to identify and quantify Class 2 solvents as per ICH Q3C guidelines.

2. Scope

This procedure is applicable to the Analytical Method Development (AMD) department for the analysis of residual solvents in raw materials, APIs, intermediates, and finished dosage forms where gas chromatography (GC) is not feasible or practical.

3. Responsibilities

• Analytical Chemist: Executes method development, prepares standard and test samples, performs injections, and evaluates results.
• Reviewer: Reviews system suitability, linearity, detection limits, and confirms recovery accuracy.
• QA Officer: Ensures documentation is complete and method complies with ICH Q3C and regulatory expectations.
• Head – AMD: Reviews and approves the method for validation and routine analysis.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring the residual solvent method developed by HPLC is scientifically justified, validated, and suitable for regulatory filing.

5. Procedure

5.1 Pre-Development Considerations

1. List likely residual solvents based on manufacturing history or ICH Q3C classification (Class 1, 2, 3).
2. Assess solvent UV absorbance properties. HPLC estimation is suitable for UV-active or derivatized solvents.
3. Document solvent list in Annexure-1: Solvent Risk Assessment Sheet.

5.2 HPLC Method Setup

1. Column: C18, 250 mm × 4.6 mm, 5 µm
2. Mobile Phase: Water:Acetonitrile (50:50) or buffer-based if necessary
3. Detection: UV at 210–220 nm or refractive index detector if available
4. Flow Rate: 1.0 mL/min
5. Injection Volume: 20 µL
6. Record in Annexure-2: HPLC Setup Log

5.3 Standard and Sample Preparation

1. Standard: Prepare individual solvent solutions and a mixed standard at relevant ICH Q3C concentration limits (e.g., 5000 ppm for Class 2 solvents).
2. Sample: Weigh suitable amount of API or formulation (e.g., 100 mg) and dissolve in diluent (water/MeOH or DMF).
3. Filter all solutions with 0.45 µm filter and transfer to HPLC vials.
4. Document in Annexure-3: Sample and Standard Preparation Log

5.4 System Suitability and Linearity

1. Inject blank, individual solvents, mixed standard, and test samples.
2. System Suitability:
   • RSD of replicate standard injections ≤ 2.0%
   • Resolution between closest eluting solvents ≥ 1.5
3. Linearity range: LOQ to 120% of specification limit (e.g., 1000–6000 ppm).
4. R² ≥ 0.999 required for each solvent.
5. Record in Annexure-4: System Suitability and Linearity Log

5.5 Accuracy and Recovery

1. Spike blank matrix with known solvent quantities at 50%, 100%, and 150% levels.
2. Calculate % recovery:
   
   % Recovery = (Recovered Concentration / Spiked Concentration) × 100
3. Acceptance criteria: 85%–115% recovery
4. Document in Annexure-5: Recovery Study Summary

5.6 LOD and LOQ Determination

1. Inject decreasing concentrations of solvent until S/N ≥ 3 (LOD) and ≥ 10 (LOQ) is achieved.
2. Inject six replicates at LOQ level and ensure %RSD ≤ 10%
3. Document in Annexure-6: LOD and LOQ Summary

5.7 Sample Analysis and Reporting

1. Inject sample solution in duplicate.
2. Quantify solvent content using calibration curve or response factor.
3. Ensure results meet the ICH Q3C limits for respective solvents.
4. Summarize results in Annexure-7: Residual Solvent Analysis Report

6. Abbreviations

• HPLC: High-Performance Liquid Chromatography
• LOD: Limit of Detection
• LOQ: Limit of Quantification
• ppm: Parts Per Million
• SOP: Standard Operating Procedure

7. Documents

1. Solvent Risk Assessment Sheet – Annexure-1
2. HPLC Setup Log – Annexure-2
3. Sample and Standard Preparation Log – Annexure-3
4. System Suitability and Linearity Log – Annexure-4
5. Recovery Study Summary – Annexure-5
6. LOD and LOQ Summary – Annexure-6
7. Residual Solvent Analysis Report – Annexure-7

8. References

• ICH Q3C (R8) – Impurities: Guideline for 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 Sheet

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

Annexure-2: HPLC Setup Log

Column	Mobile Phase	Detector	λ	Flow Rate
C18	Water:ACN (50:50)	UV	210 nm	1.0 mL/min

Annexure-3: Sample and Standard Preparation Log

ID	Type	Concentration	Diluent	Prepared By
STD-Mix	Standard	5000 ppm	MeOH	Rajesh Kumar

Annexure-4: System Suitability and Linearity Log

Parameter	Observed	Specification	Status
RSD (n=5)	1.1%	≤ 2.0%	Pass

Annexure-5: Recovery Study Summary

Spike Level	Theoretical (ppm)	Recovered (ppm)	% Recovery
100%	5000	4962	99.2%

Annexure-6: LOD and LOQ Summary

Solvent	LOD (ppm)	LOQ (ppm)	RSD @ LOQ
Toluene	5	15	6.8%

Annexure-7: Residual Solvent Analysis Report

Sample ID	Solvent	Result (ppm)	Limit (ppm)	Status
API-2025-01	Toluene	832	890	Complies

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Included recovery, LOD/LOQ annexures and risk classification table	Annual SOP Review