Sterilizing Grade Membrane Filtration Validation Study Report|Filter Validation Report|0.22 Micron Filter Validation Report

1.0 OBJECTIVE:

The objective of this study is to validate the sterilizing-grade filter (0.22 µm Nylon-66 Membrane) used for XXXXXX Injection filtration to ensure it meets regulatory and performance criteria. This report summarizes the observations and conclusions based on the executed protocol.

2.0 SCOPE:

This validation study applies to the sterile filtration process in Injection Manufacturing area using a 0.22 µm Nylon-66 membrane filter for XXXXX Injection.

3.0 RESPONSIBILITY

Responsibilities of different department/ personnel involved in different activities related to the Filter Validation of the equipment are defined below:

4.0 FILTER VALIDATION TESTS & OBSERVATIONS

The following tests were conducted as per the validation protocol, and the observations are recorded below.

4.1 Integrity Testing (Pre- & Post-Filtration)

4.1.1 Objective:

To confirm the filter integrity before and after filtration using the Bubble Point Test and Diffusive Flow Test.

5.2 Filter Throughput Study

5.2.1 Objective:

To determine whether the filter can process the required batch volume efficiently.

CONTAMINATION CONTROL STRATEGY FOR STERILE MANUFACTURING FACILITY

1.0PURPOSE:

The development of the CCS requires thorough technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g., pyrogen, endotoxins) as well as particulate matter (e.g., glass and other visible and sub-visible particulates)."

The elements to be considered are listed below:

• Design of both the facility and processes, including the associated documentation.

• Premises and equipment.

• Personnel.

• Utilities.

• Raw material controls – including in-process controls.

• Product containers and closures.

• Vendor approval includes key component suppliers, sterilization of components and single-use systems (SUS), and critical service providers.

• Management of outsourced activities and availability/transfer of critical information between parties, e.g. contract sterilization services.

• Process risk assessment.

• Process validation.

• Validation of sterilization processes.

• Preventative maintenance – maintaining equipment, utilities, and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination.

• Cleaning and disinfection.

• Monitoring systems – including an assessment of the feasibility of introducing scientifically sound, alternative methods that optimize the detection of environmental contamination.

• Prevention mechanisms – trend analysis, detailed, investigation, root cause determination, corrective and preventive actions (CAPA), and the need for comprehensive investigational tools.

2.0SCOPE:

Contaminations control strategy applicable to the all the sterile product manufactured at XZY Ltd. (Company Name)

3.0RESPONSIBILITIES:

1. Quality Assurance (QA): Owner of the CCS; ensures periodic review (annual or post-major changes); monitors implementation effectiveness.

2. Production: Implements CCS controls during manufacturing; ensures personnel adhere to contamination prevention practices.

3. QC Microbiology: Develops, executes, and trends environmental and personnel monitoring programs; investigates excursions.

4. Engineering: Maintains utilities and facility in validated state; ensures preventive maintenance.

5. Validation Team: Performs risk assessments, qualification, and requalification of facilities, utilities, and processes.

6. Warehouse & Supply Chain: Ensures material flow and vendor qualification align with CCS principles.

4.0PROCEDURES:

4.1INTRODUCTION

This is best achieved using quality risk management principles and supporting riskassessmentsforcontaminationcontrolandmonitoring(detectabilityofcontaminationevent).

• • Microbial contamination

  • Sterility assurance

  • Facility design

  • Chemical contamination

  • Particle contamination (visible and sub-visible)

Other forms of contamination that can arise from mix-ups, damaging primary orsecondarypackaging,distributionproblems,andenvironmentalfluctuations.

It is recognized that any contamination control strategy represents a cyclical process,designed to prompt the manufacturers to identify and resolve risk, and hence one thatrequires periodicreviewand update.

Contamination control is also supported by the overall Pharmaceutical Quality System(PQS)ThePQSclarifiestheexpectationsforaneffectivequalitysystemwhichincludesensuring that the organization has sufficient knowledge and expertise in relation to theproducts they aremanufacturingandthatdecisions aredocumented.

Quality control strategy: based on an understanding of risk with control of criticalqualityattributesinamanufacturingprocessmeetingregulatoryrequirements.

Contamination control strategy: including cross contamination control that may include requirements for containment/ product segregation.

4.2CONTROL MEASURES

1. The underlying requirement of the CCS is with understanding the product and process in enough detail to be able to effectively assess the hazards to product quality from contamination and ensure control measures are in place which proactively mitigates the risk of the product becoming contaminated.

2. This is achieved through a series of measures:

   1. Effective design, qualification and validation of the facility and equipment in conjunction.

   2. During manufacture of the product having systems in place to monitor and trend the performance of the process.

   3. Ensuring systems are in place investigate process deviations which may impact product quality using a documented system of risk assessment. Pertinent findings from deviations should feed back into the CCS.

   4. To have in place a risk assessment process in order to correct and prevent contamination deviations occurring (either for the first time or again). Ideally there will be in place a formal risk assessment for each process step. This means, beginning with the start of the manufacturing process, capturing sterile processing, through to capping and packaging. Under Good Distribution Practice, risk assessments extend to the point where the recipient receives the product (of particular concern here is packaging and container closure integrity).

Once the CCS is implemented it needs to be maintained regularly and may become part of theperiodic product quality review to confirm that any changes to any part of the process have beenimplementedin accordancewith theCCSandGMP

4.3STERILE MANUFACTURING

1. A CCS is especially important for sterile manufacturing, and especially for aseptic manufacturing. The objective of a contamination control strategy, for aseptically filled products, is sterility assurance and the production of a sterile product (a product devoid of viable microorganisms). This is because:

   1. With aseptic processing the imperative is to prevent microbial ingress.

   2. A statistical assurance cannot be provided.

   3. The manufacturer is heavily reliant upon a good contamination control strategy.

Sterility assurance is a holistic concept, concerning the wider embracement of the aspects of GMP which are designed to protect the product from contamination at all stages of manufacturing (from in-coming raw materials through to finished products) and thus it forms an integral part of the quality assurance system.

4.4DETAIL OF THE CONTROL MEASURES

1. CONTROL OF PREMISES

The control of premises is one of the most critical pillars of contamination control. A robust facility design, qualification, and ongoing monitoring program must be implemented to ensure that the manufacturing environment consistently protects product sterility and patient safety. Central to this control is the cleanroom, which serves as the controlled environment for sterile operations. Cleanrooms are designed, constructed, qualified, and operated in compliance with ISO 14644 standards and EU GMP Annex 1 (2022):

1. Facility Design

The design of the facility and associated cleanrooms is the foundation of the Contamination Control Strategy (CCS). A well-designed facility must ensure that the environment in which sterile manufacturing is performed supports consistent maintenance of aseptic conditions, minimizes contamination risks, and integrates with the overall Pharmaceutical Quality System (PQS).

The CCS evaluates the following aspects of facility design:

• Cleanroom Specification

• Contamination Cascade & HVAC Integration

• Airflow Visualization (Smoke Studies)

• Environmental Monitoring Program (EMP) Integration

• Qualification & Requalification Requirements

• Control of Human Interventions (RABS/LAF)

vCleanroom Specification

• Classification: Cleanrooms are classified as per ISO 14644-1 and EU GMP Annex 1

  • Grade A: Critical aseptic processing zones (filling, stopper addition, open vial/ampoule exposure).

  • Grade B: Background environment for Grade A operations.

  • Grade C: Preparation of solutions, support areas.

  • Grade D: Less critical operations (e.g., component preparation).

• Key Parameters defined in CCS:

  • Airborne non-viable particles (≥0.5 µm and ≥5.0 µm)

  • Viable microorganisms (cfu/m³, settle plates, contact plates)

  • Temperature and relative humidity (e.g., 25±2 °C, 55±5% RH)

  • Air change rate (ACPH) based on classification and occupancy.

• Controlled Material Flow: Separate flows for personnel, raw materials, and waste, ensuring no cross-over.

vContamination Cascade

The pressure differential system is critical to preventing cross-contamination and ingress of contaminated air:

• Positive pressure cascade: Minimum 15 Pa differential maintained between adjacent rooms of different grades (e.g., Grade B vs. Grade C).

• Monitoring: Continuous electronic monitoring of pressure differentials with alarms linked to Building Management System (BMS).

• Air supply: 100% HEPA-filtered air supplied to Grade A/B, with return air filtered before recirculation.

• Rationale in CCS: The cascade ensures airflow from the cleanest to less clean areas, protecting the product.

vAirflow Visualization (Smoke Studies)

The Purpose of Smoke Studies is to demonstrate that airflow design prevents ingress of particles/microorganisms into critical zones.

• Methodology:

  • Performed both at rest and in operation.

  • Conducted at all critical processing steps (e.g., filling/sealing/container transfer/Sampling etc.).

  • Documented with high-definition video for regulatory evidence.

• Acceptance Criteria:

  • Unidirectional airflow over Grade A critical zones.

  • No turbulence or reverse flow observed.

  • Protection maintained during personnel interventions.

vEnvironmental Monitoring Program (EMP) Integration

• Design Linkage: EMP sampling points must correspond to airflow patterns and contamination risks.

• Routine Monitoring Includes:

  • Non-viable particles: continuous monitoring in Grade A by using online particle counter system.

  • Viable monitoring: settle plates, active air samplers, and surface contact plates.

  • Pressure, temperature, humidity: Monitoring of parameters and maintained the records.

vCleanroom Qualification & Requalification

• Initial Qualification: Performed in line with ISO 14644 & Annex 1:

  • Airflow velocity/volume measurements.

  • HEPA integrity testing (PAO challenge).

  • Non-viable particle testing (at rest/operational).

  • Viable contamination testing.

  • Pressure differentials, temperature, humidity mapping.

  • Recovery Studies

  • Air Flow Pattern

• Requalification:

  • Grade A/B: at least Half Yearly.

  • Grade C/D: Annually.

  • For cause requalification: triggered by events such as major HVAC repairs, cleanroom shutdown, or modifications.

vControl of Human Interventions

• People = highest risk factor for contamination in aseptic processing.

• Mitigation in CCS:

  • Use of RABS/LAF (Restricted Access Barrier Systems) to reduce direct interventions.

  • Interlocked material/personnel airlocks to prevent simultaneous opening of doors.

  • Automated or single-use transfer systems to reduce contamination risks.

  • Gowning procedures linked to qualification and requalification of operators.

  • Restricted personnel access to critical Grade A/B zones

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PROTOCOL FOR CONTAINER CLOSURE INTEGRITY TESTING OF AMPOULES/VIALS

1.0 OBJECTIVE:

The objective of this study is to describe procedure for the Container Closure Integrity Testing of filled & sealed Ampoules/Vials. This ensures that the container closure system (CCS) maintains its sterility, prevents microbial or particulate ingress and protects the product from contamination throughout its shelf life and complies with regulatory requirements. This study will simulates real-world transport and storage conditions, including pressure fluctuations and temperature variations and will evaluate critical aspects of Container Closure Integrity Testing performance, including:

• Sealing Integrity of the Closure System – evaluate the ability of the closure system to maintain a sterile barrier and prevent any external contaminants from entering the vial/ampoule.
• Detection of Microbial or Particulate Pathways – evaluate if there are any unintended pathways or defects in the closure system (such as cracks, gaps, pin hole or loose seals) that could provide a route for microbial or particulate ingress.
• Performance Under Stress Conditions – evaluate how the container closure system behaves under real-world stress conditions, such as pressure fluctuations during transport or storage, which may affect the closure system's integrity.
• Detection of Microscopic Leaks or Imperfections in the Seal – Detect the even microscopic defects in the closure system that may not be detectable via visual inspection.

This validation study aims to establish robust acceptance criteria for container closure integrity testing performance, ensuring compliance with Good Manufacturing Practices (GMP) and regulatory guidelines.

2.0 SCOPE:

The scope of this protocol covers the sterile drug products in clear, transparent glass ampoules/vials are manufactured at XYZ (Company Name).

3.0 RESPONSIBILITY

Responsibilities of different department/ personnel involved in different activities related to the Validation of Container Closure Integrity Testing of ampoules/vials are defined below:

4.0 CONTAINER CLOSURE INTEGRITY TESTING VALIDATION TEST PLAN

5.1Validation test shall include following test:

5.1.1Validation Test Matrix

6.0 Frequency of Testing:

• Introduction to new container closure system
• Change in Sealing Machine

7.0 Methodology:

7.1Dye Ingress Method:

7.1.1      Instrument & Material:

• Vacuum Leak Test Apparatus
• UV-Vis Spectrophotometer
• Test Ampoules/Vials
• Positive Control & Negative Control Ampoules/ Vials
• Methylene Blue solution 0.5% w/v
• Purified Water/WFI
• Lint-free wipes

ENCLOSED DOCUMENTS

Following documents are enclosed as part of container closure integrity testing of ampoules/vials Validation Study protocol and shall be pre-approved as a part of the main protocol.

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