Standard Operating Procedure for Cleaning and Sanitization of Bioreactors in Biosimilar Manufacturing
| Department | Biosimilars |
|---|---|
| SOP No. | SOP/BS/098/2025 |
| Supersedes | SOP/BS/098/2022 |
| 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 validated cleaning and sanitization procedures for bioreactors used in biosimilar manufacturing, ensuring removal of residues and microbial control in accordance with cGMP standards.
2. Scope
This SOP applies to stainless-steel bioreactors and single-use bioreactor systems (SUBs) used in upstream processes of biosimilar production.
3. Responsibilities
- Manufacturing: Execute cleaning/sanitization as per validated protocols and document activities.
- Engineering: Maintain CIP/SIP systems, validate cleaning cycles, and troubleshoot equipment.
- QA: Approve cleaning validation reports and review cleaning logs.
4. Accountability
The Manufacturing Manager is accountable for ensuring bioreactors are cleaned and sanitized according to this SOP before and after each production batch.
5. Procedure
5.1 Cleaning of Stainless-Steel Bioreactors
- Ensure the bioreactor is empty and all harvest lines are drained.
- Initiate CIP cycle using the control panel:
- Pre-rinse with WFI or RO water for 10 minutes.
- Alkaline wash (e.g., 1% NaOH at 60°C for 20 minutes).
- Intermediate rinse with WFI until conductivity <1 µS/cm.
- Acid wash (e.g., 0.5% nitric acid) if required.
- Final rinse with WFI.
- Inspect internal surfaces using a borescope if accessible.
5.2 Sanitization (SIP) of Stainless-Steel Bioreactors
- Perform SIP using clean steam (121°C) through all ports for minimum 30 minutes hold time.
- Validate temperature probes reach ≥121°C during cycle.
- Maintain log of time, temperature, and pressure (Annexure-2).
5.3 Cleaning and Sanitization of Single-Use Bioreactors
- Use pre-sterilized bags with gamma irradiation certification.
- If pre-use rinse required:
- Rinse with sterile WFI for 5–10 minutes at ambient temperature.
- Post-run, discard bag and sanitize shell with 70% IPA.
5.4 Cleaning Verification
- Swab rinsing ports and interior for residual protein or cleaning agent.
- Conduct TOC or conductivity test on rinse water; limits:
- TOC < 500 ppb
- Conductivity < 1.3 µS/cm
5.5 Documentation
- Record all activities in Bioreactor Cleaning Log (Annexure-1).
- Attach SIP printouts and cleaning validation results.
6. Abbreviations
- CIP: Clean-In-Place
- SIP: Sterilize-In-Place
- TOC: Total Organic Carbon
- QA: Quality Assurance
7. Documents
- Bioreactor Cleaning Log – Annexure-1
- SIP Cycle Monitoring Sheet – Annexure-2
8. References
- ICH Q9 – Quality Risk Management
- WHO TRS 1010 Annex 4 – GMP for Biological Products
9. SOP Version
Version: 2.0
10. Approval Section
| Prepared By | Checked By | Approved By | |
|---|---|---|---|
| Signature | |||
| Date | |||
| Name | |||
| Designation | |||
| Department |
11. Annexures
Annexure-1: Bioreactor Cleaning Log
| Date | Bioreactor ID | CIP Cycle Type | Operator | TOC Result | Remarks |
|---|---|---|---|---|---|
| 04/05/2025 | BR-SS-500L | Standard | Ajay Verma | 410 ppb | Pass |
Annexure-2: SIP Cycle Monitoring Sheet
| Date | Cycle Start | Hold Start | Hold End | Min Temp (°C) | Operator |
|---|---|---|---|---|---|
| 04/05/2025 | 09:00 | 09:10 | 09:40 | 122.3 | Sunita Reddy |
Revision History:
| Revision Date | Revision No. | Revision Details | Reason for Revision | Approved By |
|---|---|---|---|---|
| 04/05/2025 | 2.0 | Included single-use bioreactor sanitization and TOC limits | Periodic GMP review |