Standard Operating Procedure for Buffer Exchange Using TFF in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/158/2025
Supersedes	SOP/BS/158/2022
Page No.	Page 1 of 10
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To define the procedure for performing buffer exchange of biosimilar monoclonal antibody (mAb) intermediates using tangential flow filtration (TFF) systems to enable downstream purification or formulation compatibility.

2. Scope

This SOP applies to all operations involving TFF-based buffer exchange processes in downstream processing (DSP) of biosimilar proteins, using either reusable or single-use TFF systems.

3. Responsibilities

• Production: Set up, execute buffer exchange cycles, and document process parameters.
• QA: Review TFF logs, approve buffer preparations, and verify completion of exchange.
• Engineering: Ensure TFF skid maintenance and calibration.

4. Accountability

The Downstream Manufacturing Manager is accountable for GMP-compliant execution of TFF buffer exchange operations and ensuring data integrity.

5. Procedure

5.1 Pre-Operational Setup

1. Verify TFF skid status, tubing integrity, and membrane compatibility with product.
2. Document membrane type, lot number, and molecular weight cutoff (MWCO) in Annexure-1.
3. Sanitize system with 0.1 M NaOH and flush with WFI to achieve neutral pH.
4. Prime the system with process buffer to ensure wetting of membrane.

5.2 Buffer Preparation

1. Prepare target buffer (e.g., 20 mM Histidine, 150 mM NaCl, pH 6.0).
2. Filter buffer through 0.22 µm filter into sanitized holding tank.
3. Record buffer details in Annexure-2: Buffer Preparation Record.

5.3 Buffer Exchange Operation

1. Load product pool into TFF feed tank.
2. Set TFF parameters:
   • Transmembrane pressure (TMP): 1.0–1.5 bar
   • Crossflow rate: 300–500 mL/min (depending on skid capacity)
   • Diafiltration volume: Typically 5–8× of retentate volume
3. Initiate diafiltration by adding target buffer and removing filtrate simultaneously.
4. Monitor conductivity and pH in permeate and retentate until buffer exchange is confirmed.
5. Record cycle parameters and sample analysis in Annexure-3.

5.4 Post-Process Steps

1. Upon completion, collect retentate for further purification or formulation.
2. Flush membrane with WFI or sanitizing solution and clean system as per cleaning SOP.
3. Inspect pressure gauges, flow sensors, and record cleaning data.

5.5 Acceptance Criteria

1. Buffer exchange is complete when:
   • Permeate conductivity = target buffer conductivity ±10%
   • pH = target buffer ± 0.2 units

6. Abbreviations

• TFF: Tangential Flow Filtration
• MWCO: Molecular Weight Cut-Off
• TMP: Transmembrane Pressure
• DSP: Downstream Processing

7. Documents

1. TFF Setup and Membrane Log – Annexure-1
2. Buffer Preparation Record – Annexure-2
3. Buffer Exchange Process Record – Annexure-3

8. References

• ICH Q8 – Pharmaceutical Development
• WHO TRS 999 – GMP for Biotherapeutics
• OEM TFF Skid Operating Manual – Sartorius, Pall, or equivalent

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 Setup and Membrane Log

Date	Skid ID	Membrane Type	MWCO	Lot No.	Sanitized By
04/05/2025	TFF-102	Hollow Fiber	30 kDa	HF-3071	Ajay Verma

Annexure-2: Buffer Preparation Record

Date	Buffer Name	pH	Conductivity	Filter Lot No.	Prepared By
04/05/2025	20 mM Histidine + 150 mM NaCl	6.0	12.1 mS/cm	FL-2204	Sunita Reddy

Annexure-3: Buffer Exchange Process Record

Time	TMP	Flow Rate	Conductivity	pH	Remarks	Operator
14:15	1.2 bar	400 mL/min	11.9 mS/cm	6.1	Exchange complete	Ajay Verma

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
04/05/2025	2.0	Added diafiltration volume specification and post-process checks	Process control enhancement