Standard Operating Procedure for Recrystallization for API Purification in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/028/2025
Supersedes	SOP/API/028/2022
Page No.	Page 1 of 11
Issue Date	13/04/2025
Effective Date	15/04/2025
Review Date	13/04/2026

1. Purpose

To define a standardized procedure for the recrystallization of APIs or intermediates to enhance product purity and meet defined quality specifications while complying with GMP regulations.

2. Scope

This SOP is applicable to all recrystallization operations performed in the API manufacturing facility using single-solvent or mixed-solvent systems for purification purposes.

3. Responsibilities

• Production Operator: Perform recrystallization as per BMR.
• Process Chemist: Determine solvent suitability and solubility profiles.
• QA Officer: Verify process parameters, sampling, and documentation.
• Engineering Team: Ensure reactor, condenser, and utilities are functional.

4. Accountability

The Production Head is accountable for execution, and the QA Head is accountable for review and compliance verification.

5. Procedure

5.1 Preparation and Pre-Checks

1. Review the BMR for:
   • Solvent type and volume
   • Temperature range
   • Cooling rate
2. Ensure equipment (reactor, stirrer, condenser, vacuum line) is clean and ready.
3. Verify calibration of temperature probes and solvent tanks.

5.2 Dissolution

1. Charge the crude API to the reactor.
2. Add specified solvent gradually with agitation.
3. Heat the mixture to the defined temperature (e.g., 60–90°C) until a clear solution is obtained.
4. Maintain temperature for 15–30 minutes to ensure complete dissolution.

5.3 Filtration (If Required)

1. If any insoluble material remains, filter the hot solution through a pre-heated filter assembly or sparkler filter.
2. Collect filtrate in a clean dry vessel.

5.4 Crystallization

1. Initiate cooling of the clear solution under controlled conditions:
   • Rapid cooling for nucleation
   • Slow cooling for crystal growth
2. Maintain agitation throughout the cooling phase.
3. Optional: Seed crystals may be added to induce crystallization as per BMR.
4. Cool to 0–5°C or specified temperature and hold for minimum 2 hours.

5.5 Filtration and Drying of Crystals

1. Filter the crystal slurry using Nutsche or centrifuge.
2. Wash crystals with chilled solvent to remove impurities.
3. Collect and label wet cake; send for drying.
4. Record weight, time, and observations in “Recrystallization Logbook” (Annexure-1).

5.6 Post-Recrystallization Cleaning

1. Flush reactor with solvent or water depending on product compatibility.
2. Clean filters and centrifuge as per respective SOPs.
3. Document cleaning in “Equipment Cleaning Record.”

6. Abbreviations

• SOP: Standard Operating Procedure
• BMR: Batch Manufacturing Record
• QA: Quality Assurance
• API: Active Pharmaceutical Ingredient

7. Documents

1. Recrystallization Logbook (Annexure-1)
2. Equipment Cleaning Record (Annexure-2)
3. Solvent Usage Record (Annexure-3)

8. References

• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• USP <761> – Solubility Guidelines
• 21 CFR Part 211 – Current Good Manufacturing Practice

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Recrystallization Logbook

Batch No.	Solvent	Heating Temp	Cooling Temp	Crystallization Start Time	End Time	Yield (%)
API-202504	IPA	75°C	5°C	11:00	14:00	92.4%

Annexure-2: Equipment Cleaning Record

Equipment ID	Cleaned On	Cleaned By	Verified By	Remarks
R-102	13/04/2025			Clean and Dry

Annexure-3: Solvent Usage Record

Date	Batch No.	Solvent	Quantity Used (L)	Recovered (L)	Operator
13/04/2025	API-202504	IPA	80	68

Revision History:

Revision Date	Revision No.	Revision Details	Reason for Revision	Approved By
01/01/2022	1.0	Initial SOP Release	New Process Inclusion	QA Head
13/04/2025	2.0	Included Seeding and Mixed-Solvent Guidance	Process Optimization	QA Head