4.5.1 Target Animal Safety Testing Exemption

1. Overview

Safety testing in animals has been a component of the approval process for each serial of product 

released by the Center for Veterinary Biologics (CVB) since the Program’s inception. This 

serial release testing is conducted to provide assurance that each serial of product will be safe in 

the target animal and without adverse reactions, local or systemic. Depending on the type of 

product, animal safety testing may be conducted in mice, guinea pigs, or the host or target 

animal. The Standard Requirement (SR) must be specified in the Outline of Production. If the 

SR (stipulated in Title 9, Code of Federal Regulations) for a product does not specify the animal 

safety test method, Section V.B of the Outline of Production must specify a method and state the 

animal species to be used in safety testing. 

With the number of serials produced by all currently licensed and permitted manufacturers, the 

number of animals used for safety testing is substantial. Historical data for some products 

indicate no adverse safety or sterility testing results have occurred. Historical data would include 

data collected post licensure. The timeframe would depend on the type of product and number of 

serials produced and tested. Data generated from all products with similar platform based 

systems may be considered to support the exemption for a single platform technology product, 

with appropriate justification, including consideration of consistency in formulation, equipment, 

and location, timing (e.g., campaigning), and method of production. In addition, many products 

in the biologics industry are manufactured under well-documented manufacturing processes and 

under Outlines of Production with parameters set to control process variation. These products 

have a history of safety and consistency in manufacturing processes and may be considered as 

candidates for an animal safety testing exemption.

The procedure to consider an exemption from target animal safety testing is presented below. It 

applies to all products for which target animal safety testing is currently specified in Section 

V.B. of the Outline, and to all target animal safety testing specified in Section V.B. of those 

Outlines. The USDA’s consideration of an exemption to target animal safety testing is 

consistent with the VICH Steering Committee’s recommendations aimed to minimize the use of 

target animal safety tests and the principles of reducing, refining, and replacing the use of 

animals in testing.

2. Related Documents/Regulations

• Veterinary Services (VS) Memorandum No. 800.116 Animal Safety Testing Exemption

• VSM 800.204 (for guidance regarding adverse event reporting)

• VSM 800.100 (exemption to mouse safety testing for equine plasma products)

• 9 CFR 113.100 General safety requirements for inactivated bacterial products

• 9 CFR 113.200 General safety requirements for killed virus vaccines

• 9 CFR 113.300 General safety requirements for live virus vaccines

• 9 CFR 113.40 Dog safety testing

• 9 CFR 113.39 Cat safety testing

3 of 4

2. An updated Outline of Production that addresses Items a-g

below, submitted with an APHIS Form 2015, should be included with the initial request for 

an animal safety testing exemption. The following items in the Outline of Production should 

be considered to determine if manufacturing processes are controlled. Appropriate revisions 

to the Outline of Production are required prior to approval of the exemption.

a. Consistency in concentration steps: Adequate detail and specifications must be 

provided.

b. Consistency in antigen input: the firm should propose an upper antigen limit and 

provide justification. Lower limits must also be specified, and pre-inactivation 

titers should be considered for killed products.

c. Appropriate ranges must be specified for all critical steps and specifications (e.g. 

temperature, time, concentration, pH, volume)

d. Section V.A. sterility testing must be conducted in accordance with 9 CFR 113.26 

for all products. 9 CFR 113.27(a)(7)(ii) allows for growth in 1/10 test vessels in 

the initial test, or 19/20 vessels in the retest to meet satisfactory requirements. In 

order to be considered for an animal safety test exemption, if growth in any test 

vessel of the final test is observed, the serial should be considered unsatisfactory, 

as per 9 CFR 113.26(c)(3). If the sterility test is valid, for example in the case of 

a justified “no test,” a retest may be allowed. Other than that, no sterility retests 

will be allowed for products considered for the animal safety testing exemption. 

Supplemental Assay Method 908 provides guidance regarding how to conduct 9 

CFR 113.27(a) sterility testing. Sterility retests may nullify the animal safety 

testing exemption.

1. For oral antibody products; identification of contaminants is also required. 

2. The approval date of dilution of preservative studies must be provided in 

Section V.A.

3. Media used in sterility testing should be validated for growth promotion as 

per 9 CFR 113.25(b) or an approved exemption should be documented in 

the Outline of Production.

4. In general, if 3 consecutive serials, or 3 serials within a short period of time 

yield unsatisfactory sterility results, the animal safety testing exemption 

may be nullified for the product, unless acceptable justification based on 

mitigating circumstances is provided.

e. The Outline of Production must include methods to ensure confirmation that the 

adjuvant is sterile.

f. For inactivated products, the methods describing the inactivation check test must 

be specified in detail in Section IV. The test method must be determined to be 

adequate.

g. Confirmation of dating approval must be provided in Section VI.C.

Documentation of the Target Animal Safety testing exemption

The target animal safety testing should remain in Section V.B of the Outline. After the 

exemption is approved, the date the exemption was approved should be added to the Outline