drug products. The method ensures compliance with ICH Q3C guidelines and supports regulatory submissions.

2. Scope

This SOP applies to the Analytical Method Development (AMD) department and is applicable for residual solvent analysis in raw materials, intermediates, and finished drug products, where GC is the preferred or required technique due to the volatility and boiling points of solvents.

3. Responsibilities

• Analytical Chemist: Conducts solvent selection, prepares standards, optimizes chromatographic conditions, and performs method development activities.
• Reviewer: Reviews chromatographic performance, method suitability, and validation parameters.
• QA Officer: Ensures that all documentation complies with GMP and ICH standards.
• Head – AMD: Approves method development strategy, validation design, and final reports.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that the GC method developed is accurate, precise, robust, and suitable for quantifying residual solvents within regulatory limits.

5. Procedure

5.1 Identification of Target Solvents

1. Review process and formulation documents to list potential solvents.
2. Classify solvents per ICH Q3C:
   • Class 1 (to be avoided)
   • Class 2 (to be limited)
   • Class 3 (low toxic potential)
3. Record solvent list in Annexure-1: Solvent Risk Assessment Table.

5.2 Instrument Setup

1. GC with Flame Ionization Detector (FID) or Headspace GC for volatile solvents.
2. Column: DB-624 or equivalent, 30 m × 0.32 mm ID, 1.8 μm film thickness.
3. Carrier Gas: Helium or Nitrogen at constant flow (1.0 mL/min).
4. Injection Mode: Split (20:1) or splitless based on concentration range.
5. Detector Temperature: 250°C; Injector Temperature: 200°C; Oven Program: 40°C (5 min) to 220°C (15 min) at 10°C/min.
6. Record setup in Annexure-2: GC Configuration Log.

5.3 Preparation of Standards and Samples

1. Standard Preparation: Prepare individual and mixed solvent standards in suitable diluent (e.g., DMSO or DMF).
2. Sample Preparation: Weigh 500 mg sample and dissolve in 10 mL of diluent.
3. For headspace: Use 20 mL vials sealed with PTFE/silicone septa; incubate at 80–100°C for 30 minutes.
4. Document in Annexure-3: Sample and Standard Preparation Log.

5.4 Method Optimization

1. Optimize:
   • Retention time separation of solvents
   • Peak shape and area response
   • Absence of interference from matrix
2. Perform specificity test with:
   • Diluent blank
   • Placebo
   • Standard and sample
3. Overlay chromatograms and confirm no co-elution at solvent RTs.
4. Record results in Annexure-4: Method Optimization Worksheet.

5.5 Linearity and Sensitivity

1. Prepare linearity solutions for each solvent at 50%, 80%, 100%, 120%, and 150% of their ICH limits.
2. Inject each level in duplicate and plot calibration curve.
3. Calculate R² and ensure it is ≥ 0.995.
4. Determine LOD and LOQ:
   • LOD: S/N ≥ 3
   • LOQ: S/N ≥ 10
5. Record in Annexure-5: Linearity and Sensitivity Report.

5.6 Precision and Accuracy

1. Precision: Inject six replicates of standard solution and calculate %RSD.
2. Accuracy: Spike placebo matrix at three levels (e.g., 50%, 100%, 150%).
3. Acceptable recovery: 95%–105%; %RSD ≤ 5%.
4. Document in Annexure-6: Precision and Recovery Report.

5.7 Robustness and System Suitability

1. Evaluate method performance with small changes in:
   • Column oven ramp rate
   • Split ratio
   • Incubation temperature (for headspace)
2. System Suitability:
   • Resolution ≥ 1.5 between critical pairs
   • %RSD ≤ 5% for major solvent peaks
3. Record in Annexure-7: System Suitability and Robustness Log.

6. Abbreviations

• GC: Gas Chromatography
• FID: Flame Ionization Detector
• ICH: International Council for Harmonisation
• LOD: Limit of Detection
• LOQ: Limit of Quantification
• SOP: Standard Operating Procedure

7. Documents

1. Solvent Risk Assessment Table – Annexure-1
2. GC Configuration Log – Annexure-2
3. Sample and Standard Preparation Log – Annexure-3
4. Method Optimization Worksheet – Annexure-4
5. Linearity and Sensitivity Report – Annexure-5
6. Precision and Recovery Report – Annexure-6
7. System Suitability and Robustness Log – Annexure-7

8. References

• ICH Q3C(R8) – Impurities: Residual Solvents
• ICH Q2(R1) – Validation of Analytical Procedures
• USP <467> – Residual Solvents
• USP <621> – Chromatography

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Solvent Risk Assessment Table

Solvent	Class	ICH Limit (ppm)	Source
Methanol	Class 2	3000	API synthesis
Toluene	Class 2	890	Crystallization

Annexure-2: GC Configuration Log

Instrument	Column	Detector	Gas	Oven Program
Agilent 7890	DB-624, 30m	FID	He	40–220°C

Annexure-3: Sample and Standard Preparation Log

ID	Type	Solvent(s)	Diluent	Prepared By
STD-001	Mixed Std	MeOH, Toluene	DMSO	Rajesh Kumar

Annexure-4: Method Optimization Worksheet

Parameter	Value	Observation	Action
Split Ratio	20:1	Broad peak	Reduced to 10:1

Annexure-5: Linearity and Sensitivity Report

Solvent	R²	LOD (ppm)	LOQ (ppm)
Toluene	0.9994	4	12

Annexure-6: Precision and Recovery Report

Solvent	% Recovery	% RSD	Status
Methanol	98.8%	1.6%	Pass

Annexure-7: System Suitability and Robustness Log

Change	Result	Status
Oven ramp ±2°C/min	No impact on resolution	Acceptable

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Added headspace option and robustness annexure	Regulatory Update