product safety and patient health.

2. Scope

This SOP is applicable to the Quality Control department performing routine testing of residual solvents in raw materials, intermediates, and finished injectable drug products at all stages of production including stability samples.

3. Responsibilities

• QC Analyst: Prepares samples and standards, operates GC equipment, documents results.
• QC Supervisor: Reviews analytical data and calculations, approves test results.
• QA Executive: Verifies the compliance of procedures and reports to applicable standards.
• Head QC: Ensures method validation, regulatory compliance, and overall procedure adherence.

4. Accountability

The Head of Quality Control is accountable for ensuring this SOP is implemented and followed without deviation, and that all results are scientifically and legally justifiable.

5. Procedure

5.1 Classification of Residual Solvents

• Class 1: Solvents to be avoided (e.g., benzene, carbon tetrachloride).
• Class 2: Solvents to be limited (e.g., methanol, toluene).
• Class 3: Solvents with low toxic potential (e.g., ethanol, acetone).

5.2 General Testing Procedure

1. Prepare standard solutions of residual solvents based on target compounds.
2. Weigh accurately the sample into a headspace vial and seal with a crimped cap.
3. Inject samples using a validated Gas Chromatograph equipped with a headspace sampler and flame ionization detector (FID).
4. Compare retention times and response factors against known standards.
5. Calculate concentrations using calibration curves or response factors.

5.3 Sample Preparation

1. Weigh 500 mg of the injectable formulation into a clean headspace vial.
2. Add a specified volume of solvent (e.g., DMSO or water) as per validated method.
3. Seal the vial using crimp caps with Teflon-coated septa.
4. Sonicate for 10 minutes, if necessary, and allow to equilibrate at 60°C for 30 minutes before injection.

5.4 Standard Preparation

1. Prepare stock solutions of individual solvents in DMSO or water.
2. Use Class 2 solvents for calibration standards at various concentrations (e.g., 10 ppm, 100 ppm, 500 ppm).
3. Store all standards under refrigeration and label with expiry dates.

5.5 Instrumental Conditions

• Column: DB-624 or equivalent
• Detector: FID
• Carrier Gas: Nitrogen or Helium
• Flow Rate: 1.5 mL/min
• Oven Temp Program: 40°C to 200°C
• Run Time: 20–30 minutes

5.6 Acceptance Criteria

• Results must comply with limits outlined in ICH Q3C.
• Typical limits:
  • Methanol: ≤ 3000 ppm
  • Toluene: ≤ 890 ppm
  • Benzene: Not Detected (ND)
• Signal-to-noise ratio must be ≥ 10 for the lowest calibration level.

5.7 Documentation and Reporting

1. Record all data, chromatograms, and calculations in the Residual Solvent Test Report (Annexure-1).
2. Maintain audit trails and instrument logs.
3. Review by QC Supervisor and QA before batch disposition.

5.8 Handling OOS Results

1. Initiate OOS investigation as per SOP/QC/056.
2. Repeat injection using the same sample preparation to confirm reproducibility.
3. Perform root cause analysis for deviation.

5.9 Safety Considerations

• Use PPE: gloves, goggles, and lab coats.
• Handle Class 1 solvents inside fume hoods.
• Dispose of organic solvents as per hazardous waste guidelines.

6. Abbreviations

• SOP: Standard Operating Procedure
• QC: Quality Control
• FID: Flame Ionization Detector
• GC: Gas Chromatography
• OOS: Out of Specification
• ICH: International Council for Harmonisation

7. Documents

1. Residual Solvent Test Report – Annexure-1
2. Calibration Record Sheet – Annexure-2
3. Instrument Logbook – Annexure-3

8. References

• ICH Q3C – Impurities: Residual Solvents
• USP <467> – Residual Solvents
• FDA Guidance on Analytical Procedures

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation	QC Analyst	QA Executive	Head QC
Department	Quality Control	Quality Assurance	Quality Control

11. Annexures

Annexure-1: Residual Solvent Test Report

Sample ID	Solvent	Result (ppm)	Limit (ppm)	Status
INJ-B154	Methanol	1875	3000	Pass
INJ-B154	Toluene	642	890	Pass

Annexure-2: Calibration Record Sheet

Date	Solvent	Calibration Range	R² Value	Performed By
22/06/2025	Methanol	10–5000 ppm	0.9995	Anjali Singh

Annexure-3: Instrument Logbook

Date	Instrument ID	Activity	Analyst
22/06/2025	GC-003	Residual Solvent Analysis	Ravi Mehra

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
10/02/2022	1.0	Initial SOP	New requirement	Head QC
24/06/2025	2.0	Updated for ICH Q3C alignment and annexures	Annual review	Head QC