Standard Operating Procedure for Risk Assessment in Upstream Failure Events in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/131/2025
Supersedes	SOP/BS/131/2022
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 structured approach for performing risk assessment in the event of upstream processing failures during biosimilar manufacturing, ensuring timely identification of root causes, impact analysis, and implementation of corrective and preventive actions (CAPA).

2. Scope

This SOP applies to all upstream operations including seed train development, bioreactor runs, inoculation, media preparation, and nutrient feed failures within biosimilar production facilities.

3. Responsibilities

• Production: Report and document upstream deviations and failures.
• Engineering: Provide data on equipment or utility malfunction during events.
• QA: Lead risk assessment meetings and ensure CAPA implementation and documentation.

4. Accountability

The Quality Assurance Head is accountable for ensuring that upstream deviations are risk-assessed using ICH Q9 principles and that findings are reviewed before product release decisions.

5. Procedure

5.1 Identification and Reporting

1. All upstream failures (e.g., cell growth arrest, pH excursions, contamination, DO instability) must be reported within 2 hours of detection.
2. Fill Annexure-1: Upstream Deviation Report with supporting data logs (SCADA, batch records).

5.2 Risk Assessment Initiation

1. QA shall initiate risk assessment within 24 hours using a cross-functional team (QA, Production, Engineering, QC).
2. Determine event criticality based on:
   • Impact on product quality or yield
   • Occurrence frequency
   • Detectability
3. Use Annexure-2: Risk Assessment Matrix (Severity x Occurrence x Detection).

5.3 Root Cause Analysis (RCA)

1. Conduct RCA using tools like:
   • 5-Why Analysis
   • Fishbone Diagram
   • Fault Tree Analysis
2. Identify whether the failure is process, equipment, utility, or personnel driven.

5.4 CAPA and Implementation

1. Based on RCA, define:
   • Immediate correction
   • Long-term preventive measures
2. Assign responsible departments and target dates in Annexure-3: CAPA Tracker.

5.5 Impact Assessment and Documentation

1. QA to assess:
   • Batch disposition (reject, reprocess, or conditional release)
   • Impact on downstream and product quality
2. Update final assessment in deviation closure form and link to batch documentation.

6. Abbreviations

• CAPA: Corrective and Preventive Action
• RCA: Root Cause Analysis
• QA: Quality Assurance
• SCADA: Supervisory Control and Data Acquisition

7. Documents

1. Upstream Deviation Report – Annexure-1
2. Risk Assessment Matrix – Annexure-2
3. CAPA Tracker – Annexure-3

8. References

• ICH Q9 – Quality Risk Management
• WHO TRS 981 Annex 2 – GMP for Biotech
• Internal SOP on Deviation Management

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Upstream Deviation Report

Date	Batch No.	Failure Description	Detected By	Initial Action
04/05/2025	BS-STR-045	DO dip below 10%	Ajay Verma	Increased air flow

Annexure-2: Risk Assessment Matrix

Severity	Occurrence	Detection	Risk Score	Risk Level
High	Medium	Low	12	Medium

Annexure-3: CAPA Tracker

CAPA No.	Description	Assigned To	Due Date	Status
CAPA-135	Install DO probe alarm	Engineering	10/05/2025	Open

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
04/05/2025	2.0	Added annexures for deviation and CAPA tracking	Periodic Review