Standard Operating Procedure for Deviation Handling in Downstream Processing (DSP) in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/197/2025
Supersedes	SOP/BS/197/2022
Page No.	Page 1 of 10
Issue Date	04/05/2025
Effective Date	06/05/2025
Review Date	04/05/2026

1. Purpose

To define a systematic and GMP-compliant approach for identifying, documenting, investigating, and resolving deviations observed during downstream processing (DSP) of biosimilar drug substances.

2. Scope

This SOP applies to all deviations encountered during DSP activities such as chromatography, filtration, buffer preparation, bulk storage, and equipment operations within biosimilar manufacturing facilities.

3. Responsibilities

• Process Operators: Immediately report any deviation or abnormality observed during DSP operations.
• Manufacturing Supervisor: Document the deviation, initiate preliminary impact assessment, and notify QA.
• QA: Lead the deviation investigation, assign root cause analysis (RCA), approve CAPA, and ensure closure.
• Department Head: Approve investigation summary and assess need for process requalification if applicable.

4. Accountability

The Head of Quality Assurance is accountable for ensuring that all DSP-related deviations are addressed in a timely, documented, and compliant manner as per GMP and regulatory standards.

5. Procedure

5.1 Identification and Initial Reporting

1. Operators must report any unexpected event, parameter deviation, or equipment malfunction during DSP activities.
2. Examples include:
   • Chromatography pressure spikes
   • Filter integrity failure
   • Buffer pH out of range
   • Equipment alarms or unplanned shutdowns
3. Record initial details in the Deviation Form (Annexure-1) and notify the supervisor and QA.

5.2 Documentation and Categorization

1. Assign deviation number and classify as:
   • Minor: No direct impact on product or process
   • Major: Potential impact on product/process but controlled
   • Critical: Confirmed impact on product quality, safety, or regulatory compliance
2. Enter deviation in the Deviation Register (Annexure-2).

5.3 Investigation and Root Cause Analysis

1. Form cross-functional team including QA, Production, and Engineering to perform RCA.
2. Use Fishbone, 5-Why, or FMEA tools to identify root cause.
3. Document investigation report, evidence, and interviews in Annexure-3.

5.4 CAPA Implementation

1. Define Corrective Actions to fix the immediate issue (e.g., retraining, equipment repair).
2. Define Preventive Actions to prevent recurrence (e.g., SOP revision, parameter tightening).
3. Assign responsibility and timeline. QA to verify CAPA effectiveness after implementation.

5.5 Product Impact and Disposition

1. Assess product impact in consultation with QA, QC, and regulatory affairs.
2. Batch may be:
   • Accepted with justification
   • Reprocessed (if permitted)
   • Rejected and disposed
3. Document final disposition in the Batch Manufacturing Record (BMR).

5.6 Deviation Closure

1. QA ensures all investigation steps, CAPA actions, and approvals are complete.
2. Update Deviation Register and archive records for minimum 5 years.

6. Abbreviations

• DSP: Downstream Processing
• CAPA: Corrective and Preventive Action
• QA: Quality Assurance
• BMR: Batch Manufacturing Record

7. Documents

1. Deviation Reporting Form – Annexure-1
2. DSP Deviation Register – Annexure-2
3. Investigation and RCA Template – Annexure-3

8. References

• ICH Q9 – Quality Risk Management
• EU GMP Chapter 1 – Pharmaceutical Quality System
• FDA QMS Guidelines for Biologics

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Deviation Reporting Form

Date	Time	DSP Area	Description	Reported By
04/05/2025	14:15	Chromatography Skid	Pressure exceeded 3 bar	Ajay Verma

Annexure-2: DSP Deviation Register

Deviation No.	Date	Area	Classification	Status
DSP-DEV-045	04/05/2025	Filtration	Major	Closed

Annexure-3: Investigation and RCA Template

Deviation No.	Investigation Summary	Root Cause	CAPA	QA Reviewer
DSP-DEV-045	Filter bypass observed	Loose clamp	Clamp replacement, retraining	Dr. Neha Rao

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Expanded CAPA and product impact assessment sections	Process harmonization with QA policy