Standard Operating Procedure for Use of Agitators and Mixing Uniformity Checks in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/033/2025
Supersedes	SOP/API/033/2022
Page No.	Page 1 of 10
Issue Date	13/04/2025
Effective Date	15/04/2025
Review Date	13/04/2026

1. Purpose

To define a standardized procedure for operating agitators and evaluating mixing uniformity during API manufacturing, ensuring proper dispersion, homogeneity of reaction mass, and consistency in critical processing steps.

2. Scope

This SOP applies to all reactors and mixing vessels equipped with mechanical agitators used in API synthesis, crystallization, neutralization, and blending operations.

3. Responsibilities

• Production Operator: Operate agitators as per process parameters defined in the BMR.
• Process Engineer: Determine optimal agitation speed and perform uniformity checks.
• QA Personnel: Review documentation and observe uniformity tests during validation batches.

4. Accountability

The Production Head is accountable for proper operation and documentation. The QA Head is responsible for compliance to process and GMP requirements.

5. Procedure

5.1 Pre-Operation Checklist

1. Verify equipment cleanliness and readiness for operation.
2. Ensure agitator blades are intact, aligned, and securely fastened.
3. Check gearbox oil level and inspect for any leakage or vibration issues.
4. Confirm availability of batch manufacturing record and agitation parameters.
5. Record observations in “Agitator Pre-Use Checklist” (Annexure-1).

5.2 Agitator Operation

1. Start the agitator at slow speed and gradually increase to the required RPM.
2. Observe flow pattern (vortex formation, suspension) through sight glass or top opening.
3. Maintain agitation speed and duration as per BMR or process validation protocol.
4. Avoid sudden speed changes or dry running.
5. Ensure agitation continues during critical operations (e.g., reagent addition, crystallization).

5.3 Mixing Uniformity Checks

1. For liquid mixing: Collect samples from top, middle, and bottom of the reactor using a sampling thief or dip rod.
2. For slurry mixing: Allow sampling during recirculation to avoid sediment bias.
3. Analyze samples for critical quality attributes (e.g., pH, concentration, turbidity).
4. If variation between layers exceeds predefined specification, extend agitation duration or adjust speed.
5. Record results in “Mixing Uniformity Log” (Annexure-2).

5.4 Post-Operation

1. Switch off the agitator after completion of process or as instructed in BMR.
2. Inspect the agitator blades for any material deposition or signs of erosion.
3. Clean agitator and vessel as per cleaning SOP.
4. Document cleaning in “Equipment Cleaning Log.”

6. Abbreviations

• SOP: Standard Operating Procedure
• BMR: Batch Manufacturing Record
• QA: Quality Assurance
• RPM: Revolutions Per Minute

7. Documents

1. Agitator Pre-Use Checklist (Annexure-1)
2. Mixing Uniformity Log (Annexure-2)
3. Equipment Cleaning Log (Annexure-3)

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals
• Internal Process Validation Reports

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Agitator Pre-Use Checklist

Date	Equipment ID	Blade Status	Oil Level	RPM Set	Remarks
13/04/2025	R-205	OK	Full	120	Ready

Annexure-2: Mixing Uniformity Log

Batch No.	Top Sample	Middle Sample	Bottom Sample	Variation (%)	Result
API-202504	98.2%	97.9%	98.1%	0.3%	Uniform

Annexure-3: Equipment Cleaning Log

Equipment ID	Date	Cleaned By	Verified By	Remarks
R-205	13/04/2025			Clean

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial SOP Creation	New Process Requirement	QA Head
13/04/2025	2.0	Added Mixing Uniformity Sampling Guidance	GMP and Audit Requirements	QA Head