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United States Department of Agriculture

Center for Veterinary Biologics

Standard Operating Policy/Procedure 

 Outlines of Production & Special Outlines

Date: August 14, 2023

Reference Number: CVB-SOP-0067.03

Contact: Center for Veterinary Biologics, 515-337-6100 

United States Department of Agriculture 

Animal and Plant Health Inspection Service 

P. O. Box 844

Ames, IA 50010 

INTERNAL USE ONLY 

Mention of trademark or proprietary product does not constitute a guarantee or warranty of the product 

by USDA and does not imply its approval to the exclusion of other products that may be suitable. 
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Source Document: CVB-MAN-5100, CVB Operations Manual, Chapter 7 

Table of Contents 

1. Overview

2. Flow of Information

3. Definitions

4. General Review Guidelines







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Physical Stamp Examples:

#5 Stamp #6 Stamp

 Electronic Stamp Examples:

#5 Stamp #6 Stamp

3. Definitions

APHIS Form 2015: Also called a 2015. Transmittal of Labels and Circulars or Outlines. 

This form must accompany all paper submissions of Outlines, Special Outlines, or labeling 

materials. The top part of the form is filled out by the firm to identify the accompanying 

submission. The bottom part is filled out by the CVB, and the form is returned with the firm’s 

copy of the reviewed document. 

APHIS Form 2049: The transmittal form for electronic submissions. The 2049 interface is 

what the portal user completes prior to making a submission. It is not a separate form.

Special Outline: An auxiliary Outline that describes a particular manufacturing process or 

testing method. Special Outlines (SOs) often apply to a group of products and, thus, are cited 

in Outlines to avoid repeating the same text in numerous locations. Special Outlines are 

numbered and are cited in Outline(s) of Production. Hard copy SOs may follow any format 

the manufacturer chooses, but it is recommended they use a format similar to what is found in

the NCAH Portal User Guide. NCAH Portal users should use the SO template and guidance 

found at the NCAH Portal User Guide website. It is recommended SOs that describe a 

potency assay list the product codes the SO applies to after the title page. SOs may include 

product codes in the title and add additional codes after licensure of new codes. A list of 

applicable product codes should appear after the title page unless all codes are stated in the 

title of the SO.
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Combination package: A product license that consists of two or more individually licensed

components, packaged together. The license for the combination package authorizes the 

licensee to package the components together and to label the product with instructions to mix 

the component products prior to administration. Note this is not the same as a combination 

product which is a multivalent product in a single vial. 

4. General Review Guidelines

1. Check all references to other documents (SOs, other Outlines).

a. Does the referenced document really exist? Beware of documents that may have 

become obsolete since the last Outline revision. 

b. Does the referenced document contain information that is sufficient and correct? 

c. Watch for “circular” references (e.g., Outline of Production says information is in 

Special Outline, but Special Outline says the same information is found in the 

Outline of Production). 

d. Ensure that the referenced document contains the pertinent information and does 

not simply reference a third document as the source of information. Avoid creating 

“document chains.” 

e. Avoid duplication of information—If information is in the Special Outline, it does 

not need to be repeated in the Outline of Production. When information is 

duplicated and subsequently amended, it is very easy to forget to update one of the 

locations where the information is found. 

2. Pay particular attention to syntax that may allow for variable production or testing 

methods. Ensure that the language used is appropriate for the purpose. “Should” 

means that the procedure/value is recommended, but not necessarily mandatory. 

3. Deviations from the described procedure are not necessarily out of compliance. 

Likewise, “may” permits a procedure, but does not require it. 

a. Shall/Must/will” means that the procedure/issue is mandatory. Deviations are out of 

compliance. Example: Use “must/will” to describe serial release test parameters.

b. Use care with the phrase “or equivalent.” Since this phrase is open-ended and 

subject to interpretation, do not permit the use of this phrase in situations where an 

alternative, not yet reviewed or approved by the CVB, might make a critical 

difference to the outcome of the procedure. Example: “Read the ELISA plate with 

the Dynatech 3000 ELISA reader or equivalent” is appropriate, as another brand of 

ELISA reader could reasonably be expected to give equivalent results. “Use 

Reference Bacterin 309 or equivalent” is not appropriate because Reference 

Bacterin 309 is the only approved reference. New references, even though they 
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may be formulated to be equivalent to #309, must be approved by the CVB before 

they are used (and incorporated into the Outline). New references are to be lot 

number controlled and new or replacement references are to be documented on 

when the CVB accepts the use of the reference. 

c. “and” vs. “or”: And means that both conditions must be met. Or means that either 

condition (but not necessarily both) must be met. 

4.

Review amended paper pages in the context of the entire Outline. (Only Complete 

Revisions are allowed for electronic Outlines.) It is permissible to ask firms to submit 

other paper pages (or a complete revision) if deficiencies are noted on pages that are not 

currently under official review. 

 5. When possible, support requests for revisions with citations from the regulations or 

guidance documents. (Example: “Revise section VI.C to include the component codes 

for this combination package, per VSM 800.206.) 6. In general, “either/or” options are not acceptable in Outlines of Production because 

manufacturing and testing procedures should not be subject to variability. If an 

ingredient or process is optional (e.g., adding extra nutrient solution during 

fermentation), then the conditions under which it is added or utilized should be clearly 

defined (e.g., add an amount not to exceed X mg/L if the pH drops below 6.9). Data 

may be necessary to demonstrate that the quality of the product is not affected by 

optional ingredients or procedures. 

 Alternative procedures or tests are often proposed for globally marketed products to 

satisfy the various regulatory requirements of different importing countries. If 

alternative procedures or tests clearly are not interchangeable, then it is likely that two 

separate product licenses are needed—one for each method.

Only one Master reference and one Working reference per fraction should be indicated 

in an Outline although if a fraction uses multiple potency tests, it is possible each test 

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There is no written policy regarding whether a firm should submit amended paper pages or 

a complete paper revision, and individual firms vary widely in their approach to this. In 

general, if the amended paper pages account for at least half of the total paper Outline, a 

complete revision, instead of individual pages, should be submitted. The portal does not 

allow revisions of individual pages so only complete revisions are accepted electronically, 

even if only one page has been changed.

CVB evaluates submissions from manufacturers in which the manufacturer requests 

permission to change or update one or more aspects of the manufacturing, testing, or 

distribution methods in a filed Outline of Production. Once CVB has finished reviewing the 

request, a response letter to the manufacturer either approving or denying the request is 

returned to the manufacturer. If the request is approved, the response letter will instruct the 

manufacturer to submit an updated Outline of Production which will become the new 

CVB-approved version of the Outline of Production after review. Center for Veterinary 

Biologics-Inspection and Compliance (CVB-IC) makes decisions about serial release and 

compliance during inspections based on information in the filed Outline of Production. 

During the time period between CVB approval of a change and approval of a subsequently 

submitted updated Outline of Production, CVB-IC has experienced delays releasing 

products to market and has observed unintended compliance issues during inspections. 

In order to address this issue, CVB will not consider a change in manufacturing, testing, or 

distribution methods to be in effect or applicable for regulatory purposes unless the change 

is in the CVB-approved Outline of Production. The manufacturer is responsible for 

updating the Outline of Production with accurate and sufficient information, including any 

changes to manufacturing, testing, or distribution addressed in the acceptance letter. The 

Outline of Production must be updated to include the date of the CVB approval letter and 

the associated mail log number in the appropriate sections. Product may be prepared and 

tested by the manufacturer prior to the approval of the data and Outline of Production but 

must not be submitted for market release until the updated Outline of Production is filed 

with CVB. 

The reviewer has the authority to request a complete review, and if necessary, revision to 

address inadequacies or insufficiencies at any time; such a request is probably warranted if 

the Outline is several years old and does not meet current standards for content or format. 

Special considerations for Outline changes for Rabies Vaccines 

In the past, we did not allow Outline changes (even very minor ones) for licensed rabies 

products without redoing full efficacy studies. We had publicly assured State and Federal 

public health authorities that even the most minor production procedure changes for rabies 

products will be supported by full efficacy data. However, Center for Veterinary Biologics 

Notice 06-23, Production changes for Rabies Vaccines, is now rescinded. Now minor 

changes, associated with data to support equivalency, are allowed post licensure. 
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. An Outline revision will only be approved upon 

satisfactory completion of the plan as provided in a response letter to each submission. 

Specific Review Considerations

Vaccines, Bacterins, Toxoids, Antigens

References: 9CFR Section 114.9(d)

This 9CFR section contains the sections and subheadings that must appear in all Outlines 

of Production. Hardcopy Outlines should be formatted according to 9 CFR Part 

114.9. NCAH Portal users should use the OP templates and guidance in the NCAH Portal 

User Guides. This does not preclude a firm from adding additional subheadings, as 

appropriate, to specific Outlines of Production per VSM 800.206. Veterinary Services Memorandum 800.206 This guidance document provides details regarding what should be included in Outlines of 

Production. 

Cover page

Paper: Typically, the cover page of the Outline is replaced only with complete revisions. 

In certain circumstances (e.g., change of Establishment name), it may be prudent to submit 

amended cover pages even though the Outline has not been completely revised. If this 

occurs, the amended cover page should continue to list the date of the last complete 

revision. Underneath this date, the firm should add a statement “Cover page 

updated<date>.” (This explains why the revision date on the cover page and the date of the 

CVB approval stamp may be widely disparate.)

Electronic: All submissions are complete revisions. Follow the NCAH Portal User Guides. Section I

 1. Ensure that Section I contains all of the information specified in VSM 800.206. When 

the Master Seed is the property of another firm in an FFM relationship, complete seed 

information is included in the FFM firm’s Outline. Therefore, complete information 

may be in the FFM or FUP outline, but not always both. Similarly, complete 

information may not always be in a combination package Outline of Production. The 

CVB should not require release of confidential business information between firms. 

Note that in general Master Seed should be sourced from the United States or countries 

considered free, low risk, or not affected with foreign animal diseases of concern (as 
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defined in VSM 800.51, Section IV.A) and with negligible or controlled risk of bovine 

spongiform encephalopathy (BSE), according to APHIS’ Animal Disease Status 

designations. 

2. This section should be completed in all Outlines and should not cite another Outline 

(except in certain split manufacture scenarios). 

3. For products licensed based on Production Platform technology, indicate in Section I.A. 

that this product is licensed based on production platform technology specific for 

gene(s) of the XYZ protein, derived from the ABCD pathogen, and utilizing JKLQ 

Technology developed by XXX corporation. The XYZ protein sequence from different 

ABCD pathogen isolates may be exchanged as per VSM 800.213. 

4. In Section I.E of the Outline of Production of a Production Platform technology 

product, include a table of approved sequences (constructs). An example of the 

appropriate information to include in the table is summarized below.

Section II 

Sections II-IV can be difficult to review because the subheadings required by 9 CFR 

114.9 do not always lend themselves to describing production in a stepwise manner. 

Ensure that all critical production steps are covered in these sections and that it is 

possible to understand how the product is made, even though the descriptions may 

not be optimally organized. 

Plasmid 

Designation 

Firm 

Designation 

code 

CVB Identity 

Code

Gene 

Source/date 

of accession

Number of 

Nucleotides

Map 

Location

pPlasmid 

ABCD 

mmddyyyyx

yz1 

Est#_product

Code_mmddy

yyy-xyz1-001 

ZZZZz 

(GeneBank 

accession 

No.)

10000 Addendum 1

pPlasmidABCD mmddyyyyxyz2 Est#_Product

Code_mmddy

yyy-xyz2-002 

ZZZZx 

(GeneBank 

accession 

No.)

10032 Addendum 1

pPlasmidABCD mmddyyyyxyz3 Est#_Product

Code_mmddy

yyy-xyz3-003 

ZZZZy 

(GeneBank 

accession 

No.)

10044 Addendum 1
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Section-Specific Reference: VSM 800.65 (products made with eggs, poultry) 

1. All outlines must address the source of ingredients of animal origin in Section II. Often 

this is specified in Section II.C. The following statement is acceptable:

 Ingredients of animal origin are sourced from the United States or countries considered 

free, low risk, or not affected with foreign animal diseases of concern (as defined in 

VSM 800.51, Section IV.A) and with negligible or controlled risk of bovine 

spongiform encephalopathy (BSE), according to APHIS’ Animal Disease Status 

designations. Each lot of ingredient additive of animal origin used to prepare an 

administered biological product must be sterilized or tested as prescribed in 9 CFR 

113.53, unless a risk-based exemption is provided by the CVB upon request by the 

firm.

The firms also may generate their own versions of this statement, and the following 

guidelines apply:

a. The CVB considers minimal risk regions with regard to BSE to include the United 

States, Canada, Australia, and New Zealand. Control measures in place assure the 

safety of bovine derived materials sourced from these countries. Regions where 

BSE exists, or regions that have import requirements less restrictive than those that 

would be acceptable for import into the United States are not acceptable sources of 

ingredients of animal origin. If it is not possible to adequately evaluate the control 

measures of another country, then it is advisable to not use ingredients of animal 

origin from that country. 

b. The statement should not include any disclaimers that it only pertains to ingredients 

purchased after a country is officially declared at risk for BSE. (i.e., We do not 

want them to continue to use ingredients purchased the day before an 

announcement is made.) 

c. If in doubt, use the default statement listed above. 

d. The statement should be included even for those products containing only highly 

processed ingredients of animal origin (e.g., casein digest). Although ingredients 

such as these were not the primary target of concern when we implemented this 

policy, it is easier to be all-inclusive now. 

e. A comprehensive list of all ingredients of animal origin used in production of 

biological products should be maintained. This list should include the name of the 

material, the supplier, the country of origin, and the date of purchase of each lot. 

This list may be reviewed, and certification of materials required at the time of 

inspection by the CVB-IC, or as requested by the CVB. This list may be referenced 

in the Outline of Production or in a Special Outline. Even if the list is not 

referenced in the Outline of Production, however, it should be maintained and 

available upon request. 

f. Section A Ingredients of Animal Origin statements in VSM 800.51 should be 

referenced in the ingredients of animal origin statement in the Outline of 

Production. 





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Section VI

Section-specific reference: VS Memorandum 800.202, GLC Section 4.2 

1. Section VI.A

a. For prescription product and autogenous serials in which less than 50 vials are 

manufactured, no confirmatory testing is done, and thus no samples need to be 

submitted. 

2. Section VI.B 

a. The expiration date should be calculated from the date of initiation of the first 

potency test. An Outline should list only one dating period. 

b. The appropriateness of the dating period should be confirmed with real-time data 

(9CFR 114.13). When confirmatory data have been accepted by APHIS, the 

acceptance ML# and/or date should be recorded in Section VI.C. Outline reviews 

performed by Reviewers is a good time to identify that confirmation of dating 

studies are complete and recorded appropriately in the Outline. 

c. Combination packages: this section must identify the component products 

contained in the combination package. See VS Memorandum 800.206 for standard 

syntax. 

d. Typically, diagnostic test kits are initially assigned 12-month dating, 

killed/nonviable products are initially assigned 24-month dating, and modified live 

products are initially assigned 18 months dating at licensure, pending confirmation 

of dating. 

3. Section VI.C 

a. This section should include all approved species of animals, routes/schedules of 

administration, duration of immunity (if applicable), and label claims. If 

appropriate, this section may contain approved label text verbatim. However, be 

aware that the firm may have approved claims that it does not elect to place on its 

labels (or only on certain labels). Poultry products for manual administration may 

have that route only indicated on smaller dose sizes. In these cases, the Outline 

and the labels may not agree exactly. 

b. Label claims should be updated to be consistent with single tier requirements for 

products licensed prior to November 1, 2016, and eligible for the claim per VSM 

800.54. Permission may be granted to continue using 4-tier language indefinitely 

for certain export markets and wording should be maintained in the Outline. It is 

recommended that firms include in their Outline what countries the 4-tier language 

applies to. 

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 3. FFM Outlines and Outline for final use products that contain FFM should contain 

information about transfer of the FFM product from one manufacturer to the other, per 

VS Memorandum 800.61. 

4. Split manufacture outlines (FFM and the final use product (FUP)) should clearly 

specify which steps are done by each licensee. Often firms attempt to write Outlines in 

a split manufacture, so each component Outline covers complete product manufacture, 

from start to finish. The FFM Outline should describe only those procedures performed 

by the FFM licensee. Outline sections not applicable to the FFM product should state 

“Not applicable”; they should not describe downstream procedures performed by the 

next licensee. 

 The FUP outline should simply cite the FFM Outline for all steps performed by the 

FFM licensee; it should not describe those steps in a manner that suggests they may be 

performed by the FUP licensee. The composition and form of the product received 

from the FFM licensee should be adequately described, and complete Outline 

information from that production point onward should be included.

Combination Package Outlines 

A combination package does not undergo testing and is not subject to release by CVB IC 

because it is made up of individual licensed products. Each component product is subject to 

serial release. It is critical to ensure that individual components included in a combination 

package are subject to serial release, since the combination package is not subject to serial 

release, although some flexibility may be considered regarding how this is accomplished. If 

one of the component products is manufactured by another firm, typically the firm that 

licenses the combination package has a final use product license associated with the 

antigens manufactured. 

When licensing a combination package that includes live desiccated vaccine, ensure the 

inactivated liquid product is not viricidal, as per 9 CFR 113.35. Check to make sure the 

antibiotics in the combination package comply with 9 CFR 114.10. 

Special Outlines 

Reference: CVB Notice 14-16

Sometimes a Special Outline that describes a serial release test is in sufficiently acceptable 

format to be processed, but it still needs minor revisions, or the described procedure still 

needs validation or confirmatory testing before it is acceptable for official use. To 
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document that the SO is not yet ready for use in serial release, it is stamped with a #5 

stamp. 

Improvements are sometimes made to testing methods already used for licensed products. 

Ideally the firm should create a new SO when substantial assay improvements are 

proposed. In this way, the new method can be kept separate from the method currently 

being used for serial release. If, however, the firm has a strong preference to retain the 

existing SO #, new SO versions created during assay development and validation may need 

to remain unprocessed. Do not replace a SO currently approved for serial release with a 

version having a #5 stamp. The firm needs to retain an approved version of a test method 

to continue serial release while any assay improvements are being reviewed and approved. 

Antibody Products

References: Outline guide in 9CFR 114.9(c)

VS Memorandum 800.100

Chapter on Antibody Products in this manual

Diagnostic Test Kits

References: VS Memorandum 800.73 

Outline guide in 9CFR 114.9(f) and VS Memorandum 800.206

CVB Notice 02-08

Chapter on Diagnostic Test Kits in this manual 

Allergenic Extracts

References: Outline guide in 9CFR 114.9(e)

VS Memorandum 800.106 

Production Platform Products

References:VS Memorandum 800.213 

Prescription Platform Products 

References: VS Memorandum 800.214
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Estimating Relative Potency 

See above comment for Outlines of Production, Sec. V, point #8, regarding inactivation of 

RelPot software and SAM 318. 

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