Q3C guidelines.

2. Scope

This SOP is applicable to the Analytical Method Development and Quality Control departments responsible for testing residual solvents in granules produced during pharmaceutical formulation development and manufacturing.

3. Responsibilities

• Analytical Scientist: Develops and validates GC methods for targeted solvents.
• QC Analyst: Executes routine testing and records results.
• QA Executive: Reviews and verifies data compliance and documentation accuracy.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring validated detection and quantification of residual solvents in granules, ensuring adherence to ICH limits.

5. Procedure

5.1 Selection of Residual Solvents

• Identify Class 1 (toxic), Class 2 (limited use), and Class 3 (low toxicity) solvents based on manufacturing process.
• Target solvents must be listed as per ICH Q3C or internal specifications.

5.2 Sample Preparation

1. Weigh approximately 500 mg of granules into a headspace vial.
2. Add 5 mL of diluent (e.g., N,N-Dimethylformamide, water, or DMSO depending on solubility).
3. Seal vial and allow equilibrium in the headspace autosampler (e.g., 80°C for 30 minutes).

5.3 Standard Preparation

1. Prepare individual stock solutions of each target solvent in the same diluent.
2. Prepare mixed working standard solutions covering ICH limits (e.g., 50%, 100%, 150%).

5.4 Gas Chromatography Conditions

• Column: Fused silica capillary column (e.g., DB-624, 30 m × 0.32 mm × 1.8 µm)
• Detector: Flame Ionization Detector (FID)
• Carrier Gas: Helium or Nitrogen
• Injection Mode: Headspace autosampler
• Oven Program: 40°C (5 min), ramp to 220°C at 10°C/min, hold for 5 min

5.5 Method Validation

1. Specificity: No interference from granule matrix or other excipients.
2. Linearity: r² ≥ 0.995 across 50%–150% of ICH limits.
3. LOD/LOQ: Determine by signal-to-noise ratio of 3:1 and 10:1 respectively.
4. Accuracy: Recovery of 95%–105% for spiked solvents.
5. Precision: RSD ≤ 5% for 6 replicates.

5.6 Acceptance Criteria

• Each residual solvent must be below ICH-permitted daily exposure (PDE) limits:
• Class 1: Not Detected or NMT specified ppm (e.g., Benzene NMT 2 ppm)
• Class 2: NMT limits as per ICH Table 2 (e.g., Methanol NMT 3000 ppm)
• Class 3: NMT 5000 ppm (unless otherwise specified)

6. Abbreviations

• GC: Gas Chromatography
• FID: Flame Ionization Detector
• PDE: Permitted Daily Exposure
• LOD: Limit of Detection
• LOQ: Limit of Quantification

7. Documents

1. GC Chromatogram and Area Report – Annexure-1
2. Residual Solvent Quantification Sheet – Annexure-2
3. Validation Summary Report – Annexure-3

8. References

• ICH Q3C (R8): Impurities – Guidelines for Residual Solvents
• USP <467>: Residual Solvents
• Ph. Eur. 2.4.24: Identification and Control of Residual Solvents

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name	Mehul Kapoor	Sapna Joshi	Sunita Reddy
Designation	GC Analyst	QA Reviewer	Head – AMD
Department	Analytical Method Development	QA	Analytical Method Development

11. Annexures

Annexure-1: GC Chromatogram and Area Report

Includes peaks for Class 1, 2, and 3 solvents. Retention time, peak area, and calculated concentration provided.

Annexure-2: Residual Solvent Quantification Sheet

Solvent	RT (min)	Amount (ppm)	Limit (ppm)	Status
Methanol	2.45	850	3000	Pass
Benzene	5.20	ND	2	Pass

Annexure-3: Validation Summary Report

The GC method for residual solvent detection in granules was validated as per ICH Q3C and USP <467>. The method demonstrated adequate specificity, sensitivity, and accuracy for regulatory use.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
21/05/2025	2.0	Updated GC oven program and included full validation criteria	Annual Review	Sunita Reddy
15/10/2022	1.0	Initial SOP Release	New SOP	QA Head