Standard Operating Procedure for Cross-Verification of IPC Data by QA in API Manufacturing

1. Purpose

To define a systematic procedure for Quality Assurance (QA) to cross-verify In-Process Control (IPC) data documented during the manufacturing of Active Pharmaceutical Ingredients (APIs), ensuring integrity, traceability, and adherence to GMP.

2. Scope

This SOP is applicable to all IPC test data generated and recorded during batch manufacturing of APIs at various stages—reaction, drying, milling, blending, and packing.

3. Responsibilities

• QA Officer: Verify IPC results in real-time or post-process and ensure records are accurate and compliant.
• Production Chemist: Ensure timely entry of IPC data in Batch Manufacturing Record (BMR).
• QC Analyst: Provide analytical test results and support QA during data review.

4. Accountability

The QA Head is accountable for execution and oversight of IPC data verification and regulatory compliance.

5. Procedure

5.1 IPC Data Recording by Production

1. Production personnel shall record IPC observations (pH, LOD, temperature, yield, color, etc.) in the BMR at the time of activity using indelible ink.
2. Each entry shall be dated and signed by the responsible person.
3. Corrections shall follow GDP practices—strike through, write correct entry, sign, date, and justify.

5.2 QA Verification Method

1. QA Officer shall:
   • Review IPC entries for completeness and legibility
   • Verify results against applicable specifications from MFR or IPC protocols
   • Ensure sampling and test frequency align with defined criteria
   • Check calculations and transcriptions for accuracy
2. For analytical data (e.g., HPLC, TLC), QA shall ensure:
   • Chromatograms are attached and traceable
   • Results match analytical worksheets and reports

5.3 Handling Discrepancies

1. In case of missing, incorrect, or questionable entries, QA shall:
   • Notify the Production Head immediately
   • Document findings in IPC Verification Observation Form (Annexure-1)
   • Initiate deviation as per SOP if discrepancy impacts product quality
2. Corrective and Preventive Actions (CAPA) shall be proposed and monitored by QA.

5.4 Verification Frequency

1. QA shall verify IPC data:
   • During batch manufacturing (at least once per shift)
   • During BMR review for batch release

5.5 Documentation and Records

1. All QA reviews must be documented and signed with date and time.
2. IPC Verification Observation Forms shall be retained with the corresponding BMR.

6. Abbreviations

• IPC: In-Process Control
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record
• MFR: Master Formula Record
• CAPA: Corrective and Preventive Action

7. Documents

1. IPC Verification Observation Form (Annexure-1)
2. Batch Manufacturing Record
3. Deviation Form (if applicable)

8. References

• ICH Q10 – Pharmaceutical Quality System
• 21 CFR Part 211 – US FDA GMP
• WHO TRS 986 – GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Verification Observation Form

Revision History:

Standard Operating Procedure for Management of IPC Outliers and Investigations in API Manufacturing

1. Purpose

To define the procedure for the identification, documentation, investigation, and resolution of Out of Trend (OOT) or Out of Specification (OOS) in-process control (IPC) results in API manufacturing, ensuring consistent process control and compliance with GMP.

2. Scope

This SOP applies to all IPC tests conducted during API production where the results fall outside established limits or exhibit abnormal trends requiring investigation and corrective action.

3. Responsibilities

• Production Operator: Immediately report any IPC result outside specification or expected range.
• QC Analyst: Verify the result, initiate rechecking if justified, and inform QA for deviation handling.
• QA Officer: Lead the investigation, determine root cause, and initiate CAPA as needed.

4. Accountability

The Production Head and QC Head are accountable for accurate reporting and timely investigation of IPC outliers. QA Head is responsible for closure of investigation and ensuring regulatory compliance.

5. Procedure

5.1 Identification of Outlier Results

1. Any IPC result deviating from the target or defined specification limit must be flagged immediately.
2. Examples include unexpected pH, LOD, yield, color, assay, or TLC/HPLC profiles.
3. Use predefined limits from MFR or IPC test methods for comparison.

5.2 Initial Assessment

1. Production and QC jointly assess potential assignable causes:
   • Instrument error
   • Sampling error
   • Calculation mistake
   • Human error
2. If assignable cause is identified and justifiable, recheck may be allowed with QA approval.

5.3 Repeat Testing Criteria

1. Repeat analysis must be justified and documented in IPC Outlier Investigation Form (Annexure-1).
2. Only two re-tests permitted; original result must not be discarded or replaced without investigation closure.
3. If retest confirms the outlier, initiate deviation and stop further processing if needed.

5.4 Investigation and Documentation

1. QA initiates formal investigation using deviation or non-conformance form.
2. Include details such as:
   • Batch No., IPC test performed, date/time
   • Initial and retest results
   • Possible causes, corrective action, preventive action (CAPA)
3. Root cause analysis may involve tools like 5-Why or Fishbone diagram.

5.5 Disposition and Closure

1. QA Head reviews investigation report and decides on batch status: Reprocess, reject, or proceed.
2. Final decision and justification to be recorded in the batch record.
3. Investigation should be closed within 10 working days.

6. Abbreviations

• IPC: In-Process Control
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• OOT: Out of Trend
• OOS: Out of Specification
• CAPA: Corrective and Preventive Action

7. Documents

1. IPC Outlier Investigation Form (Annexure-1)
2. Batch Manufacturing Record
3. CAPA Register / Logbook

8. References

• ICH Q7 – GMP for APIs
• ICH Q10 – Pharmaceutical Quality System
• 21 CFR Part 211 – US FDA GMP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Outlier Investigation Form

Revision History:

Standard Operating Procedure for Sampling Frequency and Quantity Guidelines in API Manufacturing

1. Purpose

To establish uniform guidelines for the frequency and quantity of samples to be collected during various stages of API manufacturing for in-process checks, intermediate testing, and final product evaluation.

2. Scope

This SOP applies to sampling activities conducted by Production and Quality Control personnel during receipt of raw materials, reaction monitoring, drying, milling, blending, and packing stages of API production.

3. Responsibilities

• Production Chemist: Collect in-process samples as per defined frequency and quantity.
• QC Analyst: Receive and analyze the sample, and log receipt and testing status.
• QA Officer: Review compliance with sampling plan and maintain traceability records.

4. Accountability

The Production Head is accountable for sampling at defined intervals. The QA Head is responsible for approving sampling plans and reviewing deviations.

5. Procedure

5.1 General Sampling Principles

1. Use cleaned, labeled, and approved sampling tools and containers.
2. Wear appropriate PPE while sampling.
3. Ensure samples are representative of the bulk material by collecting from top, middle, and bottom (where applicable).

5.2 Sampling Frequency

1. Refer to MFR/BMR for specific instructions. If not defined, use the following general guidance:
   • Raw Materials: Each container or as per reduced testing protocol.
   • Reaction Monitoring: Every 30–60 minutes or at defined critical stages.
   • Drying: Every 2 hours or until LOD is within range.
   • Milling/Blending: Start, middle, and end of batch.
   • Packing: One sample per 25 kg or per container.
2. Additional sampling may be required based on deviations or unexpected results.

5.3 Sampling Quantity Guidelines

1. Refer to product specification or method of analysis. If not defined:
   • Assay / HPLC: 1–2 g
   • LOD / Moisture: 2–3 g
   • Identification: 0.5–1 g
   • Impurity profiling: 5 g
   • Reserve / Retain sample: 25–50 g
2. In case of liquids: Collect 5–10 mL using pipettes or sampling bottles.

5.4 Labeling and Documentation

1. Label each sample with:
   • Product name
   • Batch number
   • Date and time of sampling
   • Stage of sampling
   • Sampled by
2. Record in the Sampling Logbook (Annexure-1).
3. QC to log sample receipt and usage in Analytical Work Log.

5.5 Deviations

1. If sampling frequency or quantity deviates from defined protocol, record deviation with justification and obtain QA approval.
2. Document deviation in the Batch Record and initiate deviation form if required.

6. Abbreviations

• SOP: Standard Operating Procedure
• QC: Quality Control
• QA: Quality Assurance
• BMR: Batch Manufacturing Record
• MFR: Master Formula Record
• LOD: Loss on Drying

7. Documents

1. Sampling Logbook (Annexure-1)
2. Batch Manufacturing Record
3. Deviation Report (if applicable)

8. References

• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• WHO TRS 986 – GMP Guidelines
• 21 CFR Part 211 – US FDA GMP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Sampling Logbook

Revision History:

Standard Operating Procedure for Real-Time Yield Monitoring During Reactions in API Manufacturing

1. Purpose

To define the procedure for real-time yield monitoring during chemical reactions in the manufacturing of Active Pharmaceutical Ingredients (APIs) in order to assess process efficiency, trigger corrective actions, and support in-process control.

2. Scope

This SOP applies to all chemical synthesis processes in API manufacturing where reaction progress and intermediate product yields are calculated in real time for monitoring and optimization.

3. Responsibilities

• Production Chemist: Monitor reaction time and record in-process yield data.
• QC Analyst: Analyze samples for yield determination (e.g., by HPLC, gravimetric, titrimetric methods).
• QA Officer: Review records and ensure results are documented as per GMP.

4. Accountability

The Production Head is accountable for implementation. QA Head is responsible for compliance review and deviation handling.

5. Procedure

5.1 Yield Monitoring Plan

1. Define yield checkpoints in the Batch Manufacturing Record (BMR) based on reaction stages (e.g., after 30%, 60%, and 100% theoretical conversion).
2. Use validated methods for quantitative analysis, e.g., HPLC assay, LOD correction, or titration.

5.2 Sampling

1. Collect ~2–5 mL (or as required) of reaction mass in clean, dry containers at defined time points.
2. Label sample with Batch No., Reaction Stage, Date, Time, and Initials.
3. Deliver sample immediately to QC; store under controlled conditions if delayed.

5.3 Analytical Testing

1. Perform testing to quantify desired product concentration.
2. Document result as concentration (% w/w or % area) or mass obtained per volume sampled.

5.4 Yield Calculation

1. Calculate yield as per formula:
   % Yield = (Actual Amount of Product / Theoretical Amount) × 100
2. Use molecular weights and stoichiometry as defined in the MFR.
3. Adjust for dilution factors, LOD (moisture), or assay correction if applicable.

5.5 Trending and Response

1. Plot yield data on control charts for trend evaluation.
2. If yield is outside target range (e.g., ±5% of expected), inform QA and investigate root cause.
3. Delay or abort next stage if yield is critically low or shows unexpected decline.

5.6 Documentation

1. Record all yields, calculations, and time stamps in the Reaction Yield Log (Annexure-1).
2. Attach corresponding QC report or test printouts.
3. Review and sign by Production Supervisor and QA Reviewer.

6. Abbreviations

• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• QC: Quality Control
• QA: Quality Assurance
• BMR: Batch Manufacturing Record
• LOD: Loss on Drying

7. Documents

1. Reaction Yield Log (Annexure-1)
2. Batch Manufacturing Record
3. Analytical Test Reports

8. References

• ICH Q8 – Pharmaceutical Development
• 21 CFR Part 211 – US FDA GMP
• WHO TRS 986 – GMP for APIs

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Reaction Yield Log

Revision History:

Standard Operating Procedure for Use of Conductivity Meter in API Manufacturing

1. Purpose

To define the procedure for using conductivity meters in API manufacturing processes to measure and monitor the conductivity of solutions during synthesis, purification, and equipment cleaning to ensure process control and GMP compliance.

2. Scope

This SOP applies to all conductivity meters used within the API manufacturing facility for in-process checks, water quality testing, and final rinse conductivity monitoring during cleaning validation.

3. Responsibilities

• Production Operator: Operate the conductivity meter and perform measurements as per batch and cleaning procedures.
• QC Analyst: Verify calibration and results as needed for analytical or compliance purposes.
• Engineering: Maintain and service instruments per schedule.
• QA Officer: Review and retain conductivity measurement records.

4. Accountability

Production Head is accountable for proper usage and timely calibration. QA Head is responsible for ensuring data integrity and regulatory compliance.

5. Procedure

5.1 Instrument Check and Calibration

1. Verify calibration status before use. Calibration must be performed daily using certified standards (e.g., 84 µS/cm, 1413 µS/cm).
2. Record calibration details in the Conductivity Meter Calibration Log (refer Annexure-1).

5.2 Sample Collection

1. Collect process or cleaning solution samples in clean, dry glass beakers or plastic containers (non-reactive).
2. Ensure sampling point is flushed and representative of the bulk material.

5.3 Conductivity Measurement

1. Switch ON the instrument and allow stabilization for 5 minutes.
2. Rinse probe with distilled water and blot dry with lint-free tissue.
3. Immerse probe in sample ensuring full submersion of sensors.
4. Allow reading to stabilize (typically 30–60 seconds).
5. Record conductivity in µS/cm or mS/cm, along with temperature if auto-compensated.

5.4 Post-Measurement Cleaning and Storage

1. Rinse probe with distilled water after each use.
2. Store probe as per manufacturer’s instructions (e.g., in protective cap with storage solution).
3. Turn off the device when not in use.

5.5 Acceptance Criteria and Deviations

1. Refer to the BMR or cleaning protocol for conductivity limits (e.g., NMT 10 µS/cm for final rinse).
2. If out of limits, repeat measurement or escalate as deviation to QA.

5.6 Documentation

1. Enter results in the Conductivity Measurement Log (Annexure-2) and in-process or cleaning record.
2. Include date, time, batch number, sample type, and operator initials.

6. Abbreviations

• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record
• µS/cm: Microsiemens per centimeter

7. Documents

1. Conductivity Meter Calibration Log (Annexure-1)
2. Conductivity Measurement Log (Annexure-2)
3. Batch Manufacturing Record / Cleaning Record

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• USP <645> – Water Conductivity
• 21 CFR Part 211 – US FDA GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Conductivity Meter Calibration Log

Annexure-2: Conductivity Measurement Log

Revision History:

Standard Operating Procedure for Calibration of pH Meter Used in Production in API Manufacturing

1. Purpose

To define the procedure for routine calibration of pH meters used in production areas for accurate and reliable pH measurements in process solutions during API manufacturing.

2. Scope

This SOP applies to all benchtop and portable pH meters installed or used in production environments for in-process pH monitoring during synthesis, extraction, purification, or cleaning activities.

3. Responsibilities

• Production Operator: Perform daily or before-use calibration of pH meter and record in calibration log.
• QC/QA Officer: Verify calibration records and ensure traceable standard solutions are used.
• Engineering/Instrument Team: Perform preventive maintenance and annual calibration certification.

4. Accountability

The Production Head is accountable for proper execution of calibration. The QA Head is responsible for ensuring compliance with calibration standards.

5. Procedure

5.1 Calibration Frequency

1. Daily before first use or before any batch-wise measurement.
2. After each maintenance or probe replacement.
3. Whenever abnormal readings or drift is observed.

5.2 Required Materials

1. Standard buffer solutions (pH 4.00, 7.00, and 9.20 ± 0.02 at 25°C).
2. Clean beakers, distilled water, tissue paper, labeling pen.
3. Calibration Logbook or Electronic Log System.

5.3 Calibration Steps

1. Switch ON the pH meter and allow it to stabilize for 5 minutes.
2. Rinse the electrode with distilled water and gently blot dry.
3. Immerse the electrode in pH 7.00 buffer first and wait until reading stabilizes.
4. Set or confirm the reading at pH 7.00 and press “calibrate” or “enter.”
5. Repeat with pH 4.00 and pH 9.20 buffers following the same steps.
6. Rinse the electrode between each buffer and avoid contamination.
7. After completing 2 or 3-point calibration, recheck with a standard buffer to confirm accuracy.
8. If readings deviate > ±0.05 pH units, repeat calibration or inform Engineering/QC.

5.4 Documentation

1. Record the following in the pH Meter Calibration Log (Annexure-1):
   • Date
   • Instrument ID
   • Buffer values and observed readings
   • Calibration result (Pass/Fail)
   • Name and signature of the person performing calibration
2. Retain calibration records as part of batch documentation or instrument history file.

5.5 Precautions

1. Use fresh buffer solutions; discard opened buffers after 30 days or as per label.
2. Ensure the pH probe is stored in recommended storage solution when not in use.
3. Do not wipe probe with tissue after calibration—rinse and blot gently.

6. Abbreviations

• pH: Potential of Hydrogen
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control

7. Documents

1. pH Meter Calibration Log (Annexure-1)
2. Instrument Calibration Certificate
3. Batch Manufacturing Record (where applicable)

8. References

• USP General Chapter <791> – pH
• ICH Q7 – GMP for APIs
• 21 CFR Part 211 – US FDA cGMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: pH Meter Calibration Log

Revision History:

Standard Operating Procedure for Documentation of In-Process Control Results in API Manufacturing

1. Purpose

To establish a standard procedure for documenting all in-process control (IPC) test results generated during the manufacture of Active Pharmaceutical Ingredients (APIs), ensuring traceability, accuracy, and compliance with GMP and data integrity principles.

2. Scope

This SOP applies to the documentation of IPC tests performed by production and QC personnel throughout the manufacturing lifecycle of intermediates and APIs, including parameters such as pH, LOD, temperature, yield, appearance, and assay.

3. Responsibilities

• Production Chemist/Operator: Record IPC results promptly in the BMR and applicable logbooks.
• QC Analyst: Review and verify the IPC results and record them in lab worksheets.
• QA Officer: Review completed documentation for correctness and compliance.

4. Accountability

Production Head is accountable for complete and accurate recording of IPC results. QA Head is responsible for reviewing and ensuring data integrity and traceability.

5. Procedure

5.1 IPC Parameters and Records

1. IPC parameters shall be defined in the Master Formula Record (MFR) and include:
   • Appearance
   • pH
   • LOD
   • Conductivity
   • Assay
   • TLC or HPLC results
   • Temperature and time records
2. These shall be recorded during sampling or observation, using indelible ink (blue/black only) in the Batch Manufacturing Record (BMR).

5.2 Recording of Results

1. Enter values in the respective IPC table format within the BMR at the time of observation or immediately after analysis.
2. Each entry shall include:
   • Result
   • Date and time
   • Initials of person performing the test
3. Use “NA” (Not Applicable) if a test is not required; do not leave fields blank.
4. Use “NR” (Not Recorded) only when a result is unavailable due to an explainable reason, and document justification.

5.3 Corrections and Deviations

1. For corrections:
   • Strike through the incorrect entry with a single line.
   • Do not use correction fluids.
   • Write the correct entry, sign, date, and provide reason for correction.
2. For any result falling outside the specification:
   • Stop processing immediately.
   • Notify QA and initiate deviation documentation as per relevant SOP.

5.4 Archiving and Retention

1. All IPC records must be attached to the BMR and stored in the QA archive room.
2. Electronic records, if applicable, must comply with 21 CFR Part 11 standards.
3. Retention period: Minimum of 5 years or as per regulatory/customer requirement.

6. Abbreviations

• IPC: In-Process Control
• SOP: Standard Operating Procedure
• BMR: Batch Manufacturing Record
• MFR: Master Formula Record
• QA: Quality Assurance
• QC: Quality Control
• LOD: Loss on Drying

7. Documents

1. In-Process Control Results Logbook (Annexure-1)
2. Batch Manufacturing Record
3. Deviation Form (if applicable)

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – US FDA cGMP
• WHO TRS 986 – Good Manufacturing Practices

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: In-Process Control Results Logbook

Revision History:

Standard Operating Procedure for Color and Odor Assessment in Intermediates in API Manufacturing

1. Purpose

To establish a procedure for the visual and olfactory assessment of color and odor in API intermediates to ensure product consistency and detect abnormal process variations during manufacturing.

2. Scope

This SOP applies to all intermediate materials produced during the synthesis of Active Pharmaceutical Ingredients (APIs) where color and odor are specified as in-process quality checks.

3. Responsibilities

• Production Chemist: Perform initial observation and record any deviations in the Batch Manufacturing Record (BMR).
• QC Analyst: Confirm and document the observations in laboratory logs and compare with reference standards.
• QA Officer: Review recorded observations and manage deviations or investigations if required.

4. Accountability

Production Head is accountable for proper in-process monitoring. QC Head is responsible for ensuring accuracy and compliance in documentation.

5. Procedure

5.1 Sample Collection

1. Collect ~5–10 g of the intermediate in a clean, dry glass container immediately after the relevant process step (e.g., filtration, drying, or crystallization).
2. Ensure the sample is representative by sampling from multiple locations if applicable.
3. Label the container with Product Name, Batch No., Sampling Stage, Date, and Time.

5.2 Color Assessment

1. Place the sample against a white background under daylight equivalent light (D65 or 6000–6500 K).
2. Compare color visually with standard/reference material or documented appearance in BMR.
3. Describe color using standard terminology (e.g., off-white, pale yellow, brownish grey).
4. If deviation is observed, document using “Color and Odor Deviation Form” (Annexure-1) and notify QA.

5.3 Odor Assessment

1. Carefully waft vapor from the sample towards the nose without direct inhalation.
2. Use a clean fume hood if required for hazardous materials.
3. Compare odor with process expectations (e.g., sulfur-like, solvent odor, acidic, aromatic, odorless).
4. Note intensity (e.g., mild, strong, pungent) and any unusual smells that may indicate impurity or degradation.

5.4 Acceptance Criteria

1. Color and odor must match the specification or range mentioned in the Master Formula Record (MFR) or analytical method.
2. Deviations must be evaluated through additional analytical testing (e.g., HPLC, GC) if needed.
3. QA shall assess impact on product quality and decide on batch disposition.

5.5 Documentation and Records

1. Enter observations in the Batch Manufacturing Record and QC worksheet.
2. Attach reference color photograph or comparator (if available) for traceability.
3. Maintain all forms and logs as per documentation SOP.

6. Abbreviations

• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• BMR: Batch Manufacturing Record
• MFR: Master Formula Record
• QC: Quality Control
• QA: Quality Assurance

7. Documents

1. Color and Odor Deviation Form (Annexure-1)
2. Batch Manufacturing Record
3. Reference Color Comparator (if applicable)

8. References

• ICH Q8 – Pharmaceutical Development
• 21 CFR Part 211 – US FDA cGMP
• Internal Visual Inspection and Sensory Evaluation SOP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Color and Odor Deviation Form

Revision History:

Standard Operating Procedure for LOD Testing During Drying Stage in API Manufacturing

1. Purpose

To outline a standard procedure for performing Loss on Drying (LOD) testing during the drying stage of API manufacturing for real-time monitoring of residual moisture and to determine the endpoint of drying.

2. Scope

This SOP is applicable to all API and intermediate drying processes conducted in Fluid Bed Dryers (FBD), Vacuum Tray Dryers (VTD), and Tray Dryers within the API manufacturing facility.

3. Responsibilities

• Production Operator: Collect and weigh samples as per procedure and record observations.
• QC Analyst: Perform LOD testing and verify compliance with limits.
• QA Officer: Review logbooks and ensure procedural adherence.

4. Accountability

Production Head is accountable for sampling and coordination with QC. QC Head is responsible for the accuracy and documentation of test results.

5. Procedure

5.1 Sampling for LOD

1. Ensure drying has reached a steady phase (based on time or visual judgment).
2. Open sampling port or tray cover in a clean area; avoid contaminating the bulk.
3. Collect approximately 2–5 grams of material from at least 3 different trays or regions (top, middle, bottom).
4. Use a clean, dry stainless-steel spatula and sample container labeled with batch number and stage.

5.2 Sample Handling and Transfer

1. Label the sample container with Product Name, Batch No., Sampling Point, Date, and “In-Process LOD”.
2. Transfer the sample to QC immediately; if delay exceeds 30 minutes, store in desiccator.
3. Record sampling details in the “LOD Sampling Log” (Annexure-1).

5.3 LOD Testing Procedure (Gravimetric Method)

1. Use a pre-weighed clean and dry LOD bottle/tin.
2. Accurately weigh ~1 to 2 g of the sample into the container and record weight (W1).
3. Place the container in a hot air oven set at 105°C ±2°C for 3 hours or as per method validation.
4. Remove and cool the sample in a desiccator to room temperature.
5. Reweigh and record weight (W2). Repeat until a constant weight is achieved (≤0.5 mg difference).
6. Calculate LOD using:
   LOD (%) = ((W1 – W2) / W1) × 100

5.4 Acceptance Criteria

1. Compare observed value with specification (e.g., LOD NMT 1.0%).
2. If LOD is within limits, continue drying for additional 30 minutes and repeat sampling for confirmation.
3. If out of limits, continue drying and recheck at defined intervals (e.g., every 30 minutes).

5.5 Cleaning and Documentation

1. After testing, clean the glassware and record cleaning in the laboratory logbook.
2. Ensure all calculations are verified and signed by a second analyst or reviewer.
3. Attach LOD worksheet in the BMR and archive as per QA documentation policy.

6. Abbreviations

• LOD: Loss on Drying
• QC: Quality Control
• QA: Quality Assurance
• BMR: Batch Manufacturing Record
• NMT: Not More Than

7. Documents

1. LOD Sampling Log (Annexure-1)
2. LOD Worksheet
3. Batch Manufacturing Record

8. References

• Ph. Eur / USP General Chapter < Loss on Drying >
• ICH Q2(R1) – Validation of Analytical Procedures
• 21 CFR Part 211 – US FDA cGMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: LOD Sampling Log

Revision History:

Standard Operating Procedure for Conductivity Measurement in Process Solutions in API Manufacturing

1. Purpose

To describe a standardized method for measuring the conductivity of process solutions in API manufacturing to monitor ionic strength, validate cleaning processes, and ensure consistency in intermediate reactions and aqueous washings.

2. Scope

This SOP applies to conductivity checks performed during aqueous extractions, reaction monitoring, washing of intermediates, and equipment cleaning verification in the API manufacturing facility.

3. Responsibilities

• Production Chemist/Operator: Collect and measure samples as per process instructions.
• QC Analyst: Verify conductivity meter calibration and review results.
• QA Officer: Audit logbooks and ensure compliance with procedural accuracy.

4. Accountability

The Production Head is accountable for operational control. The QC Head is responsible for analytical accuracy and data integrity.

5. Procedure

5.1 Instrument Calibration

1. Calibrate the conductivity meter using certified standard solutions (e.g., 84 µS/cm and 1413 µS/cm) as per manufacturer’s instructions.
2. Document calibration readings in the Conductivity Meter Calibration Log (Annexure-1).
3. Do not use equipment with expired calibration or with deviation in standard reading beyond ±2%.

5.2 Sample Collection

1. Collect process solution in clean, dry, and inert beakers or flasks.
2. If sampling from a reactor or tank, ensure sample represents bulk solution and not surface layer.
3. Allow solution to cool if collected from hot reaction mass (not above 40°C unless validated).

5.3 Measurement Technique

1. Rinse the conductivity probe with distilled water and pat dry with lint-free tissue.
2. Insert the probe into the sample ensuring full immersion of electrodes.
3. Allow the reading to stabilize (typically 30 seconds to 1 minute).
4. Record the value in µS/cm or mS/cm along with temperature (if auto-compensated).
5. Document the reading in the Conductivity Measurement Log (Annexure-2) and BMR.

5.4 Acceptance Criteria and Interpretation

1. Refer to the approved process or cleaning validation protocol for acceptance ranges (e.g., conductivity NMT 10 µS/cm for final rinse).
2. If outside limit, notify QA and repeat measurement using fresh sample.
3. Initiate deviation report if reading remains out of specification.

5.5 Post-Use Maintenance

1. After use, rinse the probe thoroughly with distilled water and store in 3M KCl or as recommended.
2. Turn off the instrument and cover the probe to avoid dust or drying.

6. Abbreviations

• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record
• µS/cm: Microsiemens per centimeter
• mS/cm: Millisiemens per centimeter

7. Documents

1. Conductivity Meter Calibration Log (Annexure-1)
2. Conductivity Measurement Log (Annexure-2)
3. Batch Manufacturing Record

8. References

• ICH Q2(R1) – Validation of Analytical Procedures
• 21 CFR Part 211 – US FDA cGMP
• WHO TRS 986 – Good Manufacturing Practices

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Conductivity Meter Calibration Log

Annexure-2: Conductivity Measurement Log

Revision History: