Title: Establishment Licenses
Release Date: 23 Feb 2023 Author: Document Number: CVB-SOP-0065.02
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Specified Information, by Block on the Form 2001:

3.1.1 Name and address of applicant (Block 4): This should include the
complete name (no acronyms) and the /egal address. The address should include a
street address (or some other descriptor of the physical location of the premises),
not just a post office box number. If the application is submitted because of a
name or ownership change, ensure the appropriate legal paperwork (in addition to
the APHIS Form 2001 and letter from the firm) is included to support the change.
In the case of an establishment ownership change only (no name change), legal
documents other than the application (APHIS Form 2001) and the firm’s letter are
required to show official transfer of the company, but reissuance of the current
license is not necessary if the contents remain the same.

3.1.2 Address for official mail from the CVB (Block 5): Although this is usually
the same as the legal address and/or one of the licensed premises, firms may elect
to have mail delivered to an alternate address. Firms with multiple premises must
designate a single address for all CVB correspondence.

3.1.3 Proof of incorporation (Block 12): If the applicant is a corporation, they
must submit their Articles of Incorporation. The applicant name in Block 4 should
agree with the name on the Articles of Incorporation.

In some corporate structures, the name of the applicant is separate from the name
of the parent company. In such cases, both the applicant name and the parent
company should be listed on the APHIS Form 2001.

3.1.4 Subsidiaries (Block 7): Applicants may elect to declare subsidiaries on
their establishment license application. Subsidiaries are special designations
because a subsidiary name can be used in lieu of the licensee’s name on product
labels.

The CVB has a strict legal definition for a subsidiary (9 CFR 101.2): a subsidiary
is a corporation in which the corporate licensee owns in excess of 50 percent of

3.1.5 Divisions (Block 8): The codified definition (9 CFR 101.2) for a division
is a marketing unit established by the licensee which may be named on labels,
advertisements and promotional material in addition to the name and address of
the producer (licensee).

3.1.6 Licensed premises (Block 9): This section should include all of the
locations where regulated activities take place. In most cases, the legal address is
also one of the licensed premises, but exceptions exist (e.g., if the legal address
only contains corporate office space). Each of the licensed premises appears on

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Title: Establishment Licenses

Release Date: 23 Feb 2023 Author: Document Number: CVB-SOP-0065.02

6.

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5.1 Once the applicant has met all requirements for licensure or permitting, an
establishment license is issued simultaneously with the first product license for the
establishment (2 documents). A licensed establishment must have at least one valid
product license at all times. The permit is issued as one document (the permit).

5.2 Anestablishment checklist is available in Section 8 of the Reviewer Manual
(CVB-WI-0295) to ensure that all of the requirements for the establishment have been
met. Enclose a completed checklist when the licensing or permitting package (all relevant
submissions and responses, checklists, etc.) is sent forward for issuance. See Section 5.5
of this document.

5.3. Ensure that all necessary corrections to the establishment license or permit
application have been made prior to sending the licensing or permitting package to the
support staff for processing. This may require having the applicant submit a corrected
copy of the application (Form 2001, 2003, or 2005) or a new portal submission (Form
2005) to supersede the information in the original submission.

5.4

5.5 See the Reviewer’s Manual chapter titled, Final Steps for Licensure (CVB-SOP-
0063) for additional details regarding procedures for preparing a license package and
issuance. The CVB Director’s signature is the final approval in issuing a license or permit
for Distribution and Sale.

Miscellaneous “Establishments”

Reviewers often interact with companies/institutions that will never be licensees because they do
not desire to produce and market biologics on a commercial scale. Examples include:

Academic institutions

Government research facilities
Contract research or test companies
“Think tank” research groups
Diluent manufacturers

They are often involved in the transfer of technology to biologics manufacturers and thus are
frequently in contact with the CVB regarding early submissions for product licensure and/or
requests to ship experimental product.

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Title: Establishment Licenses
Release Date: 23 Feb 2023 Author: ii Document Number: CVB-SOP-0065.02
CONTROLLED//PROPIN//BASIC

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Each of the premises that appear on the establishment license must be inspected by CVB-
IC prior to licensure and must be found satisfactory for the purpose for which it will be

If years pass between the prelicense
inspection and licensure, it may be necessary for CVB-IC to perform a follow-up
inspection to ensure that the facility remains adequate.

Reviewers should submit requests for prelicense inspections using the “Make Request”
function in the MailLog. Unlike inspections after licensure (generally unannounced),

prelicense inspections are usually announced. Details regarding requesting a “special
HEA “special inspection” may also occur post-licensure, in response to an event or
finding.

The Specialist should update the reviewer following the facility inspection. Before
recommending an establishment for licensure, reviewers should confirm with the
specialist leading the prelicense inspection to verify that the inspection was satisfactory
and the applicant is ready for licensure. This also applies to situations where an
establishment requests a new establishment license to add new premises.

3.5 Personnel documents (the APHIS Form 2007)

Part of the requirements for an establishment license is provision of evidence that the
personnel operating the facility are competent by education and experience to
consistently produce a quality product under the Outline of Production. Individuals with
key responsibilities within the establishment must file an APHIS Form 2007; see
Veterinary Services Memorandum 800.63 for additional details.

The establishment must designate a Liaison to interact with the CVB. Alternate Liaisons
also may be designated. Even though the establishment proposes the liaison and
alternates, it is the responsibility of the reviewer to determine whether the designation is
appropriate and to accept the proposals. A Liaison must be designated and approved prior
to issuance of the establishment license or permit, and must be US resident. The firm may
also designate one or more Alternate Liaisons. This is generally done by the recognized
Liaison, and the request is accompanied by a Form 2007. The CVB discourages the use
of too many Alternate Liaisons.

Each licensed establishment must have one government liaison representing all premises
listed on the establishment license. This liaison is responsible for and should handle all
government submissions and correspondence and will coordinate inspection activities

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Title: Establishment Licenses
Release Date: 23 Feb 2023 Author: a Document Number: CVB-SOP-0065.02
CONTROLLED//PROPIN/IBASIC

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the Establishment License, as locations where the licensee is “hereby licensed to
maintain...an establishment for the preparation of biological products...”

Each entry in Block 9 should include a street address. Rural Route numbers may
not be used. The street address may be a Locatable Address Conversion System
address (a “911” address). If no other specific method is available, a description
relative to the nearest named intersecting roads may be used.

CVB-Inspection and Compliance (CVB-IC) inspects each of the licensed
premises. Inspections are conducted by the Biologics Specialist (“inspector”).
Ensure that the list of licensed premises is complete and accurate by conferring
with the Specialist who performed the prelicense inspection of the establishment
or the inspection of new premises that are being added to the license.

3.1.7 Signature/date (Blocks 17-19): The application must have an original,
dated signature or valid digital signature. The firm’s USDA Liaison (other
appropriate person, if the Liaison is not yet designated) should sign the form.

3.2 Blueprints/legends/plot plans of the facilities

CVB-IC reviews and approves facility documents. New applicants sometimes submit

The location of third party testing facilities, when applicable, must be disclosed prior to
CVB approval. Facility documents of the third party site must be submitted, as well as a
letter from the third party clearly allowing CVB-IC to inspect the facilities. If the site is
acceptable, it will be added to the establishment license. The CVB does not consider
inclusion of a location on the establishment license to imply ownership, but to
identify the sites that are officially acceptable for preparation, storage, and distribution of
veterinary biologics. In certain instances, potency and safety testing may be conducted in
unlicensed facilities, in accordance with Veterinary Services Memorandum 800.115;
these facilities are not listed on the Establishment license.

3.3 Water quality statement

Regulations (9 CFR 108.11) specify that applicants must file a document verifying that
the effluent waste (not incoming water) for the facility meets local regulatory standards.
Some municipalities (or rural areas) do not have any regulations regarding effluent waste.
In such cases, the applicant should submit a letter from the appropriate local authority
stating that the area has no regulations in this regard.

3.4 Satisfactory prelicense inspection

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Title: Establishment Licenses
Release Date: 23 Feb 2023 Author: Document Number: CVB-SOP-0065.02
CONTROLLED//PROPIN//BASIC

CVB-SOP-0065.02
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Portal users should follow the NCAH Portal User Guide 29 and enter the information
electronically. Non-portal users must fill out the hard copy APHIS Form 2005.

As with the APHIS Form 2001, the LIE should check the portal entry or the Form 2005
prior to routing the submission to the reviewer. The reviewer should carefully examine
the application form and verify all items. Note: Only some of the data blocks on the
application are applicable to permits for Sale and Distribution. See the list below for
clarification regarding some items:

4.3.1 The name and address of the applicant (Block 3 on paper submissions):
This should specify the full name of the permittee and the permittee’s legal
address in the United States (not just a P.O. box number). Although there is no
designated space for a separate mailing address on the permit application,
permittees are allowed to designate an alternate mailing address within the United
States (such as a P.O. box). The mailing address is specified on the issued permit.
Additional information not fitting on the Form 2005 may be attached to it.

4.3.2. The name and address of the producer (Block 4 on paper submissions):
This should contain the name and address of the foreign manufacturer.

4.3.3. The address of the storage facilities (Block 11 on paper submissions): A
permittee must have an adequate facility to receive and store imported product
(adequate “quarantine site”). Each serial of the product must be held there until it
is released by CVB-IC for distribution and sale in the United States.

4.3.4 An applicant for a permit for distribution and sale must specify a U.S. port
of entry (Block 8), and this information is listed on the permit. The applicant must
designate which port it will routinely use. More than one port or the designation
“multiple” is acceptable (on the Form 2005).

4.3.5 The type of organization (Blocks 12-13 on paper submissions): This
pertains to the organizational structure of the permittee, not the foreign
manufacturer.

4.3.6 Principal Officers or Partners (Block 14 on paper submissions): This
pertains to the organization in the United States. Accountability is based on the
Articles of Incorporation (which should be submitted with the Form 2005).

4.3.7 Signature of authorized official (Block 16 on paper submissions): This
should be the signature of the permittee, not an official of the foreign
manufacturer.

5. Preparing to License an Establishment or Issue a Permit — Final Steps pursuant to
issuance.

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Title: Establishment Licenses
Release Date: 23 Feb 2023 Author: Document Number: CVB-SOP-0065.02
CONTROLLED//PROPIN//BASIC

Health Inspection Establishment Licenses
Service

Veterinary Services

Center for Veterinary
Biologics

1920 Dayton Avenue
PO Box 844
Ames, IA 50010

(515) 337-6100

Document Number: CVB-SOP-0065 Revision: 02
Previous Number: PEL Reviewer Manual Ch. 3.1

Vault: CVB-Released

Section/Area: CVB-SOP-PEL-REV

Effective Date: 23 Feb 2023

Notes:

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Signature Manifest Title: Establishment Licenses Page 1 of 1
Release Date: 23 Feb 2023 Author: ay Document Number: CVB-SOP-0065.02
CONTROLLED//PROPIN/IBASIC
Signature Manifest
Document Number: CVB-SOP-0065 Revision: 02

Title: Establishment Licenses
Effective Date: 23 Feb 2023
All dates and times are in Central Standard Time.
CVB-SOP-0065 01 Establishment Licenses
Review for Doc Format
Name/Signature Title Date Meaning/Reason
CROSLEY HERR (CRHERR) —_—_QA Specialist/C VB MC SME 22 Sep 2021, 12:38:07 PM Approved
Director Final Approval
Name/Signature Title Date Meaning/Reason
DAVID WHITE (DMWHITE) PEL Director 28 Jan 2023, 08:54:59 PM Approved
Final Quality Check and Assign Training
Name/Signature Title Date Meaning/Reason
CROSLEY HERR (CRHERR) —_QA Specialist/CVB MC SME 23 Feb 2023, 12:11:46 PM Approved
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file:///E:/Mastercontrol/Pub/installedServices/publishingGL V T/adlib/work/mcjobs/all/A7E17C57... 2/23/2023


Title: Establishment Licenses
Release Date: 23 Feb 2023 Author Document Number: CVB-SOP-0065.02
CONTROLLED//PROPIN//BASIC

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Title: Establishment Licenses
Release Date: 23 Feb 2023 Author: Document Number: CVB-SOP-0065.02
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and compliance. The licensee should designate a Site Contact that is approved by the
CVB to coordinate compliance and unannounced inspections at locations beyond a
reasonable travel time from the normal location of the liaison. See Veterinary Services
Memorandum 800.87 for additional information.

CVB-IC directly receives, reviews, and files most Forms 2007. Requests for proposed
Liaisons (and Alternate Liaisons) should be submitted to IC and then looped to the
reviewer. Once the reviewer has accepted (or rejected) the proposed Liaison, the child
loop is closed and CVB-IC is responsible for database entry and filing. If more than one
reviewer are responsible for the firm, include an em: notification to each reviewer.

4 Reviewing Permittee Information on applications for a permit for Sale and
Distribution

Regulations regarding permits for distribution and sale are covered in 9 CFR 104.5. See also
VSM 800.101. Many of the establishment requirements for licensees, described earlier in this
chapter, also apply to permittees. The following are differences:

4.1 A permittee must be a U.S. resident. Foreign companies often wish to market their
products directly in the United States, but this is not allowed. The permittee, who must

reside within the United States, takes legal responsibility for the product once it enters the
a a

Some foreign manufacturers will contact the CVB directly at first, promising to identify a
permittee shortly. Reviewers should ensure that a valid applicant exists before
spending too much time reviewing submissions. Critical submissions should be
submitted by the permittee, not the foreign manufacturer, so that the permittee
takes legal responsibility for the submissions.

4.2 CVB-IC must inspect the permittee’s domestic facilities, called a “quarantine
site,” where product is stored and held until released by the CVB for sale, AND the
foreign manufacturing site. The permittee must agree to periodic re-inspection by CVB-
IC of both the foreign manufacturing facility and the quarantine site. The foreign

manufacturer or the permittee must agree to pay expenses for the inspection, as stated on
the permit restriction.

4.3. The APHIS Form 2005 is used to apply for a Permit for Sale and Distribution.
The 2005 is used for three types of CVB permits, but the one most relevant to reviewers
is the permit for General Sale and Distribution. The other types are permits for research
and evaluation, and permits for transit shipment through the United States. These are
issued by the Office of the Assistant Director, CVB, Ames. IA.

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Title: Establishment Licenses
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Once the Establishment No. and the first Product Code and True Name (and abbreviated True
Name, if applicable) have been assigned, that information should be provided to the firm. This
could be done in an initial letter, or could be included in the reviewer’s response to a different
submission, such as the Outline or firm’s license plan. New firms should also be told to request
approval of a USDA Liaison (by submission of an APHIS Form 2007), and it may be helpful to
direct them to the CVB web site for applicable documents located there, such as the guidance for
new firms located at USDA APHIS ‘or New Biologics Applicants. a

3. Reviewing Establishment License Applications

Regulations regarding biologics establishments are found in title 9, Code of Federal Regulations
(9 CFR), sections 102.4 and 108. The following are required to support an establishment license
application:

3.1 The APHIS Form 2001

When appropriate, supporting legal documentation
should be requested.

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Title: Establishment Licenses
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1. Purpose and Scope

This chapter focuses on the initial, administratively-oriented steps involved in proceeding to
licensure or permitting, and briefly, to related steps occurring just before licensure or permitting.
Biologics manufacturers located in the United States are called licensees. Licensees must have an
establishment license that is separate from their product licenses. The establishment license is
evidence that the Center for Veterinary Biologics (CVB) considers the facilities, and personnel
operating them, to be adequate to produce consistent, quality biologics.

U.S. companies (or individuals) that import biological products made in foreign countries so that
they can be distributed and sold in the United States are called permittees. They are not
“licensed”; they obtain a Biological Product Permit for Sale and Distribution for each product.
Each permit combines aspects of establishment and product approvals.

2. Establishment and Permit Codes

Licensees and permittees are issued establishment and permittee codes (numbers), respectively.

A single company can serve both as a licensee and a permittee if it produces biologics
domestically as well as importing foreign-made products. In such cases, the same base number is

used.

Example:

Separate permits are issued for each imported product. If a permittee imports products from
several different foreign manufacturers, a different alphabetic suffix is used to differentiate the
permits issued to the same applicant, to denote different foreign manufacturers.

Requesting a code assignment (Establishment, Permit. or Product): Codes should be assigned
upon receipt of the application (APHIS Form 2001, 2003, or 2005) and the first submission to

which the reviewer can respond (generally the Outline of Production). Do not assign codes to
companies or individuals merely inquiring about licensing procedures or requesting guidance
about the regulatory jurisdiction of their proposed product. Prompt code assignment is important
so that submissions can be tracked and filed efficiently.

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Title: Establishment Licenses
Release Date: 23 Feb 2023 Auth: Document Number: CVB-SOP-0065.02
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Establishments and Permittees

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.

Table of Contents

1. Purpose and Scope

2. Establishment and Permit Codes

3. Reviewing Establishment License Applications

4, Reviewing Permittee Information on Permit Applications
5. Preparing to License an Establishment or Issue a Permit
6. Miscellaneous “Establishments”

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