Standard Operating Procedure for Handling of Exothermic Reactions in API Manufacturing
| Department | API Manufacturing |
|---|---|
| SOP No. | SOP/API/024/2025 |
| Supersedes | SOP/API/024/2022 |
| 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 the procedure for the safe handling of exothermic reactions during API manufacturing, ensuring thermal control, process safety, and compliance with regulatory standards.
2. Scope
This SOP applies to all operations involving exothermic chemical reactions performed in reactors within the API manufacturing facility, including pilot and production-scale equipment.
3. Responsibilities
- Production Operator: Execute the reaction according to the BMR and monitor temperature and pressure closely.
- Process Engineer: Evaluate heat release data and define charging rate and safety controls.
- QA Personnel: Ensure the process is performed in accordance with validated procedures and GMP compliance.
- EHS Personnel: Provide risk mitigation tools and emergency response support.
4. Accountability
The Production Head and EHS Head are accountable for ensuring process safety during exothermic reactions and prompt management of any deviations.
5. Procedure
5.1 Prerequisites and Controls
- Verify the BMR for:
- Reaction enthalpy
- Maximum temperature (Tmax)
- Critical process parameters
- Ensure:
- Reactor temperature probe is calibrated
- Emergency cooling system is functional
- Pressure relief valve is in place
- Gas scrubber (if applicable) is operational
- Keep antifoaming and quenching agents ready at the site.
5.2 Charging Strategy for Exothermic Reactions
- Begin agitation and maintain initial temperature as per BMR.
- Use controlled or metered addition for critical reagents (e.g., acids, oxidizers).
- For manual additions, follow the “Split Charging” technique:
- Add initial 5–10% of material and observe heat rise
- Wait for stabilization and proceed in increments
- Record charging start and end time, rate, and interval in the “Exothermic Reaction Log” (Annexure-1).
5.3 Monitoring During Reaction
- Monitor:
- Jacket and mass temperature
- Pressure build-up
- Foaming or gas evolution
- Use “Temperature-Time Profile Chart” for continuous trend plotting (Annexure-2).
- Do not exceed defined Tmax by more than 2°C; initiate hold or quenching if required.
5.4 Emergency Handling
- In case of temperature runaway:
- Stop reagent addition
- Initiate cooling via jacket/chiller
- Add quenching agent (if validated)
- Evacuate area if vapors evolve excessively
- Document deviation using the “Exothermic Incident Report Form” (Annexure-3).
- Restart batch only after QA and EHS approval.
5.5 Post-Reaction Documentation
- Ensure complete recording of:
- All parameters monitored
- Any deviation actions taken
- Residual heat observed post-reaction
- Attach reactor trend reports (DCS or manual).
- Sign and archive records with batch documentation.
6. Abbreviations
- SOP: Standard Operating Procedure
- BMR: Batch Manufacturing Record
- QA: Quality Assurance
- EHS: Environment, Health & Safety
- Tmax: Maximum Allowable Temperature
7. Documents
- Exothermic Reaction Log (Annexure-1)
- Temperature-Time Profile Chart (Annexure-2)
- Exothermic Incident Report Form (Annexure-3)
8. References
- ICH Q9 – Quality Risk Management
- ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
- 21 CFR Part 211.100 – Written procedures; deviations
9. SOP Version
Version: 2.0
10. Approval Section
| Prepared By | Checked By | Approved By | |
|---|---|---|---|
| Signature | |||
| Date | |||
| Name | |||
| Designation | |||
| Department |
11. Annexures
Annexure-1: Exothermic Reaction Log
| Date | Batch No. | Reagent | Start Time | End Time | Rate | Temp Range |
|---|---|---|---|---|---|---|
| 13/04/2025 | API-EX202504 | H2SO4 | 09:00 | 09:45 | 10 mL/min | 25–38°C |
Annexure-2: Temperature-Time Profile Chart
| Time | Jacket Temp (°C) | Mass Temp (°C) | Pressure (bar) | Operator |
|---|---|---|---|---|
| 09:00 | 26 | 27.5 | 1.1 | |
| 09:15 | 27 | 29.2 | 1.1 |
Annexure-3: Exothermic Incident Report Form
| Date | Batch No. | Deviation | Action Taken | Reviewed By (QA) |
|---|---|---|---|---|
| 13/04/2025 | API-EX202504 | Temp exceeded 42°C | Hold added, cooling applied |
Revision History:
| Revision Date | Revision No. | Revision Details | Reason for Revision | Approved By |
|---|---|---|---|---|
| 01/01/2022 | 1.0 | Initial Release | New SOP Creation | QA Head |
| 13/04/2025 | 2.0 | Added Emergency Response Actions | Process Safety Update | QA Head |