Providing Lot Release Protocol Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Providing Lot Release Protocol
Submissions to the Center for
Biologics Evaluation and Research
(CBER) in Electronic Format
Guidance for Industry
This guidance is for immediate implementation.
FDA is issuing this guidance for immediate implementation in accordance with
21 CFR 10.115(g)(4)(i). Submit one set of either electronic or written comments on this
guidance at any time. Submit electronic comments to https://www.regulations.gov/. Submit
written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with
docket number FDA-1998-D-0095 (formerly docket number 1998D-0315).
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010 or email at ocod@fda.hhs.gov,
or from the Internet at
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
February 2019

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DISCUSSION .................................................................................................................... 2
A. 	Format for Electronic Lot Release Protocol Submissions................................. 3
1. 	Hypertext Links and Bookmarks ...................................................................... 3
2. 	Electronic Lot Release Protocol Signature Letter ............................................. 4
3. 	Naming the Electronic Lot Release Protocol File............................................. 4
B. 	Electronic Lot Release Protocol Submissions Through FDA’s Electronic
Submissions Gateway ........................................................................................... 4
1. 	Preparatory Steps for Using the ESG................................................................ 5
2. 	Procedures Following the Completion of the Preparatory Steps ...................... 6
3. 	Help and Information ........................................................................................ 7
C. 	Electronic Lot Release Protocol Submissions on CD-ROM ............................. 8
1. 	Labeling the CD-ROM ..................................................................................... 8
2. 	Packaging and Shipping.................................................................................... 8
3. 	Delivery Address .............................................................................................. 9
D. 	Feedback on Your Electronic Lot Release Protocol Submission...................... 9
E. 	Shipping Samples to FDA When Using the ESG to Submit the Associated Lot
Release Protocols ................................................................................................... 9
APPENDIX 1: 	EXAMPLE OF A TABLE OF CONTENTS WITH BOOKMARKS FOR
AN ELECTRONIC LOT RELEASE PROTOCOL ................................................................ 10
APPENDIX 2: 	EXAMPLES OF CD-ROM LABELS ......................................................... 11
APPENDIX 3: 	CHECKLIST PRIOR TO SUBMITTING AN ELECTRONIC LOT
RELEASE PROTOCOL ............................................................................................................ 12

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Providing Lot Release Protocol Submissions to the Center for
Biologics Evaluation and Research (CBER) in Electronic Format
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	INTRODUCTION
We, the Center for Biologics Evaluation and Research (CBER), within the U.S. Food and Drug
Administration (FDA, the agency, or we), are issuing this guidance under Title 21 of the Code of
Federal Regulations (CFR) 601.14(a) to assist you, manufacturers of biological products
regulated by CBER,1 in submitting lot release protocols in electronic format to CBER’s Product
Release Branch, within the Office of Compliance and Biologics Quality (OCBQ). This guidance
updates and supersedes the similarly named guidance, “Guidance for Industry, Providing
Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in
Electronic Format - Lot Release Protocols,” dated November 2007 (2007 guidance). We are
updating this guidance to include the submission of electronic lot release protocols through the
FDA’s Electronic Submissions Gateway (ESG).2
In the Federal Register of December 8, 1995 (60 FR 63048),3 we announced that we no longer
require routine lot-by-lot release for specified categories of biological products subject to
licensure, previously referred to as well-characterized therapeutic recombinant DNA-derived and
monoclonal antibody biotechnology products (see 21 CFR 601.2(c)). This guidance is not
intended to modify that document.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidance means that something is suggested or
recommended but not required.
1 Although most lot release protocols and products that are submitted for the lot release program are regulated by
CBER, the program also receives a small number of lot release protocols for products that are regulated by the
Center for Drug Evaluation and Research (CDER).
2 For general information about regulatory submissions in electronic format for biological products, see
https://www.fda.gov/biologicsbloodvaccines/developmentapprovalprocess/ucm163685.htm.
3 Federal Register notice entitled “Interim Definition and Elimination of Lot-by-Lot Release for Well-Characterized
Therapeutic Recombinant DNA-Derived and Monoclonal Antibody Biotechnology Products.”

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II. 	BACKGROUND
The ESG is an agency-wide solution for accepting electronic regulatory submissions. The ESG
enables the secure submission of premarket and postmarket regulatory information to FDA for
review. It is the central transmission point for sending secure information electronically to the
agency. Within that context, the ESG is a conduit along which submissions travel to reach the
proper FDA Center or Office.
Lot release is a system that permits FDA to verify product quality through protocol review and
sample testing of many biological products that we regulate. In accordance with 21 CFR
610.2(a), CBER may require you to submit for CBER review and confirmatory testing samples
of any lot of any licensed product, together with the protocols showing results of applicable tests
when deemed necessary for the safety, purity, or potency of the product.
III. 	DISCUSSION
Submission of your lot release protocol submissions, consistent with lot release requirements
applicable to your product, in an electronic format that is readily accessible will facilitate our
review of your submission.
FDA has encouraged applicants to submit lot release protocols electronically through the ESG
since 2009. This guidance is being updated to provide information on using the ESG. It
includes a high-level description of the procedures that are necessary for manufacturers to use
the ESG to submit lot release protocols to CBER; however, we also refer manufacturers to
various website links for more detailed information on using the ESG for this purpose. The
information available on our website is updated periodically.
Pursuant to 21 CFR 11.2(b)(2), FDA has identified lot release protocols as one of several
submission types described in Public Docket 1992S-0251 that the agency accepts in electronic
format. We encourage the use of FDA’s ESG for submitting electronic lot release protocols to
CBER because it facilitates our ability to receive and review these submissions. If
manufacturers are not able to provide these submissions to us using the ESG, manufacturers may
use other means to submit their lot release protocols to the agency, such as mailing a compact
disc read-only memory (CD-ROM4).5 This guidance is intended to provide you with
4 CBER’s Product Release Branch accepts lot release protocol submissions on digital video disc or digital versatile
disc (DVDs) in addition to CD-ROMs. The submission process for DVDs is identical to the submission process for
CD-ROMs that is described in this guidance.
5 We discourage the submission of lot release protocols in paper format, but we continue to accept these submissions
when firms are not able to submit their lot release protocols electronically.

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recommendations for submitting lot release protocols showing results of applicable tests in an
electronic format, as provided in 21 CFR Part 11.6
A secure email account should be established with FDA to protect proprietary and confidential
information and to facilitate communication. A secure email address allows for encrypted
exchange between the manufacturer and the agency, for example, about your electronic lot
release protocol.7 CBER-generated email regulatory communication will only be sent via secure
email.8 For information on how to establish a secure email account with CBER, you may
contact the agency at SecureEmail@fda.hhs.gov.
A. 	Format for Electronic Lot Release Protocol Submissions
Manufacturers should submit their lot release protocols in a portable document format
(PDF) file when transmitting electronically to CBER’s Product Release Branch. We
request this format when submitting electronically through the ESG as well as when
submitting electronically by CD-ROM. The lot release protocol PDF file should be
placed in an electronic folder, and the folder name should be the 6-digit submission
tracking number (STN).9 Manufacturers who are currently submitting their lot release
protocols to CBER using a paper format should only need minor modifications for the
conversion to PDF. The PDF version should be full-text searchable and not simply a
static scan of the entire paper protocol. We recommend that you do not use the security
option and passwords for the submission, as these could make it difficult for us to access
your data. You may send an email message to the Product Release Branch at
CBERLotRelease@fda.hhs.gov to receive a lot release protocol template.
1. 	Hypertext Links and Bookmarks
Lot release protocols vary in length, depending on the specific content. We
recommend that you use functional bookmarks or a hypertext linked Table of
Contents to facilitate navigating the protocol, especially for larger ones. An
example of a Table of Contents with bookmarks is provided in Appendix 1 at the
end of this guidance.
6 FDA issued a “Guidance for Industry: Part 11, Electronic Records; Electronic Signatures - Scope and
Application,” dated August 2003 (September 5, 2003, 68 FR 52779), describing a policy of enforcement discretion
relating to certain Part 11 requirements (see
https://www.fda.gov/RegulatoryInformation/Guidances/ucm125067.htm). We update guidance periodically. To
ensure that you have the most recent version of a guidance, check the FDA Drugs guidance webpage at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
7 Electronic lot release protocols should not be emailed to the agency.
8 See FDA “SOPP 8119: Use of Email For Regulatory Communications,” Version 3, dated October 1, 2018, at
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresS
OPPs/UCM585760.pdf.
9 For allergenic products that use the second level STN to identify the product, you should use the primary and
secondary level numbers, separated by an underscore, as the folder name.

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2. 	Electronic Lot Release Protocol Signature Letter
For purpose of signing the lot release protocol in PDF, you should use the
electronic lot release protocol (e-LRP) Signature Letter, which includes
information about your company and the lot release protocol that you are
submitting.10 The e-LRP Signature Letter should be included as the first page of
the lot release protocol PDF file.11 You may send an email message to the
Product Release Branch at CBERLotRelease@fda.hhs.gov to receive information
on the latest e-LRP Signature Letter template to use.
3. 	Naming the Electronic Lot Release Protocol File
The e-LRP, in PDF, must be assigned a unique filename for each product lot. The
filename is composed of alphanumeric characters. You should not use any
special characters in the filename. The first four numbers represent the year of
the submission (e.g., 2018). The next four numbers represent the sequential lot
submitted for that year (e.g., 0001, 0002, 0003, etc.), and these 8 numbers are
followed by a dot. The final two to three alphanumeric characters represent the
type of submission (.P0 (zero) specifies an original protocol, and .PC specifies a
corrected protocol). Thus, 20180003.P0 represents the original protocol for the
third lot submitted in the year 2018.
A corrected lot release protocol is a submission to correct minor clerical or
transcription errors or to clarify lot release information in response to questions by
FDA. For submissions under a corrected lot release protocol, designate each
corrected protocol using “.PC,” followed by the correction number (i.e., .PC1
represents the first corrected protocol, .PC2 represents the second corrected
protocol, etc.). Thus, 20180003.PC1 represents the first correction of the original
protocol for the third lot submitted in the year 2018.
B. 	Electronic Lot Release Protocol Submissions Through FDA’s Electronic
Submissions Gateway
Currently, our preferred method of transmitting lot release protocols is through FDA’s
ESG. The FDA’s ESG provides a single point of entry for receiving and processing all
electronic submissions in a highly secure environment. It complies with secure
Hypertext Transfer Protocol (HTTP) messaging standards and uses digital certificates for
secure communication. The electronic submission process through the ESG encompasses
the receipt, acknowledgment of receipt (to the sender), routing, and notification (to a
receiving FDA Center or Office) of an electronic submission.
Manufacturers have two options for sending submissions through the ESG to the agency:
WebTrader or Applicability Statement 2 (AS2).
10 The authorized official noted on the first page of the electronic lot release protocol should be the same person who
signs the e-LRP Signature Letter.
11 The signed e-LRP Signature Letter portion of the PDF file does not need to be text searchable.

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WebTrader is a Web interface designed for low volume submitters and is likely the most
appropriate method for manufacturers who want to submit lot release protocols to the
agency. This web-based interface, which involves installing software on the submitter’s
computer, is used to send documents and receive receipts and acknowledgments from
FDA. The WebTrader application makes communication with FDA simple, cost-
effective, and time-independent. WebTrader requires each user from an industry partner
to register for his or her own unique WebTrader account.
AS2 is a system-to-system connection (also referred to as a “server-to-server” or
“gateway-to-gateway” connection) to exchange information with FDA. AS2 requires a
gateway software implementation on the submitter’s end, requiring a server(s) and
software procurement and configuration. AS2 provides an automated connection to FDA
for submissions, receipts, and acknowledgments. System-to-system communication
requires one user from an organization to register for the organizational account.
The ESG User Guide, available on our website,12 provides manufacturers with an
overview of the ESG registration process, the preparatory steps that are necessary for
establishing an ESG account, and the specific steps that are necessary for establishing a
WebTrader (Web interface) ESG account,13 in addition to other resources. The User
Guide explains how to send documents through the ESG, including the creation of test
and production accounts. We recommend that manufacturers refer to the ESG User
Guide and the additional links that are on our ESG webpage for current and complete
information on how to use the ESG. 14
There are several preparatory steps that are needed prior to beginning the ESG
registration process. In this guidance, we provide a high-level overview of these
preparatory steps. Considerations for each preparatory step are covered in more detail in
the ESG User Guide.
1. 	Preparatory Steps for Using the ESG
a. 	Send an Email Message to the ESG Help Desk
Send an email message to ESGHelpDesk@fda.hhs.gov, indicating that
you would like to register for an ESG account.
b. 	Submit a Letter of Non-Repudiation Agreement
The non-repudiation agreement allows FDA to receive electronically
signed submissions in compliance with 21 CFR 11.100.
12 See https://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm334359.htm for the ESG User Guide.
13 The ESG User Guide also includes information for establishing an AS2 ESG account.
14 See https://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm for general information on the
ESG.

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c. 	Obtain a Digital Certificate
Digital certificates ensure private and secure submission of electronic
documents. The digital certificate binds together the owner’s name and a
pair of electronic keys (a public key and a private key) that can be used to
encrypt and sign documents.
d. 	Understand the Submission Guidelines, Including File Naming
Conventions
The guidelines for preparing lot release protocol submissions are
described in section III.A. of this guidance.
e. 	Determine the Submission Method
Manufacturers who want to submit lot release protocols can use the ESG
Web Interface by creating a WebTrader account or using an AS2 gateway-
to-gateway account. WebTrader is designed for low-volume submitters
and is likely the most appropriate method for manufacturers who want to
submit lot release protocols to the agency.
f. 	Review and Ensure that the Connection Requirements for the
Selected Submission Method Are Met
The ESG User Guide lists the requirements for each method, including
Web browsers, software, disk space, and connection speed.
2. 	Procedures Following the Completion of the Preparatory Steps
After completing the preparatory steps, manufacturers may consult the ESG User
Guide for the steps that are necessary to submit lot release protocols through the
ESG by establishing a WebTrader account (Chapter 4), or an AS2 connection
(Chapter 5). The following steps are necessary to establish an ESG production
account for submitting your lot release protocols to CBER through the ESG:15
a. 	Obtain Access to the Electronic Submissions Gateway
The ESG User Guide explains how to set up a test account and a
production account. Once a test account is approved and set up for a
WebTrader account, a profile will need to be established for each
individual who will need access. For example, if more than one person
will be submitting electronic lot release protocols from the same
15 We provide a high-level summary of the steps that are necessary to establish an ESG production account in this
guidance. We recommend that manufacturers consult the ESG User Guide and the additional information that we
have on our ESG webpage for a more detailed description.

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manufacturing facility, each person will need to create his or her own
profile and send a test submission.
b. 	Send a Test Submission Through the ESG
To receive an ESG production account, which permits manufacturers to
submit lot release protocols through the ESG, manufacturers should first
successfully submit a lot release protocol test submission that is formatted
as described in section III.A. of this guidance. You may use a previously
submitted lot release protocol in PDF as your test submission.
Lot release protocol PDF files should be placed in an electronic folder
prior to sending them through the ESG, and the folder name should be the
6-digit STN. Placing the lot release protocol PDF file in a folder prior to
sending it through the ESG helps to ensure that the filename is maintained.
For WebTrader accounts, each individual who establishes a profile should
send one test submission through the ESG. The same test submission may
be used by multiple individuals.
c. 	ESG Notification
The ESG system will immediately notify you when your test submission
has been successfully received through the ESG. If you do not receive a
successful transmission notification, contact the ESG Help Desk at
ESGHelpDesk@fda.hhs.gov and inform them that you have not received a
communication indicating that the transmission was received.
d. 	Feedback on the ESG Test Submission
Manufacturers should send an email message to CBER’s Product Release
Branch at CBERLotRelease@fda.hhs.gov after sending the test
submission to ensure that the Branch has received it. When the Product
Release Branch successfully receives your test submission and confirms
that it is in the proper format, you will be notified by ESG Help Desk
personnel that your access has been upgraded to an ESG production
account. You may then proceed to send your lot release protocols to
CBER through the ESG.
3. 	Help and Information
If you need assistance with establishing an ESG account or using your ESG
production account, you may send an email message to FDA’s ESG Help Desk at
ESGHelpDesk@fda.hhs.gov.

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If you have questions for CBER, regarding submission standards and formatting,
you may send an email message to CBER Electronic Submissions (ESUB) at
esubprep@fda.hhs.gov.
C. 	Electronic Lot Release Protocol Submissions on CD-ROM
If manufacturers are not able to submit lot release protocol files through the ESG, you
may submit your electronic files on CD-ROM as an alternative to our preferred method.
Creation and file naming of an electronic lot release protocol in a PDF file for submitting
on a CD-ROM involves the same procedures as those for creating an electronic lot
release protocol for submitting through the ESG (see section III.A. of this guidance).
1. 	Labeling the CD-ROM
You should label your CD-ROM and CD-ROM case to identify your submission
with the following information:
a. 	Manufacturer name;
b. 	Date of submission in the format of DD-MMM-YYYY, with DD
and YYYY being numerical and MMM being the first three letters
of the month (e.g., “AUG” for August);
c. 	STN, license number, and type of lot (“FC” for final container, “B”
for bulk, “C” for Concentrated);
d. 	Electronic lot release protocol filename(s); and
e. 	Lot number(s).
We provide examples of labeled CD-ROMs and their corresponding CD-ROM
cases in Appendix 2 at the end of this guidance. We recommend that you label
your CD-ROM in a manner that does not interfere with data retrieval.
2. 	Packaging and Shipping
CD-ROMs should be packaged carefully to ensure that they arrive in a usable
condition. CD-ROM cases are less vulnerable when shipped in envelopes with
bubble-type protective material or stiff backing. Mailing envelopes padded with
paper material, only, typically do not provide adequate protection for shipping
CD-ROMs.

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3. 	Delivery Address
CD-ROMs should be sent to the address below. If you are sending lot release
samples along with your CD-ROM, you must use a courier service (see 21 CFR
600.2(c)).
Food and Drug Administration
Center for Biologics Evaluation and Research
Sample Custodian
10903 New Hampshire Avenue
WO75-G707
Silver Spring, MD 20993-0002
D. 	Feedback on Your Electronic Lot Release Protocol Submission
A checklist to help ensure that your electronic lot release protocol is in the proper format
prior to submitting it to CBER is provided in Appendix 3 at the end of this guidance.
Once your lot release protocol in electronic format has been received and reviewed by the
Product Release Branch, the Branch staff will contact you if your submission is not in the
proper format. Modifications or resubmissions may be needed, particularly for your
initial electronic lot release protocol submission, and we will work with you to ensure an
adequate submission.
E. 	Shipping Samples to FDA When Using the ESG to Submit the Associated Lot
Release Protocols
Often lot samples are submitted well before the lot release protocol, while the lot is still
in release testing by the manufacturer, to help facilitate sample processing and CBER
concurrent testing. If you submit lot samples while release testing is ongoing, you should
include a concurrent testing letter along with your samples. You may send an email
message to the Product Release Branch at CBERLotRelease@fda.hhs.gov to receive the
latest template for the appropriate Concurrent Testing Letter (the Concurrent Testing
Letter for general use or the Concurrent Testing Letter for test kits).

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APPENDIX 1: EXAMPLE OF A TABLE OF CONTENTS WITH BOOKMARKS FOR
AN ELECTRONIC LOT RELEASE PROTOCOL
1. STN/License No./Type of Lot [Bulk, Final Container, Concentrated]
2. Lot Number
3. Proper Name of Product
4. Firm Name and Address
5. Reason for Submission
6. Test Result Pass Statement
7. Signature Block
8. Electronic Protocol: 20180001.P0
9. Test Results
a. Potency
b. Specific Activity
c. pH
d. Moisture
e. Total Protein
f. Solubility
g. Sterility
i. Sterility Bulk
ii. Sterility Final Container
h. Purity
i. Limulus Amoebocyte Lysate (LAL)
ii. Pyrogen
i. Laser Densitometer (LD) Scan
i. LD Scan
ii. LD Scan Reference

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APPENDIX 2: EXAMPLES OF CD-ROM LABELS
A) Single Product Submission 	B) Multiple Product Submission
ABC Pharmaceuticals
DD-MMM-YYYY
123456_0 / 0999-B
File Name
20180084.PC1
20180085.P0-20180089.P0
ABC Pharmaceuticals
DD-MMM-YYYY
License #: 0999
123456_0-B 	123457_0-FC
File Name 	File Name
20180095.P0 	20180098.P0
20180096.P0 	20180099.P0
123456_0-FC
File Name
20180094.PC1, 20180097.P0
C) CD Case for Disc A 	D) CD Case for Disc B
0999 ABC Pharmaceuticals
DD-MMM-YYYY
123456_0-B
Lot # 	Filename
8799795A 	20180084.PC1
8799989B 	20180085.P0
9567428C 	20180087.P0
9567428D 	20180088.P0
9567429K 	20189989.P0
0999 ABC Pharmaceuticals
DD-MMM-YYYY
STN 	Lot # 	Filename
123456_0-B 	8899989B 	20180095.P0
123456_0-B 	8899995A 	20180096.P0
123456_0-FC 	9567415B 	20180094.PC1
123456_0-FC 	9567418C 	20180097.P0
123457_0-FC 	9567418D 	20180098.P0
123457_0-FC 	9567419K 	20180099.P0

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APPENDIX 3: CHECKLIST PRIOR TO SUBMITTING AN ELECTRONIC LOT
RELEASE PROTOCOL
 	Confirm that the e-LRP Signature Letter is the first page of the electronic lot release protocol
PDF file
 	Confirm that the authorized official noted on the first page of the electronic lot release
protocol is the same person who signs the e-LRP Signature Letter
 	Confirm that the file name for the electronic lot release protocol is in the correct format (see
section III.A.3. of this guidance)
 	Confirm that the folder name is correct (see section III.A. of this guidance)
 	Confirm that the “reason for submission” section is on the first page of the electronic lot
release protocol and on the e-LRP Signature Letter
 	Confirm that the appropriate box for the “reason for submission” is marked
 	Confirm that your entire electronic lot release protocol is text-searchable
 	Confirm that your electronic lot release protocol file is virus-free