Standard Operating Procedure for Real-Time Yield Monitoring During Reactions in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/090/2025
Supersedes	SOP/API/090/2022
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 the procedure for real-time yield monitoring during chemical reactions in the manufacturing of Active Pharmaceutical Ingredients (APIs) in order to assess process efficiency, trigger corrective actions, and support in-process control.

2. Scope

This SOP applies to all chemical synthesis processes in API manufacturing where reaction progress and intermediate product yields are calculated in real time for monitoring and optimization.

3. Responsibilities

• Production Chemist: Monitor reaction time and record in-process yield data.
• QC Analyst: Analyze samples for yield determination (e.g., by HPLC, gravimetric, titrimetric methods).
• QA Officer: Review records and ensure results are documented as per GMP.

4. Accountability

The Production Head is accountable for implementation. QA Head is responsible for compliance review and deviation handling.

5. Procedure

5.1 Yield Monitoring Plan

1. Define yield checkpoints in the Batch Manufacturing Record (BMR) based on reaction stages (e.g., after 30%, 60%, and 100% theoretical conversion).
2. Use validated methods for quantitative analysis, e.g., HPLC assay, LOD correction, or titration.

5.2 Sampling

1. Collect ~2–5 mL (or as required) of reaction mass in clean, dry containers at defined time points.
2. Label sample with Batch No., Reaction Stage, Date, Time, and Initials.
3. Deliver sample immediately to QC; store under controlled conditions if delayed.

5.3 Analytical Testing

1. Perform testing to quantify desired product concentration.
2. Document result as concentration (% w/w or % area) or mass obtained per volume sampled.

5.4 Yield Calculation

1. Calculate yield as per formula:
   % Yield = (Actual Amount of Product / Theoretical Amount) × 100
2. Use molecular weights and stoichiometry as defined in the MFR.
3. Adjust for dilution factors, LOD (moisture), or assay correction if applicable.

5.5 Trending and Response

1. Plot yield data on control charts for trend evaluation.
2. If yield is outside target range (e.g., ±5% of expected), inform QA and investigate root cause.
3. Delay or abort next stage if yield is critically low or shows unexpected decline.

5.6 Documentation

1. Record all yields, calculations, and time stamps in the Reaction Yield Log (Annexure-1).
2. Attach corresponding QC report or test printouts.
3. Review and sign by Production Supervisor and QA Reviewer.

6. Abbreviations

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

7. Documents

1. Reaction Yield Log (Annexure-1)
2. Batch Manufacturing Record
3. Analytical Test Reports

8. References

• ICH Q8 – Pharmaceutical Development
• 21 CFR Part 211 – US FDA GMP
• WHO TRS 986 – GMP for APIs

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Reaction Yield Log

Date	Batch No.	Stage	Sample Time	Yield (%)	Performed By	Remarks
13/04/2025	API-20250413	60% Conversion	14:20	62.3		Within expected

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial SOP Release	New Process Implementation	QA Head
13/04/2025	2.0	Added real-time trending and control chart instruction	Audit Compliance	QA Head