residues, microbial load, and contaminants in accordance with GMP, WHO, and ICH guidelines.

2. Scope

This SOP applies to all lyophilizers installed in sterile injectable manufacturing areas that are equipped with CIP functionality. It includes procedures for cleaning initiation, system checks, chemical cycles, post-cleaning verification, documentation, and release for reuse.

3. Responsibilities

• Production Operator: Responsible for initiating, monitoring, and recording the CIP cycle as per SOP.
• Maintenance Engineer: Responsible for ensuring the CIP system is functioning correctly and for any troubleshooting.
• QA Officer: Responsible for verifying cleaning effectiveness, reviewing documentation, and approving equipment for next use.
• QC Analyst: Responsible for conducting TOC and microbial swab testing post-cleaning, if applicable.

4. Accountability

The Head of Production and Head of Quality Assurance are accountable for ensuring adherence to this SOP and compliance with GMP requirements.

5. Procedure

5.1 Pre-Cleaning Checks

1. Ensure the lyophilizer is not under vacuum and the previous product batch is completely removed.
2. Check for visible residue and remove bulk particles manually using lint-free wipes and WFI.
3. Ensure the lyophilizer doors and ports are securely closed and sealed.
4. Verify availability of validated cleaning agents such as sodium hydroxide 0.5%, nitric acid 0.5%, and sterile WFI.
5. Ensure the temperature, flow rate, and pressure sensors in the CIP system are calibrated.
6. Affix “Under Cleaning” status label near the lyophilizer control panel.

5.2 CIP System Operation

1. Access the CIP system interface via the HMI (Human Machine Interface) panel.
2. Select the appropriate validated CIP cycle based on the product cleaned previously.
3. Start the automated cleaning sequence which includes the following stages:
   • Pre-Rinse with WFI at 60–70°C for 10 minutes
   • Alkaline Wash with 0.5% NaOH at 75°C for 15 minutes
   • Intermediate Rinse with WFI until pH reaches below 9
   • Acid Rinse with 0.5% Nitric Acid for 10 minutes at ambient temperature
   • Final Rinse with WFI until conductivity is below 1.3 µS/cm
4. Monitor and document parameters such as cycle time, temperature, flow rate, and pH during each stage in Annexure-1.

5.3 Cleaning Validation and Verification

1. Upon completion of the CIP cycle, open the lyophilizer and inspect all surfaces for cleanliness.
2. Collect rinse water samples and submit for TOC analysis and conductivity testing.
3. If applicable, perform microbial swab testing of internal surfaces using sterile swabs and submit for bioburden testing.
4. All test results must comply with established acceptance criteria:
   • TOC < 500 ppb
   • Conductivity < 1.3 µS/cm
   • Microbial Count < 10 CFU/100 cm²
5. Record and attach laboratory test reports in Annexure-2.

5.4 Post-Cleaning Activities

1. Remove all cleaning labels after QA approval.
2. Re-connect any accessories or ports removed during preparation.
3. Ensure the lyophilizer is placed in ‘Ready for Use’ status in the equipment logbook and BMR.
4. Update the cleaning status in the equipment cleaning schedule.

5.5 Special Considerations

• Repeat CIP cycle if test results exceed acceptance criteria.
• In case of manual intervention, document reasons and corrective actions taken.
• Do not operate lyophilizer without QA clearance post-CIP.

6. Abbreviations

• SOP: Standard Operating Procedure
• CIP: Clean-In-Place
• HMI: Human Machine Interface
• TOC: Total Organic Carbon
• WFI: Water for Injection
• CFU: Colony Forming Units
• BMR: Batch Manufacturing Record

7. Documents

1. Annexure-1: CIP Execution and Parameter Log
2. Annexure-2: Laboratory Cleaning Test Results
3. Annexure-3: Cleaning Checklist and QA Release

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• WHO Technical Report Series No. 937 Annex 4
• 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation	Manufacturing Executive	QA Executive	Head QA
Department	Production	Quality Assurance	Quality Assurance

11. Annexures

Annexure-1: CIP Execution and Parameter Log

Date	Lyophilizer ID	Cycle Type	Temp (°C)	Flow (L/min)	Time (min)	Operator
23/06/2025	LYO-02	Full Cycle	75	50	60	Ajay Rao

Annexure-2: Laboratory Cleaning Test Results

Sample ID	TOC (ppb)	Conductivity (µS/cm)	Microbial Count (CFU)	Status	Analyst
RIN-157	115	1.2	2	Pass	Ritika Sharma

Annexure-3: Cleaning Checklist and QA Release

Item	Checked (Y/N)	Comments	QA Verified By
All visible residue removed	Y	Clean	Sunita Reddy
All cycle parameters within range	Y	Validated	Sunita Reddy
Lab results attached	Y	Compliant	Sunita Reddy

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
15/03/2022	1.0	Initial SOP Release	New Equipment	QA Head
24/06/2025	2.0	Cycle parameters and annexures updated	Periodic Review	QA Head