Attachment II - Page 45 
Federal Register / 
1G6, 167), the Organic Act of September 
21, 1944 (7 U.S.C. 147a), the Noxious 
Weed Act of 1974 (7 U.S.C. 2801 et seq.), 
the Federal Seed Act (7 U.S.C. 551 et 
seq ), the Plant Variety Act (7 U.S.C. 
2321 et seq.), the Federal Meat 
Inspection Act (21 U.S.C. 601 et seq.), 
and the Poultry Products Inspection Act 
(21 U.S.C. 451 et seq.). These are the 
authorities USDA expects to be most 
relevant to present or potential 
developers and producers of agricultural 
products of the modem biotechnology. 
B. Veterinary Biological Products 
Under authority of the Virus-Serum 
Toxm Act of 1913 referred to below as 
"Vbf Act,” the USDA ha3 regulatory 
responsibility over all veterinary 
biologies imported into the United 
States or shipped or delivered for 
shipment interstate. Such products may 
not be shipped or delivered for shipment 
interstate or imported if they are 
worthless, contaminated, dangerous, or 
harmful. Products prepared for interstate 
shipment must be prepared in a USDA- 
licensed establishment under 
regulations promulgated by the 
Secretary. Those which are imported 
into the United States must be imported 
under a permit issued by the Secretary. 
The pertinent regulations are found in 9 
CFR Parts 101 through 117. 
Veterinary biological products are 
defined in 9 CFR 101. 2(w) as “all 
viruses, serums, toxins, and analogous 
products of natural or synthetic origin, 
such as diagnostics, antitoxins, 
vaccines, live microorganisms, killed 
microorganisms, and the antigenic or 
immunizing components of 
microorganisms intended for use In the 
diagnosis, treatment, or prevention of 
diseases of animals." 
The licensing provisions are found in 
9 CFR 102 of the regulations. A U.S. 
Veterinary Biological Product License is 
required for each veterinary biological 
product authorized to be produced in a 
licensed establishment. 
Requirements for Product License 
The issuance of a product license 
requires the satisfactory completion of 
the following requirements discussed 
below to assure purity, safety, potency, 
and efficacy. 
1. A detailed "Outline of Production" 
that describes all procedures used to 
produce each serial of a product must be 
prepared and filed with the USDA. 
2. To assist in maintaining uniformity 
of product, licensees are required to 
establish a Master Seed of bacteria, 
viruses, or other microorganisms at a 
specific passage level to be used as the 
source of all seed materials. Master 
Seed and each product are tested to 
Vol. 49, No. 252 / Monday, December 
assure purity, safety, identity, and 
immunogenicity as provided in 9 CFR 
113. 
3. Ingredients of animal origin used in 
production must meet accepted 
standards of purity and quality. Special 
tests for extraneous agents are required 
by 9 CFR 113.53 for all materials not 
subject to heat sterilization. 
4 . Primary cells and cell lines used for 
production of Master Seed or vaccine 
must be tested in accordance with 9 
CFR 113.51 and 113.52, respectively. All 
cell substrates must be shown to be free 
of bacteria, fungi, mycoplasma, viruses, 
and other extraneous agents. Cell lines 
must also be characterized and 
karyotyped to establish genetic stability 
through the maximum number of 
passages used for production. 
Tumorogenicity and oncogenicity tests 
must also be conducted on cell lines if 
direct or indirect evidence indicates that 
the cell may induce malignancies in the 
species for which the product is 
intended. 
5. Immunogenicity of vaccines must be 
supported by statistically valid host 
animal immunization and challenge 
studies. These studies are conducted 
using products produced to represent 
minimum levels of antigenic mass as 
provided in the filed Outline of 
Production. Studies must be designed to 
correlate the host animal efficacy of the 
reference product with a potency test 
that will be used to test each market 
serial prior to release. Inactivated 
products are correlated with animal 
potency tests or quantitative in vitro 
procedures. For live vaccines, host 
animal immunogenicity tests are 
correlated with bacterial counts or virus 
titers. Release of live vaccines for 
marketing requires a bacterial count or 
virus titer sufficiently greater than that 
used in the immunogenicity test to 
assure that when tested within the 
expiration period, each serial and 
subserial has at least a bacterial count 
two times or a virus titer 10°- 7 greater 
than that used in the host animal 
immunogenicity test. 
6. Firms are also required to 
demonstrate their ability to produce 
each product in a consistently 
satisfactory manner. Three consecutive 
satisfactory serials of product must be 
produced in accordance with an 
approved Outline of Production in 
licensed production facilities. Samples 
of these serials are forwarded to 
National Veterinary Services 
Laboratories for prelicense testing to 
confirm the manufacturer’s results. 
7. Safety of products must be 
demonstrated by laboratory and host 
animal studies. Tests may also include 
31, 1984 / Notices 50fl99 
field trials conducted under normal 
husbandry conditions. 
Upon satisfactory completion of all 
requirements, including review and 
acceptable of labels, a U.S. Veterinary 
Biological Product License may be 
issued. 
Products Derived From Modem 
Biotechnology 
Veterinary biological products 
prepared using modem biotechnological 
procedures such as recombinant DNA, 
chemical synthesis, or hybridoma 
technology will be treated similarly to 
products prepared by conventional 
techniques. The unlimited number and 
kind of products that may result from 
these modem biotechnology procedures 
make it impossible to define all 
requirements in specific terms. Each 
product is evaluated individually to 
determine what will be necessary to 
establish its purity, safety, potency, and 
efficacy. Scientific considerations may 
dictate areas of generic concerns or the 
use of certain tests for specific 
situations. Special assays, preferably 
using in vitro methods, may be required 
for potency and stability determinations. 
Additional tests may be required to 
assure safety, especially when live 
microorganisms are present in the 
biological products. 
The Animal and Plant Health 
Inspection Service (APHIS) will 
continue to avail itself of additional 
expertise from the Public Health Service 
"Interagency Group to Monitor Vaccine 
Development, Production, and Usage.” 
This interagency committee will be 
utilized to consider potential human 
health hazards from the use of 
veterinary biological products and to 
review issues such as those arising from 
the possible use of viruses potentially 
pathogenic to man or animals. 
In order to provide guidance to 
current or prospective manufacturers 
employing modem biotechnological 
methods, the following discussion of 
points likely to be useful is presented. 
1. Recombinant DNA-Derived 
Products. This technology encompasses 
the isolation, characterization, and 
insertion of foreign DNA into vectors for 
the production of foreign gene products 
in suitable expression systems. 
The genetic information coding for the 
product of interest and other sequences 
not indigenous to the host are referred to 
as foreign DNA. The specific cloned 
nucleotide segment coding for the 
desired product or other foreign DNA 
segments must be defined in data 
supporting each license application. 
These data must also include a 
description of the source of the DNA, 
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