Standard Operating Procedure for Filter Sterilization of Final Bulk in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/195/2025
Supersedes	SOP/BS/195/2022
Page No.	Page 1 of 9
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To define the GMP-compliant procedure for filter sterilization of final biosimilar bulk drug substance using validated 0.22 µm filters to ensure microbial safety prior to formulation or fill-finish operations.

2. Scope

This SOP applies to all biosimilar final bulk drug substances intended for sterile formulation, where final sterile filtration is the last step before release or fill-finish transfer.

3. Responsibilities

• Production: Perform sterile filtration using validated equipment and handle product aseptically.
• QA: Review sterilization batch records, filter integrity tests, and approve batch release.
• Engineering: Maintain filtration skids, perform calibration of integrity testers, and support troubleshooting.

4. Accountability

The Head of Manufacturing is accountable for ensuring that filter sterilization is carried out under validated and aseptic conditions, and that integrity testing is performed before and after filtration.

5. Procedure

5.1 Preparation and Setup

1. Verify QA clearance of the bulk solution for sterile filtration.
2. Gather materials:
   • Pre-sterilized 0.22 µm filter (PVDF or PES membrane)
   • Sterile hoses, clamps, and connectors
   • Integrity tester (calibrated)
3. Ensure filtration assembly is performed in a Grade A/B environment.
4. Record filter lot number, expiry date, and serial number in Annexure-1.

5.2 Pre-Use Integrity Test (Optional)

1. If required by product-specific validation, perform pre-use Bubble Point Test or Diffusion Test.
2. Record test results in Annexure-2. Proceed only if filter passes.

5.3 Filtration Process

1. Connect feed vessel to filter inlet and sterile final container to filter outlet using sterile transfer lines.
2. Prime the filter slowly with bulk solution to avoid air entrapment.
3. Begin filtration at pressure ≤ 2.5 bar. Avoid backpressure buildup.
4. Monitor flow rate and collect filtrate into sterile hold vessels or bags.
5. Ensure filtration is completed in one continuous process (no filter change).

5.4 Post-Use Integrity Test

1. Immediately after filtration, disconnect the filter and connect to integrity tester.
2. Perform either Bubble Point, Diffusion Flow, or Pressure Hold Test per filter manufacturer’s specification.
3. Acceptable limits should be as per filter validation protocol.
4. Document results in Annexure-2. Product is considered sterile only if filter passes integrity test.

5.5 Labeling and Documentation

1. Label final bulk container with:
   • Product name
   • Batch number
   • Filtration date/time
   • Storage condition (e.g., 2–8°C)
2. Attach completed filter sterilization log to the BMR and submit to QA for review.

5.6 Deviation Handling

1. In case of filter failure during post-use integrity test:
   • Quarantine the batch
   • Initiate deviation report (Annexure-3)
   • Perform root cause analysis and retest backup samples

6. Abbreviations

• BMR: Batch Manufacturing Record
• QA: Quality Assurance
• PES: Polyethersulfone
• PVDF: Polyvinylidene Difluoride

7. Documents

1. Filter Details Log – Annexure-1
2. Integrity Test Report – Annexure-2
3. Deviation Form – Annexure-3

8. References

• ICH Q8 – Pharmaceutical Development
• FDA Guidance for Industry: Sterile Drug Products by Aseptic Processing
• PDA Technical Report No. 26 – Sterilizing Filtration of Liquids

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Filter Details Log

Filter Lot No.	Serial No.	Membrane Type	Expiry Date	Operator
FLS-8012	SX-10987	PES 0.22 µm	30/11/2025	Ajay Verma

Annexure-2: Integrity Test Report

Date	Test Type	Result	Limit	Status	Performed By
04/05/2025	Bubble Point	54 psi	≥ 50 psi	Pass	Sunita Reddy

Annexure-3: Deviation Form

Date	Batch No.	Deviation	Root Cause	Disposition	QA Reviewed By
04/05/2025	BS-FB-204	Post-use filter failure	Clogging due to protein load	Batch rejected	Dr. Neha Rao

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Updated integrity test limits and filter material types	Validation update