Standard Operating Procedure for Harvest Decision and Timing in Bioreactor Operations for Biosimilars
| Department | Biosimilars |
|---|---|
| SOP No. | SOP/BS/086/2025 |
| Supersedes | SOP/BS/086/2022 |
| Page No. | Page 1 of 12 |
| Issue Date | 04/05/2025 |
| Effective Date | 06/05/2025 |
| Review Date | 04/05/2026 |
1. Purpose
To establish a standardized procedure for determining the optimal time to harvest bioreactor cultures during biosimilar production, based on defined critical process parameters and quality attributes.
2. Scope
This SOP applies to all production-scale bioreactor operations in biosimilar manufacturing where mammalian or microbial cells are cultured for protein expression and product harvest.
3. Responsibilities
- Production Technician: Monitor in-process parameters and notify the production lead when criteria for harvest are met.
- Process Development Team: Define titer and viability thresholds in the Process Description.
- QA Officer: Authorize harvest activity based on batch documentation and release of in-process results.
4. Accountability
The Production Manager is accountable for approving the harvest decision, ensuring all release criteria are met, and documenting the harvest initiation.
5. Procedure
5.1 Harvest Criteria Definition
- Define critical harvest criteria before batch execution in the BMR:
- Cell viability (e.g., ≥80%)
- Target titer (e.g., ≥1.5 g/L)
- Metabolite profile (e.g., lactate ≤3 g/L, ammonia ≤1.5 mM)
- Stability of pH and DO for ≥12 hours
5.2 Real-Time Monitoring
- Record daily values of:
- Viability (Trypan Blue or flow cytometry)
- Titer (protein assay)
- Metabolites (glucose, lactate, ammonia)
- Plot viability and titer trends in Annexure-1.
5.3 Decision-Making Process
- When viability drops below the threshold and titer plateaus, notify the shift in-charge.
- Conduct final analysis for titer, pH, and viability.
- QA verifies:
- All in-process testing is within specification
- No pending deviations that could impact product quality
- Upon QA clearance, document harvest decision and record timestamp.
5.4 Harvest Timing Execution
- Schedule harvest within 2 hours of QA clearance.
- Stop feed additions, sparging, and agitation based on the defined process.
- Transfer harvest to hold tank or clarification system (refer SOP/BS/087/2025).
5.5 Documentation
- Record harvest decision, timestamp, and basis of decision in Harvest Decision Log (Annexure-2).
- Ensure authorized personnel sign the log prior to initiating harvest.
6. Abbreviations
- BMR: Batch Manufacturing Record
- QA: Quality Assurance
- DO: Dissolved Oxygen
- g/L: Grams per Liter
7. Documents
- Harvest Criteria Trend Chart – Annexure-1
- Harvest Decision Log – Annexure-2
8. References
- ICH Q8 – Pharmaceutical Development
- WHO TRS 1025 Annex 2 – GMP for Biotech Products
9. SOP Version
Version: 2.0
10. Approval Section
| Prepared By | Checked By | Approved By | |
|---|---|---|---|
| Signature | |||
| Date | |||
| Name | |||
| Designation | |||
| Department |
11. Annexures
Annexure-1: Harvest Criteria Trend Chart
| Date | Time | Viability (%) | Titer (g/L) | pH | Operator |
|---|---|---|---|---|---|
| 04/05/2025 | 10:00 | 82 | 1.62 | 6.98 | Rajesh Kumar |
Annexure-2: Harvest Decision Log
| Date | Time | Batch No. | Harvest Authorized By | Viability (%) | Titer (g/L) | Remarks |
|---|---|---|---|---|---|---|
| 04/05/2025 | 11:15 | BS-086-B04 | QA Clearance | 80 | 1.65 | Meets threshold |
Revision History:
| Revision Date | Revision No. | Revision Details | Reason for Revision | Approved By |
|---|---|---|---|---|
| 04/05/2025 | 2.0 | Added titer trends and QA clearance requirement | Process optimization and compliance |