method-related failures or inconsistencies and implement corrective actions while maintaining data integrity and regulatory compliance.

2. Scope

This SOP applies to all analytical methods developed in the AMD department for drug substances, intermediates, and drug products that encounter issues during method development, validation, technology transfer, or routine application.

3. Responsibilities

• Analytical Scientist: Initiates troubleshooting, performs systematic checks, and documents findings.
• Team Lead: Reviews investigation reports and supports root cause analysis (RCA).
• QA: Verifies documentation and ensures CAPA implementation aligns with quality systems.
• Head – AMD: Approves troubleshooting reports and authorizes any method changes or revalidation activities.

4. Accountability

The Head of AMD is accountable for ensuring that analytical method issues are resolved scientifically and documented thoroughly, maintaining compliance with ICH, WHO, and GMP guidelines.

5. Procedure

5.1 Identification of Method Issue

1. Issues may be reported by analysts, validation teams, or QC during:
   • Development trials
   • System suitability failures
   • Reproducibility concerns
   • Unexpected peak behavior (ghost peaks, co-elution)
2. Record the issue in Annexure-1: Method Issue Reporting Form.

5.2 Preliminary Review

1. Review relevant documents:
   • Method development report
   • Chromatograms/spectra
   • Raw data logs
2. Interview analyst and review instrument calibration, column history, mobile phase prep, and standard solution handling.

5.3 Root Cause Analysis (RCA)

1. Apply structured tools such as:
   • Ishikawa (Fishbone) Diagram
   • 5 Whys
   • Cause-Effect Matrix
2. Categorize probable root causes into:
   • Method design-related
   • Instrument-related
   • Sample/standard preparation errors
   • Environmental factors
3. Document findings in Annexure-2: RCA Worksheet.

5.4 Corrective Actions

1. Depending on root cause, perform actions such as:
   • Re-prepare mobile phase/standard
   • Replace column or filter
   • Adjust flow rate, injection volume, or gradient program
   • Use different buffer/salt/solvent
2. Perform method modifications only after QA and HOD review and approval.
3. Document outcomes in Annexure-3: Corrective Action Log.

5.5 Verification of Resolution

1. Repeat system suitability runs and recovery tests using adjusted method.
2. Ensure RSD, retention time, and resolution are within expected ranges.
3. Attach evidence to Annexure-4: Troubleshooting Resolution Summary.

5.6 Change Control and Documentation

1. If method parameters are revised:
   • Initiate change control
   • Update method version and method report
   • Perform partial or full revalidation if applicable
2. Submit all annexures and investigation report to QA for closure and archiving.

6. Abbreviations

• AMD: Analytical Method Development
• QA: Quality Assurance
• RCA: Root Cause Analysis
• RSD: Relative Standard Deviation
• CAPA: Corrective and Preventive Action

7. Documents

1. Method Issue Reporting Form – Annexure-1
2. RCA Worksheet – Annexure-2
3. Corrective Action Log – Annexure-3
4. Troubleshooting Resolution Summary – Annexure-4

8. References

• ICH Q14 – Analytical Procedure Development
• ICH Q10 – Pharmaceutical Quality System
• WHO TRS 996 – Annex 3

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 Issue Reporting Form

Date	Reported By	Method ID	Issue Description
14/05/2025	Ajay Mehra	HPLC/AMD/078	Baseline drift observed post 6 minutes

Annexure-2: RCA Worksheet

Cause Category	Details	RCA Tool Used	Root Cause Identified
Mobile Phase	Old buffer used	5 Whys	Buffer degradation

Annexure-3: Corrective Action Log

Corrective Step	Performed By	Date	Remarks
Prepared fresh buffer with new lot	Sunita Reddy	15/05/2025	Baseline stabilized

Annexure-4: Troubleshooting Resolution Summary

Parameter	Before	After	Status
%RSD	4.8%	1.6%	Resolved
Baseline Drift	Yes	No	Resolved

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Added annexures and structured RCA process	GMP audit recommendation