through robust analytical practices.

2. Scope

This SOP applies to the Analytical Method Development (AMD) team responsible for impurity profiling of active pharmaceutical ingredients, focusing specifically on impurities originating from raw materials, intermediates, reagents, solvents, and catalysts used during synthesis.

3. Responsibilities

• Analytical Scientist: Executes method development, impurity detection, and structural characterization.
• Process Chemist: Provides synthesis pathway and identifies probable process impurity candidates.
• QA Officer: Ensures integrity of records and confirms that identified impurities meet regulatory criteria.
• Head – AMD: Approves analytical strategy, verifies impurity classification, and validates identification reports.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring the accuracy and regulatory fitness of impurity identification data before submission to RA or inclusion in the DMF.

5. Procedure

5.1 Review of Synthetic Route and Raw Materials

1. Obtain detailed synthesis pathway, including:
   • Starting materials and intermediates
   • Reagents and solvents
   • Catalysts and processing aids
2. Identify potential sources of impurities at each stage.
3. Document in Annexure-1: Process Map and Risk Assessment Sheet.

5.2 Initial Detection of Impurities

1. Perform HPLC/UPLC analysis using a stability-indicating method.
2. Compare chromatograms of process samples with pure API reference standard.
3. Detect and record unknown peaks by RT, RRT, and area %.
4. Document findings in Annexure-2: Impurity Detection Log.

5.3 Classification of Process Related Impurities

1. Categorize detected impurities as:
   • Residual intermediates
   • Starting material traces
   • Reagent and catalyst residues
   • By-products or over-reaction products
2. Prioritize for identification those with:
   • Level ≥ 0.10%
   • Toxicological concern (e.g., heavy metals, genotoxic risk)

5.4 Structural Elucidation

1. Use LC-MS, GC-MS, and NMR to identify unknown impurities.
2. For known process chemicals, confirm identity using:
   • Retention time and UV spectrum comparison
   • Spiking experiments
3. Record interpretations in Annexure-3: Spectral Interpretation Sheet.

5.5 Qualification and Documentation

1. Evaluate toxicological relevance of each impurity.
2. If qualification thresholds are exceeded:
   • Initiate toxicology study or literature justification
   • Perform method validation for quantification
3. Compile findings in Annexure-4: Impurity Qualification Report.

5.6 Risk Mitigation and Communication

1. Inform process development team for route optimization or purification steps.
2. Establish routine monitoring limits and include impurities in the API specification where applicable.
3. Communicate final impurity list with justification to regulatory affairs.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• HPLC: High-Performance Liquid Chromatography
• UPLC: Ultra-Performance Liquid Chromatography
• LC-MS: Liquid Chromatography-Mass Spectrometry
• NMR: Nuclear Magnetic Resonance
• SOP: Standard Operating Procedure

7. Documents

1. Process Map and Risk Assessment Sheet – Annexure-1
2. Impurity Detection Log – Annexure-2
3. Spectral Interpretation Sheet – Annexure-3
4. Impurity Qualification Report – Annexure-4

8. References

• ICH Q3A(R2) – Impurities in New Drug Substances
• ICH Q11 – Development and Manufacture of Drug Substances
• USP General Chapter <1086> – Impurities

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Process Map and Risk Assessment Sheet

Step	Reagent/Intermediate	Potential Impurity	Risk Level
Step 3	Thionyl Chloride	SO2 residual	Medium

Annexure-2: Impurity Detection Log

Sample ID	RT (min)	RRT	Area %	Impurity Code
API-Batch-X21	10.45	1.25	0.34%	IMP-P1

Annexure-3: Spectral Interpretation Sheet

Technique	Result	Interpretation
LC-MS	m/z = 237	Likely acylated by-product
1H NMR	δ 3.4–3.6 ppm	Methylene adjacent to nitrogen

Annexure-4: Impurity Qualification Report

IMP-P1 confirmed as residual by-product from condensation stage. Detected at 0.34%. Toxicological profile assessed and deemed acceptable under ICH Q3A qualification threshold. Included in specification as identified impurity.

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Expanded procedure for impurity classification and mitigation	Annual SOP Review