FDA ESG: Complete Guide to the Electronic Submissions Gateway

FDA ESG (Electronic Submissions Gateway) is the FDA's secure, internet-based portal for receiving electronic regulatory submissions from pharmaceutical, biologic, and medical device sponsors. The ESG serves as the primary entry point for all eCTD submissions to CDER, CBER, and CVM, processing over 150,000 electronic submissions annually. The modernized ESG NextGen platform now provides three submission methods: the Unified Submission Portal (USP), API integration, and AS2 connections.

If you're preparing to submit an IND, NDA, BLA, ANDA, or other regulatory application to FDA, understanding the ESG is essential. Gateway rejections due to technical errors can delay your submission by days or weeks, while account setup issues can block your ability to submit entirely.

In this guide, you'll learn:

• How to set up and configure your FDA ESG account for electronic submissions
• Which submission types require the Electronic Submissions Gateway
• Technical requirements and file format specifications for ESG
• Step-by-step troubleshooting for common ESG submission errors
• Best practices for successful gateway transmission

What Is FDA ESG? Understanding the Electronic Submissions Gateway

What this means: The ESG is the government's official filing system for drug submissions-think of it as the FDA's mail box for regulatory documents. If you're submitting a drug to the FDA, your application MUST go through ESG. There's no alternative pathway for most commercial submissions.

Key characteristics of the FDA ESG:

• Mandatory submission pathway for eCTD format applications
• 24/7 availability for submission receipt (except scheduled maintenance)
• Automated technical validation against FDA specifications
• Secure transmission using AS2 or WebTrader protocols
• Real-time acknowledgment generation within minutes of receipt

The ESG replaced earlier submission methods including paper submissions, physical media (CDs/DVDs), and direct file transfer. Since May 2017, the ESG has been the mandatory submission pathway for commercial INDs, NDAs, BLAs, and ANDAs in eCTD format.

FDA ESG vs. Other Submission Methods

FDA Electronic Submissions Gateway: Architecture and Components

The FDA Electronic Submissions Gateway consists of several integrated components that work together to receive, validate, and route electronic submissions.

ESG System Architecture

The FDA electronic submissions gateway architecture includes:

1. Transmission Layer

• AS2 (Applicability Statement 2) secure connection
• WebTrader browser-based interface
• Encryption using digital certificates

2. Validation Layer

• Technical validation against eCTD specifications
• File integrity verification (checksum validation)
• Structure compliance checking
• Regional DTD/schema validation

3. Routing Layer

• Application type identification
• Division assignment based on submission content
• Acknowledgment generation and delivery

4. Acknowledgment System

• Technical acknowledgment (TA1) for transmission receipt
• Technical acknowledgment (TA2) for validation status
• Routing confirmation to appropriate review division

FDA ESG Connection Methods

The modernized ESG NextGen platform offers three connection methods for submitting to FDA:

Unified Submission Portal (USP):

• Web-based interface replacing legacy WebTrader
• Enables submission tracking and status monitoring
• Supports FileCatalyst TransferAgent for uploads
• Note: Accounts automatically deactivate after 60 days of inactivity

API Integration:

• Programmatic submission capability
• Enables direct integration with publishing workflows
• Automated submission and acknowledgment handling
• Ideal for sponsors with high submission volumes

AS2 Gateway Connection:

• System-to-system automated data exchange
• Requires dedicated AS2 server software
• Supports automated batch submissions
• Most reliable during platform updates - typically unaffected by USP outages

FDA ESG Account Setup: Step-by-Step Registration

Creating an FDA ESG account is a prerequisite for electronic submissions. The FDA ESG account setup process involves multiple steps and typically requires 2-4 weeks for complete configuration.

ESG Account Registration Process

Step 1: Create an FDA Account

Before accessing ESG, you need a general FDA account:

1. Navigate to the FDA Account Management portal
2. Click "Create Account"
3. Provide organization and contact information
4. Verify email address
5. Complete identity verification

Step 2: Request ESG Access

Once your FDA account is active:

1. Log into the FDA Unified Registration and Listing System (FURLS)
2. Navigate to the ESG registration section
3. Select your organization type (sponsor, CRO, regulatory service provider)
4. Identify the submission types you will send
5. Submit the ESG access request form

Step 3: Configure Connection Method

Choose and configure your gateway connection:

Step 4: Complete Trading Partner Agreement

For AS2 connections, you must:

1. Download the FDA Trading Partner Agreement
2. Complete organizational information
3. Provide technical contact details
4. Submit signed agreement to FDA
5. Await FDA confirmation (typically 5-10 business days)

Step 5: Test Your Connection

Before submitting production applications:

1. Send a test submission through your configured connection
2. Verify receipt of technical acknowledgment (TA1)
3. Confirm routing acknowledgment (TA2)
4. Resolve any connectivity issues identified
5. Document successful test for audit trail

ESG Account Maintenance

Maintaining your FDA ESG account requires ongoing attention:

ESG Submission Types: What Goes Through the Gateway

The FDA Electronic Submissions Gateway accepts multiple submission types across FDA centers. Understanding which submissions require the ESG ensures compliance with electronic submission requirements.

Submission Types by FDA Center

CDER (Center for Drug Evaluation and Research):

CBER (Center for Biologics Evaluation and Research):

CVM (Center for Veterinary Medicine):

Non-eCTD Submissions Through ESG

The FDA ESG also accepts certain non-eCTD format submissions:

• Pre-submission meeting requests
• FDA Form 1571 (initial IND) - certain cases
• Promotional material submissions (OPDP/APLB)
• Certain correspondence and amendments

These submissions use different technical specifications than eCTD but still route through the ESG for receipt and processing.

Electronic Submission FDA Technical Requirements

Successful ESG submission requires adherence to specific technical requirements. These requirements ensure your submission can be received, validated, and processed by FDA systems.

File Format Specifications

eCTD Technical Requirements:

PDF Document Requirements for Electronic Submission FDA:

Transmission Requirements

AS2 Connection Specifications:

Unified Submission Portal (USP) Requirements:

Naming Convention Requirements

File and folder naming for electronic submission FDA must follow strict conventions:

Allowed Characters:

• Lowercase letters (a-z)
• Numbers (0-9)
• Hyphens (-)
• Underscores (_) - limited use

Prohibited:

• Spaces
• Special characters (@, #, $, %, etc.)
• Uppercase letters in extensions
• Non-ASCII characters

Maximum Length:

• 64 characters including extension
• Full path should not exceed 180 characters

ESG Submission Process: Step-by-Step Guide

Successfully submitting through the FDA ESG requires following a systematic process. This step-by-step guide covers the ESG submission workflow from preparation to acknowledgment receipt.

Pre-Submission Preparation

1. Validate Your Submission Locally

Before transmitting to ESG:

• Run eCTD validation against current FDA DTD
• Verify all checksums match calculated values
• Check PDF compliance for all documents
• Validate hyperlinks and cross-references
• Confirm file naming conventions

2. Verify ESG Account Status

Confirm your account is ready:

• Check certificate expiration dates
• Verify contact information is current
• Confirm acknowledgment email routing
• Test connectivity if not submitted recently

3. Prepare Transmission Package

Package your submission:

• Compress submission folder to ZIP format
• Verify ZIP integrity after compression
• Note submission size for transmission planning
• Document submission contents for tracking

Transmission Steps

For Unified Submission Portal (USP) Users:

1. Log into FDA ESG NextGen Unified Submission Portal
2. Select submission type and application number
3. Upload submission file via FileCatalyst TransferAgent
4. Complete submission metadata form
5. Confirm upload completion
6. Note confirmation number
7. Track submission status in the portal
8. Monitor for acknowledgment emails

For API Integration Users:

1. Authenticate using API credentials
2. Prepare submission payload per API specifications
3. Submit via programmatic API call
4. Capture response with tracking information
5. Monitor for acknowledgment via API or email

For AS2 Users:

1. Configure submission in AS2 software
2. Set destination to FDA ESG endpoint
3. Initiate transmission
4. Monitor for MDN (Message Disposition Notification)
5. Log transmission completion
6. Monitor for acknowledgment emails

Acknowledgment Processing

The ESG generates two types of technical acknowledgments:

TA1 - Transmission Acknowledgment:

• Generated within minutes of receipt
• Confirms file received by ESG
• Does not indicate validation status
• Includes ESG tracking number

TA2 - Technical Validation Acknowledgment:

• Generated within 1 business day (typically hours)
• Indicates pass/fail of technical validation
• Lists specific errors if validation fails
• Confirms routing to review division if successful

Troubleshooting Common FDA ESG Errors

ESG submission errors fall into several categories. Understanding common errors and their solutions enables faster resolution and resubmission.

Connection and Transmission Errors

Technical Validation Errors

XML Schema Errors:

File Validation Errors:

PDF Validation Errors:

Resolving TA2 Failures

When your submission receives a failed TA2 acknowledgment:

1. Review the error report - TA2 includes specific error codes and locations
2. Categorize errors - Group by error type (XML, PDF, structure)
3. Fix errors in priority order - Start with blocking errors
4. Revalidate locally - Run full validation after fixes
5. Resubmit - Submit corrected package through ESG
6. Monitor for new TA2 - Verify all errors resolved

Common Error Patterns and Prevention

FDA ESG Best Practices

Following best practices for FDA ESG submissions reduces rejection rates and accelerates processing.

Pre-Submission Best Practices

1. Validate Early and Often

• Run validation during publishing, not just at completion
• Use validation tools that match current FDA specifications
• Document validation results for audit trail

2. Test Connectivity Regularly

• Submit test packages quarterly to verify connection
• Check certificate status monthly
• Maintain backup submission pathway

3. Plan for Submission Window

• Avoid submission during FDA maintenance windows
• Allow buffer time before regulatory deadlines
• Have contingency plan for transmission failures

Transmission Best Practices

1. Document Everything

• Screenshot confirmation screens
• Save all acknowledgment emails
• Log transmission times and tracking numbers
• Maintain submission history records

2. Monitor Actively

• Watch for TA1 within 15 minutes
• Expect TA2 within 4-24 hours
• Escalate if acknowledgments not received
• Have FDA ESG support contact ready

3. Maintain Audit Trail

• Archive original submission package
• Save all ESG communications
• Document any resubmissions
• Track submission lifecycle

Account Management Best Practices

Key Takeaways

Next Steps

Setting up and maintaining FDA ESG access is foundational to regulatory submission success. However, passing gateway validation is just the first step - ensuring your eCTD content is complete, consistent, and compliant requires comprehensive validation beyond what ESG checks.

Organizations managing regulatory submissions benefit from automated validation tools that catch errors before gateway rejection. Assyro's AI-powered platform validates eCTD submissions against FDA, EMA, and Health Canada requirements, providing detailed error reports and remediation guidance before submission.

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