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:

Standard Operating Procedure for Sampling of Viscous and Sticky Materials in API Manufacturing

1. Purpose

To define a systematic procedure for the correct sampling of viscous and sticky materials in API manufacturing, ensuring representative samples are collected safely and accurately for IPC and quality testing.

2. Scope

This SOP applies to all stages of manufacturing where materials such as heavy syrups, thick pastes, gums, and tar-like residues require sampling during processing or after isolation.

3. Responsibilities

• Production Chemist: Ensure availability of clean, suitable sampling tools and containers.
• QC Analyst: Provide guidance on sample quantity and labeling requirements.
• QA Officer: Review sampling records and ensure compliance with sampling plan.

4. Accountability

The Production Head is accountable for ensuring samples are collected safely and in a representative manner. The QA Head is responsible for overall procedural compliance.

5. Procedure

5.1 Preparation for Sampling

1. Verify sampling requirement from the BMR or sampling plan.
2. Use tools such as:
   • PTFE or SS spatulas
   • Viscous material samplers (rod samplers or syringes with wide bore)
   • Pre-labeled HDPE or glass containers with wide mouths
3. Wear appropriate PPE: gloves, goggles, apron.
4. Ensure tools and containers are dry, clean, and inert to the material sampled.

5.2 Sampling Method

1. Stir the material if possible to obtain a uniform consistency before sampling.
2. Collect sample from at least three locations if material volume permits:
   • Top
   • Middle
   • Bottom
3. If the material is in a drum or wide vessel, insert rod sampler or scoop diagonally to capture layered sample.
4. For very sticky substances, lubricate sampler with small quantity of the same material to ease collection.
5. Transfer sample into labeled container using a spatula or low-friction scraper.
6. Seal the container immediately to avoid material sticking to lid threads.

5.3 Sample Labeling

1. Use IPC Sample Label (Annexure-1) indicating:
   • Sample Code
   • Batch Number
   • Date & Time of Sampling
   • Stage
   • Sampler Name
2. Attach label securely. Do not apply directly to wet or sticky surfaces.

5.4 Cleaning of Equipment

1. Clean sampling tools immediately using suitable solvent (e.g., IPA) or warm water if water-soluble.
2. Dry and inspect for residual material before next use.

5.5 Documentation

1. Record sampling in the IPC Sampling Logbook (Annexure-2) including:
   • Date and Time
   • Material Name and Batch No.
   • Quantity Sampled
   • Tool Used
   • Remarks
2. QC shall acknowledge receipt of sample and initiate testing within defined timeframe.

6. Abbreviations

• SOP: Standard Operating Procedure
• IPC: In-Process Control
• QC: Quality Control
• QA: Quality Assurance
• PPE: Personal Protective Equipment

7. Documents

1. IPC Sample Label (Annexure-1)
2. IPC Sampling Logbook (Annexure-2)

8. References

• ICH Q7 – GMP 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: IPC Sample Label

Annexure-2: IPC Sampling Logbook

Revision History:

Standard Operating Procedure for Destruction of Used IPC Samples in API Manufacturing

1. Purpose

To define the procedure for safe, compliant, and documented destruction of In-Process Control (IPC) samples after testing and analysis are complete, ensuring traceability and adherence to regulatory requirements.

2. Scope

This SOP applies to all IPC samples (solid, semi-solid, liquid) collected and tested during API manufacturing processes and retained temporarily within QC labs or IPC stations.

3. Responsibilities

• QC Analyst: Identify and segregate used IPC samples, initiate destruction procedure, and record entries.
• QA Officer: Review destruction records and approve the destruction log before disposal.
• Production Chemist: Provide traceability reference (batch number, stage, sample type) to QC as needed.

4. Accountability

The QC Head is accountable for execution of destruction, while the QA Head is responsible for approval and oversight of sample destruction in accordance with GMP practices.

5. Procedure

5.1 Identification of Used IPC Samples

1. Upon completion of testing, segregate samples marked as “Used” or “Tested” and ready for disposal.
2. Ensure samples are no longer required for re-analysis, investigation, or training purposes.
3. Check if hold samples or retention samples are separate and not impacted by the destruction batch.

5.2 Documentation Prior to Destruction

1. Record details of used samples in the IPC Sample Destruction Logbook (Annexure-1).
2. Each entry should include:
   • Batch Number
   • Stage of Sampling
   • Sample Quantity
   • Date of Destruction
   • Reason for Destruction
3. QA shall verify and sign off before physical disposal of the sample.

5.3 Destruction Methods

1. Use the following destruction methods based on sample type:
   • Solid and Powdered Samples: Mix with inert absorbent material and dispose in non-recoverable containers, marked as pharmaceutical waste.
   • Liquid Samples: Neutralize if reactive, absorb into disposal granules or dispose through waste solvent drain as per SOP.
   • Semi-solid Samples: Absorb using disposal tissue/pads and discard as per solid waste disposal SOP.
2. All destroyed samples must be rendered non-recoverable and unidentifiable.

5.4 Disposal Coordination

1. Disposed samples shall be transferred to the designated Waste Collection Area.
2. Coordinate with EHS (Environment, Health & Safety) team or disposal vendor (if applicable) as per waste disposal SOP.
3. Maintain records of batch disposal along with sample disposal forms, signed by QC and QA.

5.5 Special Situations

1. For samples associated with OOS or Deviations, retain them until the investigation is closed.
2. Destruction for such samples must be reviewed with QA and investigation number should be referenced.

6. Abbreviations

• SOP: Standard Operating Procedure
• IPC: In-Process Control
• QC: Quality Control
• QA: Quality Assurance
• OOS: Out of Specification
• EHS: Environment, Health & Safety

7. Documents

1. IPC Sample Destruction Logbook (Annexure-1)
2. Waste Disposal Record (As per Waste Management SOP)
3. Investigation Closure Summary (if applicable)

8. References

• ICH Q7 – GMP Guide for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – US FDA cGMP
• WHO TRS 986 – GMP Guidelines
• Company SOP on Waste Disposal

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Sample Destruction Logbook

Revision History:

Standard Operating Procedure for Process Hold Time and Sample Tracking in API Manufacturing

1. Purpose

To establish a standardized procedure for monitoring and controlling hold times for in-process materials during various stages of API manufacturing and to ensure traceable tracking of IPC and QC samples from collection to final disposition.

2. Scope

This SOP applies to all hold periods of intermediates, wet cake, dry powder, filtrates, and solutions before further processing, and to all IPC/QC samples drawn and submitted during batch manufacturing in the API facility.

3. Responsibilities

• Production Chemist: Record start and end of hold periods and collect samples as per schedule.
• QC Analyst: Receive and acknowledge samples, track test results, and report timelines.
• QA Officer: Review and approve hold time extensions, ensure hold times comply with validated limits.

4. Accountability

Production Head is accountable for in-process hold time control. QA Head is responsible for procedural compliance and timely oversight of sample tracking.

5. Procedure

5.1 Hold Time Definition

1. Hold time is defined as the duration between the completion of a process step and initiation of the next step.
2. Refer to the approved Master Formula Record (MFR) for allowable hold time limits per stage.

5.2 Types of Hold Times

1. Pre-filtration solution hold
2. Post-filtration (wet cake) hold
3. Crude drying hold
4. Intermediate hold during blending or sieving

5.3 Recording Hold Times

1. Enter the start time when process is stopped or paused.
2. Enter the end time when the next process resumes.
3. Record total duration and reason (if applicable) in Hold Time Log (Annexure-1).
4. If the hold exceeds approved limits, document deviation and QA shall evaluate product quality risk.

5.4 Sample Collection and Tracking

1. Collect IPC or QC samples as per the sampling plan or when hold extends beyond 25% of validated time.
2. Label each sample with unique Sample Code, Batch No., Date, Stage, and Sampler Initials (Annexure-2).
3. Submit sample to QC with completed Sample Forwarding Form (Annexure-3).
4. QC shall enter receipt in the Sample Receipt Log and assign test request reference.

5.5 Sample Status Updates

1. QC to update sample testing status in the tracking log within 2 hours of receipt.
2. Any delay must be informed to QA and Production immediately.
3. For samples under investigation or out-of-spec, QA shall initiate appropriate action.

5.6 Hold Time Extensions

1. In case of unavoidable delay:
   • Production must raise a Hold Time Extension Request
   • QA shall evaluate based on storage conditions, stage, and risk
   • Extension may be granted with justification and supported data
2. Record the extension in the deviation log and Hold Time Logbook.

6. Abbreviations

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

7. Documents

1. Hold Time Logbook (Annexure-1)
2. Sample Label Template (Annexure-2)
3. Sample Forwarding Form (Annexure-3)

8. References

• ICH Q7 – GMP Guide for Active Pharmaceutical Ingredients
• 21 CFR Part 211 – US FDA cGMP
• WHO TRS 986 – Annex 2 GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Hold Time Logbook

Annexure-2: Sample Label Template

Annexure-3: Sample Forwarding Form

Revision History:

Standard Operating Procedure for Use of Thermocouples in Process Monitoring in API Manufacturing

1. Purpose

To establish a standard procedure for the selection, placement, operation, and maintenance of thermocouples used to monitor temperature during critical process stages of API manufacturing.

2. Scope

This SOP is applicable to all thermocouple devices used in monitoring temperature during chemical reactions, crystallization, solvent recovery, and drying operations in the API manufacturing facility.

3. Responsibilities

• Production Chemist: Ensure correct placement and usage of thermocouples during batch processes.
• Engineering Department: Calibrate and maintain thermocouples according to schedule.
• QA Officer: Verify thermocouple calibration and compliance with GMP documentation requirements.

4. Accountability

The Engineering Head is accountable for maintenance and calibration. The Production Head is accountable for operational use, and the QA Head is responsible for ensuring regulatory compliance.

5. Procedure

5.1 Types of Thermocouples

1. Use Type K (Nickel-Chromium/Nickel-Alumel) or Type J thermocouples for general purpose temperature monitoring unless otherwise specified.
2. Thermocouples must be selected based on:
   • Process temperature range
   • Chemical compatibility
   • Length and diameter suitable for reactor size

5.2 Pre-Use Inspection

1. Verify calibration label and due date before each use.
2. Ensure insulation sheath is intact, wire tips are clean, and no physical damage is observed.
3. Check for proper sensor response using hot water or calibration source (if applicable).

5.3 Installation and Placement

1. Insert the thermocouple through the designated port of the vessel/reactor/dryer.
2. Ensure the tip reaches the center/mass of the material for accurate readings.
3. Secure the thermocouple with clamps or fittings to avoid movement or displacement.
4. Connect the thermocouple to a calibrated temperature indicator or digital data logger.

5.4 During Operation

1. Monitor temperature at defined intervals as per BMR.
2. Record readings manually or ensure automated data capture is functioning.
3. Ensure that temperature alarms or control loops using thermocouple inputs are functional.

5.5 Post-Use Care

1. Carefully remove thermocouple from equipment after process completion.
2. Clean the thermocouple with 70% IPA or suitable solvent, ensuring no residues are left on the sheath.
3. Inspect for damage. If damaged, label as “Out of Use” and inform Engineering for replacement.

5.6 Calibration and Maintenance

1. Thermocouples shall be calibrated annually or as per the calibration SOP.
2. Calibration shall be traceable to national/international standards and documented in the Calibration Record (Annexure-2).
3. Calibration status shall be indicated by a visible label with due date, serial number, and calibrated by information.

5.7 Documentation

1. Record the following in the Thermocouple Usage Log (Annexure-1):
   • Thermocouple ID
   • Date of use
   • Batch number
   • Equipment name
   • Process stage
   • Initial and final readings

6. Abbreviations

• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• QA: Quality Assurance
• BMR: Batch Manufacturing Record

7. Documents

1. Thermocouple Usage Log (Annexure-1)
2. Thermocouple Calibration Record (Annexure-2)

8. References

• ICH Q7 – GMP Guidelines for APIs
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals
• USP <1058> – Analytical Instrument Qualification

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Thermocouple Usage Log

Annexure-2: Thermocouple Calibration Record

Revision History:

Standard Operating Procedure for Control Sample Collection and Labeling in API Manufacturing

1. Purpose

To define the procedure for systematic collection, accurate labeling, and proper storage of control samples from each batch of API manufactured, to support future investigations, re-analysis, or stability studies as per regulatory requirements.

2. Scope

This SOP is applicable to production, quality control, and quality assurance personnel involved in sampling, labeling, and retention of control samples for both intermediates and final APIs.

3. Responsibilities

• Production Chemist: Coordinate with QC for control sample collection after batch processing.
• QC Analyst: Label, log, and store control samples as per defined procedures.
• QA Officer: Ensure sample integrity, verify labeling accuracy, and approve storage location and duration.

4. Accountability

The QA Head is accountable for ensuring control sample management complies with cGMP requirements and regulatory expectations.

5. Procedure

5.1 Sample Quantity

1. Collect at least twice the quantity required for a complete retesting of the material.
2. For APIs: minimum 200 g or as per regulatory/customer-specific requirement.
3. For intermediates (if retained): 50 g to 100 g depending on material nature.

5.2 Timing and Method of Collection

1. Collect control samples after batch is declared conforming and QA-approved.
2. Use clean, dry, inert, and appropriately sized containers (glass or HDPE with screw caps).
3. Avoid exposure to air, light, or moisture during transfer.

5.3 Labeling Requirements

1. Affix a control sample label (Annexure-1) with the following details:
   • Product Name
   • Batch Number
   • Manufacturing Date
   • Retest/Expiry Date
   • Storage Condition
   • Quantity Retained
   • Sample Code / Reference No.
   • Signature and Date
2. Use indelible ink or pre-printed labels with QA verification.

5.4 Storage Conditions

1. Store samples in a designated Control Sample Room or Chamber.
2. Conditions must be 25°C ± 2°C and 60% RH ± 5% unless specified otherwise.
3. Samples must be segregated batch-wise, product-wise, and year-wise in clean labeled bins or racks.

5.5 Duration of Retention

1. Retain samples for:
   • 1 year after batch expiry/retest date
   • Or as per contract/market regulations (e.g., 5 years for regulated markets)
2. After expiry of the retention period, discard samples with QA authorization following the Sample Disposal SOP.

5.6 Documentation

1. Record control sample collection in the Control Sample Logbook (Annexure-2).
2. QA shall verify entry and sign off.
3. Attach copy of label and sampling form to the Batch Manufacturing Record (BMR).

6. Abbreviations

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

7. Documents

1. Control Sample Label Template (Annexure-1)
2. Control Sample Logbook (Annexure-2)
3. Sample Disposal Authorization Form

8. References

• ICH Q7 – GMP for APIs
• 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: Control Sample Label

Annexure-2: Control Sample Logbook

Revision History:

Standard Operating Procedure for IPC Training to Operators and Chemists in API Manufacturing

1. Purpose

To define the procedure for conducting systematic training for production operators and chemists on In-Process Control (IPC) practices relevant to API manufacturing, ensuring understanding and compliance with cGMP requirements.

2. Scope

This SOP applies to all new and existing operators and chemists engaged in the execution, supervision, and documentation of IPC checks during API batch processing.

3. Responsibilities

• QA Officer: Prepare and approve training materials and ensure training records are maintained.
• Production/QA Trainer: Conduct classroom and on-the-job training sessions for IPC procedures.
• Line Manager: Ensure that personnel attend training and are assessed before deployment.
• Trainee (Operator or Chemist): Actively participate in training, seek clarifications, and demonstrate competence during assessment.

4. Accountability

The QA Head is accountable for overseeing the IPC training program. The Production Head is accountable for ensuring that only trained personnel perform IPC activities.

5. Procedure

5.1 Training Needs Identification

1. Identify training requirements for new joinees, role changes, or updates to IPC SOPs.
2. Prepare a monthly IPC training calendar and circulate to Production and QC.
3. Topics shall include:
   • Introduction to IPC
   • GMP principles for IPC documentation
   • Stage-wise IPC checks (e.g., pH, LOD, yield, color, crystal size)
   • Sampling techniques
   • Use of IPC equipment (e.g., IR balance, pH meter)

5.2 Training Methods

1. Conduct sessions through a mix of:
   • Classroom training with presentations and SOP reviews
   • Hands-on training during batch execution under supervision
   • Demonstration of documentation practices in IPC logbooks

5.3 Training Material

1. Prepare training material approved by QA, including:
   • Copy of SOPs
   • Visual aids showing correct and incorrect practices
   • Short tests for post-training evaluation

5.4 Evaluation and Certification

1. Conduct a written or oral assessment post-training using a pre-approved questionnaire (Annexure-1).
2. Minimum passing score shall be 80%.
3. Personnel failing the assessment shall undergo retraining before reassessment.
4. Maintain individual training records (Annexure-2) in QA-controlled files.
5. Issue training completion certificates signed by QA and department head.

5.5 Refresher and Annual Training

1. Conduct annual refresher training on IPC practices for all staff involved in manufacturing.
2. Update staff promptly on any procedural changes or regulatory updates.

5.6 Documentation

1. Maintain the following records:
   • Training attendance sheet
   • Evaluation sheet
   • Training summary report
   • Signed IPC SOP acknowledgement forms

6. Abbreviations

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

7. Documents

1. IPC Training Evaluation Sheet (Annexure-1)
2. Training Record Form (Annexure-2)
3. Training Calendar
4. Training Acknowledgement Log

8. References

• ICH Q7 – GMP for APIs
• 21 CFR Part 211 – cGMP for Finished Pharmaceuticals
• WHO TRS 986 – Annex 2 GMP Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Training Evaluation Sheet

Annexure-2: IPC Training Record Form

Revision History: