Standard Operating Procedure for Documentation Format for IPC Logbooks in API Manufacturing

1. Purpose

To define a standard and GMP-compliant format for documenting In-Process Control (IPC) observations, results, and decisions in designated IPC logbooks during API manufacturing processes.

2. Scope

This SOP applies to all production personnel, QC analysts, and QA reviewers responsible for recording, reviewing, and maintaining IPC-related data in logbooks across all stages of API manufacturing.

3. Responsibilities

• Production Chemist: Record real-time IPC data in the approved logbook format during batch execution.
• QC Analyst: Review recorded IPC results, ensure legibility and data accuracy.
• QA Officer: Approve the logbook format and periodically verify compliance during internal audits or batch review.

4. Accountability

The Production Head is accountable for adherence to documentation practices. The QA Head is accountable for format approval and overall data integrity.

5. Procedure

5.1 Logbook Identification and Control

1. Each IPC logbook shall be uniquely identified with:
   • Logbook Title (e.g., “IPC Logbook – Drying Stage”)
   • Logbook ID Number
   • Department Name
   • Date of Issue
   • Issued By (QA)
2. The cover page shall be stamped and signed by QA before use.

5.2 Logbook Format Requirements

1. Each logbook page must contain a structured table with the following fields:
   • Date
   • Batch Number
   • Stage of IPC (e.g., Drying, Milling)
   • Parameter Checked (e.g., pH, LOD, temperature)
   • Observed Result
   • Acceptance Criteria
   • Observation Time
   • Performed By (Name and Signature)
   • Reviewed By (Name and Signature)
   • Remarks (if any)

5.3 Documentation Instructions

1. Write entries using permanent blue ink only.
2. Ensure entries are clear, legible, and free of overwriting.
3. In case of correction:
   • Strike through the incorrect entry with a single line.
   • Write the correct value above or beside it.
   • Sign, date, and provide reason for correction.
4. Do not leave blank rows. If a row is not applicable, write “NA” and strike it across.
5. Each page shall be signed by the personnel making entries and reviewed by the supervisor or QC officer.

5.4 Logbook Storage and Handling

1. Store logbooks in a dedicated cabinet accessible only to authorized personnel.
2. Do not remove logbooks from the department without QA authorization.
3. Protect logbooks from dust, spillage, and physical damage.

5.5 Closing and Archiving

1. Once filled, the logbook shall be closed with a summary page indicating:
   • Total pages used
   • Period of use (From – To)
   • Summary of any deviations
2. Submit completed logbook to QA for archival.
3. QA shall archive the logbook in the document control room as per SOP for a minimum of 5 years.

6. Abbreviations

• IPC: In-Process Control
• QA: Quality Assurance
• QC: Quality Control
• SOP: Standard Operating Procedure
• LOD: Loss on Drying

7. Documents

1. IPC Logbook Template (Annexure-1)
2. Logbook Issue Record (Annexure-2)
3. Deviation Form (if applicable)

8. References

• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals
• WHO TRS 986 – GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Logbook Template

Annexure-2: Logbook Issue Record

Revision History:

Standard Operating Procedure for Monitoring of Crystallization End-Point in API Manufacturing

1. Purpose

To define a systematic procedure for monitoring and confirming the end-point of crystallization during the manufacturing of Active Pharmaceutical Ingredients (APIs), ensuring consistency, purity, and yield of the final product.

2. Scope

This SOP applies to production chemists, QC analysts, and QA officers involved in crystallization monitoring during the synthesis of APIs in pilot or commercial scale manufacturing.

3. Responsibilities

• Production Chemist: Perform in-process monitoring of crystallization and document observations.
• QC Analyst: Perform confirmatory testing to verify end-point if required.
• QA Officer: Review documentation and ensure compliance with GMP standards.

4. Accountability

The Production Head is accountable for monitoring and decision-making regarding crystallization completion. The QA Head ensures procedural compliance.

5. Procedure

5.1 Preparation for Crystallization

1. Confirm the reaction is complete and the solution is ready for crystallization.
2. Cool the solution gradually to the specified temperature as per MFR.
3. Initiate seeding if applicable (as per validated procedure).

5.2 Monitoring Parameters

1. Visual Observation:
   • Check crystal growth visually at defined intervals (e.g., every 30 minutes).
   • Uniform and consistent crystal formation indicates nearing completion.
2. Temperature Monitoring:
   • Ensure crystallization temperature range is maintained.
   • Deviation may lead to improper crystal formation.
3. Mother Liquor Clarity:
   • Take ~5 mL of supernatant and check under good lighting for clarity.
   • Absence of suspended solids indicates crystallization is near complete.

5.3 Confirmatory Tests (If Applicable)

1. Send sample of mother liquor to QC for residual assay or LOD.
2. If compound-specific, perform TLC or HPLC to detect uncrystallized material.
3. Continue crystallization if active material is detected in the supernatant.

5.4 Documentation

1. Record temperature, time, visual observation, and sampling in the Crystallization Monitoring Logbook (Annexure-1).
2. Include any observations regarding crystal size, shape, or non-uniformity.
3. Once complete, proceed with filtration or centrifugation as per next process step.

6. Abbreviations

• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• QC: Quality Control
• QA: Quality Assurance
• LOD: Loss on Drying
• TLC: Thin Layer Chromatography
• MFR: Master Formula Record

7. Documents

1. Crystallization Monitoring Logbook (Annexure-1)
2. Batch Manufacturing Record
3. QC Result Reports (if applicable)

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• 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: Crystallization Monitoring Logbook

Revision History:

Standard Operating Procedure for In-Process Filtrate Clarity Testing in API Manufacturing

1. Purpose

To define a standardized procedure for performing clarity testing of filtrates collected during filtration steps in API manufacturing, ensuring absence of particulate matter and confirming filtration integrity.

2. Scope

This SOP applies to all visual clarity checks carried out during intermediate and final filtration steps in API manufacturing processes.

3. Responsibilities

• Production Chemist: Collect samples for clarity testing and perform initial visual observation.
• QC Analyst: Review and document results of clarity observations and initiate re-filtration if required.
• QA Officer: Approve clarity test reports and verify documentation accuracy.

4. Accountability

The Production Head is accountable for implementing clarity checks. QA Head is responsible for ensuring compliance and traceability of the filtration monitoring process.

5. Procedure

5.1 Sampling

1. Collect ~50 mL of filtrate sample in a clean, transparent glass beaker or vial immediately after filtration.
2. Ensure the sample is free from any contamination introduced during collection.

5.2 Visual Clarity Observation

1. Place the beaker against a white and black background under adequate illumination (minimum 1000 lux).
2. Observe for any visible particulate matter, turbidity, or haziness.
3. If necessary, use a flashlight at a 45-degree angle to enhance visibility of suspended matter.
4. Compare sample with a standard blank (solvent or clean filtered water) for reference.

5.3 Acceptance Criteria

1. The filtrate must appear clear and free from any suspended particles or haziness.
2. In case of visible particles:
   • Repeat filtration using the same or finer filter media.
   • Record deviation and escalate to QA if multiple occurrences are noted.

5.4 Documentation

1. Record clarity test results in the Filtrate Clarity Logbook (Annexure-1).
2. Include:
   • Date and time of test
   • Batch number
   • Filtration stage
   • Observation (Clear / Hazy / Particulate matter)
   • Initials of observer
3. Attach photographic evidence if required by QA or SOP deviation process.

6. Abbreviations

• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record

7. Documents

1. Filtrate Clarity Logbook (Annexure-1)
2. Batch Manufacturing Record
3. Deviation Form (if applicable)

8. References

• ICH Q7 – Good Manufacturing Practice for APIs
• 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: Filtrate Clarity Logbook

Revision History:

Standard Operating Procedure for IPC Sample Retention Procedure in API Manufacturing

1. Purpose

To define the procedure for the collection, labeling, handling, storage, and retention of In-Process Control (IPC) samples taken during API manufacturing to ensure traceability and availability for re-testing or investigation, if required.

2. Scope

This SOP applies to all IPC samples collected during different manufacturing stages of Active Pharmaceutical Ingredients (APIs), including reaction, isolation, drying, milling, and blending.

3. Responsibilities

• Production Chemist: Collect IPC samples as per the sampling plan and transfer them with appropriate labeling.
• QC Analyst: Verify labeling, store samples under defined conditions, and maintain sample retention records.
• QA Officer: Review retention compliance and initiate disposal approval post-retention period.

4. Accountability

Production and QC Heads are accountable for sample integrity, and the QA Head is accountable for procedural compliance and record maintenance.

5. Procedure

5.1 Collection of IPC Samples

1. IPC samples shall be collected from designated sampling points as mentioned in the MFR/BMR.
2. Use cleaned and labeled containers suitable for the sample type (e.g., glass or polypropylene).
3. Each sample must be representative and collected using sanitized tools.

5.2 Labeling of IPC Samples

1. Label each IPC sample with:
   • Product Name
   • Batch Number
   • Stage (e.g., post-reaction, drying)
   • Date and Time of Sampling
   • Sampled By

5.3 Sample Transfer and Logging

1. Transfer samples to QC in a closed tray or container.
2. Enter sample details in the IPC Sample Retention Logbook (Annexure-1).

5.4 Retention Conditions

1. Store IPC samples in a designated cabinet or chamber in the QC area, labeled as “IPC Retention Area.”
2. Maintain storage conditions as per product requirements (e.g., 25°C ± 2°C / 60% RH ± 5%).
3. Ensure proper segregation from raw material and finished product samples.

5.5 Retention Period

1. Retain IPC samples until batch release and a minimum of 30 days thereafter.
2. In case of batch failure or investigation, retain until disposition or closure.
3. Post-retention, discard samples as per SOP for Sample Disposal with QA approval.

5.6 Handling Deviations

1. Any missing, mislabelled, or degraded samples must be reported to QA immediately.
2. Document deviation using the Deviation Report form and investigate root cause.

6. Abbreviations

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

7. Documents

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

8. References

• ICH Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• 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 Sample Retention Logbook

Revision History:

Standard Operating Procedure for Sampling of Toxic and Potent Compounds in API Manufacturing

1. Purpose

To define a safe, controlled, and GMP-compliant procedure for the sampling of highly potent and/or toxic compounds during API manufacturing using containment equipment and appropriate personal protective equipment (PPE).

2. Scope

This SOP applies to production and QC personnel involved in the sampling of toxic, hazardous, or highly potent materials classified as Category 3 and above (OEB 3, OEB 4, etc.) during raw material receiving, in-process checks, or final sampling in API manufacturing.

3. Responsibilities

• Production Chemist: Execute sampling procedure using defined safety controls.
• QC Analyst: Label, receive, and analyze the samples; review safety data before handling.
• QA Officer: Ensure compliance with PPE protocols, training records, and approve sampling documentation.

4. Accountability

The Production Head is accountable for implementation of the procedure. EHS and QA Heads are jointly accountable for ensuring containment practices and regulatory compliance.

5. Procedure

5.1 Pre-Sampling Preparation

1. Ensure approved Safety Data Sheet (SDS) and classification documents are available for the compound.
2. Check that personnel involved are trained in handling potent and toxic substances and certified for respirator use (if applicable).
3. Verify availability of PPE: full-body suit, nitrile gloves (double), chemical splash goggles, and PAPR (Powered Air Purifying Respirator) or suitable respirator.
4. Ensure the use of:
   • Dispensing booth or isolator (negative pressure)
   • HEPA-filtered exhaust system
   • Antistatic tools and approved sampling scoop

5.2 Sampling Steps

1. Sanitize gloves, isolator port, and sampling tools with 70% IPA before starting.
2. Verify container label, batch number, and material identity before opening.
3. Open container inside the containment system without direct exposure.
4. Using a pre-cleaned sampling device, withdraw the required sample quantity (as per protocol or specification) and transfer to a labeled container.
5. Securely close both primary and secondary containers.
6. Remove the sample through a pass box or transfer hatch using decontamination procedure.

5.3 Sample Labeling and Transfer

1. Label the sample container with:
   • Product/Material Name
   • Batch No.
   • Sampling Date
   • Sampled By
   • Hazard Class (Toxic/Potent)
2. Deliver sample to QC under secure, double-contained conditions.
3. Avoid hand-carrying; use dedicated trolleys with containment enclosures.

5.4 Decontamination and Waste Disposal

1. Wipe down all surfaces using detergent followed by 70% IPA.
2. Dispose of used PPE in red-labeled biohazard bags or designated incineration containers.
3. Log decontamination activity in the cleaning register (Annexure-2).

5.5 Documentation

1. Record sampling event in the Toxic Compound Sampling Log (Annexure-1).
2. Attach a photocopy of the sample label and QA approval slip to the Batch Manufacturing Record (BMR).

6. Abbreviations

• SOP: Standard Operating Procedure
• PPE: Personal Protective Equipment
• QA: Quality Assurance
• QC: Quality Control
• SDS: Safety Data Sheet
• PAPR: Powered Air Purifying Respirator
• BMR: Batch Manufacturing Record

7. Documents

1. Toxic Compound Sampling Log (Annexure-1)
2. Decontamination Record (Annexure-2)
3. Batch Manufacturing Record

8. References

• ICH Q7 – GMP for APIs
• OSHA 1910.1200 – Hazard Communication
• 21 CFR Part 211 – US FDA GMP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Toxic Compound Sampling Log

Annexure-2: Decontamination Record

Revision History:

Standard Operating Procedure for Visual Inspection of Semi-Solid Intermediates in API Manufacturing

1. Purpose

To define the standard procedure for performing visual inspection of semi-solid intermediates during API manufacturing for monitoring appearance, color, uniformity, and identification of foreign particles or physical non-conformities.

2. Scope

This SOP applies to semi-solid intermediates such as wet cake, slurry, or partially dried mass generated during the synthesis and isolation stages of API production.

3. Responsibilities

• Production Chemist: Perform routine visual inspections during each processing stage and record observations.
• QC Analyst: Assist in confirming and documenting any abnormalities detected during inspection.
• QA Officer: Review records and approve or reject batches based on inspection findings and risk assessment.

4. Accountability

Production Head is accountable for conducting inspections. QA Head is accountable for reviewing outcomes and ensuring GMP compliance.

5. Procedure

5.1 Inspection Conditions

1. Perform inspection under good illumination (minimum 1000 lux) and neutral background (preferably white or grey).
2. Wear gloves, mask, and protective garments to avoid contamination.
3. Use a clean stainless-steel spatula to collect a small quantity of the intermediate into a glass or SS dish for evaluation.

5.2 Visual Parameters

1. Observe and record the following parameters:
   • Color: Compare with expected color range mentioned in the BMR or MFR.
   • Consistency: Evaluate whether the intermediate is homogenous, lumpy, granular, pasty, or oily.
   • Phase Separation: Check for any liquid phase settling in slurry or semi-solid form.
   • Foreign Matter: Inspect for presence of fibers, dust, glass, rubber particles, metal fragments, or black spots.
   • Odor (if applicable): Smell should be characteristic and within acceptable threshold.

5.3 Acceptance Criteria

1. Color, consistency, and odor should match with standard batch or MFR description.
2. No visible foreign particles should be present. If found, segregate sample and escalate for investigation.
3. If inconsistencies are observed in uniformity, perform mixing or homogenization and reinspect.

5.4 Documentation

1. Record findings in the Visual Inspection Logbook (Annexure-1) with date, batch number, stage, and initials.
2. Affix photograph (if required by protocol or investigation).
3. For deviations, initiate deviation form and seek QA decision before further processing.

6. Abbreviations

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

7. Documents

1. Visual Inspection Logbook (Annexure-1)
2. Batch Manufacturing Record
3. Deviation Form (if required)

8. References

• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• 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: Visual Inspection Logbook

Revision History:

Standard Operating Procedure for Intermediate Moisture Check using IR Balance in API Manufacturing

1. Purpose

To define a standardized procedure for conducting moisture content analysis of intermediate materials using an infrared (IR) moisture balance during the manufacturing of Active Pharmaceutical Ingredients (APIs).

2. Scope

This SOP applies to all in-process intermediate stages in API manufacturing where moisture content needs to be evaluated rapidly and accurately using an IR balance for drying decision-making and process control.

3. Responsibilities

• Production Chemist: Collect and test intermediate samples using the IR balance.
• QC Analyst: Verify moisture values and ensure proper calibration and use of the instrument.
• QA Officer: Review moisture records and ensure compliance with GMP documentation requirements.

4. Accountability

Production Head is accountable for performing timely and accurate moisture checks. QC Head is accountable for calibration compliance. QA Head ensures adherence to documentation and review requirements.

5. Procedure

5.1 Instrument Verification

1. Ensure IR moisture balance is clean, calibrated, and powered ON.
2. Verify calibration status from the Calibration Sticker and Calibration Certificate.
3. Warm up the instrument for 15 minutes if starting from OFF state.

5.2 Sample Collection

1. Collect ~2–3 g of intermediate sample from the drying, filtration, or crystallization stage using a clean spatula.
2. Avoid exposure to ambient moisture; sample must be immediately transferred to the balance pan.
3. Record batch number, sampling location, time, and initials on the IR Moisture Log (Annexure-1).

5.3 Moisture Check Procedure

1. Open the IR moisture balance lid and tare the pan.
2. Evenly spread the sample across the pan to ensure uniform drying.
3. Close the lid and set the parameters:
   • Drying temperature: as per method or 105°C default
   • Drying time: Auto or Manual stop after 10–15 minutes
4. Start the test and observe drying curve or live result.
5. Once stable, record the % Moisture (Loss on Drying).

5.4 Acceptance Criteria and Interpretation

1. Compare result with intermediate moisture specification (e.g., NMT 1.5%).
2. If within limit, continue with downstream processing.
3. If not, continue drying and retest after suitable interval.
4. Record decision in BMR and obtain QA concurrence if deviation is observed.

5.5 Cleaning and Shutdown

1. Clean the pan and surrounding area using lint-free tissue and soft brush.
2. Do not use wet cloth inside the chamber.
3. Close the lid and switch off the instrument after use.

6. Abbreviations

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

7. Documents

1. IR Moisture Balance Logbook (Annexure-1)
2. Batch Manufacturing Record
3. Instrument Calibration Certificate

8. References

• ICH Q7 – GMP for APIs
• USP <731> – Loss on Drying
• 21 CFR Part 211 – US FDA GMP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IR Moisture Balance Logbook

Revision History:

Standard Operating Procedure for Testing of Reaction Completion by TLC in API Manufacturing

1. Purpose

To establish a standardized procedure for the use of Thin Layer Chromatography (TLC) in determining the completion of chemical reactions during the manufacturing of Active Pharmaceutical Ingredients (APIs).

2. Scope

This SOP applies to all production and quality control personnel performing TLC as an in-process control method to evaluate the endpoint of chemical reactions during API synthesis.

3. Responsibilities

• Production Chemist: Collect reaction samples and perform TLC as per method.
• QC Analyst: Confirm TLC results when required and provide training/support for method development.
• QA Officer: Review TLC data and ensure compliance with documentation practices.

4. Accountability

Production Head is accountable for proper sampling and testing during the reaction. QC Head is responsible for method compliance and training. QA Head ensures overall adherence to GMP standards.

5. Procedure

5.1 Preparation

1. Use pre-coated silica gel TLC plates (e.g., silica gel 60 F254).
2. Ensure proper availability of standard/reference compound and suitable solvent system (mobile phase) as defined in the method.
3. Use capillaries or micropipettes for sample spotting.

5.2 Sampling for TLC

1. Draw ~1 mL of the reaction mixture using a clean pipette or glass rod.
2. Quench if necessary (e.g., by adding ice or diluent) to stop the reaction before spotting.
3. Prepare two spots:
   • Standard/reference compound (starting material or desired product)
   • Reaction mixture

5.3 TLC Procedure

1. Mark a baseline (~1 cm from bottom edge of the plate).
2. Spot ~1–2 μL of sample and standard using a capillary tube.
3. Develop the plate in a TLC chamber pre-saturated with mobile phase.
4. Allow solvent front to migrate ~2/3 of the plate.
5. Remove the plate and mark the solvent front immediately.
6. Dry the plate and visualize under UV light (254 nm) or by spraying with iodine, ninhydrin, or appropriate visualizing agent.

5.4 Interpretation

1. Compare the R_f values of the sample and reference spots.
2. Absence of starting material or presence of single spot corresponding to the desired product indicates reaction completion.
3. If starting material is still visible, continue reaction and repeat test after a defined interval (e.g., 30 minutes).

5.5 Documentation

1. Paste the developed TLC plate in the Batch Manufacturing Record (BMR) or retain a photo copy if the plate is used for multiple batches.
2. Record the following in the TLC Observation Log (Annexure-1):
   • Date and Time
   • Batch No.
   • Reaction Stage
   • Solvent System
   • Result (Completed/Incomplete)
   • Initials

5.6 Precautions

1. Use fresh solvents and standard materials.
2. Avoid touching the silica surface with fingers.
3. Ensure uniform spot size for reproducibility.

6. Abbreviations

• TLC: Thin Layer Chromatography
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record
• Rf: Retention Factor

7. Documents

1. TLC Observation Log (Annexure-1)
2. Batch Manufacturing Record
3. Reaction Monitoring Checklist

8. References

• ICH Q7 – GMP for APIs
• USP General Chapter <1058> Analytical Instrument Qualification
• 21 CFR Part 211 – US FDA GMP

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: TLC Observation Log

Revision History:

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: