Standard Operating Procedure for Handling Temperature Excursions During Fermentation in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/132/2025
Supersedes	SOP/BS/132/2022
Page No.	Page 1 of 12
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To outline the procedure for detecting, documenting, investigating, and responding to temperature excursions during fermentation processes in biosimilar manufacturing, ensuring product quality and regulatory compliance.

2. Scope

This SOP applies to all fermentation operations involving mammalian, bacterial, or yeast systems in upstream biosimilar production, where temperature is a critical process parameter (CPP).

3. Responsibilities

• Production: Monitor and immediately report temperature deviations.
• Engineering: Investigate equipment or utility faults and rectify.
• QA: Evaluate deviation impact and disposition of the affected batch.

4. Accountability

The Production Head is accountable for ensuring that all temperature excursions during fermentation are promptly addressed, risk-assessed, and documented as per GMP requirements.

5. Procedure

5.1 Monitoring and Detection

1. Fermenter temperature must be continuously monitored via SCADA or validated data logger.
2. Alarm should be triggered when temperature deviates by ±0.5°C from the setpoint for ≥5 minutes.
3. Operator shall acknowledge alarm and record in Annexure-1: Excursion Log Sheet.

5.2 Immediate Action

1. Identify nature of excursion:
   • High temperature (> upper limit)
   • Low temperature (< lower limit)
2. Switch to manual temperature control if needed.
3. Contact engineering for verification of:
   • Jacket heating/cooling loop
   • Temperature sensor calibration
   • Utility supply stability

5.3 Documentation

1. Log event details including:
   • Start and end time
   • Minimum/Maximum temperatures reached
   • Duration of excursion
2. Fill Annexure-2: Temperature Excursion Investigation Form.

5.4 Risk Assessment and Batch Impact Evaluation

1. QA shall lead cross-functional evaluation considering:
   • Stage of fermentation during excursion
   • Duration and deviation magnitude
   • Historical impact on product quality (titer, impurity)
2. Decision to continue, reprocess, or reject must be documented in Annexure-3.

5.5 Corrective and Preventive Action (CAPA)

1. CAPA shall be initiated if:
   • Excursion repeats
   • System fault identified
   • Deviation affects product CQAs
2. Assign responsible person, timeline, and closure details in Annexure-4.

6. Abbreviations

• CPP: Critical Process Parameter
• CQA: Critical Quality Attribute
• SCADA: Supervisory Control and Data Acquisition
• CAPA: Corrective and Preventive Action

7. Documents

1. Excursion Log Sheet – Annexure-1
2. Temperature Excursion Investigation Form – Annexure-2
3. Batch Disposition Summary – Annexure-3
4. CAPA Log – Annexure-4

8. References

• ICH Q8 – Pharmaceutical Development
• ICH Q9 – Quality Risk Management
• EU GMP Annex 15 – Qualification and Validation

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Excursion Log Sheet

Date	Batch No.	Setpoint	Deviation	Time In/Out	Action Taken
04/05/2025	BS-FER-108	37°C	38.3°C	03:10–03:25	Manual reset

Annexure-2: Temperature Excursion Investigation Form

Batch No.	Description	Suspected Cause	Impact Summary	Investigated By
BS-FER-108	Temp spike above 1.3°C	Steam valve stuck	No quality impact	Sunita Reddy

Annexure-3: Batch Disposition Summary

Batch No.	Review Outcome	Disposition	QA Signoff
BS-FER-108	Acceptable excursion	Released	QA

Annexure-4: CAPA Log

CAPA No.	Issue	Action	Owner	Status
CAPA-157	Frequent valve malfunction	Install new control module	Engineering	Open

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
04/05/2025	2.0	Annexures added, manual control steps clarified	Audit Finding