Standard Operating Procedure for Tangential Flow Filtration (TFF) Skid Operation in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/180/2025
Supersedes	SOP/BS/180/2022
Page No.	Page 1 of 10
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To establish a standardized procedure for the operation of Tangential Flow Filtration (TFF) skids during biosimilar downstream processes, including setup, membrane installation, parameter monitoring, and documentation to comply with GMP guidelines.

2. Scope

This SOP is applicable to all automated and manual TFF skids used for ultrafiltration and diafiltration steps in the purification of biosimilar drug substances.

3. Responsibilities

• Production Operator: Operate TFF skid, record all processing parameters, and ensure compliance with the batch protocol.
• Engineering: Perform routine maintenance, calibration, and troubleshooting of TFF skid components.
• QA: Review completed records and ensure adherence to validated process conditions.

4. Accountability

The Downstream Process Manager is accountable for proper use and performance of TFF systems in biosimilar manufacturing campaigns.

5. Procedure

5.1 Pre-Operation Checks

1. Verify that TFF skid has undergone cleaning and sanitization per SOP.
2. Check calibration status of pressure transmitters, flow meters, and conductivity sensors.
3. Confirm that the correct membrane module (MWCO, surface area) is available and intact.

5.2 System Assembly and Leak Test

1. Connect the feed, retentate, and permeate lines per the skid flow diagram.
2. Install membrane in the cassette holder or housing per manufacturer instructions.
3. Perform leak test using WFI or buffer at 1.5 bar for 10 minutes and document in Annexure-1.

5.3 Membrane Flushing and Equilibration

1. Flush membrane with 2–3 system volumes of WFI to remove storage solution.
2. Equilibrate with the process buffer and stabilize transmembrane pressure (TMP).

5.4 UF/DF Processing

1. Start circulation at target flow rate (e.g., 6–8 L/min/m² membrane area).
2. Adjust TMP between 1.0–1.5 bar using retentate pressure and permeate control valves.
3. Monitor feed pressure, permeate flow, TMP, and protein concentration at regular intervals.
4. Collect diafiltration permeate and maintain constant retentate volume during buffer exchange.

5.5 Completion and Harvest

1. Concentrate product to final target value and confirm using UV absorbance or protein assay.
2. Transfer retentate to sterile hold vessel under aseptic conditions.

5.6 Cleaning and Post-Use Maintenance

1. Flush the system with WFI until clear and free of protein.
2. Perform cleaning using 0.1 N NaOH or validated cleaning agent.
3. Rinse with WFI and dry or store membrane per reusability status.

6. Abbreviations

• TFF: Tangential Flow Filtration
• TMP: Transmembrane Pressure
• WFI: Water for Injection
• MWCO: Molecular Weight Cut-Off

7. Documents

1. TFF System Leak and Setup Checklist – Annexure-1
2. Filtration Parameter Log Sheet – Annexure-2

8. References

• ICH Q8 – Pharmaceutical Development
• FDA Guidance – Process Validation for Biologics
• WHO TRS 999 – GMP for Biotherapeutics

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: TFF System Leak and Setup Checklist

Activity	Status	Operator	Date
Membrane Installed	Yes	Ajay Verma	04/05/2025
Leak Test Performed	Pass	Ajay Verma	04/05/2025
Flush Completed	Yes	Ajay Verma	04/05/2025

Annexure-2: Filtration Parameter Log Sheet

Time	Feed Pressure (bar)	Retentate Pressure (bar)	Permeate Flow (L/hr)	TMP (bar)	Remarks
10:00	1.4	1.2	18.5	1.1	Stable
12:00	1.3	1.0	16.7	1.05	Normal

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Expanded filtration and cleaning procedures	Validation alignment