a systematic, risk-based, and knowledge-driven methodology as described in ICH Q8, Q9, Q10, and Q14.

2. Scope

This SOP applies to all analysts, team leads, and QA reviewers involved in analytical method development and validation using the QbD approach in the Analytical Method Development (AMD) department.

3. Responsibilities

• Analytical Scientist: Designs the method using QbD principles including defining ATP, conducting risk assessments, and executing DOE.
• Team Lead: Reviews the QbD design elements and verifies MODR and control strategy.
• QA: Ensures documentation integrity and compliance with regulatory expectations.
• Head – AMD: Approves QbD-based method design for transfer or validation.

4. Accountability

The Head of AMD is accountable for ensuring QbD-based methods are robust, reproducible, and built on well-defined risk management and knowledge space.

5. Procedure

5.1 Define Analytical Target Profile (ATP)

1. Initiate method development with a well-defined ATP (see SOP/AMD/015/2025).
2. Specify the method objective, precision, accuracy, specificity, and intended use.
3. Document ATP in Annexure-1: ATP Summary.

5.2 Identify Critical Method Attributes (CMAs)

1. Determine analytical quality attributes that impact method performance (e.g., resolution, peak symmetry, RT, %RSD).
2. Link CMAs to product critical quality attributes (CQAs) wherever applicable.

5.3 Conduct Risk Assessment

1. Use Ishikawa diagram or FMEA to identify factors influencing CMAs:
   • Column type and dimensions
   • pH and buffer composition
   • Mobile phase ratio
   • Flow rate, injection volume, and temperature
2. Assign severity, occurrence, and detectability scores.
3. Summarize in Annexure-2: Risk Assessment Matrix.

5.4 Experimental Design (DoE)

1. Design and execute a factorial or central composite design to evaluate interaction and quadratic effects.
2. Identify critical method parameters (CMPs) based on model outputs.
3. Determine method operable design region (MODR).
4. Record study design and results in Annexure-3: DOE Study Summary.

5.5 Establish Control Strategy

1. Define controls for:
   • Mobile phase preparation
   • System suitability checks
   • Column type and age
   • Flow rate and pH
2. Document critical and non-critical parameters and their allowable range in Annexure-4: Control Strategy Table.

5.6 Robustness and Verification

1. Conduct robustness testing using fractional factorial designs or trial variation of CMPs within MODR.
2. Verify consistency of CMAs across MODR.
3. Prepare report summary in Annexure-5: Method Verification Report.

5.7 Documentation and Approval

1. Prepare QbD-based Method Development Report incorporating:
   • ATP
   • Risk assessment
   • DoE model and MODR
   • Control strategy
2. Submit for approval to QA and Head – AMD.

6. Abbreviations

• QbD: Quality by Design
• ATP: Analytical Target Profile
• MODR: Method Operable Design Region
• DoE: Design of Experiments
• FMEA: Failure Mode and Effects Analysis
• CMP: Critical Method Parameter
• CMAs: Critical Method Attributes
• QA: Quality Assurance

7. Documents

1. ATP Summary – Annexure-1
2. Risk Assessment Matrix – Annexure-2
3. DOE Study Summary – Annexure-3
4. Control Strategy Table – Annexure-4
5. Method Verification Report – Annexure-5

8. References

• ICH Q8(R2) – Pharmaceutical Development
• ICH Q9 – Quality Risk Management
• ICH Q10 – Pharmaceutical Quality System
• ICH Q14 – Analytical Procedure Development

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: ATP Summary

Analyte	Objective	Precision	Accuracy	Specificity
Amlodipine	Assay by RP-HPLC	RSD ≤ 2%	98–102%	Confirmed

Annexure-2: Risk Assessment Matrix

Parameter	Impact	Severity	Occurrence	Detection	Risk Score
pH	Peak Shape	4	3	3	36

Annexure-3: DOE Study Summary

Factor	Levels	Impact on RT	Impact on Rs
Organic Ratio	50–70%	Moderate	High

Annexure-4: Control Strategy Table

Parameter	Range	Controlled?	Justification
Flow Rate	1.0 ± 0.1 mL/min	Yes	Impacts RT and Rs

Annexure-5: Method Verification Report

Parameter	Condition	Result	Conclusion
Flow Rate	0.9 mL/min	%RSD = 1.5%	Acceptable

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Introduced MODR and Control Strategy sections	ICH Q14 alignment