manufacturing equipment surfaces as part of cleaning validation and verification programs.

2. Scope

This SOP is applicable to the Analytical Method Development (AMD) department and is used in evaluating the effectiveness of cleaning procedures in removing organic residues, including product, excipients, and cleaning agents.

3. Responsibilities

• Analytical Scientist: Designs and validates TOC methods and interprets results from rinse or swab samples.
• QC Analyst: Performs replicate testing and supports TOC system calibration and maintenance.
• QA Executive: Reviews validation reports and approves methods for GMP implementation.

4. Accountability

The Head of Analytical Method Development is accountable for the scientific validity, compliance, and implementation of TOC methods for cleaning validation programs.

5. Procedure

5.1 Instrument Setup and Calibration

1. Use TOC analyzers with high sensitivity and capability to measure total carbon (TC), inorganic carbon (IC), and total organic carbon (TOC = TC − IC).
2. Calibrate using standard potassium hydrogen phthalate (KHP) solutions at 0.5, 1.0, 2.5, and 5.0 ppm carbon.
3. Perform system suitability using USP Reference Standards with recovery within ±15% of theoretical value.

5.2 Sample Collection

1. Collect rinse samples from equipment using high-purity water (e.g., WFI) post-cleaning.
2. Use pre-cleaned glass containers to avoid carbon contamination.
3. Label and transport samples under nitrogen to minimize CO₂ absorption.

5.3 Method Development

1. Establish TOC limit based on:
   • Lowest Therapeutic Daily Dose (TDD) of previous product
   • Maximum allowable carryover (MACO)
   • TOC limit = (MACO / Equipment Surface Area) × Recovery Factor
2. Optimize instrument parameters: carrier gas flow, combustion temperature, sample injection volume.

5.4 Method Validation

1. Perform validation across following parameters:
   • Specificity: Demonstrate no interference from rinsing matrix
   • Linearity: r ≥ 0.990 in range 0.1 to 5 ppm
   • Accuracy: Recovery between 80–120%
   • Precision: %RSD ≤ 10%
   • LOD/LOQ: Determine based on signal-to-noise ratio (S/N ≥ 3 for LOD, S/N ≥ 10 for LOQ)

5.5 Recovery Factor Evaluation

1. Spike known amount of standard onto clean surface area and allow to dry.
2. Rinse or swab the surface and analyze using TOC.
3. Calculate recovery factor and include in calculation of TOC limit.

5.6 Documentation

1. Record all calibration curves, validation data, recovery studies, instrument logs, and system suitability in Annexures.
2. Prepare a TOC method validation report for QA approval.

6. Abbreviations

• TOC: Total Organic Carbon
• TC: Total Carbon
• IC: Inorganic Carbon
• MACO: Maximum Allowable Carryover
• TDD: Therapeutic Daily Dose
• RSD: Relative Standard Deviation

7. Documents

1. TOC Calibration and Linearity Log – Annexure-1
2. Recovery Factor Worksheet – Annexure-2
3. TOC Method Validation Report – Annexure-3

8. References

• USP <643> Total Organic Carbon
• ICH Q7: GMP for Active Pharmaceutical Ingredients
• FDA Guidance for Industry: Cleaning Validation
• WHO TRS 1025, Annex 8: Validation of Analytical Procedures

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name	Dr. Priya Sengupta	Ankit Sharma	Sunita Reddy
Designation	TOC Analyst	QA Reviewer	Head – AMD
Department	Analytical Method Development	QA	Analytical Method Development

11. Annexures

Annexure-1: TOC Calibration and Linearity Log

Concentration (ppm)	Response	Mean Value	% RSD
0.5	38.2	38.5	2.3
1.0	78.5	78.7	1.9
2.5	195.3	194.8	2.5

Annexure-2: Recovery Factor Worksheet

Surface	Spiked Carbon (µg)	Recovered Carbon (µg)	Recovery (%)	Status
SS-316	50	45	90%	Pass

Annexure-3: TOC Method Validation Report

The TOC method was validated for Ibuprofen equipment cleaning using WFI rinse. Linearity r = 0.994, accuracy 91–103%, and precision RSD 4.5%. Method deemed suitable for routine cleaning validation and verification.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
21/05/2025	2.0	Included MACO-based TOC limit calculation and recovery factor validation	Annual Review & Compliance Update	Sunita Reddy
05/04/2022	1.0	Initial SOP Release	New SOP	QA Head