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13 January 2007
[Federal Register: January 12, 2007 (Volume 72, Number 8)]
[Proposed Rules]
[Page 1581-1619]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12ja07-25]
[[Page 1581]]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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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
[[Page 1582]]
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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.
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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:
vikki.kinsey@fda.hhs.gov.
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: stephen.ripley@fda.hhs.gov.
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:
scott.mcnamee@fda.hhs.gov.
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: michael.popek@fda.hhs.gov.
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\
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\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.
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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
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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