Standard Operating Procedure for In-Process pH Drift Correction in Bioreactor Operations for Biosimilars

Department	Biosimilars
SOP No.	SOP/BS/084/2025
Supersedes	SOP/BS/084/2022
Page No.	Page 1 of 11
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To provide standardized guidelines for detecting and correcting in-process pH drift during bioreactor operations in biosimilar manufacturing to maintain culture conditions and ensure product consistency.

2. Scope

This SOP applies to all bioreactor systems involved in upstream processing where pH maintenance is critical for cell growth and biosimilar protein expression.

3. Responsibilities

• Bioprocess Technician: Monitor pH trends and initiate corrective measures when required.
• Instrumentation Engineer: Verify functionality of pH sensors and control loops.
• QA Officer: Review documentation of pH corrections and evaluate deviations.

4. Accountability

The Upstream Processing Supervisor is accountable for maintaining pH within defined process ranges and ensuring appropriate documentation of interventions.

5. Procedure

5.1 Acceptable pH Range

1. Defined pH range should be based on the cell line and process requirements (e.g., CHO cells: 6.8–7.2).
2. Set these limits in SCADA/HMI for continuous monitoring.

5.2 pH Drift Detection

1. Continuously monitor pH using inline sensors calibrated as per SOP/BS/082/2025.
2. Log pH values every 2 hours or as specified in the Batch Manufacturing Record (BMR).
3. Generate alert if pH drifts ±0.2 units beyond the target setpoint.

5.3 Correction Strategy

1. Automatic Control Loop:
   • If enabled, acid/base is added automatically via PID controller linked to dosing pumps.
   • Verify correction within 15–30 minutes of deviation alert.
2. Manual Intervention:
   • In case of control failure, manually add correction solution under supervision.
   • Base: 1M NaOH or NaHCO₃
   • Acid: 1M HCl or CO₂ sparging (for base drift)
   • Add in increments of 1–2 mL/L while monitoring effect on pH.

5.4 Documentation

1. Record:
   • Time of drift detection
   • pH values before and after correction
   • Volume and type of acid/base added
   • Stabilization time
2. Log all entries in Annexure-1: pH Drift Correction Log.
3. QA review required for repeated corrections (>3 times in 24 hrs).

6. Abbreviations

• pH: Potential of Hydrogen
• BMR: Batch Manufacturing Record
• SCADA: Supervisory Control and Data Acquisition

7. Documents

1. pH Drift Correction Log – Annexure-1

8. References

• ICH Q8 – Pharmaceutical Development
• USP <791> – pH Determination

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: pH Drift Correction Log

Date	Time	Batch No.	pH Before	Correction Type	Volume Added	pH After	Operator
04/05/2025	11:30	BS-084-B01	6.62	1M NaHCO₃	3 mL	6.92	Sunita Reddy

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
04/05/2025	2.0	Added manual intervention protocol and stabilization verification	GMP Compliance Update