Standard Operating Procedure for Concentration Adjustment Post-UF in Biosimilar Manufacturing
| Department | Biosimilars |
|---|---|
| SOP No. | SOP/BS/181/2025 |
| Supersedes | SOP/BS/181/2022 |
| 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 a standardized procedure for adjusting the protein concentration of biosimilar bulk drug substances after ultrafiltration (UF) to meet final specification prior to bulk storage or formulation.
2. Scope
This SOP applies to biosimilar batches requiring reconcentration or dilution following UF or diafiltration steps to achieve target concentration ranges specified in the batch manufacturing record (BMR).
3. Responsibilities
- Production: Perform dilution or reconcentration as per BMR and record processing details.
- QC: Analyze in-process samples for protein content (e.g., UV 280, Bradford, BCA).
- QA: Verify concentration adjustment log, review compliance with batch instructions.
4. Accountability
The Downstream Process Head is accountable for ensuring accurate concentration adjustment and documentation prior to batch disposition.
5. Procedure
5.1 Determination of Target Concentration
- Refer to the product-specific BMR to identify target protein concentration (e.g., 40–60 mg/mL).
- Review QC in-process result from post-UF sample to determine actual protein level.
5.2 Concentration Below Target
- If the post-UF concentration is below the acceptable range:
- Reconnect the UF system and continue filtration.
- Sample periodically and re-test until target is reached.
- Record volumes processed, flow rate, and membrane TMP in Annexure-1.
5.3 Concentration Above Target
- If the product is over-concentrated:
- Add pre-filtered formulation buffer gradually under controlled agitation.
- Mix for at least 15 minutes with slow speed stirrer.
- Take homogenized sample and analyze protein concentration.
- Repeat stepwise dilution until final concentration is within limits.
5.4 Final Mixing and Homogeneity
- Ensure complete mixing of final bulk solution by recirculation or gentle agitation for 30 minutes.
- Confirm uniformity by sampling from top, middle, and bottom locations and test for protein content.
5.5 Documentation
- Record batch number, adjustment method, volumes added/removed, and test results in Annexure-2.
- QA to review and sign off before release for next step.
6. Abbreviations
- UF: Ultrafiltration
- BMR: Batch Manufacturing Record
- QC: Quality Control
- TMP: Transmembrane Pressure
7. Documents
- UF Volume Adjustment Log – Annexure-1
- Final Concentration Adjustment Record – Annexure-2
8. References
- ICH Q8 – Pharmaceutical Development
- WHO TRS 1004 – GMP Guidelines for Biotherapeutics
- FDA Guidance – Bulk Drug Substance Handling and Controls
9. SOP Version
Version: 2.0
10. Approval Section
| Prepared By | Checked By | Approved By | |
|---|---|---|---|
| Signature | |||
| Date | |||
| Name | |||
| Designation | |||
| Department |
11. Annexures
Annexure-1: UF Volume Adjustment Log
| Time | Volume (L) | TMP (bar) | Protein Conc. (mg/mL) | Remarks |
|---|---|---|---|---|
| 09:00 | 6.0 | 1.1 | 38.2 | Under target |
| 11:00 | 5.2 | 1.2 | 42.5 | Achieved |
Annexure-2: Final Concentration Adjustment Record
| Batch ID | Initial Conc. (mg/mL) | Method | Final Conc. (mg/mL) | QC Analyst | Date |
|---|---|---|---|---|---|
| BS-PF-029 | 63.4 | Dilution | 59.8 | Sunita Reddy | 04/05/2025 |
Revision History:
| Revision Date | Revision No. | Details | Reason | Approved By |
|---|---|---|---|---|
| 04/05/2025 | 2.0 | Clarified dilution steps and added homogeneity verification | Process robustness improvement |