Standard Operating Procedure for Crystallization Process Control in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/061/2025
Supersedes	SOP/API/061/2022
Page No.	Page 1 of 10
Issue Date	13/04/2025
Effective Date	15/04/2025
Review Date	13/04/2026

1. Purpose

To establish a standard and validated procedure for carrying out crystallization in API manufacturing, ensuring consistent particle size, purity, and yield by controlling key process parameters.

2. Scope

This SOP applies to all crystallization operations of active pharmaceutical ingredients in production reactors and crystallizers, covering batch and continuous processes within the API manufacturing facility.

3. Responsibilities

• Production Operators: Follow crystallization process as per the batch record and control parameters.
• Production Supervisor: Monitor the operation, ensure adherence to parameters, and document process deviations.
• QA Department: Review records and verify compliance with GMP standards.
• QC Department: Perform sampling and testing for crystallization endpoints.

4. Accountability

The Production Head is accountable for proper execution and documentation of crystallization activities. The QA Head is responsible for ensuring process compliance.

5. Procedure

5.1 Pre-Crystallization Checks

1. Ensure reactor is cleaned and line clearance is completed.
2. Verify availability and calibration status of:
   • Temperature probes
   • pH meters
   • Agitators
3. Ensure all raw materials and solvents are issued as per BMR.

5.2 Crystallization Process Execution

1. Charge the solution/slurry into the reactor as per approved batch instructions.
2. Initiate stirring and maintain the required agitation speed (e.g., 100–200 RPM).
3. Set temperature as per process requirement (e.g., cool from 60°C to 5°C at controlled rate).
4. Add anti-solvent or seed material, if specified, slowly under continuous agitation.
5. Monitor temperature drop rate to avoid sudden precipitation or oiling-out.
6. Maintain crystallization hold time (e.g., 4–6 hrs) or until endpoint is achieved.

5.3 Monitoring and Control

1. Monitor and record:
   • Temperature every 15 minutes
   • Agitation RPM every hour
   • Visual observation of crystal formation
2. Collect in-process samples for:
   • Microscopic observation (crystal habit)
   • pH and solvent content
   • TLC (if applicable) to confirm completion
3. Record all data in the “Crystallization Monitoring Log” (Annexure-1).

5.4 Post-Crystallization

1. Allow slurry to settle (if required) before filtration or centrifugation.
2. Transfer to next process step (filtration/drying) as per batch plan.
3. Perform reactor cleaning as per cleaning SOP and document it.

6. Abbreviations

• SOP: Standard Operating Procedure
• BMR: Batch Manufacturing Record
• RPM: Revolutions Per Minute
• TLC: Thin Layer Chromatography
• QC: Quality Control
• QA: Quality Assurance

7. Documents

1. Crystallization Monitoring Log (Annexure-1)
2. Batch Manufacturing Record
3. Cleaning Record for Equipment

8. References

• ICH Q8 – Pharmaceutical Development
• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• Internal Process Validation Protocols

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Crystallization Monitoring Log

Date	Batch No.	Time	Temperature (°C)	RPM	Crystal Observation	Sample Collected
13/04/2025	CRY-20250413	09:15	30	120	Cloudy Appearance	Yes

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial SOP Release	Process Implementation	QA Head
13/04/2025	2.0	Added Detailed Sampling and Observation Steps	Process Optimization	QA Head