SOP for Handling Method Development Notebooks in the AMD Department

1. Purpose

This SOP describes the procedures for the issuance, utilization, review, and archival of Analytical Method Development (AMD) notebooks used to record method development trials, observations, and data. The objective is to ensure consistency, traceability, and compliance with ALCOA+ principles, GMP, and data integrity requirements.

2. Scope

This SOP is applicable to all bound notebooks used by scientists and analysts in the AMD department to record experimental data, observations, instrument settings, and method development outcomes related to APIs and formulations.

3. Responsibilities

• Analytical Scientist: Records entries in a timely, legible, and compliant manner in the method notebook.
• QA: Issues, reviews, and archives completed notebooks; audits for compliance with data integrity principles.
• Department Coordinator: Maintains the issuance and return log of notebooks.
• Head – AMD: Approves the closure of notebooks and ensures training of personnel on notebook handling practices.

4. Accountability

The Head of AMD is accountable for enforcing the SOP on notebook handling and ensuring no unofficial records are used for capturing method development data.

5. Procedure

5.1 Notebook Format and Structure

1. All notebooks used must be:
   • Bound with numbered pages
   • Free from removable sheets or post-its
   • Pre-labeled with a unique Notebook ID (e.g., AMD/NB/001)
2. Each notebook must include:
   • Index page
   • User identification page
   • Issued and returned dates

5.2 Notebook Issuance

1. Request new notebooks by submitting Annexure-1: Notebook Requisition Form to QA.
2. QA records issuance in Annexure-2: Notebook Issuance Log and updates master list.
3. The scientist signs the issuance log and becomes accountable for its use.

5.3 Recording Entries

1. All entries must be:
   • Made in black or blue permanent ink
   • Dated and signed by the analyst
   • Verified by a second person, where applicable
2. Experimental design, rationale, trial conditions, and observations must be recorded real-time.
3. Diagrams, chromatograms, and tables may be pasted and cross-referenced to instrument IDs.

5.4 Corrections and Blank Spaces

1. Do not overwrite or use correction fluids.
2. To correct an error:
   • Strike through with a single line
   • Initial, date, and provide justification
3. Blank spaces must be ruled off with diagonal lines and annotated as “Cancelled.”

5.5 Notebook Review and Closure

1. Upon completion, the analyst submits the notebook to QA for review and closure.
2. QA verifies:
   • Page integrity and sequence
   • Signatures, dates, and correction practices
   • Data completeness and consistency
3. QA documents review in Annexure-3: Notebook Review Checklist.

5.6 Notebook Archival

1. Closed notebooks are labeled “ARCHIVED” and stored in a secure, humidity-controlled area.
2. QA updates Annexure-4: Notebook Archival Register with retrieval tracking information.
3. Retention period shall be a minimum of 10 years unless regulatory requirements specify longer.

5.7 Loss or Damage of Notebook

1. Report immediately to QA and Head – AMD using Annexure-5: Notebook Incident Report.
2. Initiate deviation management procedure as per SOP/QMS/042/2025.
3. Impact assessment to be performed on lost data and reported in closure document.

6. Abbreviations

• AMD: Analytical Method Development
• QA: Quality Assurance
• SOP: Standard Operating Procedure
• ID: Identification

7. Documents

1. Notebook Requisition Form – Annexure-1
2. Notebook Issuance Log – Annexure-2
3. Notebook Review Checklist – Annexure-3
4. Notebook Archival Register – Annexure-4
5. Notebook Incident Report – Annexure-5

8. References

• WHO TRS 1019 Annex 5 – Good Data and Record Management Practices
• ICH Q10 – Pharmaceutical Quality System
• 21 CFR Part 11 – Electronic Records; Electronic Signatures (where applicable)

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Notebook Requisition Form

Annexure-2: Notebook Issuance Log

Annexure-3: Notebook Review Checklist

Annexure-4: Notebook Archival Register

Annexure-5: Notebook Incident Report

Revision History:

Standard Operating Procedure for Ensuring Compliance with Schedule Y Clinical Requirements in BA/BE Studies

1. Purpose

To define a standardized procedure for ensuring full compliance with the provisions of Schedule Y of the Drugs and Cosmetics Rules, 1945, during the planning and conduct of Bioavailability/Bioequivalence (BA/BE) studies in India.

2. Scope

This SOP applies to all staff involved in clinical trial operations, regulatory affairs, documentation, monitoring, and quality assurance of BA/BE studies regulated under Schedule Y in India.

3. Responsibilities

• Regulatory Affairs Manager: Ensures that all study submissions are in accordance with Schedule Y requirements.
• Principal Investigator: Complies with responsibilities outlined under Investigator obligations of Schedule Y.
• QA Officer: Audits processes and documents for compliance with Schedule Y.
• Clinical Research Coordinator: Maintains regulatory essential documents and supports audit readiness.

4. Accountability

The Head of Regulatory Affairs is accountable for ensuring that all BA/BE studies conducted are in full compliance with Schedule Y requirements from study initiation to archival.

5. Procedure

5.1 Review of Schedule Y Provisions

1. All study staff must be trained on the current version of Schedule Y.
2. Maintain a controlled copy of Schedule Y in the Quality and Regulatory Documentation Library.

5.2 Clinical Trial Authorization (CTA)

1. Ensure BE protocol is filed to CDSCO along with Form 44 and requisite fees.
2. Attach Investigator Undertaking (Form 2), Institutional Ethics Committee (IEC) approval, and reference product labeling.

5.3 Ethics Committee Compliance

1. Ensure study protocol, informed consent forms, and any advertisement material are approved by IEC before subject enrollment.
2. All SAE reporting must follow 24-hour and 14-day reporting timelines as per Schedule Y.

5.4 Volunteer Protection and Consent

1. Ensure audio-visual informed consent recording where applicable.
2. Provide complete explanation of risks, study objectives, and rights of subjects as per ethical guidelines.

5.5 Documentation Compliance

1. Maintain Investigator Site File (ISF) as per Schedule Y structure.
2. Verify availability of:
   • Form 44 approval
   • IEC approval letters
   • CRFs and subject logs

5.6 Study Monitoring and Audits

1. Schedule periodic monitoring visits by QA and sponsor monitors.
2. Ensure documentation of protocol deviations, SAEs, consent deviations, and other observations.

5.7 Reporting and Archival

1. Compile Clinical Study Report (CSR) in Schedule Y format for submission to CDSCO.
2. Archive all records for at least 5 years post study completion or as directed by sponsor.

6. Abbreviations

• BA: Bioavailability
• BE: Bioequivalence
• CDSCO: Central Drugs Standard Control Organization
• CSR: Clinical Study Report
• QA: Quality Assurance
• IEC: Institutional Ethics Committee

7. Documents

1. Schedule Y Reference Copy – Annexure-1
2. Form 44 Submission Checklist – Annexure-2
3. IEC Approval Tracking Sheet – Annexure-3
4. SAE Reporting Log – Annexure-4
5. Archival Checklist – Annexure-5

8. References

• Schedule Y – Drugs and Cosmetics Rules, 1945 (Amended 2005)
• ICH E6(R2) – Good Clinical Practice
• Indian GCP Guidelines 2001

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Schedule Y Reference Copy

Controlled version of Schedule Y guidelines – latest amendment dated 2023.

Annexure-2: Form 44 Submission Checklist

Annexure-3: IEC Approval Tracking Sheet

Annexure-4: SAE Reporting Log

Annexure-5: Archival Checklist

Revision History:

Standard Operating Procedure for Use and Maintenance of Biosafety Cabinets in Biosimilar Labs

1. Purpose

To establish standardized procedures for the safe use, routine cleaning, and maintenance of biosafety cabinets (BSCs) used in biosimilar R&D and manufacturing areas, ensuring aseptic processing and operator protection from biological hazards.

2. Scope

This SOP applies to all Class II biosafety cabinets installed in biosimilar cell culture rooms and processing labs where open handling of biological material occurs.

3. Responsibilities

• Lab Personnel: Operate the cabinet as per procedure, perform routine cleaning, and record usage.
• Engineering/Maintenance: Conduct preventive maintenance and HEPA filter checks.
• QA Team: Monitor compliance, review logs, and verify BSC certifications.

4. Accountability

The Head of Biosimilar Laboratory Operations is accountable for ensuring the operational integrity, safety, and performance verification of all biosafety cabinets.

5. Procedure

5.1 Startup Procedure

1. Ensure the sash is positioned at the indicated working height (usually 8–10 inches).
2. Switch ON the cabinet blower and allow airflow stabilization for 5–10 minutes before use.
3. Wipe internal surfaces with 70% IPA.
4. Place only necessary materials inside, arranged to minimize airflow disruption.

5.2 Aseptic Technique During Use

1. Perform all manipulations at least 4 inches inside the front grille.
2. Minimize rapid hand movements that could disrupt laminar airflow.
3. Do not block rear or front grills with equipment or arms.
4. Avoid using open flames; use flameless alternatives.

5.3 Routine Cleaning

1. Clean work surface with 70% IPA before and after each session.
2. Wipe side walls and sash inside surface daily.
3. Use sterile lint-free wipes for cleaning to avoid particle shedding.

5.4 Weekly Deep Cleaning

1. Disassemble removable trays and wipe below work surface.
2. Sanitize drain pan if accessible.
3. Record in the BSC Weekly Cleaning Log (Annexure-1).

5.5 Preventive Maintenance

1. Schedule quarterly preventive maintenance to include:
   • Inspection of blower and electrical connections
   • HEPA filter pressure differential check
   • Fan and light function tests
2. Record maintenance in the BSC Maintenance Log (Annexure-2).

5.6 Certification and Filter Integrity

1. Perform annual certification by qualified vendor, including:
   • Airflow velocity testing
   • HEPA filter leak test
   • Noise and vibration assessment
2. Maintain certificate in QA-controlled BSC File.

5.7 Shutdown Procedure

1. Remove all materials and waste.
2. Wipe down surfaces with disinfectant followed by 70% IPA.
3. Keep blower ON for 5 minutes before switching OFF.

6. Abbreviations

• BSC: Biosafety Cabinet
• IPA: Isopropyl Alcohol
• HEPA: High-Efficiency Particulate Air

7. Documents

1. BSC Weekly Cleaning Log (Annexure-1)
2. BSC Maintenance Log (Annexure-2)
3. Annual Certification Report (Annexure-3)

8. References

• WHO Biosafety Manual, 4th Edition
• EN12469 – Biotechnology: Performance criteria for microbiological safety cabinets
• Manufacturer Guidelines for Specific BSC Model

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: BSC Weekly Cleaning Log

Annexure-2: BSC Maintenance Log

Annexure-3: Annual Certification Report Summary

Revision History:

Standard Operating Procedure for Sampling Frequency and Quantity Guidelines in API Manufacturing

1. Purpose

To establish uniform guidelines for the frequency and quantity of samples to be collected during various stages of API manufacturing for in-process checks, intermediate testing, and final product evaluation.

2. Scope

This SOP applies to sampling activities conducted by Production and Quality Control personnel during receipt of raw materials, reaction monitoring, drying, milling, blending, and packing stages of API production.

3. Responsibilities

• Production Chemist: Collect in-process samples as per defined frequency and quantity.
• QC Analyst: Receive and analyze the sample, and log receipt and testing status.
• QA Officer: Review compliance with sampling plan and maintain traceability records.

4. Accountability

The Production Head is accountable for sampling at defined intervals. The QA Head is responsible for approving sampling plans and reviewing deviations.

5. Procedure

5.1 General Sampling Principles

1. Use cleaned, labeled, and approved sampling tools and containers.
2. Wear appropriate PPE while sampling.
3. Ensure samples are representative of the bulk material by collecting from top, middle, and bottom (where applicable).

5.2 Sampling Frequency

1. Refer to MFR/BMR for specific instructions. If not defined, use the following general guidance:
   • Raw Materials: Each container or as per reduced testing protocol.
   • Reaction Monitoring: Every 30–60 minutes or at defined critical stages.
   • Drying: Every 2 hours or until LOD is within range.
   • Milling/Blending: Start, middle, and end of batch.
   • Packing: One sample per 25 kg or per container.
2. Additional sampling may be required based on deviations or unexpected results.

5.3 Sampling Quantity Guidelines

1. Refer to product specification or method of analysis. If not defined:
   • Assay / HPLC: 1–2 g
   • LOD / Moisture: 2–3 g
   • Identification: 0.5–1 g
   • Impurity profiling: 5 g
   • Reserve / Retain sample: 25–50 g
2. In case of liquids: Collect 5–10 mL using pipettes or sampling bottles.

5.4 Labeling and Documentation

1. Label each sample with:
   • Product name
   • Batch number
   • Date and time of sampling
   • Stage of sampling
   • Sampled by
2. Record in the Sampling Logbook (Annexure-1).
3. QC to log sample receipt and usage in Analytical Work Log.

5.5 Deviations

1. If sampling frequency or quantity deviates from defined protocol, record deviation with justification and obtain QA approval.
2. Document deviation in the Batch Record and initiate deviation form if required.

6. Abbreviations

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

7. Documents

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

8. References

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

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Sampling Logbook

Revision History:

Standard Operating Procedure for Preservative Efficacy Testing of Creams

1. Purpose

The purpose of this SOP is to establish a standard procedure for conducting preservative efficacy testing (PET) of cream formulations. The effectiveness of preservatives in a cream formulation is critical for preventing microbial contamination during its shelf life. This test ensures that the preservatives used in the formulation are effective in inhibiting the growth of microorganisms.

2. Scope

This SOP applies to all cream formulations produced at the facility. It covers the procedure for testing the efficacy of preservatives in creams after they have been formulated and before they are released for distribution.

3. Responsibilities

• Production Team: Responsible for ensuring that the cream formulations are correctly prepared with the specified preservatives, and samples are provided for preservative efficacy testing.
• Quality Control (QC) Team: Responsible for performing preservative efficacy testing using appropriate microbiological methods and ensuring that the test results meet the required standards.
• Quality Assurance (QA) Team: Responsible for reviewing and approving the preservative efficacy test results to ensure compliance with regulatory requirements and internal specifications.

4. Accountability

The QC Manager is accountable for ensuring that preservative efficacy testing is carried out as per this SOP. The Production Supervisor is responsible for providing representative samples for testing. The QA Manager ensures that the test results comply with regulatory and internal quality standards.

5. Procedure

5.1 Pre-Test Preparation

1. Ensure that all necessary equipment for preservative efficacy testing is available, including microbiological incubators, sterilized containers, and microbiological media (e.g., tryptic soy broth, sabouraud dextrose agar).
2. Ensure that the water activity meter, autoclave, and other microbiological testing instruments are calibrated and ready for use.
3. Review the batch records to identify the cream formulations to be tested and to confirm the preservatives used in the formulation.

5.2 Sample Collection

1. Collect a representative sample of the cream formulation for preservative efficacy testing. The sample should be homogenous and free from contamination.
2. Label each sample with the batch number, sample ID, sampling date, and preservatives used in the formulation to ensure traceability during testing.
3. Ensure that the samples are collected from finished batches that have been fully processed and are ready for packaging.

5.3 Preservative Efficacy Testing Procedure

1. Prepare the test according to the microbiological testing procedure:
   • Microbial Challenge Test (Challenge Testing): Inoculate the cream sample with specific microorganisms, such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans, in concentrations that represent typical contamination levels.
   • Incubate the inoculated samples at a controlled temperature (e.g., 30°C for bacteria or 25°C for fungi) for a defined period, usually 7, 14, 21, and 28 days.
   • At each designated time interval, take a sample from the inoculated cream and perform microbial counting using suitable microbiological media (e.g., agar plates for microbial growth).
   • Perform appropriate dilution and plating techniques to quantify the microbial growth.
2. For each sampling point, calculate the log reduction of microorganisms. The preservative is considered effective if it meets the required reduction criteria as per regulatory guidelines (e.g., ≥1 log reduction in microbial count).
3. Record the microbial counts and other observations (e.g., changes in physical appearance) in the Preservative Efficacy Testing Log (Annexure-1).

5.4 Interpretation of Results

1. Compare the microbial count at each time point with the initial inoculum. A preservative efficacy test passes if the cream formulation demonstrates a ≥1 log reduction in microbial count at the end of the test period.
2. If the formulation does not meet the specified microbial reduction criteria, mark the test result as “Fail.” Investigate the cause of failure, which may include evaluating the preservative concentration, formulation, or processing methods.
3. If the formulation passes the test, mark the test result as “Pass” and proceed with the next stage of production or distribution.

5.5 Post-Test Activities

1. Record all test results, including batch number, sample ID, microbial count, test duration, and any corrective actions taken, in the Preservative Efficacy Testing Log (Annexure-1).
2. If any sample fails the test, initiate corrective actions, which may include adjusting the preservative concentration or modifying the formulation. Re-test the sample after corrective actions.
3. Submit the test results to the QA team for review and approval to ensure compliance with regulatory and internal standards.

5.6 Documentation and Record-Keeping

1. Ensure that all preservative efficacy testing records are complete, accurate, and securely stored. This includes the Preservative Efficacy Testing Log (Annexure-1) and the Deviation Log (Annexure-2) for failed tests.
2. Retain all records for a minimum of two years or as required by regulatory guidelines.
3. Ensure that records are reviewed and approved by the Quality Assurance team to verify compliance with GMP standards and regulatory requirements.

6. Abbreviations

• GMP: Good Manufacturing Practices
• QC: Quality Control
• QA: Quality Assurance
• PPE: Personal Protective Equipment
• PET: Preservative Efficacy Testing

7. Documents

1. Annexure-1: Preservative Efficacy Testing Log
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
• USP <795> – Pharmaceutical Compounding of Nonsterile Preparations

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Preservative Efficacy Testing Log

Annexure-2: Deviation Log

Revision History:

SOP for Ensuring Data Integrity During Analytical Method Development Activities

1. Purpose

This SOP outlines the principles and procedures required to ensure data integrity during analytical method development activities. It ensures that all data—whether electronic or paper-based—are accurate, complete, consistent, and secure throughout their lifecycle.

2. Scope

This SOP applies to all data generated during method development, including raw data, chromatograms, spectra, calculations, reports, electronic audit trails, and records associated with analytical instrumentation and software within the AMD department.

3. Responsibilities

• Analytical Scientists: Generate, record, and review data in accordance with ALCOA+ principles and GMP requirements.
• QA: Conducts periodic data integrity audits and reviews audit trails and logbooks.
• IT: Ensures access controls, backup, and system security for computerized systems.
• Head – AMD: Ensures enforcement of data integrity procedures and takes corrective actions for any breach.

4. Accountability

The Head of AMD is accountable for ensuring continuous enforcement of data integrity practices across all AMD activities and reporting any suspected data falsification or non-compliance to senior management.

5. Procedure

5.1 Data Integrity Principles (ALCOA+)

1. Ensure that all data meet the following criteria:
   • Attributable: Data must clearly identify the person generating it.
   • Legible: Records must be readable and permanent.
   • Contemporaneous: Recorded at the time of activity.
   • Original: First recorded observation or certified true copy.
   • Accurate: Free from errors, edited with justification if needed.
   • Complete, Consistent, Enduring, Available: ALCOA+ attributes

5.2 Electronic Data Handling

1. Use validated software systems with 21 CFR Part 11 compliance (e.g., Empower, LabSolutions).
2. Enable secure login with role-based access control.
3. Ensure electronic records are backed up on secure servers as per SOP/IT/005/2025.
4. Enable and retain audit trails without overwrite capability.
5. Printouts or exported data must be linked to original raw data for traceability.

5.3 Paper-Based Record Management

1. Entries must be made using indelible ink and signed with date/time.
2. No overwriting or backdating is permitted. Corrections must include:
   • Strike-through single line
   • Initials, date, and reason for change
3. All paper records must be stored in secure, access-controlled storage areas.

5.4 Data Review and Approval

1. All data must be reviewed by a second analyst or reviewer before final reporting.
2. Review includes:
   • Chromatograms/spectra match calculations
   • Audit trails reviewed and signed
   • Any data exclusion is justified and approved by QA
3. Document review status in Annexure-1: Data Integrity Review Checklist.

5.5 Audit Trail Monitoring

1. Audit trails of key systems (HPLC, GC, UV) shall be reviewed weekly or per method lifecycle.
2. Events monitored include:
   • Deletion of data files
   • Changes to integration parameters
   • Modifications to user access
3. Record observations in Annexure-2: Audit Trail Review Log.

5.6 Data Integrity Breach Handling

1. Suspected data manipulation or falsification must be reported immediately to QA and Head – AMD.
2. QA initiates deviation report and conducts root cause analysis.
3. Corrective actions may include:
   • User retraining
   • Revocation of access
   • Revision of SOPs
4. All incidents to be tracked using Annexure-3: Data Integrity Incident Register.

5.7 Training and Awareness

1. All analysts and reviewers must undergo annual data integrity training.
2. Training topics include ALCOA+, audit trail use, record keeping, and data falsification consequences.
3. Document participation in Annexure-4: Data Integrity Training Log.

6. Abbreviations

• AMD: Analytical Method Development
• QA: Quality Assurance
• ALCOA+: Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, Available
• SOP: Standard Operating Procedure

7. Documents

1. Data Integrity Review Checklist – Annexure-1
2. Audit Trail Review Log – Annexure-2
3. Data Integrity Incident Register – Annexure-3
4. Data Integrity Training Log – Annexure-4

8. References

• FDA Guidance on Data Integrity and Compliance with CGMP
• MHRA GxP Data Integrity Guidance
• WHO TRS 1019 Annex 5 – Good Data and Record Management Practices
• 21 CFR Part 11 – Electronic Records; Electronic Signatures

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Data Integrity Review Checklist

Annexure-2: Audit Trail Review Log

Annexure-3: Data Integrity Incident Register

Annexure-4: Data Integrity Training Log

Revision History:

Standard Operating Procedure for Reconciliation of Clinical Sample Volumes in BA/BE Studies

1. Purpose

To establish a systematic procedure for reconciling the clinical samples collected during Bioavailability/Bioequivalence (BA/BE) studies to ensure sample traceability, prevent loss or misidentification, and maintain integrity of the study.

2. Scope

This SOP applies to all clinical and sample handling staff responsible for collection, labeling, transfer, processing, storage, and reconciliation of clinical samples (e.g., blood, plasma) during BA/BE trials.

3. Responsibilities

• Clinical Research Coordinator (CRC): Ensures samples are labeled correctly and reconciled after each collection timepoint.
• Sample Processing Technician: Checks volumes post-centrifugation and maintains reconciliation records.
• QA Officer: Verifies completeness and traceability of sample records during audits and inspections.
• Principal Investigator (PI): Reviews discrepancies and approves CAPA where applicable.

4. Accountability

The Head of Clinical Operations and PI are accountable for ensuring that clinical samples are accurately reconciled, documented, and traceable from collection to analysis or disposal.

5. Procedure

5.1 Pre-Sample Collection Preparation

1. Prepare Sample Collection Labels with Volunteer ID, Study Code, and Timepoint (e.g., VOL110-001 / 0hr / BE-2025).
2. Pre-fill Annexure-1: Sample Collection Register with scheduled timepoints.

5.2 Sample Collection and Labeling

1. Collect blood samples as per the approved study protocol.
2. Label tubes immediately at bedside using waterproof marker or pre-printed barcode.
3. Document volume collected (e.g., 4 mL) in Annexure-2: Sample Volume Tracking Sheet.

5.3 Sample Transfer and Centrifugation

1. Transport samples in temperature-controlled sample carriers to processing lab within 30 minutes.
2. After centrifugation, separate plasma and record plasma volume obtained (e.g., 2.8 mL).
3. Note plasma volume in reconciliation log against each subject and timepoint.

5.4 Sample Volume Reconciliation

1. Match collected vs. expected samples for each timepoint using Annexure-3: Reconciliation Log.
2. Any missing, broken, clotted, or hemolyzed samples must be documented with reason and PI notified.
3. Sign and date reconciliation form by CRC and verified by QA or designee.

5.5 Handling Discrepancies

1. Classify discrepancies as minor (e.g., label smudge) or major (e.g., lost or untraceable sample).
2. Document in Annexure-4: Sample Discrepancy and CAPA Log.
3. CAPA to be initiated and signed by PI and QA.

5.6 Storage and Handover

1. Transfer reconciled and aliquoted plasma to storage (-20°C or -70°C) based on protocol requirements.
2. Use Annexure-5: Storage Box Inventory Sheet to document box number, position, and volume.

6. Abbreviations

• BA: Bioavailability
• BE: Bioequivalence
• CRC: Clinical Research Coordinator
• PI: Principal Investigator
• CAPA: Corrective and Preventive Action

7. Documents

1. Sample Collection Register – Annexure-1
2. Sample Volume Tracking Sheet – Annexure-2
3. Sample Reconciliation Log – Annexure-3
4. Sample Discrepancy and CAPA Log – Annexure-4
5. Storage Box Inventory Sheet – Annexure-5

8. References

• ICH E6(R2) – Good Clinical Practice
• Schedule Y – Drugs and Cosmetics Rules
• Sponsor Protocol and Sample Handling Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Sample Collection Register

Annexure-2: Sample Volume Tracking Sheet

Annexure-3: Sample Reconciliation Log

Annexure-4: Sample Discrepancy and CAPA Log

Annexure-5: Storage Box Inventory Sheet

Revision History:

Standard Operating Procedure for Double Check System During Dispensing of Materials

1. Purpose

This SOP establishes the procedure for implementing a Double Check System during the dispensing of raw materials, excipients, and solvents in the Elixir Department. It ensures that dispensing is carried out with full accuracy, traceability, and regulatory compliance, reducing the risk of human error.

2. Scope

This SOP applies to all materials dispensed for elixir manufacturing processes and must be followed by the designated dispensing operator and verifying personnel involved in material handling and weighing.

3. Responsibilities

• Dispensing Operator:
  • Perform the initial dispensing activity and fill out the required documentation.
  • Ensure readiness for second-person verification.
• Second Verifier (Supervisor or Authorized Personnel):
  • Verify material name, batch number, weight, container label, and documentation entries.
  • Sign the verification section on the dispensing log and BMR.
• QA Officer:
  • Periodically audit double check entries and approve completeness of documentation.

4. Accountability

The Production Head is accountable for enforcing this SOP and ensuring that no material is released for manufacturing without completion of double verification during dispensing.

5. Procedure

5.1 Preparation Before Dispensing

1. Ensure the dispensing booth, balance, and accessories are clean and calibrated.
2. Verify the approved status of the raw material and confirm storage conditions.
3. Prepare dispensing logbook and relevant BMR page for real-time entry and signature.

5.2 First-Person Activity

1. The dispensing operator shall:
   • Identify the material and verify label details.
   • Weigh the material as per the batch requirement.
   • Record the following:
     • Material Name
     • Batch Number
     • Weighed Quantity
     • Date
     • Sign and mention time of activity

5.3 Second-Person Verification

1. The verifier shall:
   • Cross-check the material label against the entry in the dispensing log.
   • Verify the actual weight using the same calibrated balance.
   • Ensure the container has been sealed and labeled properly after dispensing.
   • Sign the double check section of the dispensing log and mark date/time of verification.

5.4 Documentation and Labeling

1. Affix “Double Checked” status label on each dispensed container with initials of both personnel.
2. All entries in the dispensing log must be verified before transferring material to production.

5.5 Exception Handling

1. If a discrepancy is found during verification:
   • Stop further processing and inform QA immediately.
   • Document the deviation using the standard Deviation Form.
   • Retain the material in a segregated area until disposition is authorized.

6. Abbreviations

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

7. Documents

1. Material Dispensing Log with Verification Section (Annexure-1)
2. Double Checked Container Label Format (Annexure-2)
3. Deviation Reporting Form (Annexure-3)

8. References

• WHO GMP Guidelines – Pharmaceutical Production
• 21 CFR Part 211 – Current GMP for Finished Pharmaceuticals

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Material Dispensing Log with Verification Section

Annexure-2: Double Checked Container Label

Annexure-3: Deviation Reporting Form

Revision History:

Standard Operating Procedure for Real-Time Yield Monitoring During Reactions in API Manufacturing

1. Purpose

To define the procedure for real-time yield monitoring during chemical reactions in the manufacturing of Active Pharmaceutical Ingredients (APIs) in order to assess process efficiency, trigger corrective actions, and support in-process control.

2. Scope

This SOP applies to all chemical synthesis processes in API manufacturing where reaction progress and intermediate product yields are calculated in real time for monitoring and optimization.

3. Responsibilities

• Production Chemist: Monitor reaction time and record in-process yield data.
• QC Analyst: Analyze samples for yield determination (e.g., by HPLC, gravimetric, titrimetric methods).
• QA Officer: Review records and ensure results are documented as per GMP.

4. Accountability

The Production Head is accountable for implementation. QA Head is responsible for compliance review and deviation handling.

5. Procedure

5.1 Yield Monitoring Plan

1. Define yield checkpoints in the Batch Manufacturing Record (BMR) based on reaction stages (e.g., after 30%, 60%, and 100% theoretical conversion).
2. Use validated methods for quantitative analysis, e.g., HPLC assay, LOD correction, or titration.

5.2 Sampling

1. Collect ~2–5 mL (or as required) of reaction mass in clean, dry containers at defined time points.
2. Label sample with Batch No., Reaction Stage, Date, Time, and Initials.
3. Deliver sample immediately to QC; store under controlled conditions if delayed.

5.3 Analytical Testing

1. Perform testing to quantify desired product concentration.
2. Document result as concentration (% w/w or % area) or mass obtained per volume sampled.

5.4 Yield Calculation

1. Calculate yield as per formula:
   % Yield = (Actual Amount of Product / Theoretical Amount) × 100
2. Use molecular weights and stoichiometry as defined in the MFR.
3. Adjust for dilution factors, LOD (moisture), or assay correction if applicable.

5.5 Trending and Response

1. Plot yield data on control charts for trend evaluation.
2. If yield is outside target range (e.g., ±5% of expected), inform QA and investigate root cause.
3. Delay or abort next stage if yield is critically low or shows unexpected decline.

5.6 Documentation

1. Record all yields, calculations, and time stamps in the Reaction Yield Log (Annexure-1).
2. Attach corresponding QC report or test printouts.
3. Review and sign by Production Supervisor and QA Reviewer.

6. Abbreviations

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

7. Documents

1. Reaction Yield Log (Annexure-1)
2. Batch Manufacturing Record
3. Analytical Test Reports

8. References

• ICH Q8 – Pharmaceutical Development
• 21 CFR Part 211 – US FDA GMP
• WHO TRS 986 – GMP for APIs

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Reaction Yield Log

Revision History:

SOP for Validating Temperature Sensors in Aerosol Manufacturing

1. Purpose

The purpose of this Standard Operating Procedure (SOP) is to provide guidelines for the validation of temperature sensors used in aerosol manufacturing. Temperature sensors are critical for monitoring and controlling temperatures during the production process, including the filling, mixing, and curing stages. This SOP ensures that temperature sensors are accurate, reliable, and calibrated according to defined standards, ensuring that product quality and safety are maintained.

2. Scope

This SOP applies to the validation of all temperature sensors used in aerosol manufacturing processes, including those used in mixers, filling machines, storage tanks, and any other temperature-sensitive equipment. The validation process includes the calibration of the temperature sensors, verification of their accuracy, and the documentation of the results.

3. Responsibilities

• Engineering Team: Responsible for overseeing the validation process for temperature sensors, ensuring that the sensors are calibrated and functioning properly according to the defined standards.
• Production Team: Responsible for ensuring the proper operation of the temperature sensors during the manufacturing process and reporting any discrepancies or malfunctions.
• Quality Assurance (QA) Team: Responsible for reviewing and approving the temperature sensor validation documentation, ensuring that the validation meets regulatory standards and GMP requirements.
• Maintenance Team: Responsible for maintaining the temperature sensors and performing corrective actions if any issues are detected during the validation process.

4. Accountability

The Manufacturing Manager is accountable for ensuring that the temperature sensor validation process is conducted and documented in compliance with this SOP. The overall compliance with this SOP is overseen by the Quality Assurance (QA) Manager.

5. Procedure

5.1. Preparing for Temperature Sensor Validation

1. Before starting the validation process, ensure that all temperature sensors are installed correctly and in their designated locations. Verify that the sensors are properly connected to the measurement system and that the system is operational.
2. Ensure that all necessary calibration equipment is available, including calibration thermometers, standard reference materials, and temperature-controlled baths or ovens.
3. Verify that the temperature sensors are clean and free from any contaminants or damage before conducting the validation.
4. Review the manufacturer’s specifications for the temperature sensors to understand the required calibration methods, acceptable tolerance limits, and the performance characteristics of the sensors.
5. Establish the validation team, which should include representatives from the Engineering, Production, and QA teams.

5.2. Conducting the Temperature Sensor Validation

1. Perform the following tests as part of the temperature sensor validation process:
   • Calibration Test: Use a calibrated reference thermometer or temperature calibration device to measure the temperature at several points across the sensor’s operational range. The temperature sensor readings should be compared to the reference thermometer readings to verify accuracy.
   • Accuracy Test: Test the temperature sensor by measuring known temperature standards (e.g., ice water at 0°C and boiling water at 100°C) to ensure that the sensor provides accurate readings under controlled conditions.
   • Repeatability Test: Repeat the calibration test multiple times to ensure that the sensor consistently provides the same readings under the same conditions.
   • Linear Range Test: Verify that the temperature sensor provides consistent and linear readings across its specified temperature range. Use known temperature standards to confirm the sensor’s linearity.
   • Environmental Testing: Verify that the temperature sensor operates correctly under the environmental conditions in which it will be used (e.g., ambient temperature, humidity). Ensure that the sensor’s performance is not affected by factors outside the specified operating range.
2. Record all test results, including the test conditions, measured values, and any deviations observed. Document the calibration, accuracy, and repeatability results in the Temperature Sensor Validation Report (Annexure-1).

5.3. Documenting the Validation Results

1. Document the following information in the Temperature Sensor Validation Report (Annexure-1):
   • Details of the temperature sensor, including the model, serial number, and installation location
   • The reference calibration standards used for testing
   • The results of each validation test (e.g., calibration, accuracy, repeatability, linear range)
   • The name and signature of the personnel who performed the validation tests
   • The date and time of testing
2. Ensure that the validation report is signed and approved by the responsible personnel (e.g., Engineering, Production, and QA teams).

5.4. Reviewing and Approving the Validation Report

1. The QA team should review the Temperature Sensor Validation Report to ensure that all tests have been conducted according to the protocol and that the sensor meets the required accuracy and performance specifications.
2. If any deviations are observed during the validation process, they should be documented in the Deviation Log (Annexure-2), and corrective actions should be taken.
3. The QA team should approve the report once all validation activities are complete and any deviations have been addressed.

5.5. Finalizing the Validation Process

1. Once the temperature sensor is validated, it is considered ready for use in the aerosol manufacturing process. The validated sensor can be used for ongoing temperature monitoring and control during production.
2. All documentation, including the Temperature Sensor Validation Report, Deviation Log, and any corrective actions, should be archived for future audits and inspections.
3. Periodic revalidation and calibration activities should be scheduled as per the manufacturer’s recommendations and regulatory requirements.

6. Abbreviations

• GMP: Good Manufacturing Practice
• QA: Quality Assurance
• SOP: Standard Operating Procedure
• CAPA: Corrective and Preventive Action
• OQ: Operational Qualification
• PQ: Performance Qualification
• IQ: Installation Qualification

7. Documents

1. Temperature Sensor Validation Report (Annexure-1)
2. Deviation Log (Annexure-2)

8. References

This SOP is based on the following regulatory guidelines and industry standards:

• Good Manufacturing Practice (GMP) Guidelines
• FDA Code of Federal Regulations (CFR) Title 21, Part 211
• International Council for Harmonisation (ICH) Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

11. Annexures

Annexure-1: Temperature Sensor Validation Report

Annexure-2: Deviation Log

12. Revision History: