Analytical Method Development: Method Optimization Protocol – V 2.0

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Analytical Method Development: Method Optimization Protocol – V 2.0

SOP for Analytical Method Optimization Protocol in Pharmaceutical Development


Department Analytical Method Development
SOP No. SOP/AMD/010/2025
Supersedes SOP/AMD/010/2022
Page No. Page 1 of 15
Issue Date 19/05/2025
Effective Date 20/05/2025
Review Date 19/05/2026

1. Purpose

To define a systematic approach for optimizing analytical methods developed for the quantitative and qualitative analysis of pharmaceutical substances and products. This includes evaluating critical method parameters to ensure accuracy, precision, robustness, and regulatory compliance as per ICH Q2(R1).

2. Scope

This SOP applies to all personnel involved in the optimization of chromatographic, spectroscopic, titrimetric, and other analytical methods for APIs, finished products, intermediates, and excipients within the Analytical Method Development (AMD) department.

3. Responsibilities

  • Analytical Scientist: Executes method optimization experiments and records data.
  • Team Lead: Evaluates optimization study results and confirms system suitability.
  • QA Representative: Verifies optimization protocols and ensures documentation integrity.
  • Head – AMD: Reviews and approves finalized optimization reports.
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4. Accountability

The Head of AMD is accountable for ensuring optimized methods meet internal quality standards and are ready for validation, verification, or regulatory submission.

5. Procedure

5.1 Preparation and Planning

  1. Initiate optimization after feasibility assessment is complete and preliminary method is drafted.
  2. Define objectives of optimization:
    • Enhance peak shape, resolution, or separation
    • Stabilize retention time
    • Reduce run time or variability
    • Refine sample prep or injection volume
  3. Record targets in Annexure-1: Method Optimization Objective Form.

5.2 Identification of Critical Method Parameters (CMPs)

  1. Identify key parameters impacting method performance:
    • Mobile phase composition and pH
    • Column temperature
    • Flow rate and gradient program
    • Injection volume
    • Detection wavelength or mode
  2. Document initial settings in Annexure-2: CMP Log Sheet.

5.3 Experimental Optimization

  1. Perform experiments by systematically varying one parameter at a time (OVAT) or using DoE (Design of Experiments).
  2. Evaluate each condition based on:
    • Retention time consistency
    • Resolution between analyte and impurities (Rs > 2.0)
    • Peak tailing factor (T ≤ 2.0)
    • Plate count (N ≥ 2000)
    • RSD of replicate injections (≤ 2%)
  3. Record results in Annexure-3: Optimization Trial Log.
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5.4 Finalization of Optimized Parameters

  1. Select the best conditions based on system suitability and performance consistency.
  2. Repeat final condition in triplicate on different days (intermediate precision).
  3. Include robustness testing by making deliberate small changes (±10% flow rate, ±0.2 pH, ±5% organic content).

5.5 Documentation of Optimized Method

  1. Document:
    • System suitability criteria
    • Chromatographic/equipment conditions
    • Standard and sample preparation
    • Calculation formulae
  2. Use Annexure-4: Optimized Method Format and file the data pack for QA review.

5.6 Approval and Handover

  1. Submit optimization summary and system suitability results for QA verification.
  2. Obtain final approval from Head – AMD.
  3. Forward to validation team for protocol preparation.

6. Abbreviations

  • API: Active Pharmaceutical Ingredient
  • CMP: Critical Method Parameter
  • RSD: Relative Standard Deviation
  • Rs: Resolution
  • DoE: Design of Experiments
  • OVAT: One Variable At a Time
  • QA: Quality Assurance

7. Documents

  1. Method Optimization Objective Form – Annexure-1
  2. CMP Log Sheet – Annexure-2
  3. Optimization Trial Log – Annexure-3
  4. Optimized Method Format – Annexure-4

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8. References

  • ICH Q2(R1) – Validation of Analytical Procedures
  • ICH Q8 – Pharmaceutical Development
  • USP General Chapter <621> – Chromatography
  • Journal of Pharmaceutical Analysis and Research

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 Optimization Objective Form

Product Analyte Target Parameter Current Issue
Paracetamol Tablets Paracetamol Peak Symmetry Tailing observed

Annexure-2: CMP Log Sheet

Parameter Initial Setting Test Range Remarks
Flow Rate 1.0 mL/min 0.8–1.2 mL/min Impacts RT and resolution

Annexure-3: Optimization Trial Log

Date Trial No. Condition Modified Outcome Analyst
14/05/2025 3 pH changed to 3.5 Improved peak shape Sunita Reddy

Annexure-4: Optimized Method Format

Parameter Final Condition
Column C18, 250 mm × 4.6 mm, 5 µm
Mobile Phase 0.1% OPA:ACN (60:40)
Flow Rate 1.0 mL/min
Detection UV at 245 nm

Revision History:

Revision Date Revision No. Details Reason Approved By
04/05/2025 2.0 Added annexures for optimization trials and method finalization Internal harmonization
Analytical Method Development V 2.0 Tags:, , , , , , , , , , , , , , , , , , , , , , , , , , , , ,