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:

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: