format or electronic format (eTMF). TMF serves as the central repository of essential documents demonstrating compliance with Good Clinical Practice (GCP) and enabling evaluation by regulatory authorities.

Scope

This SOP applies to sponsors, CROs, investigator sites, and QA staff responsible for establishing, maintaining, and overseeing TMF/eTMF systems. It covers setup, indexing, placeholders, document classification, version control, user access, quality checks, and inspection readiness across all clinical trials.

Responsibilities

• Sponsor: Ensures TMF/eTMF is established, structured, and compliant with ICH GCP.
• CRO: May maintain TMF on behalf of sponsor but sponsor retains oversight responsibility.
• Clinical Operations: Files trial-related documents, ensures contemporaneous updates.
• QA: Audits TMF/eTMF for compliance and completeness.
• TMF Administrator: Manages indexing, placeholders, user access, and quality checks.
• Investigators: Ensure ISF aligns with sponsor TMF.

Accountability

The sponsor is accountable for TMF/eTMF compliance, regardless of outsourcing. TMF administrators and CROs are accountable for daily management, while QA ensures oversight and audit readiness.

Procedure

1. TMF/eTMF Setup
1.1 At trial initiation, establish a TMF in accordance with ICH E6 (R2/R3) §8 Essential Documents.
1.2 Define TMF structure using recognized models (e.g., DIA TMF Reference Model).
1.3 For eTMF, validate the system in compliance with 21 CFR Part 11 and Annex 11.
1.4 Create TMF/eTMF Index (Annexure-1) reflecting trial phases: before, during, and after the trial.
1.5 Ensure placeholders are created for expected documents, reducing missing documentation risk.

2. Document Classification and Filing
2.1 Classify each document as Essential Before, During, or After trial per ICH GCP.
2.2 Assign document owners responsible for timely filing.
2.3 File documents within 5 working days of finalization.
2.4 Apply version control; superseded versions archived with audit trail.
2.5 Scan and upload paper documents into eTMF if hybrid system used.

3. User Access and Security
3.1 Provide role-based access controls for TMF/eTMF.
3.2 Ensure inspectors have read-only access when required.
3.3 Maintain Access Control Log (Annexure-2).

4. Quality Control and Completeness Checks
4.1 Perform monthly QC checks on 10% of documents across sections.
4.2 Document QC results in TMF QC Log (Annexure-3).
4.3 Rectify discrepancies within 10 working days.
4.4 Perform quarterly completeness reviews using DIA TMF metrics.

5. Version Management and Audit Trails
5.1 Ensure all eTMF documents have audit trails (creation, modification, deletion).
5.2 For paper TMFs, apply dated/stamped superseded labels.
5.3 Maintain TMF Audit Trail Log (Annexure-4).

6. Inspection Readiness
6.1 TMF/eTMF must be inspection-ready at all times.
6.2 Maintain TMF Inspection Checklist (Annexure-5).
6.3 Ensure essential documents (consent, approvals, monitoring reports, IP accountability) are contemporaneous.
6.4 Provide controlled access for regulators within 5 working days of request.

7. Archiving and Migration
7.1 Archive TMF/eTMF at trial closeout in secure, access-controlled facility.
7.2 Retain documents for 15–25 years depending on jurisdiction.
7.3 Document any migration from paper to eTMF or between systems with validation and reconciliation records.

Abbreviations

• SOP: Standard Operating Procedure
• TMF/eTMF: Trial Master File / electronic Trial Master File
• QC: Quality Control
• QA: Quality Assurance
• DIA: Drug Information Association
• PI: Principal Investigator
• ISF: Investigator Site File

Documents

1. TMF/eTMF Index (Annexure-1)
2. Access Control Log (Annexure-2)
3. TMF QC Log (Annexure-3)
4. TMF Audit Trail Log (Annexure-4)
5. TMF Inspection Checklist (Annexure-5)

References

• ICH E6(R2/R3) – Essential Documents
• FDA – TMF and eTMF Guidance
• EMA – TMF Requirements
• CDSCO – TMF Guidelines
• WHO – TMF Management

Version: 1.0

Approval Section

Prepared By	Rajesh Kumar, TMF Administrator
Checked By	Sunita Reddy, QA Officer
Approved By	Dr. Anil Sharma, Head Clinical Quality

Annexures

Annexure-1: TMF/eTMF Index

Section	Document Type	Status
Before Trial	Protocol, IB, Approvals	Filed
During Trial	Monitoring reports, IP logs	Filed
After Trial	Closeout report, Archival plan	Pending

Annexure-2: Access Control Log

User	Role	Access Level	Date Assigned	Date Revoked
Meena Sharma	CRA	Read/Write	01/09/2025	–
Inspector (FDA)	Regulator	Read-only	15/09/2025	20/09/2025

Annexure-3: TMF QC Log

Date	Section	Reviewed By	Findings	Action Taken
10/09/2025	During Trial	QA Officer	2 missing CRFs	Filed corrected versions

Annexure-4: TMF Audit Trail Log

Date	User	Action	Document	Remarks
12/09/2025	CRA	Uploaded	Monitoring Report	Validated
13/09/2025	QA	Corrected	IP Accountability Log	Version 2

Annexure-5: TMF Inspection Checklist

Item	Status	Remarks
Consent forms filed	Yes	All versions present
Monitoring reports complete	Yes	Up to date
IP accountability logs	Partial	To be reconciled

Revision History

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
26/08/2025	00	Initial version	New SOP creation	Head Clinical Quality

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