Standard Operating Procedure for IPC Sign-Off on Batch Manufacturing Record in API Manufacturing

1. Purpose

To define the procedure for proper sign-off of In-Process Control (IPC) checks on the Batch Manufacturing Record (BMR) during API manufacturing. This ensures that all IPC parameters are verified, reviewed, and documented in compliance with cGMP.

2. Scope

This SOP applies to all batches of Active Pharmaceutical Ingredients (API) manufactured at the facility and includes IPC documentation across all processing stages such as charging, reaction, filtration, drying, milling, and blending.

3. Responsibilities

• Production Chemist: Record IPC data in the BMR in real-time and submit for QA review after each stage.
• QC Analyst: Review test results for accuracy and provide required input into the BMR.
• QA Officer: Verify IPC entries, sign-off the results, and ensure all critical checks are documented before stage clearance.

4. Accountability

The QA Head is accountable for ensuring the BMR is reviewed and signed for completeness and accuracy. The Production Head is responsible for maintaining BMR integrity throughout the manufacturing process.

5. Procedure

5.1 IPC Documentation in BMR

1. All IPC parameters performed at each critical stage (e.g., pH, LOD, appearance, yield) must be recorded in the designated BMR section by the production chemist.
2. Data must be:
   • Entered in real-time
   • Written in blue or black ink (non-erasable)
   • Initialed with date and time of record

5.2 QA Sign-Off Procedure

1. Upon completion of IPC testing at a stage:
   • Production shall submit the filled IPC section of BMR to QA.
   • QA Officer shall verify:
     • Completeness of entries
     • Legibility
     • Compliance with acceptance criteria
   • If compliant, QA will:
     • Write “Reviewed” or “Verified” in the remarks column
     • Sign, date, and mention designation in the corresponding row

5.3 Handling Missing or Incorrect Data

1. If any IPC result is missing or incorrectly documented:
   • QA shall hold the BMR and raise an on-the-spot discrepancy
   • Production shall investigate and record the reason using the IPC Data Correction Form (Annexure-1)
   • Correction must follow ALCOA+ principles

5.4 BMR Completion and Handover

1. Upon completion of the entire manufacturing process:
   • QA shall cross-check that all IPC sections have been signed-off and verified.
   • QA shall ensure no open fields, no missing initial/date, and all deviations are referenced and closed.
   • BMR shall then be handed over for QA archival.

6. Abbreviations

• BMR: Batch Manufacturing Record
• IPC: In-Process Control
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• ALCOA+: Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available

7. Documents

1. Batch Manufacturing Record (BMR)
2. IPC Data Correction Form (Annexure-1)
3. QA Review Checklist (Annexure-2)

8. References

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

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Data Correction Form

Annexure-2: QA Review Checklist

Revision History:

Standard Operating Procedure for Handling Discrepant IPC Observations in API Manufacturing

1. Purpose

To establish a procedure for managing discrepancies observed in IPC (In-Process Control) data during API manufacturing, including unusual, inconsistent, or unexpected results, ensuring timely identification, investigation, correction, and documentation as per cGMP.

2. Scope

This SOP applies to all IPC parameters monitored during the production of APIs and intermediates, where observed results deviate from expected trends or show inconsistencies due to operator error, equipment fault, or sampling issues.

3. Responsibilities

• Production Chemist: Immediately report any discrepant observation to QA and document the initial finding in the IPC sheet.
• QC Analyst: Assist in confirmation and repeat testing (if justified), and provide analytical insight.
• QA Officer: Initiate deviation process, perform investigation, and ensure resolution of discrepancy.

4. Accountability

The QA Head is accountable for the review, classification, and closure of discrepant IPC observations. The Production Head is accountable for ensuring timely notification and execution of corrective actions.

5. Procedure

5.1 Identification of Discrepant Observation

1. A discrepant observation is defined as:
   • Sudden variation in result from previous trend
   • Fluctuating readings within a short interval
   • Unusually high/low readings despite correct process settings
   • Observation not matching batch behavior (e.g., visual, pH, temperature)
2. On identification, halt further processing of the affected stage until QA is notified and assessment is performed.

5.2 Immediate Actions

1. Document the discrepancy in the IPC logbook with:
   • Date and time
   • Parameter and equipment used
   • Observation details
   • Operator signature
2. Notify the QA team and shift supervisor immediately.
3. Place equipment “On Hold” if malfunction is suspected.

5.3 Investigation and Classification

1. QA will initiate deviation as per SOP/API/115/2025 and conduct a root cause analysis (RCA).
2. Determine potential causes:
   • Sampling error
   • Instrument calibration or functionality error
   • Environmental influence
   • Operator error
3. Classify the discrepancy as:
   • Minor (no impact on product quality)
   • Major (requires CAPA, may affect next stage)
   • Critical (impact on product quality or safety)

5.4 Retesting Criteria

1. Retesting shall be permitted only if:
   • There is clear evidence of error in sampling or instrument use
   • QA has approved the justification for retesting
   • Retesting is documented in Deviation Form and IPC Sheet

5.5 Corrective Action

1. Implement appropriate action based on investigation outcome, such as:
   • Retraining of staff
   • Repair or recalibration of equipment
   • Procedure revision
   • Process adjustment (if deviation is accepted with impact evaluation)
2. Record action taken in Deviation Report and obtain QA approval for closure.

6. Abbreviations

• IPC: In-Process Control
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• RCA: Root Cause Analysis
• CAPA: Corrective and Preventive Action

7. Documents

1. Discrepant IPC Observation Report (Annexure-1)
2. Deviation Register
3. IPC Logbook

8. References

• ICH Q10 – Pharmaceutical Quality System
• 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: Discrepant IPC Observation Report

Revision History:

Standard Operating Procedure for Reporting Deviations in IPC Parameters in API Manufacturing

1. Purpose

To outline the procedure for identifying, documenting, evaluating, and reporting deviations in In-Process Control (IPC) parameters observed during API manufacturing, ensuring appropriate actions are taken to prevent recurrence and maintain compliance with cGMP requirements.

2. Scope

This SOP is applicable to all IPC parameters monitored during API manufacturing at each process stage, including but not limited to pH, temperature, LOD, reaction time, and assay values. It includes initial detection, documentation, investigation, and resolution.

3. Responsibilities

• Production Chemist: Immediately report any deviation in IPC parameters, document initial observations, and stop further processing if required.
• QC Analyst: Verify parameter results and assist in evaluation of deviation cause.
• QA Officer: Log the deviation, initiate investigation, ensure impact assessment, and recommend CAPA if needed.

4. Accountability

The QA Head is accountable for ensuring deviation reporting, tracking, closure, and trend analysis. The Production Head is accountable for initiating immediate action in the event of any IPC deviation.

5. Procedure

5.1 Identification of IPC Deviations

1. During IPC checks, if any parameter is found outside the established acceptance criteria:
   • Immediately stop further processing of the affected batch stage.
   • Mark the equipment status as “ON HOLD.”
2. Document the deviation in the batch manufacturing record and notify QA and the production supervisor without delay.

5.2 Documentation and Notification

1. Record the following in the IPC Deviation Reporting Form (Annexure-1):
   • Batch No., Stage, Date & Time
   • Parameter and Observed Value
   • Expected Range
   • Instrument used and person reporting
2. QA shall assign a deviation number and initiate preliminary assessment.

5.3 Investigation and Evaluation

1. QA along with production and QC shall:
   • Conduct a root cause analysis (RCA)
   • Determine whether the deviation is minor, major, or critical
   • Evaluate the impact on product quality and other batches, if applicable
2. QA shall document findings in the deviation section of the IPC logbook and update the Deviation Register.

5.4 Corrective and Preventive Action (CAPA)

1. If required, CAPA shall be initiated to:
   • Correct the current issue (corrective action)
   • Prevent recurrence in future batches (preventive action)
2. QA shall track CAPA implementation and assess effectiveness.
3. All CAPAs shall be recorded in the CAPA Log and linked with the deviation report.

5.5 Deviation Closure

1. QA shall ensure that:
   • All investigations are complete
   • Impact assessment is documented
   • CAPAs are implemented and verified
2. Deviation shall be closed formally in the Deviation Register, signed by QA Head.

5.6 Trending and Review

1. QA shall conduct monthly/quarterly review of IPC deviations to:
   • Identify recurrence patterns
   • Assess system gaps or training needs
   • Improve processes accordingly
2. Deviations trending report shall be shared during management reviews.

6. Abbreviations

• IPC: In-Process Control
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• RCA: Root Cause Analysis
• CAPA: Corrective and Preventive Action

7. Documents

1. IPC Deviation Reporting Form (Annexure-1)
2. Deviation Register
3. CAPA Log
4. BMR (Batch Manufacturing Record)

8. References

• ICH Q10 – Pharmaceutical Quality System
• 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 Deviation Reporting Form

Revision History:

Standard Operating Procedure for Sample Reconciliation Post IPC Testing in API Manufacturing

1. Purpose

To define a standardized procedure for reconciliation and documentation of In-Process Control (IPC) samples after testing is completed, ensuring traceability, proper handling of used samples, and compliance with cGMP requirements.

2. Scope

This SOP is applicable to all IPC samples collected and tested during various manufacturing stages of API production including solids, liquids, pastes, and intermediates at the facility.

3. Responsibilities

• QC Analyst: Perform sample reconciliation after IPC testing, document remaining quantity, and coordinate with QA for disposal.
• QA Officer: Verify reconciliation entries, approve final disposition of samples, and ensure retention or destruction as per policy.
• Production Chemist: Provide batch context and sampling log to assist reconciliation process.

4. Accountability

The QC Head is accountable for accurate documentation of IPC sample reconciliation. The QA Head is responsible for ensuring compliance and proper closure of sample usage logs.

5. Procedure

5.1 Sample Reconciliation Overview

1. All IPC samples collected for testing shall be labeled, logged, and stored securely in the designated IPC testing area.
2. After analysis, the remaining sample shall be reconciled and either:
   • Archived temporarily for investigation (if required)
   • Disposed of per waste management SOP

5.2 Documentation of Sample Usage

1. QC Analyst shall record the following in the IPC Sample Reconciliation Logbook (Annexure-1):
   • Date of sampling
   • Batch number
   • Initial sample quantity
   • Quantity used
   • Balance quantity
   • Disposition status
2. Any sample remaining after testing shall be labeled “Used IPC Sample – For Disposal” or “Retain for Investigation.”

5.3 Review and Verification

1. QA Officer shall:
   • Verify reconciliation data with original sample label and testing record
   • Check for consistency in quantity and status of each sample
   • Sign-off in the reconciliation logbook with comments
2. Discrepancies in quantity used, sample not found, or unlabeled vials must be documented as a deviation.

5.4 Sample Disposal

1. Destruction of used samples shall follow SOP/API/106/2025 for IPC sample disposal.
2. Record the destruction date and QA approval in the IPC Destruction Log (cross-referenced to reconciliation log).

5.5 Retention Samples

1. If IPC samples are to be retained for investigation or trending:
   • Store them in a segregated labeled container within QC lab
   • Label must indicate retention reason, retention period, and QA authorization
2. QA shall track and authorize final disposal of retained samples once no longer required.

6. Abbreviations

• IPC: In-Process Control
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• cGMP: Current Good Manufacturing Practice

7. Documents

1. IPC Sample Reconciliation Logbook (Annexure-1)
2. IPC Sample Destruction Log
3. Deviation Form (if applicable)

8. References

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

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Sample Reconciliation Logbook

Revision History:

Standard Operating Procedure for Verification of IPC Equipment Status in API Manufacturing

1. Purpose

To establish a systematic procedure for verifying the operational status, calibration, and cleanliness of IPC (In-Process Control) equipment used during API manufacturing, ensuring consistent and reliable results in compliance with cGMP guidelines.

2. Scope

This SOP applies to all IPC equipment such as pH meters, conductivity meters, thermometers, LOD balances, and TLC kits used within production areas for routine in-process checks of API batches.

3. Responsibilities

• Production Chemist: Check and record the equipment status before each use, escalate abnormalities to QA.
• QA Officer: Verify log entries, conduct random checks, and ensure compliance with calibration schedules.
• Engineering/Maintenance: Perform preventive maintenance and address reported malfunctions.

4. Accountability

The Production Head is accountable for ensuring that IPC equipment is verified before use. The QA Head is responsible for ensuring compliance and documentation as per SOP.

5. Procedure

5.1 List of IPC Equipment Requiring Verification

1. Digital/Handheld pH Meters
2. Conductivity Meters
3. Thermometers/Temperature Indicators
4. LOD Balances
5. Refractometers
6. TLC Kits/Plates and Visualization Lamps

5.2 Pre-Use Verification Steps

1. Check for Calibration Status:
   • Verify last calibration date and due date on equipment label.
   • Do not use equipment if calibration is overdue—report immediately to QA.
2. Check for Cleanliness and Physical Condition:
   • Inspect equipment for visible residues, dust, cracks, or damages.
   • Clean surfaces with lint-free cloth or as per equipment-specific SOPs.
3. Check for Functionality:
   • Power on the device and perform a self-check (if applicable).
   • Measure a standard solution (e.g., pH 7 buffer or 1413 µS/cm conductivity standard) to verify performance.
4. Record status in the IPC Equipment Verification Logbook (Annexure-1) before use.

5.3 During-Use Monitoring

1. Observe equipment response and performance during measurement.
2. Any drift, error message, or erratic readings must be reported and equipment taken out of service.
3. Replace or troubleshoot the unit as per maintenance SOPs before reuse.

5.4 Post-Use Practices

1. Switch off and clean the equipment immediately after use.
2. Place it back in the designated storage cabinet or dry area with proper labeling.

5.5 Deviation Handling

1. In case of:
   • Uncalibrated equipment use
   • Malfunctioning equipment
   • Unrecorded verification

   raise a deviation report and assess impact on process data with QA.

6. Abbreviations

• SOP: Standard Operating Procedure
• IPC: In-Process Control
• QA: Quality Assurance
• LOD: Loss on Drying
• cGMP: Current Good Manufacturing Practices

7. Documents

1. IPC Equipment Verification Logbook (Annexure-1)
2. Deviation Form (if applicable)
3. Calibration Certificate

8. References

• ICH Q7 – GMP Guidelines for API
• 21 CFR Part 211 – US FDA cGMP
• WHO TRS 986 – Annex 2

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Equipment Verification Logbook

Revision History:

Standard Operating Procedure for Stage-Wise Approval of API Manufacturing

1. Purpose

To define the procedure for obtaining stage-wise approvals during the manufacturing of Active Pharmaceutical Ingredients (APIs), ensuring product quality, process consistency, and regulatory compliance at each critical process step.

2. Scope

This SOP applies to all manufacturing batches of APIs produced at the facility and covers approval checkpoints including raw material charging, reaction monitoring, filtration, drying, milling, blending, and final product release stages.

3. Responsibilities

• Production Chemist: Notify QA at each critical manufacturing stage, provide necessary records, and await approval before proceeding.
• QA Officer: Review IPC results, perform visual inspections, verify logbook entries, and grant written stage-wise clearance.
• QC Analyst: Perform and release IPC test results required for each stage approval.

4. Accountability

The Production Head is accountable for implementing stage-wise controls. The QA Head is responsible for verifying process compliance before approving any manufacturing progression.

5. Procedure

5.1 Identified Manufacturing Stages for Approval

1. Pre-Reaction: Raw material verification and charging
2. Reaction Completion: pH, temperature, TLC results
3. Post-Reaction Work-up: Phase separation confirmation
4. Filtration: Filtrate clarity and wet cake inspection
5. Drying: Moisture content (LOD)
6. Milling and Sieving: Particle size distribution check
7. Final Blending: Uniformity and identification

5.2 Stage-Wise Approval Process

1. At each critical stage, Production shall inform QA in writing using the Stage Clearance Request Form (Annexure-1).
2. QA shall:
   • Verify compliance with BMR entries
   • Review IPC results from QC
   • Check equipment cleanliness and line clearance
   • Confirm environmental conditions (if applicable)
3. Once verified, QA shall record the decision in the Stage Approval Log (Annexure-2) and sign off the BMR page.
4. Only after written clearance, the next step in manufacturing shall be initiated.

5.3 Documentation

1. Each stage approval must include:
   • Stage description
   • Date and Time
   • Batch No.
   • Verification criteria
   • Signature of QA reviewer
2. In case of hold or rejection at any stage, deviation must be recorded, and batch must not proceed until resolution.

5.4 Re-Approval (If Required)

1. If a process deviation or batch hold is resolved:
   • QA shall reassess the stage parameters, IPC, and process justification.
   • Once acceptable, re-approval will be documented with revised date and remarks.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• BMR: Batch Manufacturing Record
• IPC: In-Process Control

7. Documents

1. Stage Clearance Request Form (Annexure-1)
2. Stage Approval Logbook (Annexure-2)
3. Batch Manufacturing Record (BMR)

8. References

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

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Stage Clearance Request Form

Annexure-2: Stage Approval Logbook

Revision History:

Standard Operating Procedure for Trending of IPC Results and Deviations in API Manufacturing

1. Purpose

To define a standardized procedure for trending In-Process Control (IPC) test results and related deviations in API manufacturing to monitor process stability, detect patterns, and facilitate continual improvement and CAPA (Corrective and Preventive Action) implementation.

2. Scope

This SOP applies to all IPC results generated during batch processing of APIs and intermediates, and any documented deviations identified at various manufacturing stages, covering parameters like pH, LOD, assay, yield, and temperature control.

3. Responsibilities

• QA Officer: Compile IPC data monthly, perform trend analysis, identify outliers or emerging trends, and generate reports.
• QC Analyst: Submit IPC data in standardized format; support analysis with raw data when required.
• Production Supervisor: Provide context for trends/deviations observed and assist in root cause analysis.

4. Accountability

The QA Head is accountable for ensuring data trending is conducted as per this SOP and that significant findings are escalated for appropriate action.

5. Procedure

5.1 IPC Data Compilation

1. QA shall collect IPC results from all batches completed during the review period (monthly/quarterly).
2. Parameters to be trended include but are not limited to:
   • pH
   • Loss on Drying (LOD)
   • Reaction Completion Time
   • Process Yield
   • Drying Temperature
3. Enter the data in the IPC Trending Template (Annexure-1) in a spreadsheet or validated software system.

5.2 Trending Methodology

1. Calculate the following for each parameter:
   • Mean
   • Standard Deviation (SD)
   • Control Limits (±3 SD)
   • Specification Limits (as per MFR/QC Specs)
2. Use line charts or control charts to visually represent data trends batch-wise.
3. Highlight any values falling outside alert or action limits.

5.3 Analysis of Deviations

1. Review all IPC-related deviations during the review period from the Deviation Register.
2. Categorize deviations as:
   • Out-of-Specification (OOS)
   • Out-of-Trend (OOT)
   • Operational Deviations
3. Summarize the deviation frequency and common root causes in the IPC Trend Report (Annexure-2).

5.4 Corrective and Preventive Action (CAPA)

1. If repetitive deviations or negative trends are observed:
   • Initiate CAPA as per the Quality System
   • Assign timeline, responsible personnel, and verification method
2. QA shall track implementation and effectiveness review of CAPA within 30 days.

5.5 Reporting and Escalation

1. QA shall issue a monthly or quarterly IPC Trending Report summarizing:
   • Summary of parameter trends
   • Deviations identified
   • CAPAs initiated
   • Recommendations (if any)
2. Share the report with Production, QC, and Management for review and follow-up.

6. Abbreviations

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

7. Documents

1. IPC Trending Template (Annexure-1)
2. IPC Trend Summary Report (Annexure-2)
3. Deviation Register

8. References

• ICH Q10 – Pharmaceutical Quality System
• ICH Q9 – Quality Risk Management
• WHO TRS 986 – GMP Guidelines
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Trending Template

Annexure-2: IPC Trend Summary Report

Revision History:

Standard Operating Procedure for Documentation Review of IPC Checks in API Manufacturing

1. Purpose

To establish a standardized procedure for reviewing and verifying the documentation of In-Process Control (IPC) checks recorded during API manufacturing, ensuring data accuracy, compliance with cGMP, and traceability for quality assurance and audits.

2. Scope

This SOP applies to all IPC documentation including but not limited to logbooks, Batch Manufacturing Records (BMRs), and supplementary analytical reports generated during each stage of API manufacturing.

3. Responsibilities

• QA Officer: Review and cross-check IPC records for completeness and accuracy, ensure that deviations are documented and resolved.
• Production Supervisor: Ensure proper documentation during batch execution and support QA in answering any queries related to IPC data.
• QC Analyst: Provide supporting analytical data and confirmation of IPC test results as required during the review process.

4. Accountability

The QA Head is accountable for the overall documentation review process, while the Production Head is responsible for ensuring that accurate IPC data is captured during operations.

5. Procedure

5.1 Review Process Initiation

1. At the end of each shift or process batch, the designated QA Officer collects all IPC documentation including logbooks, BMR sections, and electronic records.
2. The QA Officer confirms the presence of required data fields such as:
   • Date and time of entry
   • Batch number
   • Process stage and parameter measured
   • Observed results against acceptance criteria
   • Signatures/initials of responsible personnel
3. Any missing or illegible entries must be immediately reported to the Production Supervisor for immediate rectification.

5.2 Cross-Verification and Accuracy Check

1. Compare the recorded IPC data with corresponding analytical reports (e.g., pH meter readings, LOD test results, or yield calculations) for consistency.
2. If discrepancies or deviations are identified:
   • Document the discrepancy in the IPC Verification Observation Form (Annexure-1).
   • Notify the Production Supervisor and QC Analyst for further clarification and corrective action.
3. Verify that all corrections in the logbooks have been made following good documentation practices:
   • Striking through errors, with initials and date of correction

5.3 Documentation and Reporting

1. The QA Officer compiles a summary report at the end of the batch review period (e.g., daily or per batch) including:
   • Summary of IPC data reviewed
   • Any deviations or outliers identified
   • Actions taken to resolve discrepancies
2. Attach copies of all reviewed records and any deviation forms to the Batch Manufacturing Record (BMR).
3. Maintain electronic or hard copy archives as per the Document Control SOP for a minimum retention period of 5 years.

5.4 Deviations and CAPA

1. If significant discrepancies are found that may impact product quality or compliance:
   • Initiate a formal deviation or CAPA (Corrective and Preventive Action) request.
   • Ensure that a root cause analysis is performed and documented.
   • Implement corrective measures and verify through a re-review of IPC records.
2. Document the resolution and update the IPC Verification Observation Form with final QA sign-off.

5.5 Periodic Quality Audits

1. QA shall perform periodic audits of IPC records to ensure consistent adherence to the SOP and GMP requirements.
2. Audit findings should be documented and communicated to relevant departments with recommendations for improvement.

6. Abbreviations

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

7. Documents

1. IPC Verification Observation Form (Annexure-1)
2. Batch Manufacturing Record (BMR)
3. Electronic / Hard Copy Archives of IPC Data

8. References

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

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Verification Observation Form

Standard Operating Procedure for Use of Handheld pH/Conductivity Meters in API Manufacturing

1. Purpose

To establish a standardized method for using handheld pH and conductivity meters to perform in-process checks during API manufacturing. This ensures consistency in monitoring critical quality attributes and compliance with GMP.

2. Scope

This SOP applies to all handheld pH and conductivity meters used by production and QC personnel for routine monitoring of process solutions, intermediate checks, and final rinse verification.

3. Responsibilities

• Production Chemist: Perform pH/conductivity measurements, record readings, clean and store equipment.
• QC Analyst: Provide calibration solutions and verify accuracy of instruments used by production.
• QA Officer: Review logbooks for accuracy and compliance with SOP requirements.

4. Accountability

The Production Head is accountable for ensuring correct use of handheld meters. The QA Head is responsible for compliance with GMP documentation and data integrity.

5. Procedure

5.1 Pre-Use Verification

1. Check calibration status on label. Do not use if expired or overdue for calibration.
2. Ensure meter and probe are free from visible damage or residue.
3. Switch on meter and allow to stabilize for 1–2 minutes before use.

5.2 Calibration (If Required)

1. Use certified standard buffer solutions (for pH) and standard conductivity solutions.
2. Perform two-point calibration for pH (e.g., pH 4.0 and 7.0) and one-point for conductivity.
3. Document calibration details in the Equipment Calibration Logbook.

5.3 Measurement Procedure

1. Rinse electrode/probe with distilled water or process solvent compatible with the sample.
2. Immerse the probe into the sample container or reaction mass, ensuring full contact.
3. Wait until the reading stabilizes. Do not record fluctuating values.
4. Record the measurement, temperature, and time in the IPC logbook or BMR.
5. Repeat readings if result deviates from expected trend or acceptance range.

5.4 Post-Use Cleaning

1. Rinse probe with distilled water or appropriate solvent.
2. Store pH electrode in storage solution (if applicable) to prevent drying.
3. Switch off meter and store in designated safe place to avoid contamination or breakage.

5.5 Troubleshooting

1. If readings are inconsistent or error appears:
   • Recalibrate using fresh standards
   • Inspect cable connections and battery status
   • Replace probe if needed and document replacement

5.6 Documentation

1. Record the following:
   • Date and Time of Measurement
   • Batch No.
   • Stage (e.g., neutralization, washing)
   • Measured pH or Conductivity
   • Operator Initials
2. Use the format provided in Annexure-1 for IPC entry.

6. Abbreviations

• SOP: Standard Operating Procedure
• QA: Quality Assurance
• QC: Quality Control
• pH: Potential of Hydrogen
• IPC: In-Process Control

7. Documents

1. Handheld Meter Usage Log (Annexure-1)
2. Equipment Calibration Logbook
3. BMR/IPC Data Sheets

8. References

• ICH Q7 – GMP Guidelines for API
• USP General Chapter <791> – pH
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Handheld Meter Usage Log

Revision History:

Standard Operating Procedure for Online Monitoring using PAT Tools in API Manufacturing

1. Purpose

To establish a standard procedure for the use of Process Analytical Technology (PAT) tools for real-time, online monitoring of critical process parameters and quality attributes during API manufacturing to ensure consistency, compliance, and process understanding.

2. Scope

This SOP applies to all API manufacturing operations where PAT tools such as NIR, Raman spectroscopy, UV-Vis, and IR sensors are deployed for online process monitoring and control.

3. Responsibilities

• Production Chemist: Operate PAT equipment, record real-time data, and escalate deviations.
• Process Development Scientist: Configure, calibrate, and validate PAT tools for specific processes.
• QA Officer: Review PAT-based monitoring records and ensure data integrity and compliance.
• Engineering Team: Ensure sensor and software systems are maintained, calibrated, and integrated.

4. Accountability

The Process Technology Manager is accountable for PAT deployment. The QA Head is responsible for procedural compliance and approval of monitoring records.

5. Procedure

5.1 Overview of PAT Tools

1. Common PAT tools in use include:
   • NIR Spectroscopy: For blend uniformity and moisture content.
   • Raman Spectroscopy: For reaction monitoring and identity confirmation.
   • UV-Vis: For analyte concentration during synthesis.
   • FTIR/IR: For real-time process endpoint detection.

5.2 Pre-Operation Checks

1. Verify calibration status of the PAT tool and associated software.
2. Check sensor probe integrity, cleanliness, and connectivity.
3. Ensure interface with SCADA/DCS or standalone system is functional.
4. Confirm process batch parameters are loaded and approved by QA.

5.3 Installation and Monitoring

1. Install sensor probes in designated reactor ports or process lines as per validation protocol.
2. Start data acquisition using the validated software platform (e.g., SynTQ, SIEMENS SIMATIC).
3. Monitor real-time parameters and trends displayed on screen:
   • Peak shifts (in NIR or Raman)
   • Absorbance levels
   • Moisture signature
4. Document critical events or signals as per Annexure-1 (PAT Monitoring Logbook).

5.4 Alarm and Out-of-Trend Handling

1. In case of deviation or out-of-trend signals:
   • Pause process if required.
   • Notify shift in-charge and QA immediately.
   • Initiate deviation form referencing PAT log and batch number.
2. Ensure all excursions are documented and investigated.

5.5 Data Storage and Security

1. All PAT data shall be stored on secure servers with restricted access.
2. Backups shall be created daily and retained for a minimum of 5 years.
3. Audit trails must be enabled and reviewed periodically by QA.

5.6 Post-Operation Tasks

1. Remove and clean sensor probes using lint-free cloth and solvent as per SOP.
2. Switch off hardware and software systems after completion.
3. Record process summary and parameters in batch manufacturing record and Annexure-1.

6. Abbreviations

• SOP: Standard Operating Procedure
• PAT: Process Analytical Technology
• NIR: Near Infrared
• QA: Quality Assurance
• DCS: Distributed Control System
• SCADA: Supervisory Control and Data Acquisition

7. Documents

1. PAT Monitoring Logbook (Annexure-1)
2. PAT Equipment Calibration Log
3. Deviation Form

8. References

• ICH Q8 – Pharmaceutical Development
• ICH Q9 – Quality Risk Management
• US FDA Guidance on PAT Framework
• WHO TRS 1019 Annex 3 – PAT in Pharmaceutical Manufacturing

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: PAT Monitoring Logbook

Revision History: