Standard Operating Procedure for Validation of Upstream Processes in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/121/2025
Supersedes	SOP/BS/121/2022
Page No.	Page 1 of 12
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To define the procedure for validation of upstream processes used in biosimilar manufacturing, including cell culture, media preparation, inoculation, and bioreactor operations to ensure process consistency, reproducibility, and regulatory compliance.

2. Scope

This SOP applies to process validation activities in the upstream production area, covering laboratory-scale to production-scale bioreactors and all critical upstream unit operations in biosimilar manufacturing.

3. Responsibilities

• Process Development: Define critical process parameters and acceptable ranges.
• Production: Execute validation batches as per protocol.
• QA: Review and approve validation protocols and reports.
• QC: Perform and release required analytical tests.

4. Accountability

The Head of Process Validation is accountable for the planning, execution, documentation, and approval of upstream process validation activities.

5. Procedure

5.1 Preparation of Validation Protocol

1. Develop a process validation protocol including:
   • Objective
   • Scope
   • Responsibilities
   • Critical Process Parameters (CPPs)
   • Acceptance Criteria
   • Sampling and Testing Plan
   • Deviation Handling Procedure
2. Review and approve the protocol with QA and Production Heads (Annexure-1).

5.2 Execution of Validation Batches

1. Perform a minimum of three consecutive successful validation batches.
2. Maintain consistency in:
   • Cell viability and growth profile
   • Bioreactor parameters (pH, DO, agitation, temperature)
   • Metabolite profile and product titer
3. Document all process data in the Batch Manufacturing Record (BMR).

5.3 Sampling and Testing

1. Conduct in-process and final testing as per QC plan.
2. Include:
   • Cell density and viability
   • Contamination check
   • Product identity and purity
3. Record results in Annexure-2: Validation Sample Log.

5.4 Review and Conclusion

1. Compile process data and analytical results in a validation summary report.
2. QA to review the report and verify all acceptance criteria are met.
3. Finalize with recommendation: Validated / Revalidation Required.

5.5 Revalidation Criteria

1. Trigger revalidation if:
   • Change in critical equipment or parameters
   • Major deviation during production
   • Gap of more than 12 months in commercial runs

6. Abbreviations

• CPP: Critical Process Parameter
• BMR: Batch Manufacturing Record
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. Validation Protocol Template – Annexure-1
2. Validation Sample Log – Annexure-2
3. Validation Summary Report Template – Annexure-3

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: Validation Protocol Template

Section	Description
CPPs	pH, DO, Agitation, Temp.
Criteria	≥90% Viability, 10g/L Titer

Annexure-2: Validation Sample Log

Date	Sample Type	Test	Result	Analyst
04/05/2025	Harvest	Cell Viability	94%	Ajay Verma

Annexure-3: Validation Summary Report Template

Batch No.	Outcome	Comments	Reviewed By
BS-UP-VAL-001	Pass	All CPPs within limits	QA

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
04/05/2025	2.0	Expanded criteria and revalidation triggers	Annual review update