Standard Operating Procedure for Monitoring of Crystallization End-Point in API Manufacturing
| Department | API Manufacturing |
|---|---|
| SOP No. | SOP/API/100/2025 |
| Supersedes | SOP/API/100/2022 |
| 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 systematic procedure for monitoring and confirming the end-point of crystallization during the manufacturing of Active Pharmaceutical Ingredients (APIs), ensuring consistency, purity, and yield of the final product.
2. Scope
This SOP applies to production chemists, QC analysts, and QA officers involved in crystallization monitoring during the synthesis of APIs in pilot or commercial scale manufacturing.
3. Responsibilities
- Production Chemist: Perform in-process monitoring of crystallization and document observations.
- QC Analyst: Perform confirmatory testing to verify end-point if required.
- QA Officer: Review documentation and ensure compliance with GMP standards.
4. Accountability
The Production Head is accountable for monitoring and decision-making regarding crystallization completion. The QA Head ensures procedural compliance.
5. Procedure
5.1 Preparation for Crystallization
- Confirm the reaction is complete and the solution is ready for crystallization.
- Cool the solution gradually to the specified temperature as per MFR.
- Initiate seeding if applicable (as per validated procedure).
5.2 Monitoring Parameters
- Visual Observation:
- Check crystal growth visually at defined intervals (e.g., every 30 minutes).
- Uniform and consistent crystal formation indicates nearing completion.
- Temperature Monitoring:
- Ensure crystallization temperature range is maintained.
- Deviation may lead to improper crystal formation.
- Mother Liquor Clarity:
- Take ~5 mL of supernatant and check under good lighting for clarity.
- Absence of suspended solids indicates crystallization is near complete.
5.3 Confirmatory Tests (If Applicable)
- Send sample of mother liquor to QC for residual assay or LOD.
- If compound-specific, perform TLC or HPLC to detect uncrystallized material.
- Continue crystallization if active material is detected in the supernatant.
5.4 Documentation
- Record temperature, time, visual observation, and sampling in the Crystallization Monitoring Logbook (Annexure-1).
- Include any observations regarding crystal size, shape, or non-uniformity.
- Once complete, proceed with filtration or centrifugation as per next process step.
6. Abbreviations
- SOP: Standard Operating Procedure
- API: Active Pharmaceutical Ingredient
- QC: Quality Control
- QA: Quality Assurance
- LOD: Loss on Drying
- TLC: Thin Layer Chromatography
- MFR: Master Formula Record
7. Documents
- Crystallization Monitoring Logbook (Annexure-1)
- Batch Manufacturing Record
- QC Result Reports (if applicable)
8. References
- ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
- 21 CFR Part 211 – US FDA GMP
- WHO TRS 986 – GMP Guidelines
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 Logbook
| Date | Batch No. | Time | Temperature (°C) | Observation | Performed By | Remarks |
|---|---|---|---|---|---|---|
| 13/04/2025 | API-20250413 | 14:30 | 18.5 | Crystals uniform, clear mother liquor | Ready for filtration |
Revision History:
| Revision Date | Revision No. | Details | Reason | Approved By |
|---|---|---|---|---|
| 01/01/2022 | 1.0 | Initial SOP Release | Crystallization Control | QA Head |
| 13/04/2025 | 2.0 | Added Confirmatory Tests and Monitoring Logbook | Audit Compliance | QA Head |