Comprehensive SOP for Developing the Analytical Method Development (AMD) Master Plan

1. Purpose

To define the process for preparation, review, approval, implementation, and periodic revision of the Analytical Method Development (AMD) Master Plan. This SOP ensures harmonized planning aligned with GMP, ICH Q8-Q11, and WHO guidelines to support product development and regulatory submissions.

2. Scope

This SOP applies to the Analytical Method Development department responsible for developing methods for active pharmaceutical ingredients (APIs), formulations, and raw materials. It covers planning of resources, timelines, strategies, risk assessments, and project tracking across the AMD lifecycle.

3. Responsibilities

• AMD Lead: Responsible for drafting the master plan in coordination with cross-functional teams.
• QA Department: Verifies compliance with applicable regulatory standards and reviews the plan before approval.
• Head of Department (HOD): Reviews and approves the AMD Master Plan.
• Team Members: Provide input regarding scope, timelines, instrumentation, and risk management.

4. Accountability

The Head of Analytical Development is accountable for ensuring timely preparation, execution, and control of the AMD Master Plan, ensuring alignment with corporate objectives and regulatory expectations.

5. Procedure

5.1 Collection of Preliminary Information

1. Obtain information from the product development team regarding the pipeline of new drug substances and products.
2. Identify deliverables for each analytical method, including specifications, timelines, and validation expectations.
3. Refer to past development plans and historical performance data to inform planning.

5.2 Defining Objectives and Scope

1. Clearly state the objective of the AMD plan, including regulatory milestones (e.g., IND, ANDA, NDA submission).
2. Specify scope for:
   • Raw materials
   • APIs and intermediates
   • Finished products
   • Packaging materials, where applicable

5.3 Risk Assessment and Resource Planning

1. Conduct a risk assessment based on:
   • Complexity of the method (e.g., LC-MS/MS, stability-indicating assays)
   • Criticality of the attribute (e.g., assay vs. identification)
   • Equipment availability and capability
2. Document risk assessment outcomes in Annexure-1: Risk Assessment Log.
3. Allocate required analytical resources (personnel, instruments, software) accordingly.

5.4 Timeline Definition and Milestone Mapping

1. Break down method development into stages:
   • Feasibility Study
   • Method Development and Optimization
   • Robustness and Transferability Assessment
   • Validation Readiness and Draft Protocol
2. Map each phase to project timelines using Annexure-2: Gantt Chart Planner.

5.5 Documentation Structure

1. Outline document templates and storage paths for:
   • Development Protocols and Reports
   • Validation Readiness Assessment
   • Analytical Method Transfer Documents
2. Ensure all documents are coded and indexed as per the site documentation SOP.

5.6 Finalization and Approval of Master Plan

1. Compile all the sections into a formal master plan (Annexure-3 format).
2. Submit for QA review and regulatory compliance check.
3. Obtain final approval from the Head of Department.

5.7 Plan Distribution and Implementation

1. Distribute the approved plan to all stakeholders through controlled document management systems.
2. Train AMD team members on execution aspects.

5.8 Periodic Review and Revision

1. Review the master plan every 12 months or upon major project revisions.
2. Update using controlled document change protocols and document history in Annexure-4: Revision Log.

6. Abbreviations

• AMD: Analytical Method Development
• API: Active Pharmaceutical Ingredient
• GMP: Good Manufacturing Practice
• QA: Quality Assurance
• DoE: Design of Experiments
• ATP: Analytical Target Profile

7. Documents

1. Risk Assessment Log – Annexure-1
2. Gantt Chart Planner – Annexure-2
3. AMD Master Plan Template – Annexure-3
4. Revision Log – Annexure-4

8. References

• ICH Q8(R2) – Pharmaceutical Development
• ICH Q9 – Quality Risk Management
• ICH Q10 – Pharmaceutical Quality System
• WHO Technical Report Series 970, Annex 2

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Risk Assessment Log

Annexure-2: Gantt Chart Planner

Annexure-3: AMD Master Plan Template

Annexure-4: Revision Log

Revision History:

Structured SOP for Conducting Risk Assessment in Analytical Method Development

1. Purpose

To outline a systematic approach for conducting risk assessments during analytical method development (AMD) to ensure method robustness, reliability, and regulatory compliance as per ICH Q9, ICH Q8, and GMP guidelines.

2. Scope

This SOP applies to all analytical methods developed within the Analytical Method Development (AMD) department, including those for APIs, drug products, excipients, intermediates, and packaging materials.

3. Responsibilities

• AMD Scientist: Identifies and documents potential risks during method development stages.
• Team Lead: Reviews risk scores and proposes mitigation plans.
• Quality Assurance (QA): Ensures that the risk assessment process is aligned with corporate and regulatory guidelines.
• Head – AMD: Approves risk categorization and ensures implementation of mitigation strategies.

4. Accountability

The Head of Analytical Development is accountable for ensuring that risk assessments are completed, documented, and integrated into the AMD strategy for every new method.

5. Procedure

5.1 Planning the Risk Assessment

1. Conduct risk assessments as an integral part of method development planning.
2. Define the goal of the risk assessment, e.g., ensuring method robustness, minimizing instrument downtime, etc.
3. Assemble a cross-functional team including AMD scientists, QA, and where required, formulation development staff.

5.2 Risk Identification

1. Identify potential risks in method development, including:
   • Inadequate method selectivity or sensitivity
   • Unreliable sample preparation steps
   • Non-linear calibration curves
   • Equipment-related limitations
   • Variability in reagents or standards
2. Document the identified risks in Annexure-1: Risk Register.

5.3 Risk Analysis and Scoring

1. Use a quantitative or qualitative scale to assess:
   • Severity (S): Impact on product quality or regulatory compliance
   • Occurrence (O): Probability of risk materializing
   • Detectability (D): Ability to detect the failure before it affects outcomes
2. Calculate Risk Priority Number (RPN): RPN = S × O × D
3. Classify risk as:
   • Low (RPN < 40)
   • Medium (RPN 40–100)
   • High (RPN > 100)

5.4 Risk Evaluation

1. Plot risks on a risk matrix (Annexure-2) to visualize criticality.
2. Focus on high and medium risks for mitigation planning.

5.5 Risk Control and Mitigation

1. Develop action plans for high-risk areas:
   • Method redesign
   • Alternate instruments or procedures
   • Training for staff on specific procedures
   • System suitability criteria reinforcement
2. Record mitigation measures in Annexure-3: Mitigation Plan.

5.6 Documentation and Reporting

1. Prepare a risk assessment summary for inclusion in the Method Development Report.
2. Ensure all risk assessments are filed electronically and backed up.
3. Communicate findings to stakeholders during project meetings.

5.7 Periodic Review of Risks

1. Review risks during each phase of method development (feasibility, optimization, validation).
2. Update scores and mitigation status in the risk register (Annexure-1).

6. Abbreviations

• AMD: Analytical Method Development
• RPN: Risk Priority Number
• QA: Quality Assurance
• ICH: International Council for Harmonisation
• SOP: Standard Operating Procedure

7. Documents

1. Risk Register – Annexure-1
2. Risk Matrix – Annexure-2
3. Mitigation Plan – Annexure-3

8. References

• ICH Q9 – Quality Risk Management
• ICH Q8 – Pharmaceutical Development
• WHO GMP Guidelines – Annex on Quality Risk Management

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Risk Register

Annexure-2: Risk Matrix

Annexure-3: Mitigation Plan

Revision History:

Standard Operating Procedure for Handling of Pharmacopoeial Monographs in AMD

1. Purpose

To establish a controlled procedure for the identification, review, and implementation of pharmacopoeial monographs in the Analytical Method Development (AMD) laboratory in accordance with regulatory guidelines and current good manufacturing practices (cGMP).

2. Scope

This SOP applies to all AMD personnel responsible for developing or verifying analytical methods that are derived from or compared to official pharmacopoeial monographs, including those from IP, USP, BP, Ph.Eur, and JP.

3. Responsibilities

• AMD Analyst: Locates and retrieves the relevant pharmacopoeial monograph and performs comparative assessments with internal methods.
• QA Representative: Verifies proper implementation and documentation of monograph references and deviations.
• Method Development Lead: Reviews monograph adaptation rationale and approves any modifications required for practical use.
• Head – AMD: Ensures compliance and authorization of any validated in-house modifications.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that pharmacopoeial monographs are interpreted, applied, and documented correctly within the development and validation process.

5. Procedure

5.1 Access and Identification

1. Access the latest edition or supplement of official pharmacopoeias (IP, USP, BP, Ph.Eur, JP) via licensed digital or hardcopy sources.
2. Ensure access rights are valid and licenses are updated annually by the regulatory compliance officer.
3. Identify applicable monographs using either:
   • Generic drug substance or product name
   • CAS number or chemical name
   • INN/USAN (International or United States Adopted Name)

5.2 Review of Monograph Content

1. Review the following sections of each monograph:
   • Description
   • Identification Tests
   • Assay Procedure
   • Impurities
   • Other applicable tests (pH, LOD, Water Content, etc.)
2. Record the monograph version and year in Annexure-1: Monograph Review Log.

5.3 Comparison with Internal Methods

1. Compare the pharmacopoeial method with existing internal or validated methods for the same analyte or dosage form.
2. Document differences in parameters such as:
   • Column type
   • Mobile phase composition
   • Flow rate and gradient
   • Detection wavelength
   • Acceptance criteria
3. Log observations in Annexure-2: Comparative Evaluation Sheet.

5.4 Justification for Non-Compliance

1. If deviations from the monograph are necessary, provide a scientific rationale based on:
   • Product matrix
   • Specificity or sensitivity issues
   • Column incompatibility or availability
2. Document the justification in the Method Development Report and obtain QA review.

5.5 Incorporation into Method Development

1. Incorporate applicable pharmacopoeial elements into the new or revised method protocol.
2. If full adoption is feasible, proceed with method verification.
3. If modified, perform partial or full revalidation per internal validation SOP.

5.6 Documentation and Archival

1. Include a printed or PDF copy of the monograph in the method development file with version/date reference.
2. Index the monograph against the respective product name, method ID, and project code.
3. Ensure archival as per document control SOP for a minimum of 5 years or product lifecycle, whichever is longer.

6. Abbreviations

• IP: Indian Pharmacopoeia
• USP: United States Pharmacopeia
• BP: British Pharmacopoeia
• Ph.Eur: European Pharmacopoeia
• JP: Japanese Pharmacopoeia
• QA: Quality Assurance
• INN: International Nonproprietary Name
• SOP: Standard Operating Procedure

7. Documents

1. Monograph Review Log – Annexure-1
2. Comparative Evaluation Sheet – Annexure-2

8. References

• ICH Q6A – Specifications: Test Procedures and Acceptance Criteria
• Official Pharmacopoeias (USP, IP, BP, Ph.Eur, JP)
• WHO Technical Report Series No. 996

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Monograph Review Log

Annexure-2: Comparative Evaluation Sheet

Revision History:

Comprehensive SOP for Literature Review in Analytical Method Development

1. Purpose

This SOP provides guidance for conducting comprehensive literature reviews to support analytical method development in compliance with regulatory standards such as ICH, WHO, and GMP. The literature review ensures that the method is scientifically sound, appropriately justified, and supported by existing knowledge.

2. Scope

This SOP is applicable to all Analytical Method Development (AMD) personnel involved in the planning, development, and optimization of analytical methods for APIs, excipients, intermediates, and finished pharmaceutical products.

3. Responsibilities

• Analytical Scientist: Conducts the literature review using approved scientific databases and documents findings in the predefined format.
• AMD Team Lead: Reviews the literature summary and ensures its relevance and quality before including it in the method development protocol.
• QA Department: Ensures compliance with documentation standards and reviews bibliographic references.
• HOD – AMD: Approves the final literature review summary for incorporation into regulatory or internal documentation.

4. Accountability

The Head of the Analytical Method Development department is accountable for ensuring that a valid, comprehensive, and documented literature review is conducted for each analytical method under development.

5. Procedure

5.1 Planning the Literature Review

1. Initiate the literature review at the feasibility stage of method development.
2. Define objectives of the review (e.g., identifying existing methods, optimization techniques, chromatographic conditions, detection systems).
3. Use the Literature Review Plan template (Annexure-1) to define search goals.

5.2 Selection of Databases and Resources

1. Use validated and reputed scientific databases, such as:
   • PubMed
   • ScienceDirect
   • Google Scholar
   • Journals (e.g., Journal of Chromatography, Analytical Chemistry)
   • Pharmacopoeias (IP, USP, BP, Ph.Eur, JP)
   • Patent databases (WIPO, USPTO, Espacenet)
2. Document search sources in Annexure-2: Reference Log.

5.3 Search Strategy and Execution

1. Use specific and relevant keywords such as:
   • “HPLC method for [API Name]”
   • “Analytical validation [Drug Name]”
   • “Stability indicating method development”
2. Apply Boolean operators and filters for recent publications (last 10 years preferred).
3. Save all relevant articles and references in digital format in the project folder.

5.4 Data Extraction and Compilation

1. Extract the following information for each relevant article or method:
   • Author(s), title, journal, year
   • Chromatographic system (column, mobile phase, pH, flow rate)
   • Sample preparation technique
   • Validation data (specificity, LOD, LOQ, linearity, accuracy, precision)
2. Enter findings into Annexure-3: Literature Summary Table.

5.5 Analysis and Selection of Suitable Approach

1. Compare extracted data for consistency, regulatory compliance, and analytical performance.
2. Select appropriate strategies for method design based on:
   • Robustness and reproducibility
   • Ease of execution
   • Alignment with pharmacopoeial or published standards

5.6 Documentation and Review

1. Prepare a final report summarizing:
   • Databases used
   • Number of articles shortlisted
   • Summary of findings
   • Proposed approach for method development
2. Review and approval by AMD Team Lead and QA before filing into the method development protocol file.
3. Ensure all documentation is retained as per GMP record retention policy.

6. Abbreviations

• AMD: Analytical Method Development
• QA: Quality Assurance
• API: Active Pharmaceutical Ingredient
• LOD: Limit of Detection
• LOQ: Limit of Quantitation
• SOP: Standard Operating Procedure

7. Documents

1. Literature Review Plan – Annexure-1
2. Reference Log – Annexure-2
3. Literature Summary Table – Annexure-3

8. References

• ICH Q8 – Pharmaceutical Development
• ICH Q2(R1) – Validation of Analytical Procedures
• WHO TRS 996 – Annex on Analytical Methodology
• Scientific Journals, Pharmacopoeias, Patents

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Literature Review Plan

Annexure-2: Reference Log

Annexure-3: Literature Summary Table

Revision History:

Standard Operating Procedure for Selection of Analytical Techniques in Method Development

1. Purpose

This SOP provides guidance for selecting appropriate analytical techniques for method development in pharmaceutical analysis. The selection process is aligned with ICH Q2(R1), Q8, and WHO guidelines to ensure method suitability, regulatory compliance, and scientific soundness.

2. Scope

This procedure applies to all AMD personnel responsible for selecting and justifying analytical techniques for the qualitative and quantitative evaluation of drug substances, drug products, intermediates, raw materials, and excipients.

3. Responsibilities

• AMD Scientist: Evaluates analyte characteristics and proposes analytical technique options.
• Team Lead: Reviews technique suitability, feasibility, and alignment with project requirements.
• QA: Verifies that the technique selection is justified and documented appropriately.
• Head – AMD: Approves the final selected technique based on risk, cost, and performance factors.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that the selection of analytical techniques is scientifically justified, well-documented, and consistent with regulatory and project needs.

5. Procedure

5.1 Define the Analytical Objective

1. Clarify the purpose of the analysis:
   • Identification
   • Assay (quantitative)
   • Impurity profiling
   • Dissolution testing
   • Stability indicating analysis
2. Refer to Quality Target Product Profile (QTPP) and Analytical Target Profile (ATP) when applicable.

5.2 Understand the Physicochemical Properties of the Analyte

1. Review the following attributes:
   • Molecular weight
   • Solubility
   • pKa and logP
   • UV absorbance or fluorescence characteristics
   • Thermal stability
2. Document key attributes in Annexure-1: Analyte Profile Sheet.

5.3 Evaluate Available Analytical Techniques

1. List applicable techniques for the specific objective:
   • Chromatographic: HPLC, UPLC, GC, TLC
   • Spectroscopic: UV-Vis, IR, NMR, Fluorescence
   • Titrimetric: Acid-base, redox, non-aqueous
   • Thermal Analysis: DSC, TGA
   • Elemental Analysis: AAS, ICP-MS
2. Consider detection limits, linearity, accuracy, and precision of each method.
3. Prepare a technique comparison matrix using Annexure-2.

5.4 Consider Practical Feasibility

1. Evaluate:
   • Availability of equipment
   • Calibration and validation status
   • Analyst proficiency and training level
   • Sample preparation complexity
   • Cost of analysis and throughput
2. Perform risk assessment if necessary using institutional risk templates.

5.5 Final Selection and Documentation

1. Document the rationale for technique selection, including a summary of rejected techniques and reasons.
2. Obtain approval from QA and Head – AMD.
3. Include this rationale in the Method Development Protocol and later in the Method Validation Report.

5.6 Re-Evaluation and Updates

1. If the method fails to meet performance criteria during development or validation, reassess the technique selection.
2. Document changes and approvals in Annexure-3: Re-evaluation Log.

6. Abbreviations

• AMD: Analytical Method Development
• ATP: Analytical Target Profile
• QTPP: Quality Target Product Profile
• HPLC: High Performance Liquid Chromatography
• GC: Gas Chromatography
• UV-Vis: Ultraviolet-Visible Spectroscopy
• SOP: Standard Operating Procedure

7. Documents

1. Analyte Profile Sheet – Annexure-1
2. Technique Comparison Matrix – Annexure-2
3. Re-evaluation Log – Annexure-3

8. References

• ICH Q2(R1) – Validation of Analytical Procedures
• ICH Q8 – Pharmaceutical Development
• WHO Technical Report Series 970

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Analyte Profile Sheet

Annexure-2: Technique Comparison Matrix

Annexure-3: Re-evaluation Log

Revision History:

Standard Operating Procedure for Development of Test Procedures for Active Pharmaceutical Ingredients (API)

1. Purpose

This SOP defines the systematic process for developing test procedures for active pharmaceutical ingredients (API), ensuring that all analytical methods are scientifically justified, robust, and aligned with ICH Q2(R1), GMP, and regulatory expectations.

2. Scope

This SOP applies to the Analytical Method Development (AMD) team responsible for establishing test procedures including identification, assay, related substances, residual solvents, and physicochemical tests for APIs used in research, development, and commercial batches.

3. Responsibilities

• AMD Scientist: Designs and performs method development experiments based on literature review and API properties.
• Team Leader: Reviews developmental data and approves optimized test parameters.
• QA Department: Verifies adherence to protocol and documentation standards.
• Head – AMD: Provides final authorization for the developed test procedure.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that all API test procedures are scientifically sound, documented properly, and validated according to applicable regulatory guidelines.

5. Procedure

5.1 Understanding the API Profile

1. Collect the following data for the API:
   • Chemical structure, molecular weight
   • pKa, solubility, and logP
   • UV absorption, stability profile
   • Impurity profile and known degradants
2. Record API attributes in Annexure-1: API Profile Sheet.

5.2 Literature and Regulatory Review

1. Review literature, pharmacopoeias (USP, IP, BP), and previously validated methods.
2. Summarize existing analytical techniques, conditions, and parameters for similar molecules.
3. Document findings in Annexure-2: Reference Summary Log.

5.3 Experimental Design for Method Development

1. Design method development experiments based on:
   • Chromatographic technique (e.g., HPLC, GC)
   • Sample and standard preparation procedures
   • Selection of mobile phase, column, and detection wavelength
2. Ensure evaluation of peak purity, resolution, retention time, tailing factor, and plate count.

5.4 Optimization of Test Parameters

1. Optimize based on system suitability and robustness:
   • Buffer pH, ionic strength, gradient programs
   • Injection volume and flow rate
   • Detection wavelength
2. Document optimized parameters in Annexure-3: Method Optimization Log.

5.5 Drafting of Test Procedure

1. Prepare draft test procedure covering:
   • Purpose
   • Scope
   • Principle of method
   • Equipment and chemicals required
   • System suitability criteria
   • Stepwise procedure for standard and sample preparation
   • Calculation formula
2. Use Annexure-4: Draft Test Format for initial documentation.

5.6 Internal Review and Approval

1. Submit the draft to the AMD Team Lead for review.
2. Incorporate corrections and finalize the document.
3. Obtain QA review and Head – AMD approval before use.

5.7 Method Transfer and Validation Readiness

1. Once approved, initiate method transfer to Quality Control (QC) for verification or validation.
2. Ensure validation protocols are aligned with ICH Q2 requirements (specificity, precision, linearity, range, accuracy, robustness, LOD, LOQ).

5.8 Documentation and Archival

1. Store final version of the test procedure in the AMD document control system.
2. Ensure backups are maintained and version history is traceable.
3. File supporting development data with traceable links to project ID and molecule name.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• AMD: Analytical Method Development
• LOD: Limit of Detection
• LOQ: Limit of Quantitation
• HPLC: High-Performance Liquid Chromatography
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. API Profile Sheet – Annexure-1
2. Reference Summary Log – Annexure-2
3. Method Optimization Log – Annexure-3
4. Draft Test Format – Annexure-4

8. References

• ICH Q2(R1) – Validation of Analytical Procedures
• Pharmacopoeial Standards (USP, IP, BP)
• WHO GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: API Profile Sheet

Annexure-2: Reference Summary Log

Annexure-3: Method Optimization Log

Annexure-4: Draft Test Format

Revision History:

SOP for Developing Test Procedures for Pharmaceutical Formulations

1. Purpose

To establish a standardized procedure for the development of analytical test procedures for pharmaceutical formulations including tablets, capsules, oral liquids, injectables, and topical products. This ensures accuracy, precision, and regulatory compliance across product types.

2. Scope

This SOP applies to Analytical Method Development (AMD) scientists and associated personnel involved in designing and documenting analytical procedures for final product release and stability studies of pharmaceutical formulations.

3. Responsibilities

• AMD Scientist: Executes method development experiments for formulations and documents results.
• Team Leader: Reviews draft procedures and approves selected method parameters.
• QA Department: Reviews the method development documentation for completeness and compliance.
• Head – AMD: Authorizes the finalized method for validation or verification.

4. Accountability

The Head of AMD is accountable for ensuring that test procedures for formulations are developed using scientifically sound approaches and that they are suitable for regulatory submission and routine quality control.

5. Procedure

5.1 Preliminary Understanding of the Dosage Form

1. Review formulation details:
   • Dosage form (tablet, capsule, suspension, injection)
   • Strength and composition
   • Excipients used (diluents, binders, preservatives)
   • Intended use and packaging configuration
2. Summarize these attributes in Annexure-1: Formulation Profile Sheet.

5.2 Literature and Pharmacopoeial Review

1. Identify available pharmacopoeial monographs (USP, IP, BP, Ph.Eur) and relevant scientific publications.
2. Evaluate previous internal methods used for similar products or APIs.
3. Document key findings in Annexure-2: Reference Summary Table.

5.3 Development of Analytical Methods

1. Design method for the following critical quality attributes (CQAs):
   • Identification
   • Assay of active content
   • Related substances / degradation products
   • Uniformity of dosage units
   • Dissolution and disintegration (as applicable)
2. Select suitable techniques: HPLC, GC, UV, potentiometry, or titrimetry depending on the analyte.
3. Perform robustness testing by varying parameters such as pH, temperature, flow rate, and mobile phase composition.

5.4 Optimization and Standardization

1. Fine-tune method parameters based on:
   • System suitability (e.g., tailing factor, theoretical plates)
   • Precision and accuracy
   • Peak resolution and retention time
2. Record optimized conditions in Annexure-3: Method Development Log.

5.5 Preparation of Test Procedure Document

1. Draft the analytical procedure using Annexure-4: Draft Format for Test Procedure.
2. Include:
   • Objective
   • Scope
   • Principle
   • Equipment and reagents
   • Standard and sample preparation
   • System suitability
   • Calculation formulae
3. Ensure clarity and replicability by including necessary figures or chromatograms where applicable.

5.6 Internal Review and Approval

1. Submit the draft for internal review by Team Leader and QA.
2. Incorporate feedback and finalize the method.
3. Approval to be granted by the Head of AMD before initiating method validation.

5.7 Integration into Stability and QC Programs

1. Forward finalized method to Stability and Quality Control departments.
2. Ensure proper version control and training of end users prior to implementation.
3. Maintain archival copies and change control history as per QMS.

6. Abbreviations

• AMD: Analytical Method Development
• API: Active Pharmaceutical Ingredient
• HPLC: High Performance Liquid Chromatography
• USP/IP/BP: United States/Indian/British Pharmacopoeia
• QA: Quality Assurance
• CQA: Critical Quality Attribute
• QMS: Quality Management System

7. Documents

1. Formulation Profile Sheet – Annexure-1
2. Reference Summary Table – Annexure-2
3. Method Development Log – Annexure-3
4. Draft Format for Test Procedure – Annexure-4

8. References

• ICH Q2(R1) – Validation of Analytical Procedures
• ICH Q8 – Pharmaceutical Development
• WHO Technical Report Series 996
• Applicable Pharmacopoeial Monographs

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Formulation Profile Sheet

Annexure-2: Reference Summary Table

Annexure-3: Method Development Log

Annexure-4: Draft Format for Test Procedure

Revision History:

SOP for Selecting Mobile Phases in Chromatographic Method Development

1. Purpose

To define the systematic approach for selecting suitable mobile phases for chromatographic techniques such as HPLC, UPLC, and GC, ensuring reliable analyte separation, method robustness, and compliance with ICH Q2(R1) and GMP expectations.

2. Scope

This SOP is applicable to all personnel in the Analytical Method Development (AMD) department involved in developing, optimizing, or validating chromatographic methods for APIs, intermediates, excipients, and finished products.

3. Responsibilities

• Analytical Scientist: Designs experiments and selects mobile phase candidates based on analyte and matrix characteristics.
• Team Leader: Reviews mobile phase suitability and approves finalized compositions.
• QA Department: Ensures mobile phase selection rationale is documented and traceable.
• Head – AMD: Authorizes the final method incorporating the selected mobile phase.

4. Accountability

The Head of AMD is accountable for ensuring scientifically sound, reproducible, and well-documented selection of mobile phases during chromatographic method development.

5. Procedure

5.1 Assess Physicochemical Properties of Analyte

1. Determine the following parameters:
   • Molecular structure and functional groups
   • pKa, logP, solubility in various solvents
   • UV absorption range or detection feasibility
2. Record in Annexure-1: Analyte Evaluation Sheet.

5.2 Mobile Phase Selection Strategy

1. Choose between Reversed-phase, Normal-phase, or Ion-exchange chromatography based on analyte polarity:
   • RP-HPLC: Preferred for non-polar to moderately polar compounds
   • NP-HPLC: Suitable for polar analytes (e.g., sugars, steroids)
   • Ion-pairing: Used for ionizable compounds with poor retention
2. Base initial selection on literature, prior data, or pharmacopoeial methods.

5.3 Common Mobile Phase Components

1. Aqueous Phase: Water, phosphate buffers, acetate buffers (pH 2–7.5)
2. Organic Modifiers: Acetonitrile, methanol, ethanol (HPLC grade)
3. pH Adjusters: Orthophosphoric acid, triethylamine, ammonia solution
4. Ion Pairing Reagents (if applicable): Sodium dodecyl sulfate, tetrabutylammonium hydroxide

5.4 Buffer Preparation and Selection

1. Select a buffer that:
   • Maintains desired pH near analyte pKa (±1 unit)
   • Has low UV absorbance if UV detection is used
   • Is chemically compatible with column packing
2. Prepare using analytical grade reagents and HPLC-grade water.
3. Filter and degas mobile phase through 0.45 µm filters prior to use.

5.5 Gradient vs. Isocratic Mode

1. Choose gradient mode when:
   • Analyte mixture has wide polarity range
   • Late eluting peaks need separation
2. Choose isocratic mode for simple APIs or when analyte retention is stable.
3. Optimize gradient program by trial runs using different slope conditions.

5.6 Evaluation of System Suitability

1. Assess retention time (RT), resolution (Rs), theoretical plates (N), tailing factor (T), and reproducibility.
2. Ensure system suitability meets acceptance criteria before finalizing mobile phase.
3. Record observations in Annexure-2: Mobile Phase Optimization Log.

5.7 Documentation and Approval

1. Document selected mobile phase composition, preparation instructions, stability, and storage conditions.
2. Attach chromatograms from each phase of optimization.
3. Obtain QA and Head – AMD approval before proceeding to validation.

6. Abbreviations

• AMD: Analytical Method Development
• RP-HPLC: Reversed-Phase High Performance Liquid Chromatography
• UV: Ultraviolet
• pKa: Acid Dissociation Constant
• LOD: Limit of Detection
• Rs: Resolution
• RT: Retention Time

7. Documents

1. Analyte Evaluation Sheet – Annexure-1
2. Mobile Phase Optimization Log – Annexure-2

8. References

• ICH Q2(R1) – Validation of Analytical Procedures
• USP General Chapter <621> – Chromatography
• Journal of Chromatography A and B
• Pharmacopoeial Monographs (USP, IP, BP)

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Analyte Evaluation Sheet

Annexure-2: Mobile Phase Optimization Log

Revision History:

Standard Operating Procedure for Method Feasibility Evaluation in Analytical Development

1. Purpose

This SOP describes the procedure for evaluating the feasibility of analytical methods prior to method development or optimization, focusing on the assessment of technical suitability, practical execution, and expected performance in compliance with ICH Q2(R1) and GMP guidelines.

2. Scope

This SOP applies to all analytical scientists in the Analytical Method Development (AMD) department responsible for determining the viability of proposed or existing analytical methods for active pharmaceutical ingredients (APIs), formulations, raw materials, and intermediates.

3. Responsibilities

• Analytical Scientist: Conducts initial feasibility experiments and documents findings.
• Team Leader: Reviews feasibility results and determines whether method progression is justified.
• QA Department: Ensures documentation and compliance with internal and regulatory standards.
• Head – AMD: Approves final feasibility assessment report.

4. Accountability

The Head of Analytical Method Development is accountable for verifying that only feasible, robust, and regulatory-compliant methods proceed to formal development and validation stages.

5. Procedure

5.1 Initiation of Feasibility Study

1. Trigger feasibility assessment based on:
   • New product development
   • Regulatory filing needs
   • Technology transfer requirement
   • Alternative method proposal
2. Assign study to trained analyst with documented experience in the relevant technique.

5.2 Review of Available Information

1. Gather available method details from:
   • Pharmacopoeias (USP, IP, BP)
   • Published literature and patents
   • Vendor or prior client data
   • Internal method archives
2. Document review results in Annexure-1: Source Evaluation Log.

5.3 Preliminary Laboratory Evaluation

1. Conduct exploratory runs to assess:
   • Peak shape and resolution
   • Solubility and sample prep feasibility
   • Retention time and interference
   • Baseline noise and system suitability
2. Use HPLC, GC, UV, or any applicable technique based on analyte nature.
3. Record test runs in Annexure-2: Feasibility Data Log.

5.4 Feasibility Assessment Parameters

1. Evaluate the method for:
   • Specificity – No interference from blank, matrix, or excipients
   • Linearity – R² ≥ 0.990 over expected concentration range
   • Precision – RSD ≤ 2% (for assay)
   • Recovery – 98–102% (as applicable)
2. Perform at least three replicates for assay evaluation to check repeatability.
3. Document raw chromatograms and reports in the study file.

5.5 Risk Identification

1. Identify potential limitations:
   • Co-eluting peaks
   • Insoluble analytes
   • Unstable reference standards
   • Instrumental compatibility
2. Log risks and mitigations in Annexure-3: Risk Observation Sheet.

5.6 Feasibility Decision and Reporting

1. Prepare summary of findings and preliminary method attributes.
2. Use Annexure-4: Feasibility Report Format to present the conclusion.
3. Submit report for QA review and Head – AMD approval.
4. If deemed unfeasible, document justification and recommend alternate approaches.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• RSD: Relative Standard Deviation
• HPLC: High-Performance Liquid Chromatography
• UV: Ultraviolet
• QA: Quality Assurance
• AMD: Analytical Method Development

7. Documents

1. Source Evaluation Log – Annexure-1
2. Feasibility Data Log – Annexure-2
3. Risk Observation Sheet – Annexure-3
4. Feasibility Report Format – Annexure-4

8. References

• ICH Q2(R1) – Validation of Analytical Procedures
• ICH Q9 – Quality Risk Management
• Pharmacopoeial Methods (USP, IP, BP)

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Source Evaluation Log

Annexure-2: Feasibility Data Log

Annexure-3: Risk Observation Sheet

Annexure-4: Feasibility Report Format

Revision History:

SOP for Analytical Method Optimization Protocol in Pharmaceutical Development

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.

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.

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

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

11. Annexures

Annexure-1: Method Optimization Objective Form

Annexure-2: CMP Log Sheet

Annexure-3: Optimization Trial Log

Annexure-4: Optimized Method Format

Revision History: