Standard Operating Procedure for Maintaining Volume Adjustments in Elixir Manufacturing

1. Purpose

To establish a standard procedure for accurately adjusting the final volume of elixir formulations during manufacturing to ensure batch consistency and compliance with quality specifications.

2. Scope

This SOP is applicable to all elixir batches manufactured in the Elixir Department where volume adjustments are required after addition and mixing of all components, prior to bulk filtration or filling.

3. Responsibilities

• Manufacturing Operator:
  • Perform final volume adjustments using purified water or vehicle as specified.
  • Document all adjustment details in the BMR and Volume Adjustment Log.
• Production Supervisor:
  • Verify volume marking, tank calibration, and authorize adjustment.
• QA Officer:
  • Cross-verify batch volume, perform visual checks, and sign off on final volume.

4. Accountability

The Production Head is accountable for ensuring that volume adjustments are performed correctly and documented to ensure batch uniformity.

5. Procedure

5.1 Pre-Adjustment Checks

1. Ensure that all ingredients (API, solvents, sweeteners, preservatives, flavors, etc.) have been added and mixed completely as per the BMR.
2. Stop the agitator and allow bubbles to settle before taking volume readings.
3. Check the calibrated volume graduation mark on the tank or use a dipstick (calibrated rod) if required.

5.2 Adjustment Procedure

1. Determine the shortfall in volume from the target batch size (e.g., 100 L).
2. Prepare the adjustment liquid (purified water or vehicle as specified) in a clean container.
3. Restart slow agitation (e.g., 40–60 RPM).
4. Slowly add the adjustment liquid while mixing until the final desired volume is reached.
5. Stop addition immediately upon reaching target volume.

5.3 Post-Adjustment Verification

1. Take samples from top, middle, and bottom and perform:
   • Visual inspection (clarity, color, consistency)
   • pH check (if applicable)
2. Record observations and volume details in the Volume Adjustment Log (Annexure-1).
3. Get verification from Supervisor and QA before proceeding to filtration or storage.

5.4 Documentation

1. Enter all adjustment details (pre-volume, added volume, final volume, date, and time) in the BMR.
2. Attach the signed Volume Adjustment Log to the BMR set.

6. Abbreviations

• SOP: Standard Operating Procedure
• BMR: Batch Manufacturing Record
• QA: Quality Assurance
• RPM: Revolutions Per Minute

7. Documents

1. Volume Adjustment Log (Annexure-1)
2. Tank Calibration Certificate (Annexure-2)
3. Volume Verification Checklist (Annexure-3)

8. References

• WHO TRS 961 Annex 3 – GMP for Liquid Oral Preparations
• 21 CFR Part 211.101 – Production and Process Controls

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Volume Adjustment Log

Annexure-2: Tank Calibration Certificate

Annexure-3: Volume Verification Checklist

Revision History:

Standard Operating Procedure for IPC Limits Setting and Justification in API Manufacturing

1. Purpose

To define the procedure for setting and scientifically justifying IPC (In-Process Control) limits for critical quality attributes during API manufacturing, using process understanding, development studies, historical data, and validation outcomes.

2. Scope

This SOP is applicable to all IPC parameters defined in the master formula record (MFR) of APIs manufactured at the facility. It covers the setting, documentation, revision, and approval of IPC limits for new and existing products.

3. Responsibilities

• Process Development: Provide development data, define preliminary IPC ranges, and propose justifications.
• QA Department: Evaluate scientific rationale, historical consistency, and approve IPC limits for implementation.
• QC Department: Confirm analytical capability, detection ranges, and accuracy for each parameter.

4. Accountability

The Head – QA is accountable for final approval of IPC limits and their justification reports. Head – Production is responsible for implementing IPC ranges in shop floor documentation.

5. Procedure

5.1 IPC Parameter Identification

1. Critical IPC parameters shall be identified based on:
   • Process development reports
   • Risk assessment and FMEA
   • Regulatory requirements
   • Validation protocols

5.2 Sources for IPC Limit Justification

1. Sources of data to support IPC limit setting include:
   • Lab-scale and pilot batch development studies
   • Tech transfer and scale-up batches
   • Process capability studies
   • 3-batch process validation data
   • Stability data (if applicable)

5.3 IPC Limit Definition Format

1. Each IPC parameter must have the following documented:
   • Parameter name and unit of measurement
   • IPC stage (e.g., after reaction, before drying)
   • Proposed range or specification
   • Justification (scientific or statistical)
   • Source data reference (Annexure-1)
2. Summarize in the IPC Limit Justification Report format (Annexure-2).

5.4 Statistical Support

1. Where applicable, apply statistical tools to analyze data:
   • Mean ± 3 standard deviation (SD)
   • Process capability indices (Cp, Cpk)
   • Regression trend lines (if temporal behavior is studied)
2. Statistical analysis must be performed using validated software or Excel with QA oversight.

5.5 Review and Approval

1. QA shall review each IPC limit report for:
   • Consistency with validation data
   • Alignment with final product specification
   • Regulatory filing (if applicable)
2. Once approved, IPC limits shall be incorporated in:
   • Master Formula Record (MFR)
   • Batch Manufacturing Record (BMR)
   • IPC checklists and logbooks

5.6 Periodic Review and Revision

1. All IPC limits shall be reviewed annually or during PQR review.
2. Revisions to IPC limits must follow change control process with updated justification.

6. Abbreviations

• IPC: In-Process Control
• MFR: Master Formula Record
• BMR: Batch Manufacturing Record
• QA: Quality Assurance
• QC: Quality Control
• Cp/Cpk: Process Capability Indices

7. Documents

1. IPC Limit Justification Report (Annexure-2)
2. Development Report
3. Validation Report
4. Change Control Form (if applicable)

8. References

• ICH Q8 – Pharmaceutical Development
• ICH Q9 – Quality Risk Management
• ICH Q10 – Pharmaceutical Quality System
• 21 CFR Part 211 – Current Good Manufacturing Practice

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: IPC Limit Justification Summary

Annexure-2: IPC Limit Justification Report Format

Revision History:

Standard Operating Procedure for Clinical Supply Label Review and Approval in BA/BE Studies

1. Purpose

To establish a uniform procedure for the review and approval of clinical supply labels for investigational and comparator products used in bioavailability/bioequivalence (BA/BE) studies, ensuring compliance with regulatory guidelines and trial protocols.

2. Scope

This SOP applies to all labeling activities related to clinical supplies including investigational product (IP), placebo, and reference drug packaging materials within the clinical and logistics teams involved in BA/BE studies.

3. Responsibilities

• Clinical Supplies Manager: Prepares draft label text and coordinates label creation.
• Regulatory Affairs Representative: Reviews label for compliance with CDSCO/ICH labeling requirements.
• Principal Investigator: Verifies that the label content aligns with protocol specifications.
• Quality Assurance: Reviews final label proof and ensures documentation of approvals.

4. Accountability

The Head of Clinical Logistics is accountable for ensuring that no clinical material is dispensed or distributed without an approved, compliant label.

5. Procedure

5.1 Label Content Requirements

1. The clinical supply label must include:
   • Protocol number
   • Product name and strength (blinded where applicable)
   • Dose instructions (e.g., “To be taken with food”)
   • Storage conditions
   • Batch/lot number
   • Expiry date
   • “For Clinical Trial Use Only” statement

5.2 Label Drafting and Review

1. Clinical Supplies Manager creates draft label using template in Annexure-1.
2. Submit label draft to:
   • Regulatory Affairs for format and compliance check
   • PI for protocol conformity
   • QA for controlled document verification

5.3 Label Approval

1. All reviewers sign Annexure-2: Label Review and Approval Form.
2. Once approved, label artwork is locked and controlled under document ID.
3. Only the approved label version shall be printed and affixed to CTM.

5.4 Label Printing and Reconciliation

1. Label printing is executed by authorized personnel using validated printers.
2. Print quantity must match approved batch packaging log.
3. Use Annexure-3: Label Reconciliation Sheet to track label usage, destruction, and balance.

5.5 Storage and Documentation

1. Label copies and approval records are stored in the Trial Master File (TMF).
2. Retain records for a minimum of 5 years or as per regulatory requirement.

6. Abbreviations

• BA: Bioavailability
• BE: Bioequivalence
• IP: Investigational Product
• CTM: Clinical Trial Material
• QA: Quality Assurance
• TMF: Trial Master File

7. Documents

1. Label Template – Annexure-1
2. Label Review and Approval Form – Annexure-2
3. Label Reconciliation Sheet – Annexure-3

8. References

• ICH E6(R2) – Good Clinical Practice
• CDSCO Guidelines for Labeling of Investigational Products
• Schedule Y – Drugs and Cosmetics Rules, India

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Label Template

Annexure-2: Label Review and Approval Form

Annexure-3: Label Reconciliation Sheet

Revision History:

SOP for Moisture Determination in Hygroscopic Active Pharmaceutical Ingredients

1. Purpose

This SOP establishes the procedure for the development, optimization, and validation of methods to determine moisture content in hygroscopic Active Pharmaceutical Ingredients (APIs). The methods include Karl Fischer (KF) titration, loss on drying (LOD), and thermogravimetric analysis (TGA), depending on API characteristics and moisture levels.

2. Scope

This SOP is applicable to the Analytical Method Development (AMD) department and is intended for use during early-stage method development, formulation compatibility studies, stability assessments, and routine QC evaluation of hygroscopic APIs.

3. Responsibilities

• Analytical Chemist: Conducts moisture determination trials, documents procedures and results.
• Reviewer: Verifies test execution, calculations, and ensures GMP-compliant documentation.
• QA Officer: Ensures adherence to regulatory standards and internal quality procedures.
• Head – AMD: Approves validated methods for routine and regulatory application.

4. Accountability

The Head of Analytical Method Development is accountable for ensuring that accurate, validated, and scientifically justified methods for moisture determination in hygroscopic APIs are developed and documented.

5. Procedure

5.1 Method Selection

1. Assess the physicochemical nature of the API:
   • If moisture level is < 1.0% or water is tightly bound, use Karl Fischer titration.
   • If water is loosely held and thermally stable, use Loss on Drying (LOD).
   • For detailed profiles, use Thermogravimetric Analysis (TGA).
2. Document selection rationale in Annexure-1: Method Selection Justification Log.

5.2 Equipment and Conditions

1. Karl Fischer:
   • Volumetric or coulometric KF titrator
   • Dried methanol and standard water solution (e.g., 1.0 mg/mL)
   • Use sample introduction via syringe or sealed vial to minimize atmospheric moisture exposure
2. LOD:
   • Moisture analyzer or drying oven
   • Standard temp: 105°C ± 2°C; time: 3–5 hrs or until constant weight
   • Use pre-weighed crucibles or dishes
3. TGA:
   • Thermogravimetric Analyzer
   • Heating rate: 10°C/min up to 300°C in nitrogen/air
   • Measure % weight loss across temperature zones
4. Log equipment details in Annexure-2: Equipment Calibration & Condition Log.

5.3 Sample Handling and Preparation

1. Handle hygroscopic samples inside desiccator or glove box if needed.
2. Accurately weigh the required quantity:
   • 2–10 mg for KF
   • 500–1000 mg for LOD
   • 5–10 mg for TGA
3. For LOD, use previously dried and tared crucibles.
4. Document weights and sample codes in Annexure-3: Sample Handling Record.

5.4 Execution of Moisture Analysis

1. Karl Fischer:
   • Run blank titration and standardization daily
   • Inject sample into the reaction vessel using dry syringe
   • Wait until titration end-point is reached (auto or visual)
   • Calculate % moisture = (mg water / sample weight) × 100
2. LOD:
   • Weigh sample + crucible (W1)
   • Dry at 105°C for 3–5 hours (or specified temp/time)
   • Cool in desiccator and weigh (W2)
   • Moisture (%) = [(W1 – W2) / Sample weight] × 100
3. TGA:
   • Program method and load sample
   • Run thermal scan from 30°C to 300°C
   • Record initial and final weight %
   • Interpret specific weight losses as moisture, degradation, or solvent loss
4. Record all observations in Annexure-4: Moisture Measurement Log.

5.5 Method Optimization

1. Evaluate:
   • Sample size sensitivity and reproducibility
   • End-point stability and moisture drift
   • Temperature dependency and sample degradation
2. Optimize weighing time, environmental controls, and drying parameters.
3. Document optimization in Annexure-5: Method Optimization Report.

5.6 Method Validation

1. Specificity: Ensure no interference from volatile solvents, excipients, or degradation products.
2. Precision: RSD ≤ 2.0% for 6 replicates.
3. Accuracy: Spike recovery for known moisture content materials (e.g., lactose monohydrate).
4. Linearity: Demonstrated using standards (0.1–1.0 mg H₂O for KF).
5. Robustness: Evaluate small changes in drying temp, time, or sample size.
6. Summarize in Annexure-6: Validation Summary Sheet.

6. Abbreviations

• API: Active Pharmaceutical Ingredient
• LOD: Loss on Drying
• KF: Karl Fischer
• TGA: Thermogravimetric Analysis
• SOP: Standard Operating Procedure
• RSD: Relative Standard Deviation

7. Documents

1. Method Selection Justification Log – Annexure-1
2. Equipment Calibration & Condition Log – Annexure-2
3. Sample Handling Record – Annexure-3
4. Moisture Measurement Log – Annexure-4
5. Method Optimization Report – Annexure-5
6. Validation Summary Sheet – Annexure-6

8. References

• USP <921> – Water Determination
• ICH Q2(R1) – Validation of Analytical Procedures
• EP 2.5.12 – Loss on Drying
• USP <731> – Loss on Drying

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Method Selection Justification Log

Annexure-2: Equipment Calibration & Condition Log

Annexure-3: Sample Handling Record

Annexure-4: Moisture Measurement Log

Annexure-5: Method Optimization Report

Annexure-6: Validation Summary Sheet

Revision History:

Standard Operating Procedure for Setup and Sterilization of Bioreactor Vessels in Biosimilar Production

1. Purpose

To establish a standardized procedure for assembly, cleaning, and sterilization of bioreactor vessels used in the upstream processing of biosimilars, ensuring aseptic operations and regulatory compliance.

2. Scope

This SOP is applicable to stainless steel and single-use bioreactors (S.U.B.) ranging from 1L to 2000L capacity used for mammalian cell culture in biosimilar manufacturing facilities.

3. Responsibilities

• Upstream Operators: Execute vessel setup and cleaning as per protocol.
• Maintenance Team: Calibrate sensors and validate autoclave/sterilizer functions.
• QA: Review sterilization and integrity records and approve for production use.

4. Accountability

The Upstream Production Head is accountable for ensuring bioreactor vessel integrity, aseptic readiness, and traceable sterilization records.

5. Procedure

5.1 Pre-Setup Verification

1. Ensure vessel has been properly cleaned after last use and all removable components are available (gaskets, agitator shaft, sampling ports, probes).
2. Review previous batch log for any deviations, contamination alerts, or maintenance flags.

5.2 Cleaning Procedure (Stainless Steel Bioreactor)

1. Perform visual inspection for residues.
2. Rinse vessel with purified water (PW).
3. Apply validated cleaning agent (e.g., 1% NaOH) and circulate using CIP (Clean-In-Place) system for 30 minutes.
4. Perform two rinse cycles with PW followed by one rinse with Water for Injection (WFI).
5. Dry using sterile filtered air and record in Cleaning Log (Annexure-1).

5.3 Assembly of Bioreactor

1. Install pH, DO, temperature, and pressure sensors ensuring correct orientation and calibration status.
2. Fit agitator, baffles, sparger, exhaust filters, and vent filters as per P&ID.
3. Secure connections with validated clamps and sterile tubing.

5.4 Sterilization Procedure

1. For SIP (Steam-In-Place):
   • Seal all ports and initiate automated SIP cycle (e.g., 121°C for 30 minutes).
   • Verify condensate drain and temperature mapping at multiple points.
2. For Autoclave Sterilization (Small-scale vessels):
   • Wrap removable components in sterile bags and autoclave at 121°C/15 psi for 30 minutes.

5.5 Post-Sterilization Verification

1. Perform filter integrity test (Bubble Point Test) for exhaust and vent filters (Annexure-2).
2. Record SIP validation parameters in Sterilization Log (Annexure-3).
3. Apply “Sterile Ready for Use” label post-QA release.

6. Abbreviations

• SIP: Steam-In-Place
• PW: Purified Water
• WFI: Water for Injection
• CIP: Clean-In-Place

7. Documents

1. Bioreactor Cleaning Log – Annexure-1
2. Filter Integrity Test Report – Annexure-2
3. SIP Sterilization Record – Annexure-3

8. References

• EU GMP Annex 1 – Sterile Manufacturing
• ICH Q7 – GMP for Active Pharmaceutical Ingredients
• WHO TRS 1010 – Biotech Production Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Bioreactor Cleaning Log

Annexure-2: Filter Integrity Test Report

Annexure-3: SIP Sterilization Record

Revision History:

Standard Operating Procedure for Ensuring Batch-to-Batch Consistency in Cream Manufacturing

1. Purpose

The purpose of this SOP is to define the procedure for ensuring batch-to-batch consistency in the manufacturing of cream products. Consistency across batches is essential for ensuring that each batch meets the required quality standards for texture, appearance, active ingredient content, and overall efficacy. This SOP outlines the necessary steps to monitor and control the manufacturing process to maintain uniformity in each batch of cream.

2. Scope

This SOP applies to all cream formulations manufactured at the facility. It covers the procedures for maintaining consistency in the production process, from ingredient sourcing to final product testing, to ensure uniformity in each batch.

3. Responsibilities

• Production Team: Responsible for ensuring that manufacturing processes are consistently followed according to the formulation and batch records to maintain uniformity in every batch.
• Quality Control (QC) Team: Responsible for performing quality tests on each batch to confirm that the batch meets the required specifications for uniformity and consistency.
• Quality Assurance (QA) Team: Responsible for reviewing the batch records, testing results, and ensuring that any deviations from the expected quality are addressed and corrected.

4. Accountability

The QC Manager is accountable for ensuring that batch-to-batch consistency testing is performed in accordance with this SOP. The Production Supervisor is responsible for ensuring that manufacturing processes are consistently followed during production. The QA Manager is responsible for ensuring that the results of testing and manufacturing processes are reviewed and compliant with regulatory and internal standards.

5. Procedure

5.1 Pre-Manufacturing Activities

1. Ensure that the formulation and batch records are accurate and up to date. Review the batch record to ensure that all ingredients and quantities are correctly listed and that the manufacturing process follows standard operating procedures (SOPs).
2. Review the availability of raw materials to confirm that the quality and source of the ingredients remain consistent for each batch.
3. Calibrate all necessary equipment, including mixing tanks, homogenizers, and filling machines, to ensure they are functioning properly and meet specifications for consistent production.

5.2 Manufacturing Process

1. Follow the approved batch manufacturing process to ensure consistency in the mixing, blending, and homogenization of the cream formulation.
2. Monitor key parameters such as mixing time, temperature, speed, and ingredient addition to ensure they remain consistent from batch to batch.
3. Ensure that the correct quantities of ingredients are added as specified in the batch record. Use calibrated dispensing equipment to avoid deviations in the ingredient proportions.
4. Maintain proper documentation of each production step, including temperature and pressure readings, to provide traceability and support consistency checks.

5.3 Quality Control Testing

1. Perform routine quality control tests on each batch to ensure that the product meets the required specifications for consistency. These tests should include:
   • Active ingredient content
   • Viscosity
   • pH level
   • Appearance (color, texture)
   • Microbial contamination levels
2. Compare the results from each batch to the specifications to identify any potential variations in the product’s quality.
3. If the results from a batch are outside of the acceptable range, investigate the cause of the variation, which may include ingredient quality, equipment malfunction, or process deviation.

5.4 Batch-to-Batch Comparison

1. At regular intervals, perform a batch-to-batch comparison of critical parameters such as active ingredient concentration, viscosity, and pH levels. This comparison ensures that the formulation remains consistent from one batch to the next.
2. Review and document any differences observed between batches, and determine if these differences are within the acceptable limits or if corrective actions are necessary.
3. Ensure that any deviations between batches are investigated, documented in the Deviation Log (Annexure-1), and corrective actions are taken to maintain consistency.

5.5 Post-Manufacturing Activities

1. After production, complete all necessary batch records and quality control documentation, including testing results and any deviation reports.
2. Submit the batch record and testing results for review and approval by the QA team to ensure that the batch meets all specifications and complies with GMP standards.
3. If any deviations are observed, initiate corrective actions such as revising the formulation, improving manufacturing processes, or modifying equipment settings. Re-test the batch after implementing corrective actions.

5.6 Documentation and Record-Keeping

1. Ensure that all batch production records, quality control test results, and deviation reports are complete, accurate, and securely stored. This includes the Batch Manufacturing Record (Annexure-1) and the Deviation Log (Annexure-2).
2. Retain all records for a minimum of two years or as required by regulatory guidelines.
3. Ensure that all documentation is reviewed and approved by the Quality Assurance team to verify compliance with GMP and regulatory standards.

6. Abbreviations

• GMP: Good Manufacturing Practices
• QC: Quality Control
• QA: Quality Assurance
• PPE: Personal Protective Equipment

7. Documents

1. Annexure-1: Batch Manufacturing Record
2. Annexure-2: Deviation Log

8. References

• Good Manufacturing Practices (GMP) Guidelines – 21 CFR Part 211
• International Conference on Harmonisation (ICH) Q7 – Good Manufacturing Practice for Active Pharmaceutical Ingredients
• Pharmacopeial Monographs on Quality Control Testing

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Batch Manufacturing Record

Annexure-2: Deviation Log

Revision History:

Standard Operating Procedure for Sample Preservation for Investigation Purpose in API Manufacturing

1. Purpose

To establish a standard method for preserving samples for quality investigation during API manufacturing in order to ensure traceability, integrity, and compliance with regulatory requirements.

2. Scope

This SOP applies to all in-process, intermediate, or final API samples that are required to be preserved for extended evaluation or root cause investigation due to process deviations, unexpected results, or customer complaints.

3. Responsibilities

• QC Analyst: Collect and label investigation samples, record relevant details, and store under specified conditions.
• QA Officer: Review sample retention entries, verify storage conditions, and authorize release or destruction post-investigation.
• Production Chemist: Identify and notify potential sample preservation needs during batch processing.

4. Accountability

The QA Head is accountable for ensuring proper sample retention practices, documentation, and release/disposal authorization after investigation closure.

5. Procedure

5.1 Sample Collection for Investigation

1. Samples to be preserved may arise from:
   • Out-of-Specification (OOS) or Out-of-Trend (OOT) observations
   • Processing deviations
   • Customer complaint investigation
   • Visual abnormalities or inconsistent results
2. QC Analyst or Production shall collect 10–25 g (solid) or 10–25 mL (liquid) samples, depending on investigation type and analytical requirements.

5.2 Labeling Requirements

1. Each preserved sample shall bear a label clearly mentioning:
   • “Sample for Investigation” (Red label)
   • Batch No. and Sample Type
   • Date of Collection
   • Reason for Preservation (e.g., OOS, Deviation No., Complaint ID)
   • Stored By and Verified By

5.3 Documentation

1. Record the preserved sample details in the Investigation Sample Logbook (Annexure-1), including:
   • Investigation trigger (Deviation/OOS ID)
   • Storage location and conditions
   • Expected retention duration
2. Update the status in the deviation/investigation file, and assign QA tracking number.

5.4 Storage Conditions

1. Store preserved samples in a dedicated investigation cabinet with restricted access and temperature monitoring (if applicable).
2. Conditions:
   • Solids: Room temperature (15–25°C) unless otherwise specified
   • Liquids: Cool conditions (2–8°C) if stability is a concern

5.5 Sample Review and Disposal

1. Upon completion of investigation:
   • QA will assess whether the sample is required for re-analysis or retained further.
   • If no longer required, sample shall be destroyed following SOP/API/106/2025.
2. Destruction shall be documented in the Investigation Sample Disposal Record (Annexure-2).

6. Abbreviations

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

7. Documents

1. Investigation Sample Logbook (Annexure-1)
2. Investigation Sample Disposal Record (Annexure-2)
3. Deviation Report / OOS Report

8. References

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

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Investigation Sample Logbook

Annexure-2: Investigation Sample Disposal Record

Revision History:

Standard Operating Procedure for Use of Water for Injection (WFI) in Elixir Production

1. Purpose

To establish a standard procedure for the use, handling, and quality control of Water for Injection (WFI) in the manufacturing of elixir formulations to ensure compliance with GMP requirements.

2. Scope

This SOP applies to all activities involving the collection, transfer, usage, and documentation of WFI in elixir manufacturing in the Elixir Department.

3. Responsibilities

• Production Operator:
  • Collect and use WFI in accordance with batch requirements and specifications.
  • Ensure proper line flushing and container sanitization before collection.
• Production Supervisor:
  • Verify WFI collection process and temperature.
  • Monitor that WFI is used within the hold time limit.
• QA Officer:
  • Perform sampling and release of WFI prior to use.
  • Ensure all WFI usage is traceable in documentation.

4. Accountability

The Production Head is accountable for ensuring that WFI is used as per specifications and no microbial or endotoxin risk is introduced into the batch.

5. Procedure

5.1 WFI Collection

1. Ensure the WFI loop is in validated state and operating above 80°C in circulation mode.
2. Flush the sampling point or user valve for at least 2 minutes before collection.
3. Sanitize the outer nozzle of the user point with 70% IPA.
4. Collect WFI in pre-cleaned, stainless steel or HDPE containers labeled with:
   • “WFI – For Manufacturing Use Only”
   • Date and Time of Collection
   • Collected By

5.2 Quality Control of WFI

1. Send samples to QC for analysis of the following:
   • Conductivity
   • Total Organic Carbon (TOC)
   • Microbial Load
   • Endotoxin Level (if applicable)
2. WFI shall be used only after release by QA based on results.

5.3 Usage Guidelines

1. Use WFI only within 4 hours of collection if stored below 25°C, or within 8 hours if maintained at ≥70°C.
2. Do not reuse WFI from previous batches.
3. Document the WFI quantity used, batch number, and time in the BMR and WFI Usage Log (Annexure-1).

5.4 Cleaning After Use

1. Clean and dry all WFI collection containers after use.
2. Label containers as “Cleaned” with date and signature.

6. Abbreviations

• WFI: Water for Injection
• TOC: Total Organic Carbon
• QA: Quality Assurance
• SOP: Standard Operating Procedure
• BMR: Batch Manufacturing Record

7. Documents

1. WFI Usage Log (Annexure-1)
2. WFI Sampling and Test Report (Annexure-2)
3. WFI Container Cleaning Log (Annexure-3)

8. References

• USP Monograph on Water for Injection
• WHO TRS 970 – Annex 2: Pharmaceutical Water Systems
• 21 CFR Part 211.110 – Sampling and Testing

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: WFI Usage Log

Annexure-2: WFI Sampling and Test Report

Annexure-3: WFI Container Cleaning Log

Revision History:

Standard Operating Procedure for Emergency Protocol Activation in BA/BE Studies

1. Purpose

To define a clear and effective procedure for the activation and management of emergency protocols during the conduct of BA/BE studies in order to ensure immediate response, subject safety, and adherence to regulatory obligations.

2. Scope

This SOP is applicable to all staff at clinical and bioanalytical trial facilities involved in the conduct of BA/BE studies during any medical, technical, or environmental emergency.

3. Responsibilities

• Principal Investigator (PI): Oversees emergency management and ensures subject safety.
• Medical Officer: Provides immediate medical care and documents clinical management.
• Study Coordinator: Assists in communication, coordination, and execution of response activities.
• QA Personnel: Ensures all emergency actions are documented and reviewed per GCP and site SOPs.

4. Accountability

The Clinical Operations Head is accountable for ensuring timely activation, documentation, and reporting of emergency procedures in accordance with regulatory and ethical guidelines.

5. Procedure

5.1 Definition of Emergency

1. Medical emergencies (e.g., severe allergic reaction, cardiac arrest, seizures)
2. Operational emergencies (e.g., power failure, equipment breakdown)
3. Environmental hazards (e.g., fire, flooding, gas leaks)

5.2 Activation of Emergency Protocol

1. Any staff member identifying an emergency must immediately inform the Medical Officer or PI.
2. Activate Annexure-1: Emergency Protocol Activation Checklist.
3. Use public announcement system or designated emergency signal where applicable.

5.3 Subject Management During Emergency

1. Stabilize affected subject(s) using emergency equipment (e.g., oxygen, defibrillator).
2. Move subject to designated emergency care room.
3. Document event in Annexure-2: Emergency Incident Report Form.
4. Inform local emergency medical services if required.

5.4 Evacuation and Site Safety

1. Follow Annexure-3: Site Evacuation Plan in case of fire or environmental threat.
2. Ensure all subjects and staff evacuate in an orderly manner.
3. Assemble at pre-identified muster points and perform headcount.

5.5 Communication and Notification

1. Notify:
   • Sponsor/monitor within 24 hours
   • IEC/IRB within the required reporting timeline
   • Regulatory authority (e.g., CDSCO) for SAEs or critical incidents
2. Use Annexure-4: Regulatory Notification Form.

5.6 Post-Emergency Review and CAPA

1. Conduct emergency debrief within 48 hours with all involved staff.
2. Initiate CAPA using Annexure-5: Emergency CAPA Log.
3. Review procedures to identify gaps or retraining needs.

6. Abbreviations

• PI: Principal Investigator
• IEC: Institutional Ethics Committee
• SAE: Serious Adverse Event
• CAPA: Corrective and Preventive Action
• CDSCO: Central Drugs Standard Control Organization

7. Documents

1. Emergency Protocol Activation Checklist – Annexure-1
2. Emergency Incident Report Form – Annexure-2
3. Site Evacuation Plan – Annexure-3
4. Regulatory Notification Form – Annexure-4
5. Emergency CAPA Log – Annexure-5

8. References

• ICH E6(R2) – Good Clinical Practice
• Schedule Y – Drugs and Cosmetics Rules, India
• WHO Emergency Response Framework

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Emergency Protocol Activation Checklist

Annexure-2: Emergency Incident Report Form

Annexure-3: Site Evacuation Plan

Annexure-4: Regulatory Notification Form

Annexure-5: Emergency CAPA Log

Revision History:

SOP for Gas Evolution Reaction-Based Analytical Method in AMD Laboratory

1. Purpose

The purpose of this SOP is to establish a procedure for the development and validation of analytical methods based on gas evolution reactions. These methods involve quantification of analytes that release a measurable gas (e.g., CO₂, O₂, H₂) as part of their chemical reaction with specific reagents.

2. Scope

This SOP is applicable to the Analytical Method Development (AMD) laboratory and covers classical chemical methods that rely on gas evolution (e.g., carbonate determination via CO₂ evolution, peroxide determination by O₂ release) for analysis of raw materials, intermediates, and drug products.

3. Responsibilities

• Analytical Chemist: Executes method development trials, prepares reaction vessels, performs measurements, and documents observations.
• Reviewer: Verifies calculations, consistency of results, and ensures the accuracy of validation records.
• QA Officer: Ensures adherence to GMP principles and verifies documentation practices.
• Head – AMD: Reviews and approves validated methods for official use.

4. Accountability

The Head of AMD is accountable for ensuring that all gas evolution methods developed are scientifically justified, properly validated, and regulatory compliant.

5. Procedure

5.1 Method Selection and Principles

1. Select suitable gas evolution reaction based on analyte functionality. Examples:
   • Sodium bicarbonate/carbonate → CO₂ upon acid addition
   • Peroxides → O₂ evolution with potassium iodide
   • Hydrazine or metal hydrides → H₂ release in aqueous medium
2. Detection may be gravimetric (absorption in lime), volumetric (displacement), or titrimetric (back-titration after gas trapping).
3. Document rationale in Annexure-1: Method Selection Justification Log.

5.2 Apparatus and Setup

1. Use suitable reaction vessels like Kjeldahl flasks, gas burettes, or closed titration apparatus fitted with gas traps (e.g., Ba(OH)₂ or NaOH).
2. Ensure all apparatus is airtight and fitted with drying tubes if required.
3. For volumetric gas measurement, calibrate gas burette using known gas volume (e.g., atmospheric pressure water displacement method).
4. Document apparatus setup in Annexure-2: Equipment Preparation Log.

5.3 Sample Preparation

1. Weigh an accurate quantity of sample containing the analyte (e.g., 250 mg sodium bicarbonate).
2. Dissolve or suspend in distilled water if required.
3. Record sample weight and preparation in Annexure-3: Sample Preparation Log.

5.4 Reaction and Gas Collection

1. Place the prepared sample in the reaction chamber.
2. Add excess standardized reagent (e.g., HCl for carbonate analysis) through dropping funnel or septum port.
3. Allow gas to evolve and capture it in a connected gas absorption tube or volume displacement chamber.
4. Continue reaction until no further gas bubbles are visible.
5. For gravimetric methods, weigh the BaCO₃ formed from CO₂ in Ba(OH)₂.
6. For volumetric methods, note the displaced volume in burette and correct for temperature and pressure.
7. Record all reaction observations in Annexure-4: Gas Evolution Log.

5.5 Calculation

For carbonate determination by CO₂ evolution (titration method):

% Carbonate = (V × N × 0.060 × 100) / W
Where:
V = Volume of HCl consumed (mL)
N = Normality of HCl
W = Weight of sample (g)
0.060 = Equivalent weight of carbonate per mL N HCl

For gravimetric gas capture:

% Analyte = (Weight of precipitate × Conversion Factor × 100) / Sample Weight

5.6 Method Optimization

1. Optimize reaction conditions such as:
   • Acid concentration and volume
   • Reaction temperature (room temp vs. heating)
   • Rate of reagent addition to control foaming or violent reactions
2. Ensure complete gas capture by verifying plateau in evolution volume.
3. Perform duplicate trials to verify reproducibility.
4. Document outcomes in Annexure-5: Method Optimization Report.

5.7 Method Validation

1. Specificity: Use placebo matrices and excipient blanks to confirm absence of interfering gases.
2. Precision: Intra- and inter-day precision RSD ≤ 2.0% for six replicates.
3. Accuracy: Spike recovery at 80%, 100%, and 120% of target analyte level should be 98–102%.
4. Linearity: Prepare samples across 50–150% range and plot vs. gas volume evolved or titration volume.
5. Robustness: Test method sensitivity to variations in temperature, acid concentration, and reaction time.
6. Summarize all findings in Annexure-6: Validation Summary Report.

6. Abbreviations

• SOP: Standard Operating Procedure
• AMD: Analytical Method Development
• RSD: Relative Standard Deviation
• CO₂: Carbon Dioxide
• HCl: Hydrochloric Acid

7. Documents

1. Method Selection Justification Log – Annexure-1
2. Equipment Preparation Log – Annexure-2
3. Sample Preparation Log – Annexure-3
4. Gas Evolution Log – Annexure-4
5. Method Optimization Report – Annexure-5
6. Validation Summary Report – Annexure-6

8. References

• USP General Chapters <541>, <721> – Titrimetry and Volumetric Analysis
• IP Appendix 3.4 – Carbonates and Bicarbonates
• ICH Q2(R1) – Validation of Analytical Procedures
• AOAC Methods for Gas Evolution Analysis

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Method Selection Justification Log

Annexure-2: Equipment Preparation Log

Annexure-3: Sample Preparation Log

Annexure-4: Gas Evolution Log

Annexure-5: Method Optimization Report

Annexure-6: Validation Summary Report

Revision History: