Standard Operating Procedure for Stability Testing of API Batches

1. Purpose

To define the procedure for conducting stability testing of Active Pharmaceutical Ingredient (API) batches to assess product integrity over time and establish or confirm shelf-life in accordance with ICH Q1 guidelines.

2. Scope

This SOP applies to all Quality Control and Quality Assurance personnel involved in the planning, execution, evaluation, and documentation of stability studies for development, validation, and commercial batches of APIs.

3. Responsibilities

• QC Analyst: Perform stability sample testing as per defined intervals and STP.
• QA Officer: Monitor storage conditions and maintain stability chambers.
• Stability Coordinator: Maintain inventory, pull schedules, and data compilation.
• QC Reviewer: Verify results and compile interim and final stability reports.

4. Accountability

The Head – Quality is accountable for the scientific justification, regulatory compliance, and execution of the stability program for API batches.

5. Procedure

5.1 Study Design

1. Refer to ICH Q1A(R2) and ICH Q1E for designing stability protocols.
2. Include:
   • Study type (accelerated, long-term, intermediate)
   • Storage conditions (25°C/60% RH, 30°C/65% RH, 40°C/75% RH)
   • Testing intervals (e.g., 0, 3, 6, 9, 12, 18, 24 months)
   • Specifications to be monitored (appearance, assay, impurities, moisture content, etc.)

5.2 Sample Storage

1. Stability samples must be:
   • Representative of production batches
   • Packed in containers that simulate market packaging
   • Labeled with unique stability ID, batch number, storage condition, and interval schedule
2. Place samples in qualified stability chambers monitored continuously using calibrated temperature and humidity sensors.

5.3 Testing Procedure

1. At each interval, withdraw samples per schedule and perform testing as per STP.
2. Ensure all tests are conducted within ±5 days of the scheduled interval date.
3. Use validated analytical methods and retain all chromatograms and raw data for review.
4. Document observations such as color change, precipitation, or odor.

5.4 Data Compilation and Evaluation

1. Compare results against acceptance criteria and note any trends.
2. Prepare interim reports after each interval and a comprehensive report at the end of the study.
3. Include graphical trends for key parameters (e.g., assay, impurity).

5.5 Out-of-Trend or OOS Results

1. If any OOT or OOS result is observed:
   • Notify QA immediately
   • Initiate deviation/investigation
   • Conduct root cause analysis
   • Evaluate impact on shelf-life and future batches

5.6 Record Keeping and Archival

1. All stability data, test records, and reports must be retained for at least 5 years post expiry of the batch.
2. Ensure electronic and physical copies are secured and backed up.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• STP: Standard Test Procedure
• OOS: Out of Specification
• OOT: Out of Trend
• ICH: International Council for Harmonisation
• RH: Relative Humidity

7. Documents

1. Stability Protocol
2. Stability Sample Inventory Log (Annexure-1)
3. Stability Pull and Testing Log (Annexure-2)
4. Stability Reports

8. References

• ICH Q1A(R2) – Stability Testing of New Drug Substances and Products
• ICH Q1E – Evaluation of Stability Data
• 21 CFR Part 211 – US FDA cGMP
• WHO Technical Report Series 1010

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Stability Sample Inventory Log

Annexure-2: Stability Pull and Testing Log

Revision History:

Standard Operating Procedure for Sampling and Testing of Raw Materials in API Manufacturing

1. Purpose

To establish a standardized procedure for the sampling and testing of raw materials used in API manufacturing to ensure quality, identity, and compliance with approved specifications before use in production.

2. Scope

This SOP applies to Quality Control (QC) personnel responsible for sampling, testing, and approving raw materials received for use in the API manufacturing process, including active ingredients, excipients, and solvents.

3. Responsibilities

• QC Sampler: Collect samples using clean tools and label containers properly.
• QC Analyst: Test samples as per STP and record results in logbooks and reports.
• QC Reviewer: Review and approve the results; determine compliance with specifications.
• QA Officer: Ensure raw materials are not used before approval; verify traceability.

4. Accountability

The Head – QC is accountable for ensuring raw materials are sampled and tested according to validated methods and GMP standards.

5. Procedure

5.1 Material Receipt and Quarantine

1. Upon receipt, store raw materials in the quarantine area with a “To Be Sampled” status label.
2. Verify material against invoice, delivery challan, and purchase order.

5.2 Sampling Plan

1. Use appropriate sampling techniques based on material category:
   • Random sampling (for general materials)
   • Stratified sampling (for critical materials or multiple containers)
2. Follow guidelines in Annexure-1 for number of containers and sample quantity.

5.3 Sampling Technique

1. Use cleaned and dried sampling tools (e.g., thief sampler, pipette).
2. Wear gloves and PPE before sampling.
3. Open container under LAF or designated area to prevent contamination.
4. Transfer sample to clean, labeled container indicating:
   • Material Name
   • Batch/Lot Number
   • Date of Sampling
   • Sampler’s Initials
5. Seal the sample container and send it to the QC lab.

5.4 Sample Identification and Coding

1. Assign a unique Raw Material Sample Number as per internal coding format (e.g., RM/25/04/XXX).
2. Enter details in the Sampling Logbook (Annexure-2).

5.5 Analytical Testing

1. Test raw material samples as per the respective Standard Test Procedure (STP).
2. Perform identity, assay, impurity, pH, LOD, and other tests based on material specifications.
3. Record results in analytical worksheets and sign off upon completion.

5.6 Review and Release

1. Compare results against the approved specification.
2. If compliant, release the material with “Approved” status label and update inventory system.
3. If out-of-specification (OOS), initiate investigation and inform QA.

5.7 Retention Sample

1. Store a representative sample (minimum 25 g or as per policy) of each raw material batch in labeled container for reference.
2. Store retention samples under defined conditions for at least 1 year after material expiry.

6. Abbreviations

• QC: Quality Control
• QA: Quality Assurance
• RM: Raw Material
• STP: Standard Test Procedure
• OOS: Out of Specification

7. Documents

1. Sampling Logbook (Annexure-2)
2. Raw Material Specification and STP
3. Analytical Report
4. Retention Sample Log

8. References

• ICH Q7 – GMP for APIs
• 21 CFR Part 211
• WHO Technical Report Series No. 986

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Sampling Quantity Guideline

Annexure-2: Sampling Logbook

Revision History:

Standard Operating Procedure for Water Analysis by Karl Fischer (KF) Titration in API Manufacturing

1. Purpose

To define a standardized procedure for the accurate determination of water content in pharmaceutical substances, excipients, and APIs using Karl Fischer (KF) titration, ensuring reproducibility and regulatory compliance.

2. Scope

This SOP is applicable to Quality Control laboratory personnel performing water content determination using Karl Fischer titration (volumetric or coulometric) for raw materials, intermediates, and final APIs.

3. Responsibilities

• QC Analyst: Perform the titration using validated procedure and record results accurately.
• QC Reviewer: Verify the water content value, reagent standardization, and calculations.
• QA Officer: Ensure documentation, compliance, and verification during audits.

4. Accountability

The Head – QC is accountable for ensuring that Karl Fischer analysis is conducted as per validated methodology, and all data are traceable and reviewed.

5. Procedure

5.1 Equipment and Reagents

1. Karl Fischer titrator (volumetric or coulometric)
2. Dry methanol (KF grade)
3. KF reagent (e.g., Hydranal, Aquastar)
4. Certified water standard (e.g., sodium tartrate dihydrate)
5. Drying oven and desiccator (for sample preparation, if required)

5.2 Standardization of Karl Fischer Reagent

1. Weigh ~100 mg of water standard (e.g., sodium tartrate dihydrate) into a clean dry titration vessel.
2. Titrate using KF reagent until endpoint is reached.
3. Calculate KF factor:
   KF Factor = mg water / mL KF reagent consumed
4. Acceptable %RSD for three determinations: ≤ 2.0%

5.3 Sample Preparation

1. Ensure sample is finely powdered and homogenous.
2. Weigh accurately the sample (typically 10–200 mg based on expected moisture content).
3. Transfer sample to the titration vessel using dry spatula or syringe (for liquid samples).

5.4 Titration Procedure

1. Pre-titrate methanol blank before analysis.
2. Introduce the weighed sample into the titration vessel and start titration.
3. Allow the instrument to automatically reach the endpoint and display the volume used.
4. Record the final volume of reagent and perform the calculation.

5.5 Calculation

1. Use the formula:
   % Water = (Volume of KF reagent × KF Factor × 100) / Weight of Sample (mg)

5.6 Precautions

1. Handle KF reagents with care; avoid exposure to atmospheric moisture.
2. Close reagent bottles immediately after use.
3. Use gloves and eye protection while working with solvents and reagents.
4. Do not reuse reagents once contaminated.

6. Abbreviations

• KF: Karl Fischer
• QC: Quality Control
• API: Active Pharmaceutical Ingredient
• RSD: Relative Standard Deviation
• % Water: Percent water content

7. Documents

1. KF Titration Logbook (Annexure-1)
2. Reagent Standardization Record
3. Sample Analysis Report

8. References

• USP <921> – Water Determination
• ICH Q6A – Specifications
• 21 CFR Part 211 – US FDA GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: KF Titration Logbook

Revision History:

Standard Operating Procedure for LOD and Moisture Content Determination in API Manufacturing

1. Purpose

To define the procedure for determining Loss on Drying (LOD) and moisture content in Active Pharmaceutical Ingredients (APIs) using both conventional oven method and Karl Fischer titration, ensuring consistency and regulatory compliance.

2. Scope

This SOP is applicable to Quality Control personnel involved in the analysis of LOD and moisture content in raw materials, intermediates, and final APIs using gravimetric and Karl Fischer techniques.

3. Responsibilities

• QC Analyst: Perform LOD/moisture analysis and record data accurately.
• QC Executive: Review results and ensure compliance with specified limits.
• QA Officer: Audit test procedures and review LOD and KF logbooks.

4. Accountability

The Head – QC is accountable for ensuring that all LOD and moisture determinations are conducted as per validated procedures and recorded in compliance with cGMP.

5. Procedure

5.1 Loss on Drying (Oven Method)

1. Calibrate the analytical balance and drying oven before use.
2. Dry a suitable weighing bottle (with lid) in oven at 105°C for 30 minutes and cool in desiccator.
3. Weigh accurately 1-2 g of sample in the dried bottle (W1).
4. Dry the sample at specified temperature (usually 105°C) for 3 hours or as per STP.
5. Cool the bottle in a desiccator for 30 minutes and weigh again (W2).
6. Repeat drying until constant weight is achieved (not more than 0.5 mg difference).
7. Calculate LOD using the formula:
   % LOD = ((W1 – W2) / W1) × 100

5.2 Karl Fischer Method (Moisture Content)

1. Ensure Karl Fischer apparatus is calibrated with certified water standard.
2. Weigh accurately the sample (10–100 mg depending on expected moisture) and transfer to KF titration cell using syringe, septum, or direct introduction.
3. Perform blank titration and standardization if necessary.
4. Titrate until endpoint is achieved (stable measurement over 30 seconds).
5. Record volume of Karl Fischer reagent used and calculate % moisture:
   % Moisture = (Volume × Factor × 100) / Sample Weight (mg)

5.3 Acceptance Criteria

1. Compare observed results with specification mentioned in STP or pharmacopoeia (e.g., NMT 1.0% for moisture content).
2. Document results in LOD/Moisture Content Worksheet (Annexure-1).

5.4 Precautions

1. Use tongs/gloves to handle hot containers during LOD analysis.
2. Ensure reagents used in KF method are within expiry and moisture-free.
3. Keep desiccators tightly closed when not in use.

6. Abbreviations

• LOD: Loss on Drying
• KF: Karl Fischer
• STP: Standard Test Procedure
• API: Active Pharmaceutical Ingredient
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. LOD and Moisture Content Worksheet (Annexure-1)
2. KF Calibration Log
3. Drying Oven Calibration Record

8. References

• USP <921> – Water Determination
• ICH Q6A – Specifications: Test Procedures and Acceptance Criteria
• 21 CFR Part 211 – US FDA GMP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: LOD and Moisture Content Worksheet

Revision History:

Standard Operating Procedure for Impurity Profiling in API by HPLC

1. Purpose

To establish a standardized procedure for performing impurity profiling of Active Pharmaceutical Ingredients (APIs) using HPLC, ensuring accurate identification and quantification of known, unknown, and specified impurities as per regulatory and pharmacopeial requirements.

2. Scope

This SOP is applicable to all Quality Control (QC) personnel engaged in the analysis of impurities in APIs using validated HPLC methods during batch release, stability studies, or regulatory submissions.

3. Responsibilities

• QC Analyst: Prepare samples and standards, perform HPLC runs, integrate peaks, and calculate impurity levels.
• QC Reviewer: Review chromatograms, retention times, and impurity limits compliance.
• QA Officer: Verify results and ensure traceability for regulatory audits and documentation.

4. Accountability

The QC Head is accountable for ensuring that impurity testing procedures are scientifically justified, properly documented, and in accordance with approved analytical methods.

5. Procedure

5.1 Reference Documents and Preparation

1. Refer to the approved analytical method or pharmacopoeial monograph for:
   • Mobile phase composition
   • Column specification
   • Detector wavelength
   • Injection volume and flow rate
2. Prepare impurity standards and working standards in accordance with method SOPs.

5.2 System Suitability

1. Inject system suitability solution or standard mixture containing known impurities.
2. Ensure:
   • Resolution between critical peaks ≥ 2.0
   • Retention time repeatability within ±2%
   • %RSD of impurity area for repeat injections ≤ 10%

5.3 Sample Injection and Data Acquisition

1. Inject test solution and record chromatograms under validated conditions.
2. Identify peaks based on relative retention time (RRT) compared to standard.
3. Integrate all peaks above 0.05% (unless otherwise justified in validation).

5.4 Quantification

1. Calculate individual impurity % using response factor or area normalization method as per method validation.
2. Total impurity = sum of all impurities above threshold level.
3. Compare with acceptance criteria from:
   • ICH Q3A/B
   • Regulatory filing (e.g., DMF)
   • In-house specifications

5.5 Reporting Format

1. Report impurity profiling in the Impurity Profiling Report Sheet (Annexure-1) with:
   • Impurity name/RRT
   • Retention time
   • Observed area
   • Calculated percentage
   • Limit
   • Status (Pass/Fail)

5.6 Investigation of Unidentified Peaks

1. Any unknown impurity above reporting threshold must be:
   • Assigned an RRT and tracked in stability studies
   • Subject to identification via MS/NMR if consistently observed
   • Considered for toxicological evaluation if >0.1%

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• HPLC: High-Performance Liquid Chromatography
• RRT: Relative Retention Time
• RSD: Relative Standard Deviation
• DMF: Drug Master File
• ICH: International Council for Harmonisation

7. Documents

1. Impurity Profiling Report Sheet (Annexure-1)
2. System Suitability Checklist
3. Instrument Run Sequence

8. References

• ICH Q3A – Impurities in New Drug Substances
• ICH Q3B – Impurities in New Drug Products
• USP <621>, <466>, and applicable monographs

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Impurity Profiling Report Sheet

Revision History:

Standard Operating Procedure for Residual Solvent Testing by Gas Chromatography in API Manufacturing

1. Purpose

To define the procedure for the determination and quantification of residual solvents in Active Pharmaceutical Ingredients (APIs) using Gas Chromatography (GC), ensuring compliance with ICH Q3C and applicable pharmacopeial limits.

2. Scope

This SOP is applicable to all QC analysts performing residual solvent testing on raw materials, intermediates, and finished APIs using headspace or direct injection gas chromatography techniques.

3. Responsibilities

• QC Analyst: Prepare samples, standards, and run GC analysis as per validated method.
• QC Reviewer: Verify chromatograms, peak integration, and calculated values against limits.
• QA Officer: Ensure compliance with documentation and data integrity requirements.

4. Accountability

The QC Head is accountable for ensuring timely and accurate testing of residual solvents, proper qualification of GC instruments, and training of analysts.

5. Procedure

5.1 Sample and Standard Preparation

1. Prepare standard solutions using certified residual solvent reference standards as per STP.
2. Prepare sample solutions using suitable diluent (e.g., DMSO, DMF, water) under specified conditions.
3. Use headspace vials for volatile solvent extraction; seal with crimp caps.

5.2 Instrument Setup

1. Use qualified GC system equipped with FID or TCD detector and headspace or autosampler.
2. Check the following:
   • Column: Capillary column suitable for residual solvent separation
   • Carrier gas flow rate and pressure
   • Oven temperature program as per method
   • Injection volume and split ratio

5.3 System Suitability

1. Run system suitability test using standard mixture.
2. Acceptance criteria:
   • Resolution ≥ 1.5 between critical pairs
   • RSD of peak area ≤ 15% for replicate injections
   • Retention time repeatability within ±5%

5.4 Sample Analysis

1. Inject the sample solution as per sequence defined in the test method.
2. Record chromatograms and identify residual solvent peaks based on retention times.
3. Quantify using external standard calibration or area normalization method.

5.5 Calculation and Reporting

1. Calculate concentration of each solvent using calibration curve or response factor.
2. Compare against ICH Q3C and pharmacopoeial permissible limits (Class 1, 2, or 3 solvents).
3. Report result as:
   • Below detection limit (BDL) if peak not observed
   • Pass/Fail based on specification compliance

5.6 Disposal and Cleanup

1. Dispose residual solvent standards, sample remains, and headspace vials as per hazardous waste SOP.
2. Clean GC injection port, liner, and column after analysis if contamination is suspected.

6. Abbreviations

• GC: Gas Chromatography
• FID: Flame Ionization Detector
• TCD: Thermal Conductivity Detector
• BDL: Below Detection Limit
• LOD: Limit of Detection
• LOQ: Limit of Quantification
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. Residual Solvent Testing Worksheet (Annexure-1)
2. System Suitability Checklist
3. Sample Preparation Logbook

8. References

• ICH Q3C – Impurities: Guideline for Residual Solvents
• USP <467> – Residual Solvents
• 21 CFR Part 211 – US FDA GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Residual Solvent Testing Worksheet

Revision History:

Standard Operating Procedure for System Suitability Testing in HPLC for API Manufacturing

1. Purpose

To establish a standard procedure for performing system suitability testing (SST) in HPLC analysis before initiating sample analysis of API raw materials, intermediates, or finished products to verify the performance of the chromatographic system.

2. Scope

This SOP applies to all QC analysts and instruments used for HPLC-based analysis in the Quality Control (QC) laboratory involved in the testing of APIs at various manufacturing stages.

3. Responsibilities

• QC Analyst: Perform SST as per method and document results in SST logbook.
• QC Reviewer: Verify system suitability parameters before approving batch analysis.
• QA Officer: Audit SST compliance during data review and batch release.

4. Accountability

The Head – QC is accountable for ensuring that no analysis is initiated unless the HPLC system meets the system suitability criteria as per approved analytical method or pharmacopeial monograph.

5. Procedure

5.1 General Guidelines

1. System suitability must be run at the start of each sequence or analysis session.
2. Prepare the system suitability solution or standard as per the method (STP or pharmacopoeia).
3. Ensure column, detector, pump, and autosampler are stabilized.

5.2 SST Parameters

1. System suitability parameters include but are not limited to:
   • Retention time (Rt): Must be consistent (±2%)
   • Theoretical plates (N): Indicates column efficiency
   • Tailing factor (T): Should be ≤2.0 unless specified
   • Resolution (Rs): Between critical peaks must be ≥2.0
   • % RSD: For replicate injections should be within acceptance criteria (usually NMT 2.0%)

5.3 SST Execution

1. Inject the standard solution as per method (minimum 5 injections unless specified).
2. Record the chromatographic data and calculate system suitability parameters.
3. Compare the observed values with the criteria defined in the STP or monograph.
4. Document results in the SST Record Sheet (Annexure-1).

5.4 Acceptance and Continuation

1. If SST passes:
   • Proceed with sample analysis.
   • Ensure no major instrument changes are made post-SST.
2. If SST fails:
   • Do not proceed with sample analysis.
   • Investigate cause (e.g., column issue, mobile phase prep, instrument error).
   • Rectify and re-perform SST.

5.5 Frequency

1. Perform SST:
   • Before each analytical run
   • After major instrument maintenance
   • After column change or mobile phase change

6. Abbreviations

• HPLC: High-Performance Liquid Chromatography
• SST: System Suitability Testing
• Rt: Retention Time
• N: Number of Theoretical Plates
• Rs: Resolution
• RSD: Relative Standard Deviation
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. System Suitability Test Record Sheet (Annexure-1)
2. Instrument Usage Logbook
3. Analytical Method or STP

8. References

• USP <621> – Chromatography
• ICH Q2 (R1) – Validation of Analytical Procedures
• 21 CFR Part 211 – US FDA GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: System Suitability Test Record Sheet

Revision History:

Standard Operating Procedure for Analytical Balance Calibration in API Manufacturing

1. Purpose

To lay down the procedure for internal and external calibration of analytical balances used in the Quality Control (QC) laboratory to ensure that all weighing performed is accurate and traceable to national standards.

2. Scope

This SOP applies to all analytical balances used in the QC lab for the analysis of raw materials, intermediates, and finished APIs. It includes both daily calibration checks and scheduled external calibration by certified agencies.

3. Responsibilities

• QC Chemist: Perform daily internal calibration checks and document results.
• QC Executive: Review calibration records and report any deviations.
• External Calibration Vendor: Carry out certified calibration as per annual schedule.

4. Accountability

The Head – QC is accountable for ensuring that all balances are calibrated as per defined schedules and are suitable for analytical use.

5. Procedure

5.1 Internal (Daily) Calibration

1. Use certified calibration weights traceable to national standards (e.g., 10 mg, 50 mg, 100 mg, 200 mg, 500 mg, 1000 mg).
2. Ensure the balance is leveled and on vibration-free surface before use.
3. Check the zero reading of the balance before placing any weight.
4. Place each standard weight and record the displayed value.
5. Compare the result with the actual weight and calculate the deviation.
6. Deviation should be within ±0.2 mg for 1 mg readability and ±0.1% for higher weights.
7. Document the results in the Daily Balance Calibration Logbook (Annexure-1).

5.2 External Calibration

1. Performed semi-annually or annually by a government-approved or NABL-accredited external agency.
2. Ensure the calibration certificate includes:
   • Calibration date
   • Serial number of the balance
   • Calibration range and results
   • Uncertainty of measurement
   • Authorized signature
3. Attach calibration certificate in the balance file and update the Calibration Schedule Tracker.

5.3 Out-of-Tolerance Handling

1. If deviation exceeds acceptable limits:
   • Tag the balance as “Out of Service”
   • Stop using the balance for any weighing
   • Inform the QC Manager immediately
   • Initiate corrective action and impact assessment for results generated since last calibration

5.4 Precautions

1. Do not touch standard weights with bare hands; use forceps or gloves.
2. Store standard weights in their original containers when not in use.
3. Do not place samples directly on balance pan; use clean containers or weighing paper.
4. Clean the balance pan before and after use with a lint-free cloth.

6. Abbreviations

• SOP: Standard Operating Procedure
• QC: Quality Control
• NABL: National Accreditation Board for Testing and Calibration Laboratories
• OOS: Out of Specification

7. Documents

1. Daily Balance Calibration Logbook (Annexure-1)
2. External Calibration Certificate
3. Calibration Schedule Tracker

8. References

• USP <41> – Weights and Balances
• 21 CFR Part 211 – US FDA GMP
• ICH Q7 – GMP for APIs
• ISO/IEC 17025 – General requirements for testing and calibration laboratories

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Daily Balance Calibration Logbook

Revision History:

Standard Operating Procedure for Preparation of HPLC Mobile Phase in API Manufacturing

1. Purpose

To lay down the procedure for the preparation of mobile phases used in HPLC analysis to ensure consistency, accuracy, and compliance with cGMP in the QC laboratory for API manufacturing.

2. Scope

This SOP is applicable to all QC chemists involved in the preparation of aqueous, non-aqueous, and buffer-based mobile phases for HPLC systems in the analysis of raw materials, intermediates, and final APIs.

3. Responsibilities

• QC Chemist: Prepare mobile phases as per analytical method, record preparation details, and ensure proper labeling and storage.
• QC Executive: Review preparation and filtration records and approve mobile phase usage.
• QA Officer: Verify and audit compliance during inspections and reviews.

4. Accountability

The Head – QC is accountable for ensuring that all mobile phases used for HPLC are prepared and handled according to validated procedures and that records are maintained.

5. Procedure

5.1 General Instructions

1. Use only approved and AR/HPLC-grade solvents and reagents.
2. All glassware must be rinsed with the same solvents being used for mobile phase preparation.
3. Record batch number, solvent grade, and expiry date of chemicals used.

5.2 Preparation Steps

1. Refer to the approved analytical method or STP for mobile phase composition and mixing ratio.
2. Measure components using calibrated measuring cylinders or balances.
3. Prepare buffer solutions freshly and adjust pH using calibrated pH meter.
4. Mix components in a clean, dry glass bottle using magnetic stirrer (if applicable).

5.3 Filtration and Degassing

1. Filter the prepared mobile phase through 0.45 μm or 0.22 μm membrane filter using vacuum filtration assembly.
2. Degas using:
   • Ultrasonic bath for 15–20 minutes
   • Or helium sparging (if required by method)
3. Do not reuse previously filtered mobile phase without proper justification and QA approval.

5.4 Labeling Requirements

1. Each mobile phase container shall be labeled with:
   • Name: HPLC Mobile Phase
   • Composition
   • Prepared By
   • Date of Preparation
   • Use Before Date (max 7 days unless specified)
   • Storage Condition

5.5 Documentation

1. Enter details in Mobile Phase Preparation Logbook (Annexure-1).
2. Attach buffer pH adjustment records (if applicable).
3. QC Executive shall review and sign-off before first use.

5.6 Disposal of Expired Mobile Phase

1. Discard unused mobile phase after expiry or as per defined usage limit.
2. Document the disposal activity in the Mobile Phase Disposal Record (Annexure-2).

6. Abbreviations

• HPLC: High-Performance Liquid Chromatography
• SOP: Standard Operating Procedure
• STP: Standard Test Procedure
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. Mobile Phase Preparation Logbook (Annexure-1)
2. Mobile Phase Disposal Record (Annexure-2)
3. Analytical Method or STP

8. References

• ICH Q2 (R1) – Validation of Analytical Procedures
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals
• USP <621> – Chromatography

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Mobile Phase Preparation Logbook

Annexure-2: Mobile Phase Disposal Record

Revision History:

Standard Operating Procedure for Sample Receipt and Login in QC Lab for API Manufacturing

1. Purpose

To define a standard procedure for receiving, labeling, and logging samples submitted to the Quality Control (QC) laboratory from various sources including raw materials, in-process stages, intermediates, and final API batches, ensuring traceability, integrity, and GMP compliance.

2. Scope

This SOP is applicable to all QC personnel responsible for the initial handling of samples in the QC lab. It includes procedures for visual inspection, coding, sample labeling, logbook entry, and storage prior to testing.

3. Responsibilities

• QC Chemist: Receive the sample, assign sample number, label the sample, and make logbook entries.
• QC Executive: Review the sample information for completeness and correctness, and initiate analysis as per priority.
• QA Officer: Verify sample accountability during audit or review processes.

4. Accountability

The QC Head is accountable for ensuring that sample receipt and login activities are documented accurately and performed in accordance with regulatory and internal requirements.

5. Procedure

5.1 Sample Receipt from Various Sources

1. QC receives samples from:
   • Raw Material Store (for raw material testing)
   • Production (in-process/intermediate/final API)
   • Stability chamber (for stability studies)
   • External vendors or complaint samples (if applicable)

5.2 Preliminary Check

1. Upon receiving the sample, QC shall verify:
   • Label is clear and legible
   • Container is intact and sealed
   • Sample is sufficient in quantity for all required tests
   • Test request form (TRF) is attached and filled

5.3 Sample Number Assignment

1. Assign a unique QC Sample Number in the following format:
   QC/YY/MM/XXX (e.g., QC/25/04/102)
   • YY: Year
   • MM: Month
   • XXX: Serial number of the sample received that month

5.4 Sample Labeling

1. Affix the QC label with:
   • QC Sample Number
   • Date of Receipt
   • Batch Number
   • Sample Description (e.g., RM, IPC, API)
   • Storage condition (if applicable)
2. Use red labels for OOS, yellow for OOT, and green for general samples.

5.5 Entry into Sample Login Register

1. Enter all sample details in the Sample Login Register (Annexure-1), including:
   • Sample Number
   • Source
   • Batch Number
   • Date and Time of Receipt
   • Type of Analysis
   • Condition at Receipt

5.6 Sample Storage and Handover

1. Store samples under appropriate conditions until they are taken for analysis (e.g., desiccator, refrigerator, ambient shelf).
2. Hand over the sample with TRF to the designated analyst for testing as per schedule.

5.7 Sample Discrepancy Management

1. If any discrepancy is observed (e.g., leakage, labeling issue, missing TRF), inform the sender and record details in the Sample Discrepancy Logbook.
2. Do not proceed with login until resolved and documented.

6. Abbreviations

• QC: Quality Control
• QA: Quality Assurance
• API: Active Pharmaceutical Ingredient
• TRF: Test Request Form
• IPC: In-Process Control

7. Documents

1. Sample Login Register (Annexure-1)
2. Sample Discrepancy Logbook
3. Test Request Form

8. References

• ICH Q7 – GMP for APIs
• 21 CFR Part 211 – US FDA GMP Requirements
• WHO TRS 986 – GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Sample Login Register

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