Standard Operating Procedure for Cleaning-In-Place (CIP) of Chromatography Skids in Biosimilar Manufacturing

Department	Biosimilars
SOP No.	SOP/BS/168/2025
Supersedes	SOP/BS/168/2022
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 the procedure for validated cleaning-in-place (CIP) of chromatography skids used in biosimilar manufacturing, ensuring effective residue removal and equipment readiness for subsequent purification campaigns under GMP.

2. Scope

This SOP is applicable to all multi-use chromatography skids and systems equipped with integrated valves, sensors, pumps, and tubing that come in contact with biosimilar intermediates or buffers.

3. Responsibilities

• Production: Perform CIP process and document execution.
• QA: Review and verify cleaning logs, visual inspection, and cleaning validation parameters.
• Engineering: Maintain CIP programming, skid calibration, and preventive maintenance.

4. Accountability

The Downstream Processing Manager is accountable for ensuring the chromatography skid is cleaned, verified, and released before reuse in any production lot.

5. Procedure

5.1 Pre-Cleaning Check

1. Ensure the system has completed its last purification cycle and is disconnected from the column.
2. Visually inspect for product spills, leaks, or material residues. Record findings in Annexure-1.
3. Verify availability of validated cleaning solutions and filters.

5.2 CIP Setup

1. Connect CIP tanks to the skid inlet and outlet lines.
2. Ensure skid valves, pump, and pH/conductivity sensors are operational.
3. Load cleaning solution:
   • Cleaning agent: 0.5 M NaOH or 2% NaOH (as per validation)
   • Neutralizer (if required): 1 M acetic acid

5.3 Execution of CIP Cycle

1. Step 1: Pre-rinse with WFI – 1 CV at 100 cm/hr
2. Step 2: Circulate 0.5 M NaOH – 2 CV for 30 min at 25–30°C
3. Step 3: Intermediate rinse with WFI – until neutral pH is achieved
4. Step 4: Optional neutralization rinse (if acid is used)
5. Step 5: Final rinse with WFI – continue until conductivity < 1.3 µS/cm

5.4 Post-CIP Evaluation

1. Record rinse pH and conductivity of last three samples.
2. Perform visual inspection for any discoloration, leaks, or residue.
3. Attach rinse analysis reports in Annexure-2.

5.5 Cleaning Verification

1. Conduct TOC test and residue-specific swab (if applicable) after every fifth cycle.
2. Record TOC values (limit < 500 ppb) and file in Annexure-3.

5.6 Documentation

1. Complete CIP logbook entries for each cycle with date, time, operator, and solution volumes.
2. Ensure QA release and affix “CLEANED AND READY” status tag on skid panel.

6. Abbreviations

• CIP: Clean-In-Place
• TOC: Total Organic Carbon
• CV: Column Volume
• WFI: Water for Injection

7. Documents

1. Visual Inspection Checklist – Annexure-1
2. Rinse Verification Report – Annexure-2
3. TOC and Residue Test Log – Annexure-3

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• WHO TRS 999 – GMP for Biotherapeutic Products
• OEM Cleaning Recommendations (Cytiva ÄKTA, Repligen Skids)

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Visual Inspection Checklist

Skid ID	Inspection Date	Observed Issue	Status	Operator
SKD-DSP-01	04/05/2025	None	Acceptable	Ajay Verma

Annexure-2: Rinse Verification Report

Sample No.	pH	Conductivity (µS/cm)	Result	Verified By
1	6.7	1.1	Pass	Sunita Reddy

Annexure-3: TOC and Residue Test Log

Date	Skid ID	TOC Result (ppb)	Swab Test	Status	QA Reviewer
04/05/2025	SKD-DSP-01	395	Negative	Acceptable	Vinay Pawar

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Added TOC and conductivity criteria for rinse validation	QA audit requirement