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

1. 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

1. Record daily values of:
   • Viability (Trypan Blue or flow cytometry)
   • Titer (protein assay)
   • Metabolites (glucose, lactate, ammonia)
2. Plot viability and titer trends in Annexure-1.

5.3 Decision-Making Process

1. When viability drops below the threshold and titer plateaus, notify the shift in-charge.
2. Conduct final analysis for titer, pH, and viability.
3. QA verifies:
   • All in-process testing is within specification
   • No pending deviations that could impact product quality
4. Upon QA clearance, document harvest decision and record timestamp.

5.4 Harvest Timing Execution

1. Schedule harvest within 2 hours of QA clearance.
2. Stop feed additions, sparging, and agitation based on the defined process.
3. Transfer harvest to hold tank or clarification system (refer SOP/BS/087/2025).

5.5 Documentation

1. Record harvest decision, timestamp, and basis of decision in Harvest Decision Log (Annexure-2).
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

1. Harvest Criteria Trend Chart – Annexure-1
2. 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