Standard Operating Procedure for Steam-In-Place (SIP) Procedures in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/126/2025
Supersedes	SOP/BS/126/2022
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 validated and standardized procedure for executing Steam-In-Place (SIP) of bioreactors, media transfer lines, and associated components used in biosimilar manufacturing to ensure sterility before use.

2. Scope

This SOP applies to all stainless steel and single-use bioreactor systems, piping, filters, and vessels requiring SIP before aseptic processing in biosimilar upstream and downstream operations.

3. Responsibilities

• Production Staff: Initiate, monitor, and document the SIP process.
• Engineering: Maintain SIP systems, calibrate instruments, and support troubleshooting.
• QA: Review SIP cycle records and approve sterilization results before batch initiation.

4. Accountability

The Manufacturing Head is accountable for ensuring compliance with validated SIP procedures and that no equipment is used without a completed and approved SIP cycle.

5. Procedure

5.1 Pre-SIP Checks

1. Ensure equipment is cleaned as per CIP SOP and logged.
2. Confirm:
   • Steam generator is functional
   • Drain and air vent lines are open
   • Temperature and pressure sensors are calibrated
3. Record equipment ID, date, and initials in Annexure-1: SIP Preparation Checklist.

5.2 SIP Execution Parameters

1. Use validated SIP cycle:
   • Temperature: ≥121°C
   • Hold Time: Minimum 30 minutes
   • Steam Pressure: 1.0–1.5 bar
2. Start the SIP cycle using the control system or manual valve sequencing.
3. Monitor temperature at:
   • Top of vessel
   • Outlet point
   • Cold spots (as identified in qualification)

5.3 Post-SIP Procedure

1. Close all valves and isolate sterile lines using sterile caps or PTFE tape.
2. Allow equipment to cool to ambient under filtered air.
3. Visually inspect for condensate or water pooling.
4. Record SIP cycle printout and temperature graphs.
5. Fill Annexure-2: SIP Execution Record.

5.4 Verification and Release

1. QA to review SIP records and verify temperature profiles meet specifications.
2. Apply “SIP Completed” status tag and authorize for use.

5.5 Deviations and Failures

1. If cycle aborts or temperature drops below target:
   • Label equipment as “NOT STERILE – DO NOT USE”
   • Investigate root cause and document in Annexure-3
   • Repeat SIP only after clearance from Engineering and QA

6. Abbreviations

• SIP: Steam-In-Place
• CIP: Clean-In-Place
• QA: Quality Assurance
• PTFE: Polytetrafluoroethylene

7. Documents

1. SIP Preparation Checklist – Annexure-1
2. SIP Execution Record – Annexure-2
3. SIP Deviation Log – Annexure-3

8. References

• EU GMP Annex 1 – Manufacture of Sterile Medicinal Products
• WHO TRS 1019 – GMP for Biotech Manufacturing
• ISPE Baseline Guide: Sterile Manufacturing Facilities

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: SIP Preparation Checklist

Step	Status	Initials
Drain Open	Yes	AR
Steam Supply Verified	Yes	AR

Annexure-2: SIP Execution Record

Date	Equipment ID	Start Time	Hold Temp	Hold Time	Verified By
04/05/2025	BR-100L	10:00	122.5°C	32 min	Sunita Reddy

Annexure-3: SIP Deviation Log

Date	Issue	Root Cause	Corrective Action	Reviewed By
02/05/2025	Temp drop to 119°C	Steam trap leak	Trap replaced	QA

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
04/05/2025	2.0	Cycle parameters revised and deviation procedure added	Validation update