materials are separated from an animal, it may not be 
possible without records to know the following: (1) Whether the cattle 
material contains SRMs, (2) whether the material was sourced from an 
animal that was inspected and passed for human consumption, (3) whether 
the material was sourced from a nonambulatory disabled animal, and (4) 
whether the product contains mechanically separated beef. Under the 
proposed rule, applicants and manufacturers must retain records the 
varying periods of time consistent with the applicable CGMP or CGTP 
requirements (e.g., for drugs for humans, it would be at least 1 year 
after the expiration date of the drug; for drugs for humans lacking an 
expiration date, it would be at least 3 years after distribution of the 
last lot of the drug). These records would be required to be maintained 
at the applicant's or manufacturer's establishment or another 
reasonably accessible location.
    Recordkeeping requirements currently exist for applicants and 
manufacturers of medical products for humans and drugs for ruminants 
under FDA's CGMP and CGTP regulations. For drugs and biological 
products for humans and drugs for ruminants, these requirements are at 
part 210 (21 CFR part 210) and part 211 (CGMP), and the information 
collection requirements for these regulations are already approved by 
OMB under OMB Control Number 0910-0139 until September 30, 2008. For 
blood and blood components, these requirements are at 21 CFR part 606 
(CGMP), and the information collection requirements for these 
regulations are already approved by OMB under OMB Control Number 0910-
0116 until December 31, 2008. For Type A medicated articles, these 
requirements are at part 226 (CGMP), and the information collection 
requirements for these regulations are already approved by OMB under 
OMB Control Number 0910-0154 until December 31, 2007. For medical 
devices for humans, these requirements are at 21 CFR part 820 (CGMP/
quality system regulations), and the information collection 
requirements for these regulations are already approved by OMB under 
OMB Control Number 0910-0073 until September 30, 2007. For HCT/Ps, 
these requirements are at part 1271, subpart D (CGTP regulations), and 
the information collection requirements for these regulations are 
already approved by OMB under OMB Control Number 0910-0559 until 
November 30, 2007. In accordance with the previously mentioned CGMP and 
CGTP regulations, applicants and manufacturers of medical products for 
humans and drugs for ruminants would be responsible for maintaining 
records regarding use of cattle materials in, or in the manufacture of, 
their products. However, FDA estimates that, in accordance with this 
rulemaking, applicants and manufacturers would expend a small amount of 
additional effort to comply with the proposed recordkeeping 
requirements. FDA has determined, as indicated in table 7 of this 
document, that there are 1,278 applicants and manufacturers of a 
medical product for humans or drug for ruminants that would be 
responsible for recordkeeping. This would include verifying records and 
storing records that contain information on sources of cattle materials 
that are to be used in medical products for humans and drugs for 
ruminants. As discussed in the Analysis of Impact (see section VIII of 
this document), we estimate that this recordkeeping burden will be 
about 1 to 3 hours per year. For purposes of this document, we 
estimate, as indicated in table 7, that this burden would take about 2 
hours/year. Therefore, the total annual burden will be 2 hrs x 1,278 = 
2,556 hours, as shown in table 7 of this document.
    Description of Respondents: Applicants and manufacturers of medical 
products for humans and drugs for ruminants that are manufactured from, 
or otherwise contain, material from cattle slaughtered on or after the 
effective date of the regulation.

                                                        Table 6.--Estimated Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of         Frequency  per                            Hours per
                    21 CFR Section                         Respondents           Response         Total  Responses       Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
300.200(b)(2)(i) and (b)(2)(ii), 500.200(b)(2)(i) and                   3                     1                  3                120                360
 (b)(2)(ii), 600.16(b)(2)(i) and (b)(2)(ii),
 895.102(b)(2)(i) and (b)(2)(ii), and
 1271.470(b)(2)(i) and (b)(2)(ii)
--------------------------------------------------------------------------------------------------------------------------------------------------------
300.200(c)(5), 500.200(c)(5), 600.16(c)(5),                         3,787                     1              3,787                2.5            9,467.5
 895.102(c)(5), and 1271.470(c)(5)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                            9,827.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


                                                   Table 7.--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of        Annual Frequency       Total Annual        Hours per
                    21 CFR Section                         Respondents         per Response          Responses           Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
300.200(c), 500.200(c), 600.16(c), 895.102(c), and                  1,278                     1              1,278                  2              2,556
 1271.470(c)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


[[Page 1610]]

    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 to OMB 
(see DATES and ADDRESSES).

X. Environmental Impact Analysis

    FDA has carefully considered the potential environmental effects of 
this proposed rule (i.e., ban use of prohibited cattle materials in 
medical products for humans and drugs for ruminants, unless a request 
for exception or alternative to the requirements has been granted) and 
of two possible alternative actions: (1) No action and (2) in addition 
to the requirements proposed in this rule, ban use in medical products 
for humans and drugs for ruminants of all neural material from cattle 
from countries with a high or medium risk of BSE if the cattle were 
slaughtered when over 6 months old, unless a request for exception or 
alternative to the requirements has been granted. In doing so, the 
agency focused on the environmental impacts of its action, 
specifically, disposal of unused cattle byproducts (e.g., dead animals 
and slaughter byproducts) that can no longer be used in medical 
products for humans or drugs for ruminants after the rule becomes 
effective.
    The environmental assessment (EA) considered each of the 
alternatives in terms of the need to provide maximum reasonable 
protection of human health without resulting in a significant impact on 
the environment. The EA considered environmental impacts related to 
landfill, incineration, composting, and land burial. The additional 
waste that might result from the selected action would be an extremely 
small amount compared to the total amount of waste generated by the 
cattle industry.
    The agency has concluded that the proposed rule will not have a 
significant impact on the human environment and that an environmental 
impact statement is not required. FDA's finding of no significant 
impact (FONSI) and the evidence supporting that finding, contained in 
an EA prepared under 21 CFR 25.40, may be seen in the Dockets 
Management Branch (see ADDRESSES) between 9 a.m. and 4 p.m., Monday 
through Friday. FDA invites comments and submission of data concerning 
the EA and FONSI.

XI. Federalism

    We have analyzed this proposed rule in accordance with the 
principles in Executive Order 13132. We have determined that the 
proposed rule does not contain policies that have substantial direct 
effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
we have concluded that the proposed rule does not contain policies that 
have federalism implications as defined in the Executive order and, 
consequently, a federalism summary impact statement has not been 
prepared.

XII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site address, but we are not responsible for 
subsequent changes to the Web site after this document publishes in the 
Federal Register.)
    1. Johnson, R. T. and C. J. Gibbs, Jr., ``Creutzfeldt-Jakob 
Disease and Related Transmissible Spongiform Encephalopathies,'' New 
England Journal of Medicine, 339(27):1994-2004, 1998.
    2. Herzog, C., N. Sales, N. Etchegaray, et al., ``Tissue 
Distribution Of Bovine Spongiform Encephalopathy Agent in Primates 
After Intravenous or Oral Infection,'' Lancet, 363(9407):422-28, 
2004.
    3. Wells, G. A. H., S. A. C. Hawkins, R. B. Green, et al., 
``Preliminary Observations on the Pathogenesis of Experimental 
Bovine Spongiform Encephalopathy (BSE): An Update,'' Veterinary 
Record, 142:103-106, 1998.
    4. Wells, G. A. H., M. Dawson, S. A. C. Hawkins, et al., 
``Infectivity in the Ileum of Cattle Challenged Orally With Bovine 
Spongiform Encephalopathy,'' Veterinary Record, 135:40-41, 1994.
    5. Wells, G. A. H., S. A. C. Hawkins, R. B. Green, et al., 
``Limited Detection of Sternal Bone Marrow Infectivity in the 
Clinical Phase of Experimental Bovine Spongiform Encephalopathy 
(BSE),'' Veterinary Record, 144:292-294, 1999.
    6. Brown, K. L, D. L. Ritchie, P. A. McBride, and M. E. Bruce, 
``Detection of PrP in Extraneural Tissues,'' Microscopy Research and 
Technique, 50:40-45, 2000.
    7. U. S. Department of Agriculture, APHIS, ``Summary of Enhanced 
BSE Surveillance in the United States,'' 2006 accessed online at 
http://www.aphis.usda.gov/newsroom/hot_issues/bse/content/printable_version/SummaryEnhancedBSE-Surv4-26-06.pdf.
    8. Council for Agricultural Science and Technology, 
``Transmissible Spongiform Encephalopathies in the United States,'' 
Task Force Report No. 136, 2000.
    9. Prusiner, S. B., ``Prions,'' Proceedings of the National 
Academy of Sciences of the United States of America, 95(23):13363-
13383, 1998.
    10. Prusiner, S. B., ``Shattuck Lecture--Neurodegenerative 
Diseases and Prions,'' New England Journal of Medicine, 344(20): 
1516-1526, 2001.
    11. Legname, G., I.V. Baskakov, H. B. Nguyen, et al., 
``Synthetic Mammalian Prions,'' Science, 305:673-676, 2004.
    12. Collins, S. J., V. A. Lawson, and C. L. Masters, 
``Transmissible Spongiform Encephalopathies,'' Lancet, 363(9402):51-
61, 2003.
    13. Collee, J. G. and R. Bradley, ``BSE: A Decade On--Part I,'' 
Lancet, 349:636-641, 1997.
    14. Anderson, R. M., C. A. Donnelly, N. M. Ferguson, et al., 
``Transmission Dynamics and Epidemiology of BSE in British Cattle,'' 
Nature, 382:779-788, 1996.
    15. Wells, G. A. H., A. C. Scott, C. T. Johnson, et al., ``A 
Novel Progressive Spongiform Encephalopathy in Cattle,'' Veterinary 
Record, 121:419-420, 1987.
    16. Vossen, P., J. Kreysa, and M. Goll, ``Overview of the BSE 
Risk Assessments of the European Commission's Scientific Steering 
Committee (SSC) and Its TSE/BSE Ad Hoc Group,'' 2003, accessed 
online at http://www.europa.eu.int/comm/food/fs/sc/ssc/out364_en.pdf.
    17. Kimberlin, R. H. and J. W. Wilesmith, ``Bovine Spongiform 
Encephalopathy: Epidemiology, Low Dose Exposure, and Risks,'' Annals 
of the New York Academy of Sciences, 724:210-220, 1994.
    18. World Organisation for Animal Health (OIE), ``Number of 
Cases of BSE Reported in the United Kingdom,'' Accessed online at 
http://www.oie.int/eng/info/en_esbru.htm.
    19. World Organisation for Animal Health (OIE), ``Number of 
Reported Cases of bovine spongiform encephalopathy (BSE) in Farmed 
Cattle Worldwide (excluding the United Kingdom),'' accessed online 
at http://www.oie.int/eng/info/en_esbmonde.htm.
    20. Brown, P., ``The Risk of Bovine Spongiform Encephalopathy 
(`Mad Cow Disease') to Human Health,'' Journal of the American 
Medical Association, 278(12):1008-1011, 1997.
    21. Will, R. G., J. W. Ironside, M. Zeidler, et al., ``A New 
Variant of Creutzfeldt-Jakob Disease in the UK,'' Lancet, 347:921-
925, 1996.
    22. Chazot, G., E. Broussolle, C. I. Lapras, et al., ``New 
Variant of Creutzfeldt-Jakob Disease in a 26-Year-Old French Man,'' 
Lancet, 347:1181, 1996.
    23. Collinge, J., ``Prion Diseases of Humans and Animals: Their 
Causes and Molecular Basis,'' Annual Review of Neuroscience, 24:519-
550, 2001.
    24. Almond, J. and J. Pattison, ``Human BSE,'' Nature, 389:437-
438, 1997.
    25. Scott, M. R., R. Will, J. Ironside, et al., ``Compelling 
Transgenetic Evidence for Transmission of Bovine Spongiform 
Encephalopathy Prions to Humans,'' Proceedings of the National 
Academy of Sciences of the United States of America, 96(26):15137-
15142, 1999.
    26. Hill, A. F., M. Desbruslais, S. Joiner, et al., ``The Same 
Prion Strain Causes vCJD and BSE,'' Nature, 389:448-450, 1997.
    27. Collinge, J., ``Variant Creutzfeldt-Jakob Disease,'' Lancet, 
354:317-323, 1999.
    28. Lasmezas, C. I., J-G. Fournier, V. Nouvel, et al., 
``Adaptation of the Bovine Spongiform Encephalopathy Agent to

[[Page 1611]]

Primates and Comparison With Creutzfeldt-Jakob Disease: Implications 
for Human Health,'' Proceedings of the National Academy of Sciences 
of the United States of America, 98(7):4142-4147, 2001.
    29. Bruce, M. E., R. G. Will, J. W. Ironside, et al., 
``Transmissions to Mice Indicate That `New Variant' CJD Is Caused by 
the BSE Agent, Nature, 389:498-501, 1997.
    30. Brown, P., R. G. Will, R. Bradley, et al., ``Bovine 
Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease: 
Background, Evolution, and Current Concerns,'' Emerging Infectious 
Diseases, 7(1):6-16, 2001.
    31. Scientific Steering Committee, European Commission, 
``Opinion of the Scientific Steering Committee on the Human Exposure 
Risk (HER) via Food With Respect to BSE,'' 1999.
    32. The National Creutzfeldt-Jakob Disease Surveillance Unit, 
United Kingdom, accessed online at http://www.cjd.ed.ac.uk/figures.htm.
    33. Public Health Agency of Canada, ``First Canadian Case of 
Variant Creutzfeldt-Jakob Disease (Variant CJD),'' accessed online 
at http://www.phac-aspc.gc.ca/cjd-mcj/vcjd-ca_e.html.
    34. Wiersma, S., S. Cooper, R. Knight et al., ``Probable Variant 
Creutzfeldt-Jakob Disease in a U.S. Resident-Florida, 2002,'' 
Morbidity and Mortality Weekly Report, 51:927-929, 2002.
    35. ``Probable Case of Indigenous vCJD diagnosed in Ireland,'' 
Eurosurveillance Weekly, accessed online at http://www.eurosurveillance.org/ew/2004/041111.asp.
    36. Belay, E.D., J.J. Sejvar, W-J Shieh, et al., ``Variant 
Creutzfeldt-Jakob disease death, United States,'' Emerging 
Infectious Diseases, 11 (9), 1351-1354, 2005, accessed online at 
http://www.cdc.gov/ncidod/EID/vol11no09/05-0371.htm.
    37. The European and Allied Countries Collaborative Study Group 
of CJD (EUROCJD), accessed online at http://www.eurocjd.ed.ac.uk/vCJD.htm.
    38. Fuyuno, I., ``Japan Plans Blood-Donor Restrictions to Combat 
vCJD,'' Nature, 434:260, 2005.
    39. Brown, P., ``Bovine Spongiform Encephalopathy and Variant 
Creutzfeldt-Jakob Disease,'' British Medical Journal, 322:841-844, 
2001.
    40. Scientific Steering Committee, European Commission, ``Oral 
Exposure of Humans to the BSE Agent: Infective Dose and Species 
Barrier,'' 2000, accessed online at http://www.europa.eu.int/comm/food/fs/sc/ssc/out79_en.pdf.
    41. Harvard Center for Risk Analysis, Harvard School of Public 
Health, ``Evaluation of the Potential for Bovine Spongiform 
Encephalopathy in the United States,'' 2003, accessed online at 
http://www.hcra.harvard.edu/pdf/madcow.pdf.
    42. Harvard Center for Risk Analysis, Harvard School of Public 
Health, ``Harvard Risk Assessment of Bovine Spongiform 
Encephalopathy Update, Phase IA,'' 2005, accessed online at http://www.fsis.usda.gov/Science/Risk_Assessments/index.asp#bse.
    43. U.S. Department of Agriculture, APHIS, accessed online at 
http://www.aphis.usda.gov/lpa/issues/bse_testing/test_results.html.
    44. Comer, P.J. and P.J. Huntly, ``Exposure of the human 
population to BSE infectivity over the course of the BSE epidemic in 
Great Britain and the impact of changes to the Over Thirty Month 
Rule,'' 2003, accessed online at http://www.food.gov.uk/multimedia/pdfs/otmcomer.pdf.
    45. Lasmezas, C.I., J-P. Deslys, O. Robain, et al., 
``Transmission of the BSE Agent to Mice in the Absence of Detectable 
Abnormal Prion Protein,'' Science, 275:402-405, 1997.
    46. Race, R., A. Raines, G. J. Raymond, et al., ``Long-term 
Subclinical Carrier State Precedes Scrapie Replication and 
Adaptation in a Resistant Species: Analogies to Bovine Spongiform 
Encephalopathy and Variant Creutzfeldt-Jakob Disease in Humans,'' 
Journal of Virology, 75(21):10106-10112, 2001.
    47. Kimberlin, R. H., S. Cole, et al., ``Pathogenesis of Scrapie 
Is Faster When Infection Is Intraspinal Instead of Intracerebral,'' 
Microbial Pathogenesis, 2(6):405-415, 1987.
    48. Kimberlin, R. H. and C. A. Walker. ``Pathogenesis of Mouse 
Scrapie: Effect of Route of Inoculation on Infectivity Titres and 
Dose-Response Curves,'' Journal of Comparative Pathology, 88(1):39-
47, 1978.
    49. Kimberlin, R. H. and C. A. Walker, ``Pathogenesis of Mouse 
Scrapie: Dynamics of Agent Replication in Spleen, Spinal Cord and 
Brain After Infection by Different Routes,'' Journal of Comparative 
Pathology, 89(4):551-562, 1979.
    50. Baier, M., S. Norley, J. Schultz, et al., ``Prion Diseases: 
Infectious and Lethal Doses Following Oral Challenge,'' Journal of 
General Virology, 84(Pt 7):1927-1929, 2003.
    51. Gibbs, C. J., Jr., H. L. Amyx, A. Bacote, et al., ``Oral 
Transmission of Kuru, Creutzfeldt-Jakob Disease, and Scrapie to 
Nonhuman Primates,'' Journal of Infectious Diseases, 142(2):205-208, 
1980.
    52. Pattison, I. H., M. N. Hoare, J.N. Jebbett, and W.A. Watson, 
``Spread of Scrapie to Sheep and Goats by Oral Dosing With Foetal 
Membranes From Scrapie-Affected Sheep,'' Veterinary Record, 
90(17):465-468, 1972.
    53. Pattison, I. H., M. N. Hoare, J.N. Jebbett, and W.A. Watson, 
``Further Observations on the Production of Scrapie in Sheep by Oral 
Dosing With Foetal Membranes From Scrapie-Affected Sheep,'' British 
Veterinary Journal, 130(4):lxv-lxvii, 1974.
    54. Pattison, I. H. and G. C. Millson, ``Experimental 
Transmission of Scrapie to Goats and Sheep by the Oral Route,'' 
Journal of Comparative Pathology, 71:171-176, 1961.
    55. Race, R., M. Oldstone, and B. Chesebro, ``Entry Versus 
Blockade Of Brain Infection Following Oral or Intraperitoneal 
Scrapie Administration: Role of Prion Protein Expression in 
Peripheral Nerves and Spleen,'' Journal of Virology, 74(2):828-833, 
2000.
    56. Kimberlin, R. H. and Walker, C. A., ``Pathogenesis of 
Experimental Scrapie'' in Novel Infectious Agents and the Central 
Nervous System, Eds. G. Bock and J. Marsh, Wiley, Chichester (Ciba 
Foundation Symposium 135): Wiley, 37-62, 1988.
    57. Scott, J. R., J. D. Foster and H. Fraser, ``Conjunctival 
Instillation of Scrapie in Mice Can Produce Disease,'' Veterinary 
Microbiology, 34(4):305-309, 1993.
    58. Klitzman R. L., M. P. Alpers, and D. C. Gajdusek, et al., 
``The Natural Incubation Period of Kuru and the Episodes of 
Transmission in Three Clusters of Patients,'' Neuroepidemiology, 
3(1):3-20, 1984.
    59. Sugaya, M., K. Nakamura, T. Watanabe, et al., ``Expression 
of Cellular Prion-Related Protein by Murine Langerhans Cells and 
Keratinocytes,'' Journal of Dermatological Science, 28:126-134, 
2002.
    60. Scientific Steering Committee, European Commission, ``Update 
of the Opinion on TSE Infectivity Distribution in Ruminant 
Tissues,'' initially adopted by the Scientific Steering Committee at 
its meeting of January, 10-11, 2002, and amended at its meeting of 
November 7-8, 2002, following the submission of (1) a risk 
assessment by the German Federal Ministry of Consumer Protection, 
Food and Agriculture and (2) new scientific evidence regarding BSE 
infectivity distribution in tonsils, accessed online at http://www.europa.eu.int/comm/food/fs/bse/scientific_advice08_en.html.
    61. Department for Environment Food and Rural Affairs, United 
Kingdom, ``BSE: Statistics--Age at Clinical Onset in Years by Birth 
Cohort,'' accessed online at http://www.defra.gov.uk/animalh/bse/statistics/bse/age.htm.
    62. Wilesmith, J. W. and J. B. M. Ryan, ``Bovine Spongiform 
Encephalopathy: Recent Observations on the Age-Specific 
Incidences,'' Veterinary Record, 130:491-492, 1992.
    63. Health and Consumer Protection Directorate-General, European 
Commission, ``Report on the Monitoring and Testing of Ruminants for 
the Presence of Transmissible Spongiform Encephalopathy (TSE) in 
2002,'' 2003, accessed online at http://www.europa.eu.int/comm/food/food/biosafety/bse/annual_report_2002_en.pdf.
    64. Doherr, M. G., D. Heim, R. Fatzer, et al., ``Targeted 
Screening of High-Risk Cattle Populations for BSE to Augment 
Mandatory Reporting of Clinical Suspects,'' Preventive Veterinary 
Medicine, 51:3-16, 2001.
    65. Taylor, D. M., S. L. Woodgate, and M. J. Atkinson, 
``Inactivation of the Bovine Spongiform Encephalopathy Agent by 
Rendering Procedures,'' Veterinary Record, 137:605-610, 1995.
    66. Taylor, D. M., S. L. Woodgate, A. J. Fleetwood, and R. J. G. 
Cawthorne, ``The Effect of Rendering Procedures on the Scrapie 
Agent,'' Veterinary Record, 141:643-649, 1997.
    67. Wilesmith, J. W., G. A. H. Wells, M. P. Cranwell, and J. B. 
M. Ryan, ``Bovine Spongiform Encephalopathy: Epidemiological 
Studies,'' Veterinary Record, 123:638-644, 1988.
    68. World Organisation for Animal Health (OIE), ``Terrestrial 
Animal Health Code, Bovine Spongiform Encephalopathy,'' 2005, 
accessed online at http://www.oie.int/eng/normes/mcode/en_chapitre_2.3.13.htm.
    69. U.S. Department of Health and Human Services, Food and Drug 
Administration, Transcript of meeting of the Transmissible 
Spongiform Encephalopathies Advisory Committee, April 16, 1998, 
accessed online at http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3406t2.pdf.

[[Page 1612]]

    70. U.S. Department of Health and Human Services, Centers for 
Disease Control and Prevention, ``Probable Variant Creutzfeldt-Jakob 
Disease in a U.K. Citizen Who Had Temporarily Resided in Texas, 
2001-2005, November 18, 2005, accessed online at http://www.cdc.gov/ncidod/dvrd/vcjd/other/probablevcjd_texas2001_2005_111805.htm.

List of Subjects

21 CFR Part 211

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.

21 CFR Part 226

    Animal drugs, Animal feeds, Labeling, Packaging and containers, 
Reporting and recordkeeping requirements.

21 CFR Part 300

    Drugs, Incorporation by reference, Prescription drugs.

21 CFR Part 500

    Animal drugs, Animal feeds, Cancer, Incorporation by reference, 
Labeling, Packaging and containers, Polychlorinated biphenyls (PCBs).

21 CFR Part 530

    Administrative practice and procedure, Advertising, Animal drugs, 
Labeling, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Incorporation by reference, Reporting and recordkeeping 
requirements.

21 CFR Part 895

    Administrative practice and procedure, Incorporation by reference, 
Labeling, Medical devices.

21 CFR Part 1271

    Biologics, Drugs, Human cells and tissue-based products, 
Incorporation by reference, Medical devices, Reporting and 
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, and 
under authority delegated to the Commissioner of Food and Drugs, FDA 
proposes to amend 21 CFR parts 211, 226, 300, 500, 530, 600, 895, and 
1271 as follows:

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

    1. The authority citation for 21 CFR part 211 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 
U.S.C. 216, 262, 263a, 264.

    2. Section 211.116 is added to subpart F to read as follows:


Sec.  211.116  Use of cattle material.

    Use of certain cattle material in drug products and components is 
prohibited as provided by Sec. Sec.  300.200, 500.200, and 600.16 of 
this chapter.

PART 226--CURRENT GOOD MANUFACTURING PRACTICE FOR TYPE A MEDICATED 
ARTICLES

    3. The authority citation for 21 CFR part 226 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 352, 360b, 371, 374.

    4. Section 226.60 is added to subpart C to read as follows:


Sec.  226.60  Use of cattle material.

    Use of certain cattle material in Type A medicated articles for 
ruminants is prohibited as provided by Sec.  500.200 of this chapter.

PART 300--GENERAL

    5. The authority citation for 21 CFR part 300 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360b, 361, 371, 
381; 42 U.S.C. 264, 271.

    6. Section 300.200 is added to subpart C to read as follows:


Sec.  300.200  Prohibited cattle materials.

    (a) Definitions. The definitions and interpretations of terms 
contained in section 201 of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 321) apply to such terms when used in this 
section. The following definitions also apply:
    (1) Prohibited cattle materials means specified risk materials; 
small intestine of all cattle except as provided in paragraph (b)(3) of 
this section; material from nonambulatory disabled cattle; material 
from cattle not inspected and passed; or mechanically separated beef. 
Prohibited cattle materials do not include tallow that contains no more 
than 0.15 percent insoluble impurities, tallow derivatives, hides and 
hide-derived products, and milk and milk products. Prohibited cattle 
materials also do not include materials obtained from fetal calves of 
cows that were inspected and passed, as long as the materials were 
obtained by procedures adequate to prevent contamination with specified 
risk materials.
    (2) Inspected and passed means that the material is from an animal 
that has been inspected and passed for human consumption by the 
appropriate regulatory authority, and at the time the animal was 
inspected and passed, it was found to be not adulterated.
    (3) Mechanically separated beef means a meat food product that is 
finely comminuted, resulting from the mechanical separation and removal 
of most of the bone from attached skeletal muscle of cattle carcasses 
and parts of carcasses, that meets the specifications contained in 9 
CFR 319.5, the U. S. Department of Agriculture's (USDA's) regulation 
that prescribes the standard of identity for Mechanically Separated 
(Species).
    (4) Nonambulatory disabled cattle means cattle that cannot rise 
from a recumbent position or that cannot walk, including, but not 
limited to, those with broken appendages, severed tendons or ligaments, 
nerve paralysis, fractured vertebral column, or metabolic conditions.
    (5) Specified risk materials means the brain, skull, eyes, 
trigeminal ganglia, spinal cord, vertebral column (excluding the 
vertebrae of the tail, the transverse processes of the thoracic and 
lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia 
of cattle 30 months and older, and the tonsils and distal ileum of the 
small intestine of all cattle.
    (6) Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain not more than 0.15 percent insoluble 
impurities as determined by the method entitled ``Insoluble 
Impurities'' (AOCS Official Method Ca 3a-46), American Oil Chemists' 
Society (AOCS), 5th Edition, 1997, incorporated by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51, or another method 
equivalent in accuracy, precision, and sensitivity to AOCS Official 
Method Ca 3a-46. You may obtain copies of the method from the AOCS 
(http://www.aocs.org) 2211 W. Bradley Ave., Champaign, IL 61821. Copies 
may be examined at the Center for Food Safety and Applied Nutrition's 
Library, 5100 Paint Branch Pkwy., College Park, MD 20740, or at the 
National Archives and Records Administration (NARA). For information on 
the availability of this material at NARA, call 202-741-6030, or go to: 
http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
    (7) Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or 
trans-esterification may be applied to obtain the desired product.

[[Page 1613]]

    (b) Requirements. (1) At a minimum, except as provided in paragraph 
(b)(2) of this section, no drug intended for use in humans shall be 
manufactured from, or otherwise contain, prohibited cattle materials 
obtained from cattle slaughtered on or after [effective date of final 
rule].
    (2) The requirements in paragraph (b)(1) of this section with 
respect to prohibited cattle materials shall not apply if FDA grants 
written permission for an exception or alternative to such 
requirements.
    (i) To obtain written permission from FDA, you must send a written 
request to the Director of the Center for Drug Evaluation and Research, 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. 
For a drug subject to an application, your written request must 
reference its application number. The Center Director may also grant 
written permission for an exception or alternative to the requirements 
in paragraph (b)(1) of this section on his own initiative and shall 
base such a determination on an evaluation of the criteria described in 
paragraph (b)(2)(ii) of this section. You must maintain a record of any 
exception or alternative to the requirements in paragraph (b)(1) of 
this section that is granted by FDA, in accordance with paragraph (c) 
of this section.
    (ii) A written request for an exception or alternative to the 
requirements in paragraph (b)(1) of this section must include, for each 
applicable product:
    (A) A statement of the reasons why an exception or alternative is 
needed;
    (B) A description of the product, including the type of prohibited 
cattle materials used in its manufacturing, its manufacturing and 
purification processes, and its route of administration;
    (C) A description of the source of the prohibited cattle materials, 
including information on the location where the cattle were born, 
raised, and slaughtered, and any other information relevant to the 
likelihood of the cattle having ingested material prohibited under 
Sec.  589.2000 of this chapter;
    (D) A description of how the requirements in paragraph (b)(1) of 
this section are not necessary based on the risks of the prohibited 
cattle materials in the product and the benefits of the product or how 
such restrictions are not necessary to ensure the safety of the 
product; and
    (E) Any other relevant information.
    (iii) FDA shall respond in writing to all requests for an exception 
or alternative to the requirements and may impose conditions in 
granting any such request.
    (3) The small intestine is not considered prohibited cattle 
material if the distal ileum is removed by a procedure that removes at 
least 80 inches of the uncoiled and trimmed small intestine, as 
measured from the caeco-colic junction and progressing proximally 
towards the jejunum, or by a procedure that the establishment can 
demonstrate is equally effective in ensuring complete removal of the 
distal ileum.
    (c) Records. (1) Applicants and manufacturers of a drug that is 
manufactured from, or otherwise contains, cattle material must 
establish and maintain records sufficient to demonstrate that the 
material is not manufactured from, and does not contain, prohibited 
cattle materials.
    (2) Records must be retained for at least 1 year after the 
expiration date of the drug or, for drugs lacking an expiration date, 
at least 3 years after distribution of the last lot of the drug.
    (3) Records must be retained at the applicant's or manufacturer's 
establishment or at a reasonably accessible location. Records are 
considered to be reasonably accessible if they are accessible from an 
onsite location.
    (4) Records required by this section must be readily available to 
FDA for inspection and copying. All the records must be in English.
    (5) When filing entry with the U.S. Customs and Border Protection, 
the importer of record of a drug manufactured from, or otherwise 
containing, cattle material must affirm that the drug was manufactured 
from, or otherwise contains, cattle material and must affirm that the 
drug was manufactured in accordance with this section. If a drug was 
manufactured from, or otherwise contains, cattle material, then the 
importer of record must, if requested, provide to FDA within 5 days 
records that are sufficient to demonstrate that the drug is not 
manufactured from, and does not contain, prohibited cattle material.
    (d) A human drug that is not in compliance with the requirements of 
paragraph (b) of this section is adulterated under section 501(a)(2)(B) 
of the act (21 U.S.C. 351(a)(2)(B)).
    (e) Failure of an applicant or manufacturer to comply with the 
requirements of paragraph (c) of this section renders a drug 
adulterated under section 501(a)(2)(B) of the act (21 U.S.C. 
351(a)(2)(B)).
    (f) Failure of an importer of record to comply with the 
requirements of paragraph (c) of this section causes a drug to appear 
to be adulterated under section 801(a) of the act (21 U.S.C. 381(a)).
    (g) A human drug that is a new drug and that is not in compliance 
with the requirements of paragraph (b) of this section is in violation 
of section 505 of the act (21 U.S.C. 355).
    (h) Failure of an applicant or manufacturer to comply with the 
requirements of paragraph (c) of this section is a violation of section 
301(e) of the act (21 U.S.C. 331(e)).
    (i) Any person who violates the requirements of paragraph (b) or 
(c) of this section shall be subject to the penalties provided in 
section 368 of the Public Health Service Act (42 U.S.C. 271).

PART 500--GENERAL

    7. The authority citation for 21 CFR part 500 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 342, 343, 348, 351, 352, 353, 
360b, 371, 381; 42 U.S.C. 264, 271.

    8. New subpart F is added to part 500 to read as follows:

Subpart F--Substances Prohibited From Animal Drugs


Sec.  500.200  Prohibited cattle materials in drugs intended for use in 
ruminants.

    (a) Definitions. The definitions and interpretations of terms 
contained in section 201 of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 321) apply to such terms when used in this 
section. The following definitions also apply:
    (1) Prohibited cattle materials means specified risk materials; 
small intestine of all cattle except as provided in paragraph (b)(3) of 
this section; material from nonambulatory disabled cattle; material 
from cattle not inspected and passed; or mechanically separated beef. 
Prohibited cattle materials do not include tallow that contains no more 
than 0.15 percent insoluble impurities, tallow derivatives, hides and 
hide-derived products, and milk and milk products. Prohibited cattle 
materials also do not include materials obtained from fetal calves of 
cows that were inspected and passed, as long as the materials were 
obtained by procedures adequate to prevent contamination with specified 
risk materials.
    (2) Inspected and passed means that the material is from an animal 
that has been inspected and passed for human consumption by the 
appropriate regulatory authority, and at the time the animal was 
inspected and passed, it was found to be not adulterated.
    (3) Mechanically separated beef means a meat food product that is 
finely

[[Page 1614]]

comminuted, resulting from the mechanical separation and removal of 
most of the bone from attached skeletal muscle of cattle carcasses and 
parts of carcasses, that meets the specifications contained in 9 CFR 
319.5, the U. S. Department of Agriculture's (USDA's) regulation that 
prescribes the standard of identity for Mechanically Separated 
(Species).
    (4) Nonambulatory disabled cattle means cattle that cannot rise 
from a recumbent position or that cannot walk, including, but not 
limited to, those with broken appendages, severed tendons or ligaments, 
nerve paralysis, fractured vertebral column or metabolic conditions.
    (5) Specified risk materials means the brain, skull, eyes, 
trigeminal ganglia, spinal cord, vertebral column (excluding the 
vertebrae of the tail, the transverse processes of the thoracic and 
lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia 
of cattle 30 months and older and the tonsils and distal ileum of the 
small intestine of all cattle.
    (6) Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain not more than 0.15 percent insoluble 
impurities as determined by the method entitled ``Insoluble 
Impurities'' (AOCS Official Method Ca 3a-46), American Oil Chemists' 
Society (AOCS), 5th Edition, 1997, incorporated by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51, or another method 
equivalent in accuracy, precision, and sensitivity to AOCS Official 
Method Ca 3a-46. You may obtain copies of the method from AOCS (http://www.aocs.org) 2211 W. Bradley Ave., Champaign, IL 61821. Copies may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
5100 Paint Branch Pkwy., College Park, MD 20740, or at the National 
Archives and Records Administration (NARA). For information on the 
availability of this material at NARA, call 202-741-6030, or go to: 
http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
    (7) Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or 
trans-esterification may be applied to obtain the desired product.
    (8) Ruminant means any member of the suborder of animals that has a 
stomach with four compartments (rumen, reticulum, omasum, and abomasum) 
through which feed passes in digestion. The suborder includes, but is 
not limited to, cattle, buffalo, sheep, goats, deer, elk, and 
antelopes.
    (b) Requirements. (1) At a minimum, except as provided in paragraph 
(b)(2) of this section, no drug intended for use in ruminants shall be 
manufactured from, or otherwise contain, prohibited cattle materials 
obtained from cattle slaughtered on or after [effective date of final 
rule].
    (2) The requirements in paragraph (b)(1) of this section with 
respect to prohibited cattle materials shall not apply if FDA grants 
written permission for an exception or alternative to such 
requirements.
    (i) To obtain written permission from FDA, you must send a written 
request to the Director of the Center for Veterinary Medicine, 7519 
Standish Place, Rockville, MD 20855. For a drug intended for use in 
ruminants that is subject to a new animal drug application, your 
written request must reference its application number. The Center 
Director may also grant written permission for an exception or 
alternative to the requirements in paragraph (b)(1) of this section on 
his own initiative and shall base such a determination on an evaluation 
of the criteria described in paragraph (b)(2)(ii) of this section. You 
must maintain a record of any exception or alternative to the 
requirements in paragraph (b)(1) of this section that is granted by 
FDA, in accordance with paragraph (c) of this section.
    (ii) A written request for an exception or alternative to the 
requirements in paragraph (b)(1) of this section must include, for each 
applicable product:
    (A) A statement of the reasons why the exception or alternative is 
needed;
    (B) A description of the product, including the type of prohibited 
cattle materials used in its manufacturing, its manufacturing and 
purification processes, and its route of administration;
    (C) A description of the source of the prohibited cattle materials, 
including information on the location where the cattle were born, 
raised, and slaughtered, and any other information relevant to the 
likelihood of the cattle having ingested material prohibited under 
Sec.  589.2000 of this chapter;
    (D)( 1) A description of how the requirements in paragraph (b)(1) 
of this section are not necessary:
    (i) Based on the risks of the prohibited cattle materials in the 
product to the target animal and the benefits of the product to the 
target animal; and
    (ii) To ensure a reasonable certainty of no harm to humans from any 
food derived from the target animal to which the product was 
administered; or
    (2) A description of how the requirements in paragraph (b)(1) of 
this section are not necessary to ensure the safety of the product with 
respect to both the target animal and any food derived from the target 
animal to which the product is administered; and
    (E) Any other relevant information.
    (iii) FDA shall respond in writing to all requests for an exception 
or alternative to the requirements and may impose conditions in 
granting any such request.
    (3) The small intestine is not considered prohibited cattle 
material if the distal ileum is removed by a procedure that removes at 
least 80 inches of the uncoiled and trimmed small intestine, as 
measured from the caeco-colic junction and progressing proximally 
towards the jejunum, or by a procedure that the establishment can 
demonstrate is equally effective in ensuring complete removal of the 
distal ileum.
    (c) Records. (1) Applicants and manufacturers of a drug intended 
for use in ruminants that is manufactured from, or otherwise contains, 
any cattle material must establish and maintain records sufficient to 
demonstrate that the material is not manufactured from, and does not 
contain, prohibited cattle materials.
    (2) The following record retention periods apply:
    (i) Records for a Type A medicated article intended for use in 
ruminants that is manufactured from, or otherwise contains, any cattle 
material must be retained for at least 2 years after distribution by 
the manufacturer.
    (ii) Records for a drug intended for use in ruminants, other than a 
Type A medicated article, that is manufactured from, or otherwise 
contains, any cattle material must be retained for at least 1 year 
after the expiration date of the drug.
    (3) Records must be retained at the applicant's or manufacturer's 
establishment or at a reasonably accessible location. Records are 
considered to be reasonably accessible if they are accessible from an 
onsite location.
    (4) Records required by this section must be available to FDA for 
inspection and copying. All the records must be in English.
    (5) When filing entry with the U.S. Customs and Border Protection, 
the importer of record of a drug intended for

[[Page 1615]]

use in ruminants that was manufactured from, or otherwise contains, 
cattle material must affirm that the drug was manufactured from, or 
otherwise contains, cattle material and must affirm that the drug was 
manufactured in accordance with this section. If a drug was 
manufactured from, or otherwise contains, cattle material, then the 
importer of record must, if requested, provide to FDA within 5 days 
records that are sufficient to demonstrate that the drug is not 
manufactured from, and does not contain, prohibited cattle material.
    (d) A drug intended for use in ruminants that is not in compliance 
with the requirements of paragraph (b) of this section is adulterated 
under section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B)).
    (e) Failure of an applicant or manufacturer to comply with the 
requirements of paragraph (c) of this section renders a drug intended 
for use(s) in ruminants adulterated under section 501(a)(2)(B) of the 
act (21 U.S.C. 351(a)(2)(B)).
    (f) Failure of an importer of record to comply with the 
requirements of paragraph (c) of this section causes a drug intended 
for use(s) in ruminants to appear to be adulterated under section 
801(a) of the act (21 U.S.C. 381(a)).
    (g) A drug intended for use in ruminants that is a new animal drug 
and that is not in compliance with the requirements of paragraph (b) of 
this section is in violation of section 512 of the act (21 U.S.C. 
360b).
    (h) Failure of an applicant or manufacturer to comply with the 
requirements of paragraph (c) of this section is in violation of 
section 301(e) of the act (21 U.S.C. 331(e)).
    (i) Any person who violates the requirements of paragraph (b) or 
(c) of this section shall be subject to the penalties provided in 
section 368 of the Public Health Service Act (42 U.S.C. 271).

PART 530--EXTRALABEL DRUG USE IN ANIMALS

    9. The authority citation for 21 CFR part 530 is revised to read as 
follows:

    Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 351, 
352, 353, 355, 357, 360b, 371, 379e; 42 U.S.C. 264, 271.

    10. Section 530.41 is amended by removing the word ``for'' from the 
section heading, paragraph (a) introductory text, and paragraph (b) and 
adding in its place the word ``from''; and by adding paragraph (c) to 
read as follows:


Sec.  530.41  Drugs prohibited from extralabel use in animals.

* * * * *
    (c) Drugs that contain prohibited cattle material as defined in 
Sec. Sec.  300.200(a)(1) and 500.200(a)(1) of this chapter are 
prohibited from extralabel use in ruminants.
* * * * *
    11. Section 530.42 is added to subpart E to read as follows:


Sec.  530.42  Labeling requirements for new animal drugs prohibited 
from extralabel use in animals.

    (a) The labeling of any approved new animal drug that is prohibited 
from extralabel use in ruminants by Sec.  530.41(c) must bear the 
statement ``Federal law prohibits the extralabel use of this product in 
ruminants.''
    (b) Failure to comply with the labeling requirements in paragraph 
(a) of this section renders a drug misbranded under section 502(a) of 
the act.

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    12. The authority for 21 CFR part 600 is revised to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374, 381; 42 U.S.C. 216, 262, 263, 263a, 264, 271, 300aa-25.

    13. Section 600.16 is added to subpart B to read as follows:


Sec.  600.16  Prohibited cattle materials.

    (a) Definitions. The definitions and interpretations of terms 
contained in section 201 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 321), section 351 of the Public Health Service Act (the PHS 
Act) (42 U.S.C. 262), and Sec.  600.3 apply to such terms when used in 
this section. The following definitions also apply:
    (1) Prohibited cattle materials means specified risk materials; 
small intestine of all cattle except as provided in paragraph (b)(3) of 
this section; material from nonambulatory disabled cattle; material 
from cattle not inspected and passed; or mechanically separated beef. 
Prohibited cattle materials do not include tallow that contains no more 
than 0.15 percent insoluble impurities, tallow derivatives, hides and 
hide-derived products, and milk and milk products. Prohibited cattle 
materials also do not include materials obtained from fetal calves of 
cows that were inspected and passed, as long as the materials were 
obtained by procedures adequate to prevent contamination with specified 
risk materials.
    (2) Inspected and passed means that the material is from an animal 
that has been inspected and passed for human consumption by the 
appropriate regulatory authority, and at the time the animal was 
inspected and passed, it was found to be not adulterated.
    (3) Mechanically separated beef means a meat food product that is 
finely comminuted, resulting from the mechanical separation and removal 
of most of the bone from attached skeletal muscle of cattle carcasses 
and parts of carcasses, that meets the specifications contained in 9 
CFR 319.5, the U. S. Department of Agriculture's (USDA's) regulation 
that prescribes the standard of identity for Mechanically Separated 
(Species).
    (4) Nonambulatory disabled cattle means cattle that cannot rise 
from a recumbent position or that cannot walk, including, but not 
limited to, those with broken appendages, severed tendons or ligaments, 
nerve paralysis, fractured vertebral column, or metabolic conditions.
    (5) Specified risk materials means the brain, skull, eyes, 
trigeminal ganglia, spinal cord, vertebral column (excluding the 
vertebrae of the tail, the transverse processes of the thoracic and 
lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia 
of cattle 30 months and older, and the tonsils and distal ileum of the 
small intestine of all cattle.
    (6) Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain not more than 0.15 percent insoluble 
impurities as determined by the method entitled ``Insoluble 
Impurities'' (AOCS Official Method Ca 3a-46), American Oil Chemists' 
Society (AOCS), 5th Edition, 1997, incorporated by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51, or another method 
equivalent in accuracy, precision, and sensitivity to AOCS Official 
Method Ca 3a-46. You may obtain copies of the method from AOCS (http://www.aocs.org) 2211 W. Bradley Ave., Champaign, IL 61821. Copies may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
5100 Paint Branch Pkwy., College Park, MD 20740, or at the National 
Archives and records Administration (NARA). For information on the 
availability of this material at NARA, call 202-741-6030, or go to: 
http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.

[[Page 1616]]

    (7) Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or 
trans-esterification may be applied to obtain the desired product.
    (b) Requirements. (1) At a minimum, except as provided in 
paragraphs (b)(2) and (b)(4) of this section, no biological product 
intended for use in humans shall be manufactured from, or otherwise 
contain, prohibited cattle materials obtained from cattle slaughtered 
on or after [effective date of final rule].
    (2) The requirements in paragraph (b)(1) of this section with 
respect to prohibited cattle materials shall not apply if FDA grants 
written permission for an exception or alternative to such 
requirements.
    (i) To obtain written permission from FDA, you must send a written 
request to the Director of the Center for Biologics Evaluation and 
Research (see Sec.  600.2 for mailing address) or the Director of the 
Center for Drug Evaluation and Research, Food and Drug Administration, 
5600 Fishers lane, Rockville, MD 20857, depending on the Center with 
primary jurisdiction over the product. Your written request must 
reference its application number. The Center Director may also grant 
written permission for an exception or alternative to the requirements 
in paragraph (b)(1) of this section on his own initiative and shall 
base such a determination on an evaluation of the criteria described in 
paragraph (b)(2)(ii) of this section. You must maintain a record of any 
exception or alternative to the requirements in paragraph (b)(1) of 
this section that is granted by FDA, in accordance with paragraph (c) 
of this section.
    (ii) A written request for an exception or alternative to the 
requirements in paragraph (b)(1) of this section must include, for each 
applicable product:
    (A) A statement of the reasons why an exception or alternative is 
needed;
    (B) A description of the product, including the type of prohibited 
cattle materials used in its manufacturing, its manufacturing and 
purification processes, and its route of administration;
    (C) A description of the source of the prohibited cattle materials, 
including information on the location where the cattle were born, 
raised, and slaughtered, and any other information relevant to the 
likelihood of the cattle having ingested material prohibited under 
Sec.  589.2000 of this chapter;
    (D) A description of how the requirements in paragraph (b)(1) in 
this section are not necessary based on the risks of the prohibited 
cattle materials in the product and the benefits of the product or how 
such restrictions are not necessary to ensure the safety of the 
product; and
    (E) Any other relevant information.
    (iii) FDA shall respond in writing to all requests for an exception 
or alternative to the requirements and may impose conditions in 
granting any request.
    (3) The small intestine is not considered prohibited cattle 
material if the distal ileum is removed by a procedure that removes at 
least 80 inches of the uncoiled and trimmed small intestine, as 
measured from the caeco-colic junction and progressing proximally 
towards the jejunum, or by a procedure that the establishment can 
demonstrate is equally effective in ensuring complete removal of the 
distal ileum.
    (4) Biological products that are not intended for use in or on the 
body (e.g., in vitro diagnostics) are not subject to the requirements 
of paragraph (b)(1) of this section.
    (c) Records. (1) Establishments that manufacture a biological 
product intended for use in or on the body that is manufactured from, 
or otherwise contains, cattle material must establish and maintain 
records sufficient to demonstrate that the material is not manufactured 
from, and does not contain, prohibited cattle materials.
    (2) Records must be retained consistent with Sec.  600.12(b).
    (3) Records must be retained at the manufacturer's establishment or 
at a reasonably accessible location. Records are considered to be 
reasonably accessible if they are accessible from an onsite location.
    (4) Records required by this section must be available to FDA for 
inspection and copying. All the records must be in English.
    (5) When filing entry with the U.S. Customs and Border Protection, 
the importer of record of a biological product intended for use in or 
on the body that was manufactured from, or otherwise contains, cattle 
material must affirm that the product was manufactured from, or 
otherwise contains, cattle material and must affirm that the product 
was manufactured in accordance with this section. If a product was 
manufactured from, or otherwise contains, cattle material, then the 
importer of record must, if requested, provide to FDA within 5 days 
records that are sufficient to demonstrate that the product is not 
manufactured from, and does not contain, prohibited cattle material.
    (d) A biological product that is a drug and that is not in 
compliance with the requirements of paragraph (b) of this section is 
adulterated under section 501(a)(2)(B) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 351(a)(2)(B)) and not safe, pure, and potent 
under section 351 of the PHS Act (42 U.S.C. 262).
    (e) Failure of an applicant or manufacturer of a biological product 
that is a drug to comply with the requirements of paragraph (c) of this 
section renders such product adulterated under section 501(a)(2)(B) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)) and 
not safe, pure, and potent under section 351 of the PHS Act (42 U.S.C. 
262).
    (f) Failure of an importer of record to comply with the 
requirements of paragraph (c) of this section causes a biological 
product to appear to be adulterated under section 801(a) of the act (21 
U.S.C. 381).
    (g) A biological product that is a new drug and that is not in 
compliance with the requirements of paragraph (b) of this section is in 
violation of section 505 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 355) and section 351 of the PHS Act (42 U.S.C. 262).
    (h) A biological product that is a device and that is not in 
compliance with the requirements of paragraph (b) of this section is 
adulterated under section 501(g) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 351(g)) and in violation of section 351 of the 
PHS Act (42 U.S.C. 262).
    (i) Failure of an applicant or manufacturer to comply with the 
requirements of paragraph (c) of this section is a violation of section 
301(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 331(e)).
    (j) Any person who violates the requirements of paragraph (b) or 
(c) of this section shall be subject to the penalties provided in 
section 368 of the PHS Act (42 U.S.C. 271).

PART 895--BANNED DEVICES

    14. The authority citation for 21 CFR part 895 is revised to read 
as follows:

    Authority: 21 U.S.C. 331, 351, 352, 360f, 360h, 360i, 371, 381; 
42 U.S.C. 264, 271.

    15. Section 895.102 is added to subpart B to read as follows:


Sec.  895.102  Prohibited cattle materials.

    (a) Definitions. The definitions and interpretations of terms 
contained in section 201 of the Federal Food, Drug, and Cosmetic Act 
(the act) (21 U.S.C. 321) apply to such terms when used in

[[Page 1617]]

this section. The following definitions also apply:
    (1) Prohibited cattle materials means specified risk materials; 
small intestine of all cattle except as provided in paragraph (b)(3) of 
this section; material from nonambulatory disabled cattle; material 
from cattle not inspected and passed; or mechanically separated beef. 
Prohibited cattle materials do not include tallow that contains no more 
that 0.15 percent insoluble impurities, tallow derivatives, hides and 
hide-derived products, and milk and milk products. Prohibited cattle 
materials also do not include materials obtained from fetal calves of 
cows that were inspected and passed, as long as the materials were 
obtained by procedures adequate to prevent contamination with specified 
risk materials.
    (2) Inspected and passed means that the material is from an animal 
that has been inspected and passed for human consumption by the 
appropriate regulatory authority, and at the time the animal was 
inspected and passed, it was found to be not adulterated.
    (3) Mechanically separated beef means a meat food product that is 
finely comminuted, resulting from the mechanical separation and removal 
of most of the bone from attached skeletal muscle of cattle carcasses 
and parts of carcasses, that meets the specifications contained in 9 
CFR 319.5, the U. S. Department of Agriculture's (USDA's) regulation 
that prescribes the standard of identity for Mechanically Separated 
(Species).
    (4) Nonambulatory disabled cattle means cattle that cannot rise 
from a recumbent position or that cannot walk, including, but not 
limited to, those with broken appendages, severed tendons or ligaments, 
nerve paralysis, fractured vertebral column, or metabolic conditions.
    (5) Specified risk materials means the brain, skull, eyes, 
trigeminal ganglia, spinal cord, vertebral column (excluding the 
vertebrae of the tail, the transverse processes of the thoracic and 
lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia 
of cattle 30 months or older and the tonsils and distal ileum of the 
small intestine of all cattle.
    (6) Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain not more than 0.15 percent insoluble 
impurities determined by the method entitled ``Insoluble Impurities'' 
(AOCS Official Method Ca 3a-46), American Oil Chemists' Society (AOCS), 
5th Edition, 1997, incorporated by reference in accordance with 5 
U.S.C. 552(a) and 1 CFR part 51, or another method equivalent in 
accuracy, precision, and sensitivity to AOCS Official Method Ca 3a-46. 
You may obtain copies of the method from AOCS (http://www.aocs.org) 
2211 W. Bradley Ave., Champaign, IL 61821. Copies may be examined at 
the Center for Food Safety and Applied Nutrition's Library, 5100 Paint 
Branch Pkwy., College Park, MD 20740, or at the National Archives and 
Records Administration (NARA). For information on the availability of 
this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
    (7) Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or 
trans-esterification may be applied to obtain the desired product.
    (b) Requirements. (1) At a minimum, except as provided in paragraph 
(b)(2) of this section, no medical device for humans that is intended 
for use in or on the body shall be manufactured from, or otherwise 
contain, prohibited cattle materials obtained from cattle slaughtered 
on or after [effective date of final rule].
    (2) The requirements in paragraph (b)(1) of this section with 
respect to prohibited cattle materials shall not apply if FDA grants 
written permission for an exception or alternative to such 
requirements.
    (i) To obtain written permission from FDA, you must send a written 
request to the Director of the Center for Devices and Radiological 
Health, 9200 Corporate Blvd., Rockville, MD 20850. For a device subject 
to premarket approval or premarket clearance, your written request must 
reference its application number. The Center Director may also grant 
written permission for an exception or alternative to the requirements 
in paragraph (b)(1) of this section on his own initiative and shall 
base such a determination on an evaluation of the criteria described in 
paragraph (b)(2)(ii) of this section. You must maintain a record of any 
exception or alternative to the requirements in paragraph (b)(1) of 
this section that is granted by FDA, in accordance with paragraph (c) 
of this section.
    (ii) A written request for an exception or alternative to the 
requirements in paragraph (b)(1) of this section must include, for each 
applicable product:
    (A) A statement of the reasons why an exception or alternative is 
needed;
    (B) A description of the product, including the type of prohibited 
cattle materials used in its manufacturing, its manufacturing and 
purification processes, and its route of administration;
    (C) A description of the source of the prohibited cattle materials, 
including information on the location where the cattle were born, 
raised, and slaughtered, and any other information relevant to the 
likelihood of the cattle having ingested material prohibited under 
Sec.  589.2000 of this chapter;
    (D) A description of how the requirements in paragraph (b)(1) of 
this section are not necessary based on the risks of the prohibited 
cattle materials in the product and the benefits of the product or how 
such restrictions are not necessary to ensure the safety of the 
product; and
    (E) Any other relevant information.
    (iii) FDA shall respond in writing to all requests for an exception 
or alternative to the requirements and may impose conditions in 
granting any such request.
    (3) The small intestine is not considered prohibited cattle 
material if the distal ileum is removed by a procedure that removes at 
least 80 inches of the uncoiled and trimmed small intestine, as 
measured from the caeco-colic junction and progressing proximally 
towards the jejunum, or by a procedure that the establishment can 
demonstrate is equally effective in ensuring complete removal of the 
distal ileum.
    (c) Records. (1) Applicants and manufacturers of a medical device 
that is intended for use in or on the body that is manufactured from, 
or otherwise contains, cattle material must establish and maintain 
records sufficient to demonstrate that the material is not manufactured 
from, and does not contain, prohibited cattle materials.
    (2) Records must be retained consistent with Sec.  820.180(b) of 
this chapter.
    (3) Records must be retained at the applicant's or manufacturer's 
establishment or at a reasonably accessible location. Records are 
considered to be reasonably accessible if they are accessible from an 
onsite location.
    (4) Records required by this section must be available to FDA for 
inspection and copying. All the records must be in English.
    (5) When filing entry with the U.S. Customs and Border Protection, 
the

[[Page 1618]]

importer of record of a medical device intended for use in or on the 
body that was manufactured from, or otherwise contains, cattle material 
must affirm that the device was manufactured from, or otherwise 
contains, cattle material and must affirm that the device was 
manufactured in accordance with this section. If a device was 
manufactured from, or otherwise contains, cattle material, then the 
importer of record must, if requested, provide to FDA within 5 days 
records that are sufficient to demonstrate that the device is not 
manufactured from, and does not contain, prohibited cattle material.
    (d) A medical device that is intended for use in or on the body 
that is not in compliance with the requirements of paragraph (b) of 
this section is adulterated under section 501(g) of the act (21 U.S.C. 
351(g)).
    (e) Failure of an applicant or manufacturer of a medical device 
that is intended for use in or on the body to comply with the 
requirements of paragraph (c) of this section renders the device 
misbranded under section 502(t) of the act (21 U.S.C. 352(t)).
    (f) Failure of an importer of record to comply with the 
requirements of paragraph (c) of this section causes a medical device 
that is intended for use in or on the body to appear to be adulterated 
under section 801 of the act (21 U.S.C. 381).
    (g) Failure of an applicant or manufacturer to comply with the 
requirements of paragraph (c) of this section is a violation of section 
301(e) of the act (21 U.S.C. 331(e)).
    (h) Any person who violates the requirements of paragraph (b) or 
(c) of this section shall be subject to the penalties provided in 
section 368 of the Public Health Service Act (42 U.S.C. 271).

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

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

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

    17. Part 1271 is amended by adding new subpart G to read as 
follows:

Subpart G--Prohibited Cattle Materials


Sec.  1271.465  Applicability.

    The provisions set forth in this subpart are applicable only to 
HCT/Ps described in Sec.  1271.10 and regulated solely under section 
361 of the Public Health Service Act (the PHS Act) (42 U.S.C. 264) and 
the regulations in this part, and to the establishments that 
manufacture those HCT/Ps. HCT/Ps that are drugs or devices regulated 
under the Federal Food, Drug, and Cosmetic Act, or are biological 
products regulated under section 351 of the PHS Act (42 U.S.C. 262), 
are not subject to the regulations set forth in this subpart. Such 
products are subject to the applicable regulations for biological 
products and for drugs or devices.


Sec.  1271.470  Prohibited cattle materials.

    (a) Definitions. The following definitions apply to this section:
    (1) Prohibited cattle materials means specified risk materials; 
small intestine of all cattle except as provided in paragraph (b)(3) of 
this section; material from nonambulatory disabled cattle; material 
from cattle not inspected and passed; or mechanically separated beef. 
Prohibited cattle materials do not include tallow that contains no more 
than 0.15 percent insoluble impurities, tallow derivatives, hides and 
hide-derived products, and milk and milk products. Prohibited cattle 
materials also do not include materials obtained from fetal calves of 
cows that were inspected and passed, as long as the materials were 
obtained by procedures adequate to prevent contamination with specified 
risk materials.
    (2) Inspected and passed means that the material is from an animal 
that has been inspected and passed for human consumption by the 
appropriate regulatory authority, and at the time the animal was 
inspected and passed, it was found to be not adulterated.
    (3) Mechanically separated beef means a meat food product that is 
finely comminuted, resulting from the mechanical separation and removal 
of most of the bone from attached skeletal muscle of cattle carcasses 
and parts of carcasses, that meets the specifications contained in 9 
CFR 319.5, the U. S. Department of Agriculture's (USDA's) regulation 
that prescribes the standard of identity for Mechanically Separated 
(Species).
    (4) Nonambulatory disabled cattle means cattle that cannot rise 
from a recumbent position or that cannot walk, including, but not 
limited to, those with broken appendages, severed tendons or ligaments, 
nerve paralysis, fractured vertebral column, or metabolic conditions.
    (5) Specified risk materials means the brain, skull, eyes, 
trigeminal ganglia, spinal cord, vertebral column (excluding the 
vertebrae of the tail, the transverse processes of the thoracic and 
lumbar vertebrae, and the wings of the sacrum), and dorsal root ganglia 
of cattle 30 months and older, and the tonsils and distal ileum of the 
small intestine of all cattle.
    (6) Tallow means the rendered fat of cattle obtained by pressing or 
by applying any other extraction process to tissues derived directly 
from discrete adipose tissue masses or to other carcass parts and 
tissues. Tallow must be produced from tissues that are not prohibited 
cattle materials or must contain not more than 0.15 percent insoluble 
impurities as determined by the method entitled ``Insoluble 
Impurities'' (AOCS Official Method Ca 3a-46), American Oil Chemists' 
Society (AOCS), 5th Edition, 1997, incorporated by reference in 
accordance with 5 U.S.C. 552(a) and 1 CFR part 51, or another method 
equivalent in accuracy, precision, and sensitivity to AOCS Official 
Method Ca 3a-46. You may obtain copies of the method from AOCS (http://www.aocs.org) 2211 W. Bradley Ave., Champaign, IL 61821. Copies may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
5100 Paint Branch Pkwy., College Park, MD 20740, or at the National 
Archives and Records Administration (NARA). For information on the 
availability of this material at NARA, call 202-741-6030, or go to: 
http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
    (7) Tallow derivative means any chemical obtained through initial 
hydrolysis, saponification, or trans-esterification of tallow; chemical 
conversion of material obtained by hydrolysis, saponification, or 
trans-esterification may be applied to obtain the desired product.
    (b) Requirements. (1) At a minimum, except as provided in paragraph 
(b)(2) of this section, no HCT/P intended for use in humans shall be 
manufactured using, or otherwise contain, prohibited cattle materials 
obtained from cattle slaughtered on or after [effective date of final 
rule].
    (2) The requirements in paragraph (b)(1) of this section with 
respect to prohibited cattle materials shall not apply if FDA grants 
written permission for an exception or alternative to such 
requirements.
    (i) To obtain written permission from FDA, you must send a written 
request to the Director of the Center for Biologics Evaluation and 
Research (see Sec.  600.2 of this chapter for mailing address). The 
Center Director may also grant written permission for an exception or 
alternative to the requirements in paragraph (b)(1) of this section on 
his own initiative and shall base such a determination on an evaluation 
of the criteria described in

[[Page 1619]]

paragraph (b)(2)(ii) of this section. You must maintain a record of any 
exception or alternative from the requirements in paragraph (b)(1) of 
this section that is granted by FDA, in accordance with paragraph (c) 
of this section.
    (ii) A written request for an exception or alternative to the 
requirements in paragraph (b)(1) of this section must include, for each 
applicable product:
    (A) A statement of the reasons why an exception or alternative is 
needed;
    (B) A description of the product, including the type of prohibited 
cattle materials used in its manufacturing, its manufacturing and 
purification processes, and its route of administration;
    (C) A description of the source of the prohibited cattle materials, 
including information on the location where the cattle were born, 
raised, and slaughtered, and any other information relevant to the 
likelihood of the cattle having ingested material prohibited under 
Sec.  589.2000 of this chapter;
    (D) A description of how the requirements in paragraph (b)(1) of 
this section are not necessary based on the risks of the prohibited 
cattle materials in the product and the benefits of the product or how 
such restrictions are not necessary to ensure the safety of the 
product; and
    (E) Any other relevant information.
    (iii) FDA shall respond in writing to all requests for an exception 
or alternative to the requirements and may impose conditions in 
granting any request.
    (3) The small intestine is not considered prohibited cattle 
material if the distal ileum is removed by a procedure that removes at 
least 80 inches of the uncoiled and trimmed small intestine, as 
measured from the caeco-colic junction and progressing proximally 
towards the jejunum, or by a procedure that the establishment can 
demonstrate is equally effective in ensuring complete removal of the 
distal ileum.
    (c) Records. (1) Establishments that manufacture an HCT/P that is 
manufactured using, or otherwise contains, cattle material must 
establish and maintain records sufficient to demonstrate that the 
material is not manufactured using, and does not contain, prohibited 
cattle materials.
    (2) Records must be retained for the period specified in Sec.  
1271.270(d).
    (3) Records must be retained at the manufacturer's establishment or 
at a reasonably accessible location. Records are considered to be 
reasonably accessible if they are accessible from an onsite location.
    (4) Records required by this section must be available to FDA for 
inspection and copying. All the records must be in English.
    (5) When filing entry with the U.S. Customs and Border Protection, 
the importer of record of an HCT/P manufactured using, or otherwise 
containing, cattle material must affirm that the HCT/P was manufactured 
using, or otherwise contains, cattle material and must affirm that the 
HCT/P was manufactured in accordance with this section. If an HCT/P was 
manufactured using, or otherwise contains, cattle material, then the 
importer of record must, if requested, provide to FDA within 5 days 
records that are sufficient to demonstrate that the HCT/P is not 
manufactured using, and does not contain, prohibited cattle material.
    (d) An HCT/P that is not in compliance with the requirements of 
paragraph (b) or (c) of this section is a violative HCT/P that is 
subject to retention, recall, destruction, and/or cessation of 
manufacturing under Sec.  1271.440.

    Dated: December 7, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-22329 Filed 1-11-07; 8:45 am]
BILLING CODE 4160-01-S