Fundamentals of Sterile Filtration Integrity Validation in Parenteral Nutrition (TPN) Manufacturing

All equipment used in this process validation must be duly qualified and validated for its intended use and performance specifications. Equipment qualification (IQ/OQ/PQ) is assumed to be completed prior to this process validation.

Quality Target Product Profile (QTPP) and Desired Attributes of Sterile Filtration in TPN

Step 1: Define the critical attributes in the QTPP related to sterile filtration. For TPN, these include sterility assurance, particulate matter control, and compatibility with nutrient solutions.

Step 2: Determine the filtration parameters that support these attributes, such as pore size (typically 0.22 μm), filter membrane compatibility, and flow rates that prevent filter damage or product degradation.

Step 3: Establish acceptable sterility assurance levels (SAL), usually at 10⁻⁶, aligning with pharmacopeial and regulatory guidance for parenteral products.

Impact of Sterile Filtration Integrity on the QTPP and Critical Quality Attributes (CQAs)

Step 1: Detail how filter integrity directly influences sterility and microbial bioburden prevention, a core CQA of TPN.

Step 2: Describe effects on particulate matter levels, ensuring no filter shedding or compromising particulates enter the final formulation.

Step 3: Highlight considerations for maintaining nutrient composition, as filter interactions should not alter concentration, pH, or osmolarity.

Key Properties and Parameters for Sterile Filtration Integrity Validation

Step 1: Select appropriate integrity test methods, such as bubble point, diffusion rate, or pressure hold tests, based on filter type and process conditions.

Step 2: Establish test acceptance criteria aligned with the manufacturer’s specifications and validated baseline data.

Step 3: Define test timing and frequency, including preuse and postuse integrity assessment, to ensure continuous compliance throughout manufacturing.

Step 4: Evaluate filter compatibility with TPN components to avoid filter fouling or chemical interaction that might compromise integrity.

Introduction to Sterile Filtration Integrity Validation in TPN Manufacturing

Sterile filtration integrity validation is a critical process in the manufacturing of Total Parenteral Nutrition (TPN) to ensure the sterile barrier is uncompromised, preventing microbial contamination before final product filling. This validation must confirm sterile filters consistently perform within defined parameters under actual processing conditions.

Risk Assessment and Failure Mode Effects Analysis (FMEA)

Begin with a comprehensive risk assessment focusing on sterile filtration as a critical control point (CCP) in TPN manufacturing. Use FMEA to identify potential failure modes associated with the sterile filtration process:

• Failure Modes: Filter integrity breach, improper filter installation, pressure drop anomalies, filter membrane defects, equipment malfunction.
• Effects: Microbial contamination, product sterility failure, batch rejection, patient safety risk.
• Severity (S): Rate severity on a scale (e.g., 1–10), with microbial contamination controlling patient safety scoring highest.
• Occurrence (O): Estimate frequency based on historical data or similar products/processes.
• Detectability (D): Assess how reliably current monitoring detects defects or breaches.

Calculate Risk Priority Number (RPN = S × O × D) to prioritize controls. Focus validation efforts on high RPN failure modes.

Critical Process Parameters (CPP) Selection

Identify and define CPPs that impact sterile filtration integrity, including:

• Filter pore size and membrane type (e.g., 0.22 µm rated sterilizing-grade filters).
• Filtration pressure differential across the membrane.
• Flow rate during filtration.
• Filter integrity testing parameters (bubble point, diffusion test criteria).
• Filter installation procedures and filter lot usage history.
• Environmental controls in the filtration enclosure (temperature, humidity, particulate monitoring).

Document CPPs clearly with acceptance criteria aligned to regulatory guidance and filter manufacturer’s instructions.

Design of Experiments (DoE) for Process Optimization

Design experiments to understand and control CPP variability on sterile filtration integrity. A factorial DoE approach can be used to test the effects of:

• Variable filtration pressures (within established limits).
• Flow rates at low and high ends of the process range.
• Filter membrane lots or manufacturer variability.
• Operating environmental conditions.

Analyze results to confirm a robust operating range where filter integrity testing consistently passes and no breaches occur. Use this data to set acceptable process ranges.

Developing the Control Strategy

Establish a control strategy that integrates CPP monitoring with sterility assurance. Key elements include:

• Pressure Differential Monitoring: Continuous monitoring during filtration to detect membrane rupture or breach.
• Filter Integrity Testing: Conduct pre- and post-filtration integrity tests using validated methods such as bubble point or diffusion tests.
• Visual Inspection: Confirm correct filter installation, absence of damage, and intact aseptic connectors immediately before filtration.
• Environmental Monitoring: Maintain controlled cleanroom conditions with real-time viable and particulate counts.
• Procedural Controls: Standard Operating Procedures (SOPs) for filter handling, installation, aseptic techniques, and validation execution.

Defining Acceptable Ranges and Specifications

Set acceptance criteria based on process data and regulatory guidance:

• Filter Integrity Test Limits: Bubble point pressure within manufacturer’s recommended range for the specific filter type.
• Pressure Differential: Remain below maximum allowable differential to prevent filter rupture (e.g., <0.5 bar).
• Flow Rate: Maintain within validated limits ensuring no excessive filtration stress.
• Environmental Control Limits: Particulate and microbial counts per USP or ISO class requirements.

Stepwise Workflow for Sterile Filtration Integrity Validation

1. Pre-validation Preparation: Confirm all filtration equipment have completed IQ/OQ/PQ qualification. Ensure filter lot records and certificates of analysis are available.
2. Filter Installation Verification: Document installation steps with a checklist to ensure aseptic technique and correct filter orientation.
3. Conduct Pre-filtration Integrity Test: Perform bubble point or diffusion test in situ to verify filter integrity prior to process use.
4. Execute Sterile Filtration Under Standardized Conditions: Run filtration on process buffer or solution simulating TPN formulation, monitoring pressure differential and flow rate continuously.
5. Conduct Post-filtration Integrity Test: Immediately after filtration, repeat bubble point test to confirm no compromise occurred during filtration.
6. Environmental Monitoring Throughout: Capture cleanroom particulate and microbiological data for the duration of filtration and integrity testing.
7. Sample and Analysis: Collect representative samples from filtrate at predetermined intervals for microbial challenge and total bioburden testing as part of validation batches.
8. Data Review and Decision Making: Collate all test results and monitoring data. Evaluate against acceptance criteria.
9. Report and Document Findings: Summarize process capability to maintain sterile barrier integrity and justify validated status in validation protocol report.

Sampling and Decision Points

Define sampling locations and frequency according to process flow and regulatory expectations:

• Sample filtrate immediately post-filtration for microbiological testing prior to filling.
• Perform integrity tests on every batch filter pre- and post-filtration.
• Take environmental samples inside the filtration cabinet and adjacent clean zones before, during, and after filtration.
• Use trending data to assess process stability and trigger investigations for excursions.

Decision-making criteria for batch acceptance include passing sterile filter integrity tests, stable CPP parameters, and negative microbiological results.

Process Performance Qualification (PPQ) Batch Execution

Carry out PPQ batches under routine manufacturing conditions to confirm reproducibility of sterile filtration integrity. Steps to execute PPQ include:

1. Prepare batch record incorporating all sterile filtration controls and monitoring points.
2. Execute filtration with real-time monitoring of CPPs and environmental parameters.
3. Document integrity test results, environmental monitoring, and sample testing for each PPQ batch.
4. Review deviations or anomalies immediately, with defined corrective actions.
5. Finalize PPQ after three consecutive successful batches unless otherwise justified by risk assessment.
6. Submit package documentation including SOPs, qualification reports, validation protocol and report, and PPQ data for regulatory review.

Protocol Design Considerations

Construct a detailed sterile filtration integrity validation protocol addressing:

• Scope and objectives aligned to sterile filtration as a critical operation in TPN manufacturing.
• Comprehensive process description and acceptance criteria.
• Roles and responsibilities for validation execution and review.
• Methodology for pre- and post-filtration integrity testing, including calibration status of test equipment.
• Environmental monitoring plans tied to critical time points.
• Planned number of validation/PPQ batches with rationale.
• Sampling plans with defined sample sizes, types of tests, and decision rules for batch disposition.
• Data management and statistical analysis approach for CPP variability.
• Risk mitigation plan for any identified failure modes.

Batch Evaluation and Post-Validation Actions

After batch execution, perform the following:

• Compile and review all process data, including filter integrity results, CPP data, environmental monitoring, and microbiological testing.
• Evaluate any deviations or nonconformities and implement corrective and preventive actions (CAPA) as needed.
• Perform trend analysis across batches to detect emerging risks or process drift.
• Confirm sustained capability of the sterile filtration process to maintain product sterility.
• Approve final validation report documenting successful validation or justification for further investigation if failures occurred.
• Incorporate validated control strategy into routine manufacturing practices and change control protocols.

By following this rigorous, stepwise sterile filtration integrity validation procedure tailored to TPN manufacturing, firms can ensure consistent product sterility, regulatory compliance, and patient safety.

Control Strategy Development

Establish a robust control strategy encompassing all CPPs identified earlier. This strategy should include:

• Standard Operating Procedures (SOPs) for filter installation, handling, and integrity testing.
• In-process checks such as differential pressure monitoring during filtration and visual inspections.
• Automated alarms and shutdown triggers in case of process deviations (e.g., excessive pressure drop).
• Environmental monitoring within the filtration area to maintain ISO class cleanliness and suitable conditions.
• Filter lot traceability to ensure filters used meet quality specifications and are within expiry.

Document acceptable ranges for CPPs within which sterile filtration integrity is assured, based on DoE data and filter manufacturer guidance.

Process Flow and Stepwise Workflow

1. Preparation of TPN solution under aseptic conditions following formulation SOP.
2. Pre-filtration visual and particle inspection of feed solution.
3. Filter installation performed according to validated SOPs.
4. Filtration under controlled pressure and flow rate within predefined CPP limits.
5. Continuous pressure differential and flow rate monitoring during filtration.
6. Post-filtration filter integrity testing using bubble point or diffusion methods.
7. Recording and evaluation of filter integrity results against acceptance criteria.
8. Proceed to aseptic filling only if filter integrity criteria are met; otherwise, batch rejection or investigation.

Sampling and Decision Points

• Perform filter integrity testing on every filter post-filtration cycle to verify barrier function.
• Sample feed solution and filtrate for microbial and endotoxin testing as applicable.
• Establish clear decision trees: pass criteria for filter integrity, pressure differential within limits, absence of leaks or failures.
• Investigate any integrity failure or CPP excursions immediately before batch release consideration.
• Implement a hold point in the process prior to aseptic filling pending integrity test results.

Process Performance Qualification (PPQ)

Execute PPQ batches to demonstrate consistent sterile filtration integrity under routine manufacturing conditions:

• Manufacture a minimum of three consecutive batches according to validated protocols.
• Monitor CPPs and filter integrity results throughout each batch.
• Gather comprehensive data for process stability, including environmental conditions and equipment performance.
• Perform statistical analysis to confirm process capability and reproducibility of sterile filtration step.
• Document all deviations and implement corrective actions as necessary.

Successful PPQ completion supports the validated state of sterile filtration for commercial manufacturing of TPN.

Validation Protocol Design

Develop a detailed sterile filtration integrity validation protocol that includes:

• Objectives and scope clearly stating filtration validation in TPN manufacturing.
• Defined acceptance criteria for all CPPs and filter integrity test results.
• Test methods and calibration requirements for integrity instruments.
• Sampling plans and frequency for filter integrity and microbial testing.
• Roles and responsibilities of personnel performing and reviewing validation activities.
• Procedures for deviation handling, revalidation triggers, and documentation practices.

The protocol must be approved prior to execution and comply with relevant regulatory guidelines such as USP Sterilizing Filtration chapters and FDA expectations.

Batch Execution and Evaluation

During batch execution, follow the validated protocol and SOPs strictly:

• Document real-time CPP data and filter integrity results per batch.
• Ensure prompt response to CPP excursions or filter integrity test failures.
• Compile all batch records for comprehensive evaluation post-process completion.
• Perform trend analysis across batches to detect potential drifts or emerging failure modes.
• Conclude validation by submitting a report summarizing all findings, deviations, root cause analyses, and final acceptance.

Maintain robust change control aligned with validation lifecycle to preserve validated sterile filtration performance throughout TPN manufacturing.

Control Strategy Development

Develop a robust control strategy based on the CPPs and risk assessment outcomes to maintain sterile filtration integrity throughout TPN manufacturing. Key elements include:

• Standard Operating Procedures (SOPs) for filter installation, integrity testing, and maintenance.
• Defined acceptance criteria for pressure differentials and flow rates to prevent filter damage.
• Routine in-process monitoring, such as continuous pressure and flow monitoring with alarms for excursions.
• Pre- and post-filtration integrity testing using validated methods (bubble point or diffusion test) to confirm filter sterility.
• Environmental controls to maintain cleanroom standards around filtration units.

Establishing Acceptable Parameter Ranges

Set allowable parameter ranges informed by DoE results, supplier guidelines, and regulatory expectations. Critical limits must include:

• Filtration Pressure: Maintain within range to avoid filter rupture or flow restriction (e.g., 15–30 psi).
• Flow Rate: Control within validated limits (e.g., 0.1–0.3 L/min) to ensure proper filtration without exceeding membrane capacity.
• Integrity Test Criteria: Bubble point and diffusion values must meet or exceed manufacturer’s minimum thresholds.

Process Flow and Stepwise Workflow

1. Prepare filtration system and sterilize as per validated procedures.
2. Install sterilizing-grade filter with correct orientation and ensure secure connections.
3. Perform initial integrity test pre-filtration to establish baseline integrity.
4. Conduct sterile filtration of TPN solution within defined CPP parameters.
5. Conduct post-filtration integrity test immediately after filtration to confirm filter integrity.
6. Document all parameters and test results in batch records.
7. Perform environmental and operator hygiene checks concurrently.

Sampling and Decision Points

• Sample integrity test data at each filtration event for batch release decisions.
• Set go/no-go criteria based on integrity test outcomes and CPP adherence.
• Include microbial challenge test data from validation batches as supplementary assurance.
• Record all deviations and conduct root cause analysis for any filter failures or out-of-specification (OOS) events.

Process Performance Qualification (PPQ) Protocol Design

The PPQ protocol must:

• Define objectives to demonstrate sterile filtration reproducibility and robustness under commercial-scale conditions.
• Include representative batches covering worst-case CPP combinations from DoE studies.
• Detail sampling plans for integrity testing, environmental monitoring, and critical CPPs.
• Outline acceptance criteria aligned to established control strategy and risk tolerance.
• Specify documentation and review processes to capture all data and support product sterility claims.

Batch Execution and Evaluation

Execute PPQ batches strictly per protocol:

• Assign qualified operators and ensure full training on sterile filtration procedures.
• Monitor and record CPPs continuously; document any deviations immediately.
• Perform integrity testing pre- and post-filtration and log results for batch release.
• Review environmental monitoring data to confirm aseptic conditions were maintained.
• Perform comprehensive batch data review post-execution to identify trends or anomalies.
• Prepare a formal validation report summarizing compliance, deviations, and conclusions.

Control Strategy Development

Develop a robust control strategy targeting identified CPPs to ensure sterile filtration integrity. This strategy should include:

• Standard Operating Procedures (SOPs) for filter installation and handling to prevent physical damage or contamination.
• Routine pre-use integrity testing (e.g., bubble point or diffusion tests) to verify filter performance before commencing filtration.
• Continuous monitoring of pressure differential and flow rate during the filtration process, with defined acceptance criteria.
• Environmental monitoring of the filtration area to maintain sterile conditions, including particulate counts and microbiological surveillance.
• Implementation of in-process controls such as filter leak tests and visual inspections.

Acceptable Ranges and Monitoring

Define specific acceptance criteria and monitoring frequencies for each CPP, for example:

• Filter integrity test limits: bubble point pressure within ±10% of manufacturer’s specified value.
• Pressure differential: maintained within validated lower and upper limits to ensure adequate flow without risking filter damage.
• Flow rate: controlled within the validated process range to avoid filter stress or bypass.
• Environmental parameters: operated within ISO Class 5 laminar flow conditions with continuous particulate and viable counts below established thresholds.

Monitoring should be documented and deviations promptly investigated.

Process Flow and Stepwise Workflow

Outline a detailed workflow including critical filtration steps:

1. Pre-filtration preparation: verification of filter lot certificate, visual inspection, and pre-use integrity test.
2. Assembly: aseptic integration of the sterile filter into the filtration setup following validated procedures.
3. Filtration: passage of TPN solution through the filter under controlled pressure and flow rate, with continuous monitoring.
4. Post-filtration integrity test: immediate re-test of the filter integrity to confirm no breach during processing.
5. Documentation: accurate recording of all parameters and test results for batch record review.

Sampling and Decision Points

Define critical sampling points and decision criteria:

• Pre-use Integrity Test Sample: must pass before filtration can proceed.
• In-Process Parameter Monitoring: if measurements deviate beyond acceptance limits, hold or reject the batch and initiate investigation.
• Post-Use Integrity Test: failure indicates filtration breach; batch must be rejected or filtered again with a new filter.
• Microbiological Sampling: environmental and product samples taken at defined intervals to verify aseptic conditions.

Process Performance Qualification (PPQ)

Design and execute PPQ batches to confirm the filtration process consistently produces sterile TPN:

• Conduct at least three consecutive batches under normal operating conditions.
• Verify all CPPs remain within accepted ranges and filters pass all integrity tests.
• Document no microbial contaminations detected in sterility testing post-filtration.
• Evaluate cumulative data to demonstrate process capability and reproducibility.
• Confirm control strategy adequacy for routine manufacturing.

Validation Protocol Design

Develop a detailed validation protocol including:

• Objectives and scope focused on sterile filtration integrity assurance.
• Detailed description of equipment, filters, and validated procedures.
• Defined acceptance criteria based on regulatory guidelines and risk assessment.
• Sampling plans and test methods for both pre-use and post-use integrity.
• Responsibilities and timelines for each stage of the validation.
• Contingency plans for deviations and failure resolution.

Batch Execution and Evaluation

During batch execution:

• Operators must adhere strictly to the protocol and control strategy.
• Real-time monitoring data are collected and reviewed for conformance.
• Any deviations detected trigger immediate investigation and corrective action.
• Post-batch evaluation includes thorough review of all test and monitoring data, integrity test results, and environmental parameters.
• Approval or rejection decisions are based on aggregated data and compliance with predefined criteria.

Control Strategy Development

• Establish Critical Control Points (CCPs): Confirm sterile filtration as a CCP where rigorous monitoring and controls must be applied.
• Parameter Limits: Set acceptable ranges for CPPs such as filtration pressure (e.g., 0.5–1.5 bar), flow rate (e.g., 5–15 L/min), and bubble point test thresholds based on DoE results and manufacturer recommendations.
• Standard Operating Procedures (SOPs): Develop SOPs detailing filter installation, system integrity testing, and routine monitoring steps to prevent human errors.
• Environmental Controls: Maintain cleanroom conditions and monitor particulate and microbial air levels during filtration.
• Training and Competency: Ensure operators are trained on critical process steps and integrity test execution.

Stepwise Workflow for Sterile Filtration Integrity Validation

1. Pre-filtration Setup: Inspect filter assembly, verify expiry and lot numbers, install filter according to SOP.
2. System Integrity Testing: Perform initial integrity test (bubble point or diffusion test) to verify filter function before use.
3. Filtration Execution: Conduct sterile filtration of TPN solution under controlled pressure and flow rates.
4. Post-filtration Integrity Test: Immediately re-test filter integrity after filtration to confirm no breaches occurred.
5. Sampling and Microbial Testing: Collect samples from filtered product for microbial testing and endotoxin analysis as applicable.
6. Documentation: Record all test results, process parameters, and deviations in the batch record.

Sampling and Decision Points

• Integrity Test Sampling: Perform pre- and post-filtration integrity tests on each filter used per batch.
• Microbial Sampling: Take in-process and final product samples for sterility testing according to validated sampling plans.
• Acceptance Criteria: Bubble point must meet minimum pressure thresholds; microbial tests must show no growth.
• Decision Points: If integrity test fails or microbial contamination is detected, reject batch and initiate investigation and corrective actions.

Process Performance Qualification (PPQ)

1. Batch Selection: Manufacture multiple consecutive batches under defined process conditions to demonstrate consistency.
2. Data Collection: Collect and analyze all CPP and filter integrity test data, environmental monitoring results, and microbial test outcomes.
3. Statistical Analysis: Apply statistical tools to confirm process capability and control within specified limits.
4. Review and Approval: Compile validation report and submit for quality unit review and regulatory compliance confirmation.

Protocol Design and Batch Execution Evaluation

• Protocol Elements: Define objectives, scope, responsibilities, acceptance criteria for all tests, and corrective action plans.
• Pre-Validation Activities: Confirm equipment qualification (IQ/OQ/PQ), personnel training, and calibration status of instrumentation.
• Execution: Follow the stepwise workflow during PPQ batch runs, ensuring adherence to all CPPs and control measures.
• Real-Time Monitoring: Continuously monitor filtration parameters and environmental conditions, document any deviations.
• Evaluation: After batch completion, analyze all data for compliance with acceptance criteria; log deviations and implement CAPAs as needed.

Sterile Filtration Integrity Validation in Parenteral Nutrition (TPN) Manufacturing

All equipment used in this process validation must be duly qualified and validated for its intended use and performance specifications. Equipment qualification (IQ/OQ/PQ) is assumed to be completed prior to this process validation.

Preparation and Prerequisites

1. Confirm that all sterile filtration equipment, including filters, filter housings, and associated tubing, have undergone complete equipment qualification (IQ/OQ/PQ).
2. Ensure operator training for sterile filtration integrity testing has been performed and documented.
3. Verify that the manufacturing environment meets sterile processing conditions as per current Good Manufacturing Practices (cGMP) and relevant pharmacopeial regulations.
4. Gather all relevant documentation including filter certificates of analysis, batch manufacturing records, and prior integrity test reports for reference.

Selection of Filters and Validation Batches

1. Identify filter type, pore size, and membrane material suitable for sterile filtration of TPN components (typically 0.22 µm sterilizing-grade filters).
2. Select at least three consecutive commercial-scale batches of TPN for sterile filtration integrity validation to ensure reproducibility and robustness of the filtration process.
3. Document batch identification and assign unique validation batch numbers.

Conducting Filter Integrity Testing Post-Filtration

1. Immediately after sterile filtration, perform filter integrity testing using a validated method, typically the bubble point or diffusion test, as per filter manufacturer guidelines and pharmacopeial methods.
2. Record all integrity test data, including bubble point values, pressure decay measurements, or diffusion flow rates.
3. Compare results against predefined acceptance criteria for filter integrity to confirm no compromise of the sterile barrier.
4. In the event of failure, document corrective actions and repeat filtration with a new filter.

Validation Result Tabulation for Three Batches

Comparative Summary and Statistical Analysis

Analysis: The bubble point values for all batches exceed the minimum acceptance criterion of 75 psi, confirming filter integrity. The low RSD of 1.28% indicates consistency and reproducibility of the sterile filtration process.

Documentation and Verification for Continuing Process Verification (CPV)

1. Compile all raw data sheets, equipment logs, and operator records into the sterile filtration validation dossier.
2. Verify data accuracy and completeness by cross-checking against batch manufacturing records and equipment logs.
3. Prepare a validation summary report highlighting key outcomes, compliance status, deviations observed, and risk mitigation applied.
4. Include filter integrity test certificates, deviation logs (if any), and corrective removal actions documentation.
5. Ensure formal approval signatures from quality assurance and validation departments are obtained.

Routine Monitoring of Filter Integrity during Commercial Manufacturing

1. Schedule routine integrity testing for sterile filters on each batch of TPN manufactured post-validation to maintain sterility assurance.
2. Document routine test results and verify compliance with established acceptance criteria.
3. Implement trending analysis monthly or quarterly to detect any shifts or anomalies in filter performance using control charts.
4. Establish procedures for immediate investigation and corrective actions if any integrity failures occur during routine monitoring.

Annual Product Quality Review (APQR) and Trending

1. Incorporate sterile filtration integrity data into the APQR to evaluate process performance annually.
2. Analyze cumulative filter integrity trends across batches to confirm sustained process control and identify potential improvements.
3. Document all trending results, deviations, and corrective actions in the APQR report.
4. Review filter supplier quality performance and stability of filtration equipment as part of continuous improvement.

Annexure I: Filter Integrity Test Method Validation Template

Title: Filter Integrity Test Method Validation
Objective: To validate bubble point/diffusion test method for sterile filtration filters used in TPN.
Scope: Applicable to all 0.22 µm filters used for sterile filtration.
Method Description:
- Equipment used
- Test conditions (pressure, temperature)
- Acceptance criteria
Test Protocol:
- Method suitability tests
- Repeatability
- Reproducibility
Results:
- Summary tables and graphs
Conclusion:
- Method validated for intended use
Signatures:
- QA Reviewer
- Validation Lead
Date:

Annexure II: Sterile Filtration Integrity Test Log Template

Batch Number : _______________
Date of Test : _______________
Filter Model : _______________
Test Method  : Bubble Point / Pressure Decay / Other
Test Parameters:
- Pressure applied: __________ psi
- Temperature: __________ °C
Test Results:
- Measured bubble point / pressure decay: __________
Compliance Status: Pass / Fail
Operator Name: _______________
Remarks / Observations: ___________________________________________
Signature: ____________________ Date: ____________

Annexure III: Corrective Action Report (CAR) Template for Integrity Test Failure

Date: _______________
Batch Number: _______________
Description of Failure: ________________________________________________
Root Cause Analysis: _________________________________________________
Corrective Actions Taken: ____________________________________________
Preventive Measures: ________________________________________________
Verification of Effectiveness: ___________________________________________
Authorized By: _______________ Date: _______________

Annexure IV: Continuing Process Verification (CPV) Data Review Template

Batch No. | Filter Model | Test Date | Integrity Result | Compliance | Comments
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          |              |           |                  |            |

Annexure V: Annual Product Quality Review (APQR) Sterile Filtration Summary Section Template

Review Period: ____________________
Number of Batches Reviewed: _________
Summary of Integrity Test Results:
- Total passes: ___________
- Any failures: ___________
Trend Analysis Summary:
- RSD values and control chart observations
- Deviations and investigations conducted
Supplier Quality Review: _____________________________________________
Recommendations and Improvements: ___________________________________
Prepared by: _______________ Date: _______________
Approved by: _______________ Date: _______________

Comparative Summary and Statistical Analysis

Compile results from the validation batches to assess consistency and filter performance:

• Calculate the mean bubble point values and the relative standard deviation (RSD) to evaluate variability.
• Confirm that all results meet acceptance criteria, demonstrating process robustness.
• Identify trends or anomalies in filter integrity results to inform process improvements or corrective actions.

Verification and Documentation for Continued Process Verification (CPV)

Following successful validation, implement routine monitoring and verification steps:

• Establish a routine integrity testing program for sterile filters on each batch of TPN manufactured.
• Document all routine integrity test results in batch manufacturing records and quality control logs.
• Review and trend routine data periodically as part of CPV to ensure sustained process control and identify drift or deviations early.

Incorporation of Integrity Validation Results into Annual Product Quality Review (APQR)

Integrate sterile filtration integrity data into the APQR for comprehensive product quality evaluation:

• Summarize filter integrity test outcomes, any deviations, and corrective actions taken during the review period.
• Analyze trends and variances over multiple batches to evaluate process consistency and filter supplier performance.
• Recommend any necessary process optimizations or changes to filter specifications based on APQR findings.

Annexure Templates for Standardization and Record Keeping

Use standardized templates to document and maintain validation and monitoring data efficiently. Examples include:

• Annexure I: Filter Specification and Certification Log
• Annexure II: Batch Sterile Filtration Integrity Test Report
• Annexure III: Corrective Action and Preventive Action (CAPA) Record
• Annexure IV: Routine Integrity Testing Log
• Annexure V: Annual Product Quality Review (APQR) – Sterile Filtration Section

Maintaining these annexures ensures traceability and compliance with regulatory expectations for process validation documentation.