Standard Operating Procedure for Work-Up Procedure After Reaction Completion in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/031/2025
Supersedes	SOP/API/031/2022
Page No.	Page 1 of 11
Issue Date	13/04/2025
Effective Date	15/04/2025
Review Date	13/04/2026

1. Purpose

To establish a standardized procedure for executing work-up steps following the completion of a chemical reaction during API manufacturing, ensuring safe handling, efficient isolation, and regulatory compliance.

2. Scope

This SOP applies to all chemical reactions requiring post-reaction work-up operations including quenching, extraction, washing, phase separation, and solvent recovery.

3. Responsibilities

• Production Chemist: Execute the work-up operations as per BMR instructions.
• Process Engineer: Assist in process parameter optimization and monitoring.
• QA Personnel: Verify completion of reaction and record approvals before proceeding with work-up.

4. Accountability

The Production Head is accountable for correct execution of work-up operations. The QA Head is responsible for batch review and compliance assurance.

5. Procedure

5.1 Reaction Completion Confirmation

1. Collect a sample from the reaction mixture for analysis.
2. Send to QC for confirmation of reaction completion using designated analytical technique (e.g., HPLC, TLC).
3. Document the results in the BMR and obtain QA clearance before initiating work-up.

5.2 Quenching (If Applicable)

1. Cool the reaction mixture to the specified temperature (typically below 25°C).
2. Slowly add quenching reagent (e.g., water, acid, or base) under stirring.
3. Monitor pH or temperature rise during quenching and record values.
4. Continue stirring for specified time post-quenching to ensure complete neutralization or decomposition of reactive intermediates.

5.3 Extraction and Phase Separation

1. Add extraction solvent as per BMR instructions (e.g., ethyl acetate, dichloromethane).
2. Stir the mixture for defined time and allow to settle undisturbed.
3. Separate the organic and aqueous layers carefully using reactor drain or separator vessel.
4. Record layer weights/volumes and clarity in “Phase Separation Log” (Annexure-1).

5.4 Washing and Adjustment

1. Wash the product-containing layer with water, brine, or sodium bicarbonate solution as applicable.
2. Repeat wash cycles until desired pH or purity is achieved.
3. Document each washing step with time, solvent/solution used, and pH readings.

5.5 Concentration or Solvent Removal

1. Transfer the organic layer to a clean vessel or distillation unit.
2. Evaporate solvent under vacuum or atmospheric conditions as per process requirement.
3. Monitor solvent recovery temperature, pressure, and rate.
4. Collect concentrated crude product and send for filtration or crystallization as defined in the process.

5.6 Yield Check and Documentation

1. Weigh the intermediate/crude product and calculate yield after work-up.
2. Record actual vs theoretical yield in the BMR and in “Work-Up Yield Log” (Annexure-2).
3. Submit sample to QC for interim analysis.

6. Abbreviations

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

7. Documents

1. Phase Separation Log (Annexure-1)
2. Work-Up Yield Log (Annexure-2)
3. Reaction Completion Report (Annexure-3)

8. References

• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – Good Manufacturing Practice
• Internal Reaction and Work-Up SOPs

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Phase Separation Log

Date	Batch No.	Solvent	Phase Type	Volume (L)	Clarity
13/04/2025	API-202504	Ethyl Acetate	Organic	110	Clear

Annexure-2: Work-Up Yield Log

Batch No.	Stage	Yield (kg)	Theoretical (kg)	% Yield
API-202504	Post Work-Up	84.5	89.0	94.9%

Annexure-3: Reaction Completion Report

Batch No.	Sample Collected At	Time	Analyzed By	Result	Authorized By
API-202504	Reactor	08:30		Complete

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial Version	New SOP Development	QA Head
13/04/2025	2.0	Expanded Procedure and Yield Log Annexures	Process Standardization	QA Head