ingredients in the presence of degradation products, as required by ICH Q1A(R2), Q2(R1), and GMP expectations.

2. Scope

This SOP is applicable to Analytical Method Development (AMD) personnel responsible for establishing and validating stability-indicating methods for raw materials, drug substances (APIs), and drug products during development and shelf-life studies.

3. Responsibilities

• Analytical Scientist: Develops and evaluates method performance under stressed conditions.
• Team Lead: Reviews data for specificity and degradation peak resolution.
• QA Department: Verifies study protocol adherence and documentation compliance.
• Head – AMD: Approves final method as stability-indicating before transfer or validation.

4. Accountability

The Head of AMD is accountable for ensuring that only validated, scientifically sound, and regulatory-compliant stability-indicating methods are transferred to Quality Control and Regulatory Affairs teams.

5. Procedure

5.1 Pre-Requisites and Literature Review

1. Review API properties, known degradation mechanisms, and available literature.
2. Summarize findings in Annexure-1: Method Development Background Summary.

5.2 Selection of Analytical Technique

1. Choose suitable technique (e.g., HPLC, UPLC, GC, UV) based on:
   • API solubility, stability, and chromophores
   • Detection sensitivity required for degradants
2. Define the working concentration range and detection wavelength.

5.3 Development of Initial Method

1. Optimize parameters:
   • Mobile phase and buffer pH
   • Column selection (C8, C18, etc.)
   • Flow rate, injection volume, and detection settings
2. Perform system suitability checks (Rs ≥ 2.0, Tailing ≤ 2.0).
3. Document parameters in Annexure-2: Initial Method Setup Log.

5.4 Forced Degradation Studies

1. Subject API or drug product to:
   • Acidic and basic hydrolysis
   • Oxidation
   • Thermal and photolytic conditions
2. Ensure degradation is within 5–20% to simulate real-time scenarios.
3. Document sample preparation and stress conditions in Annexure-3.

5.5 Evaluation of Degradant Separation

1. Analyze degraded samples alongside:
   • Placebo
   • Blank
   • Undegraded sample
2. Confirm:
   • Baseline separation of degradants
   • Retention of main analyte peak
   • Peak purity via PDA or mass spectrometry
3. Log findings in Annexure-4: Peak Purity and Degradant Summary.

5.6 Robustness and Specificity Testing

1. Evaluate method robustness by deliberate small variations:
   • ±10% flow rate
   • ±0.2 units pH
   • ±5% organic modifier
2. Ensure no impact on system suitability or resolution.
3. Confirm specificity against known impurities and excipients.

5.7 Documentation and Finalization

1. Compile:
   • Chromatograms
   • Stress condition logs
   • Peak purity results
   • Final method parameters
2. Draft summary using Annexure-5: Stability-Indicating Method Report.
3. Obtain QA and HOD approval prior to method transfer or validation.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• AMD: Analytical Method Development
• PDA: Photodiode Array Detector
• Rs: Resolution
• HPLC: High Performance Liquid Chromatography
• GC: Gas Chromatography
• QA: Quality Assurance

7. Documents

1. Method Development Background Summary – Annexure-1
2. Initial Method Setup Log – Annexure-2
3. Forced Degradation Sample Log – Annexure-3
4. Peak Purity and Degradant Summary – Annexure-4
5. Stability-Indicating Method Report – Annexure-5

8. References

• ICH Q1A(R2) – Stability Testing of New Drug Substances and Products
• ICH Q2(R1) – Validation of Analytical Procedures
• USP General Chapters <1225> and <621>

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Method Development Background Summary

Product Name	API	Known Impurities	Reported Degradation
Amlodipine Tablets	Amlodipine Besylate	Dihydro impurities	Hydrolysis and oxidation

Annexure-2: Initial Method Setup Log

Column	Mobile Phase	Flow Rate	Detection	Injection Volume
C18, 250×4.6mm	Phosphate buffer:ACN (60:40)	1.0 mL/min	UV 237 nm	10 µL

Annexure-3: Forced Degradation Sample Log

Condition	Stress Agent	Time	Temp	Degradation (%)
Acid	0.1N HCl	2 hrs	60°C	11.5%

Annexure-4: Peak Purity and Degradant Summary

Sample	Degradant RT (min)	Resolution	Peak Purity
Acid-degraded	6.8	2.3	Pass

Annexure-5: Stability-Indicating Method Report

Section	Content
Conclusion	Method is stability-indicating with confirmed specificity and peak purity
Next Step	Proceed to validation

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Updated annexures and clarified robustness criteria	QA Review