Standard Operating Procedure for pH Monitoring During Reaction in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/082/2025
Supersedes	SOP/API/082/2022
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 standard procedure for monitoring and controlling pH during reaction stages in API manufacturing to ensure reaction efficiency, reproducibility, and product quality as per the validated process parameters.

2. Scope

This SOP applies to all chemical reaction processes requiring pH control within the API manufacturing area, including acid-base reactions, precipitation steps, phase separation, and crystallization triggers.

3. Responsibilities

• Production Chemist/Operator: Perform pH checks as per the Batch Manufacturing Record (BMR) and record results accurately.
• Production Supervisor: Ensure calibration status of pH meters and review pH data entries.
• QA Officer: Verify logbook records and ensure deviation management in case of out-of-range pH readings.

4. Accountability

The Production Head is accountable for compliance with this procedure. The QA Head is responsible for ensuring proper documentation and deviation control.

5. Procedure

5.1 pH Meter Setup and Calibration

1. Use only calibrated digital pH meters with valid calibration certificates (daily or before each shift).
2. Calibrate using standard buffer solutions (pH 4.0, 7.0, and 9.2) and record in the pH Calibration Log (Annexure-1).
3. If the meter shows drift or error during calibration, do not use and inform Engineering/QC.

5.2 pH Monitoring During Reaction

1. Ensure the sampling port and sample containers are clean and dry before collecting sample.
2. Draw ~5–10 mL of reaction mass into a beaker using appropriate sampling tools (e.g., glass rod, dip tube).
3. Insert the electrode into the sample and stir gently using a magnetic stirrer or manually.
4. Record the stable pH reading and document in the BMR along with time and initials.
5. Compare reading with defined in-process pH limits (e.g., 6.8 to 7.2) mentioned in the MFR/BMR.

5.3 pH Adjustment (If Required)

1. If pH is out of specified limits, add pH-adjusting agent (e.g., sodium hydroxide, hydrochloric acid) dropwise under stirring.
2. Wait for homogenization and re-check pH after 5 minutes.
3. Repeat the process until desired pH is achieved without overshooting.
4. Record each adjustment, including reagent used, quantity, and final pH achieved.

5.4 Cleaning and Storage of pH Electrode

1. Rinse the electrode thoroughly with distilled water after each use.
2. Store in 3M KCl solution or as recommended by manufacturer when not in use.
3. Do not leave the probe in process solvents or acids for prolonged periods.

5.5 Deviation Handling

1. In case pH deviates significantly or causes color change, phase separation, or precipitation:
   • Stop further processing and inform QA/Production Head.
   • Document deviation in the batch record and initiate deviation form.
   • Continue processing only after QA approval or CAPA recommendation.

6. Abbreviations

• SOP: Standard Operating Procedure
• QA: Quality Assurance
• BMR: Batch Manufacturing Record
• MFR: Master Formula Record
• CAPA: Corrective and Preventive Action

7. Documents

1. pH Calibration Log (Annexure-1)
2. Batch Manufacturing Record
3. Deviation Form (if applicable)

8. References

• ICH Q8 – Pharmaceutical Development
• 21 CFR Part 211 – US FDA cGMP
• Internal SOP on Analytical Equipment Qualification

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: pH Calibration Log

Date	Instrument ID	Buffer 4.0	Buffer 7.0	Buffer 9.2	Calibrated By	Remarks
13/04/2025	pH-01	4.01	7.00	9.18		Within range

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial SOP Release	New Process Monitoring Procedure	QA Head
13/04/2025	2.0	Updated deviation management and electrode handling section	Regulatory Audit Finding	QA Head