1.0 OBJECTIVE

The objective of this Process Performance Qualification (PPQ) Report is to summarize the activities completed to confirm that the manufacturing process of “Product Name with Strength (AAAADDDD CCmg)” is capable of consistently delivering product that meets the requirements of the Quality Target Product Profile (QTPP), Critical Process Parameters (CPP), Critical Quality Attributes (CQA) and Finished Product Specifications. This PPQ report evaluates the three (03) batches manufactured as per approved Batch manufacturing record ZZZZZZ/XXX/DDD-VV and approved PPQ Protocol Number:  XXX/YYYY/ZZZZ (Version No.: 00).

2.0 SCOPE

This PPQ Report summarizes the results and conclusions of the batches manufactured as per approved Batch manufacturing record ZZZZZZ/XXX/DDD-VV and approved PPQ Protocol Number XXX/YYYY/ZZZZ  Version No.: 00. Data obtained from this PPQ exercise will be used to update the commercial manufacturing documents of product “Product Name With Strength (AAAADDDD CCmg)” as per recommendations of PPQ study.

3.0 BACKGROUND

Process Performance Qualification of product Name With Strength (AAAADDDD CCmg) has been initiated due to product commercialization in USA market as per change control number CC/ZZZ/AAAA Three consecutive batches of batch size XXXXX Tablets were manufactured as per approved Batch manufacturing Record Number ZZZZZZ/XXX/DDD-VV.

The Process Performance Qualification report is prepared to compile and evaluate the process parameter data, in-process observations and analytical results to demonstrate that the manufacturing process is suitable for consistently producing the product meeting its pre-determined specifications and quality attributes.

1.0 OBJECTIVE

To establish documented evidence to provide a high degree of assurance that the manufacturing process of ‘Product Name with Strength (ABCD EF mg)’ will consistently produce the product meeting its pre-determined specifications and quality attribute.

2.0 SCOPE

This protocol is applicable to Process Performance Qualification Batches of “Product Name with Strength (ABCD EF mg)” to be manufactured as per approved Batch Manufacturing Record number- XXXXYYYYZZZZ for XYZ market with a batch size of  (XXXXXX Nos. Tablets). Reference approved change control number is XXXXXXXXXXXXXXXXXXX.

3.0 INTRODUCTION

Add the Background behind the development of product that required validation discuss the scaleup and exhibit and optimization batch and recommendation also give the details of change control reference.

At least three (03) consecutive process performance qualification batches of the drug product shall be manufactured as per approved master batch manufacturing record and shall be tested as per approved standard testing procedure to demonstrate compliance with the approved specifications.

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1.0 Objective

To lay down a procedure to be followed for Continued Process Verification by Statistical Evaluation of data, collected from manufacturing and analysis of product Name of Study Product to establish document evidence to provide a high degree of assurance that the process remains in a state of control (in validated state) during commercial manufacture of product Name of Study Product.

2.0 Scope

This continued process verification protocol is applicable for Continuous Monitoring of Manufacturing Process by the Statistical Evaluation of identified CPPs and CQAs for products Name of Study Product manufactured at Name the Facility/Site.

The Scope of this protocol will also to address:

• Collection and evaluation of information and data about the performance of the process, which allows detection of undesired process variability.

• Evaluating the performance of the process, identifies problems and determines whether action must be taken to correct, anticipate and prevent problems so that the process remains in control.

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1.0 Objective

The objective of this Continued Process Verification Report is to summarize the Statistical Evaluation of data collected from manufacturing and analysis of product Name of Study Product, for establish document evidence to provide a high degree of assurance that the process remains in a state of control (in validated state) during commercial manufacture of product Name of Study Product.

2.0 Scope

This continued process verification Report is applicable for Continuous Monitoring of Manufacturing Process by the Statistical Evaluation of identified CPPs and CQAs for products Name of Study Product manufactured at Name the facility.

The Scope of this report is limited to below listed batches

List of Batch Number which is under evaluation

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1.0 OBJECTIVE

Objective of This protocol is to provide a written guideline for the validation of the aseptic process and practices to confirm its acceptability in protecting the aseptically filled product from microbial contamination. The results can be useful to detect and identify process or procedural weakness that can lead to microbiological contamination of product.

• To demonstrate the capability of the aseptic process to produce sterile drug products.
• To evaluate the processing steps used to manufacture a sterile product, by aseptic processing.
• To qualify or certify aseptic processing personnel

2.0 SCOPE

The process simulation test shall follow as closely as possible the routine aseptic manufacturing process and include all critical subsequent manufacturing steps. All equipment shall remain the same wherever practicable for the routine process. The media fill shall emulate the regular product fill situation in terms of equipment, processes, personnel involved and time taken for filling as well as for holding. Appropriate combinations of container size and opening as well as speed of the processing line shall be used (preferably at the extremes).

This study covers Definition, Reference documents, Verification of primary packing material, Critical instruments involved, Standard operation procedure, Methodology, Rational, process flow diagram, Monitoring parameters, process details, Training details, Execution, Failure investigation and corrective action and revalidation for process simulation carried out in XXXXXXXXXX (Company Name). 

The process simulation shall represent the “worst case situation” and shall include all manipulations and interventions likely to happen during actual manufacturing process.

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1.0 OBJECTIVE:

• Aseptic Process Simulation (Media Fill) is carried out to simulate the whole Aseptic Process in order to evaluate the Sterility Confidence of the Process.
• Prospective as well as Re-Validation of Aseptic Process provides the necessary level of assurance for aseptically produced products.
• Simulations are made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of required quality.
• To establish documented evidence that the whole process is capable of performing as per specified acceptance criteria and is adequate to provide the aseptic assurance for which the process is intended.​

2.0 SCOPE:

• The scope of this protocol is to lay down the processes which include exposing the Microbiological Growth Support Medium (MGSM) to product contact surfaces of Equipment, Container Closure System, Critical Environments, and Process Manipulations to closely simulate the same exposure that the product itself will undergo.
• This Protocol is applicable for performing Process Simulation Study (Media Fill) on Dry Powder Injection Vial Size of 7.5 ml at Vial filling and sealing Line for Dry Powder Injection.    

​3.0 PRE-QUALIFICATION CRITERIA:

Any major modification to any of the existing equipment, system or area after the Aseptic Process Simulation (Media Fill), that may affect the quality of the product as intended, shall be documented through a Change Control Procedure and shall be subjected for Re-qualification.

The Re qualification shall be performed due to any of the following reasons:

• As per Validation Frequency.
• Any major modification to any of the existing Equipment, System or Area.
• Change in Environment, Disinfection Procedures, Equipment Cleaning and Sterilization (Including Containers and Closures).
• Major Maintenance and Re-Qualification of Equipments, e.g. Autoclave, Depyrogenating Tunnel, Vial Washing Machine, HVAC (Heating, Ventilation and Air Conditioning) System, Water System, etc.

Any major modification to any of the existing equipment, system or area after the Aseptic Process Simulation (Media Fill), that may affect the quality of the product as intended, shall be documented through a Change Control Procedure and shall be subjected for Re-qualification with 03 successful runs of Media Fill.

4.0 FREQUENCY OF VALIDATION:

The frequency of Periodic Validation for Aseptic Process Simulation (Media Fill) shall be once in Six Months (±30 days*) under the condition that there were no changes in the normal production procedures and no action limits were exceeded for existing system as per Matrix or as per Validation Master Plan or as when required.

* If the Media Fill is planned after Six Months, the same shall be documented through a Planned Deviation mentioning the reason for deviation.

NUMBER OF RUNS: 

At least three consecutive successful process simulations are performed when qualifying a new processes, new equipment or after critical changes of processes, equipment or environment.

• At least one semi-annual simulation for a qualified facility, line or process per shift and is mainly performed for the periodic monitoring of aseptic conditions during routine manufacturing.
• Exceeding an action level demands a re-validation. Depending on the result of the follow-up investigation this re-validation may require the inclusion of one to three satisfactory Aseptic Process Simulation tests.

DURATION OF RUNS: 

• The duration for an Aseptic Process Simulation should be sufficient to adequately challenge the aseptic process.
• The duration of Media Fill run shall be the time it takes to incorporate Aseptic Manipulations and Interventions, as well as appropriate consideration of duration of the Actual Aseptic Processing Activity / Operation. 

SIZE OF RUN :

• The number of containers used for media fills should be sufficient to enable a valid evaluation.
• The Aseptic Process Simulation (Media fill) Run Size shall be 10,000 vials, filled during Aseptic Process Simulation of each run.

SELECTION OF CONTAINER SIZE:

In general, process simulation trials should entail at least the filling of the largest and smallest containers on a given filling line based on a facility established matrix.

• Exceptions to this general rule occur when the same filling machine, on the same filling line is used for different product presentations. In these instances, the flexibility of the filler may make it necessary to evaluate more than one set of large and small containers, because the filling set-ups are so different.
• For example, if filling another size container results in a process which is significantly changed (e.g., additional manipulation or fill parts), then that size container should be included in the study.

LINE SPEED:

Each Aseptic Process Simulation (Media Fill) run shall evaluate a Single Line Speed. 

• Using the slowest fill speed for the largest container with the widest mouth as it is exposed longer to the environment
• Using the highest fill speed for the smallest container because it may be unstable and cause frequent jams thus necessitating frequent operator intervention.

SELECTION OF MEDIA:

The criteria for selection of Microbiological Growth Support Medium (MGSM) includes: low selectivity, clarity, medium concentration and filterability..

• Low Selectivity : The medium should have a low selectivity i.e. be capable of supporting growth of a wide range of microorganisms such as Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus niger and Clostridium sporogenes
• Selection of medium should also consider in-house flora (e.g. Isolates from Environmental Monitoring etc.).
• Growth Promotion Tests (GPT) should demonstrate that the Medium Supports Recovery and Growth of Low Numbers of Microorganisms, i.e. 10-100 CFU/unit or less.
• Growth Promotion Testing of media used in simulation studies should be carried out to demonstrate the ability of media to sustain growth if contamination is present. Growth should be demonstrated within 5 days at the same incubation temperature as used during the simulation test performance.
• Clarity: The medium should be clear to allow for ease in observing turbidity.
• Medium Concentration: Recommendations of the supplier should be followed unless alternative concentrations are validated to deliver equal results.
• Filterability: If a filter is used in the aseptic manufacturing process, the medium should be capable of being filtered through the same grade as used in production.
• On the basis of above selection parameters Sterile Soya Bean Casein Digest Medium has been selected as Microbiological Growth Support Medium (MGSM). The concentration of Sterile Soya Bean Casein Digest Medium (SCDM) shall be 3% w/v (As per Manufacturer’s recommendation) in Water for Injection on the basis of above selection parameters and Pre GPT Studies performed.

SELECTION OF PROCESS SIMULATION POWDER (PLACEBO):

A Process Simulation Powder / Placebo are the material which will play as a placebo of dry powder and selected placebo is sterile SCDM itself due to following:

• Flow ability of SCDM through hopper and dosing wheel is good.
• It supports the growth of wide range of micro-organisms
• SCDM is soluble in water.
• Sterile material is readily available in the market.

STERILITY TEST OF STERILE SOYABEAN CASEIN DIGEST MEDIUM:

The Sterile SCDM shall be subjected for Sterility Test.

• The detail of Sterility Test shall be recorded in Media Fill Record and Report. 

INTERVENTIONS (WORSE CASE STUDY):

Interventions shall be recorded in Media Fill Report specifying the Types of Interventions, Duration of Intervention providing for consistent production practices and assessment of these practices during Media Fills. Video recording and still photography shall be carried out through out media fill.

The Filled units after different Interventions shall be kept separately for Incubation with Proper Status Label.

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1.0 OBJECTIVE:

• Process Simulation Study (Media Fill) is carried out to simulate the whole Aseptic Process in order to evaluate the Sterility Confidence of the Process. Process Simulation studies include Compounding, Filtration and Filling with suitable media. 
• Prospective as well as Re-Validation of Aseptic Process provides the necessary level of assurance for aseptically produced products.
• Simulations are made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of required quality.
• To establish documented evidence that the whole process is capable of performing as per specified acceptance criteria and is adequate to provide the aseptic assurance for which the process is intended.

2.0 SCOPE:

• The Scope of this protocol is to lay down the processes which include exposing the Microbiological Growth Support Medium (MGSM) to Product Contact Surfaces of Equipment, Container Closure System, Critical Environments, and Process Manipulations to closely simulate the same exposure that the product itself will undergo.
• This Protocol is applicable for performing Process Simulation Study (Media Fill) at ampoule filling and sealing Line for Liquid Injection.  

3.0 RE-QUALIFICATION CRITERIA:

Any major modification to any of the existing equipment, system or area after the Process Simulation Study (Media Fill), that may affect the quality of the product as intended, shall be documented through a Change Control Procedure and shall be subjected for Re-Qualification.

The Re-Qualification shall be performed due to any of the following reasons:

• As per Validation Frequency.
• Any Major Modification to any of the existing Equipment, System or Area.
• Change in Environment, Disinfection Procedures, Equipment Cleaning and

                   Sterilization.

• Major Maintenance and Re-Qualification of Equipments, e.g. Autoclave, Sterilized ampoule Filling & Sealing Machine, HVAC (Heating, Ventilation and Air Conditioning) System, Water System, etc.

4.0 FREQUENCY OF VALIDATION:

The frequency of Periodic Validation for Process Simulation Study (Media Fill) shall be Once in Six Months (±30 days*) for existing system as per Validation Master Plan or as and when required as per point No.5.0.

* If the Media Fill is planned after Seven Months, the same shall be documented through a Planned Deviation mentioning the reason for deviation.

5.0 NUMBER OF RUNS:   

• At least three consecutive successful process simulations are performed when qualifying a new processes, new equipment or after critical changes of processes, equipment or environment.
• At least one semi-annual simulation for a qualified facility, line or process per shift and is mainly performed for the periodic monitoring of aseptic conditions during routine manufacturing.
• Exceeding an action level demands a re-validation. Depending on the result of the follow-up investigation this re-validation may require the inclusion of one to three satisfactory Aseptic Process Simulation tests.

6.0 DURATION OF RUNS:   

• The duration for an Aseptic Process Simulation should be sufficient to adequately challenge the aseptic process.
• The duration of Media Fill run shall be the time it takes to incorporate Aseptic Manipulations and Interventions, as well as appropriate consideration of duration of the Actual Aseptic Processing Activity / Operation. 

1. SIZE OF RUN:  

• The number of containers used for media fills should be sufficient to enable a valid evaluation.
• The Aseptic Process Simulation (Media fill) Run Size shall be 10,000 ampoules, filled during Aseptic Process Simulation of each run.

7.0 SELECTION OF CONTAINER SIZE:

Smallest containers on first Six Month & largest containers on next Six Month.

8.0 LINE SPEED:  

Each Process Simulation Study (Media Fill) run shall evaluate a Single Line Speed. 

• First Process Simulation Study (Media Fill) with Slow Line Speed,
• Second Process Simulation Study (Media Fill) with Optimum Line Speed
• Third Process Simulation Study (Media Fill) with Fast Line Speed.

9.0 SELECTION OF MEDIA:

• The Criteria for selection of Microbiological Growth Support Medium (MGSM) include: low selectivity, clarity, medium concentration and filterability.
• Ability to support growth of a wide range of microorganisms: The medium should have a low selectivity i.e. be capable of supporting growth of a wide range of microorganisms such as Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus niger and Clostridium sporogenes (e.g. Soya Bean Casein Digest).
• Growth Promotion Test (GPT) to demonstrate that the medium supports recovery and growth of low numbers of microorganisms, i.e. 10-100 CFU/ unit or less.
• Growth Promotion Testing of the media used in simulation studies to be carried out on completion of the incubation period to demonstrate the ability of the media to sustain growth if contamination is present. Growth should be demonstrated within 5 days at the same incubation temperature as used during the simulation test performance.
• Clarity: The medium should be clear to allow for ease in observing turbidity.
• Medium Concentration: Recommendations of the supplier shall be followed unless alternative concentrations are validated to deliver equal results.
• Filterability: If a filter is used in the Aseptic Manufacturing Process, the medium should be capable of being filtered through the same grade as used in production.

Soya Bean Casein Digest Medium is used as Microbiological Growth Support Medium (MGSM) for Process Simulation Study.

The concentration of Soya Bean Casein Digest Medium (SCDM) is selected 3% w/v in Water for Injection on the basis of above selection parameters and Pre GPT Studies performed.

10.0 INTERVENTIONS (WORSE CASE STUDY):

Interventions shall be recorded in Media Fill Report specifying the Types of Interventions, Duration of Intervention providing for consistent production practices and assessment of these practices during Media Fills.

The Filled units after different Interventions shall be kept separately for Incubation with Proper Status Label.

11.0 TYPE OF INTERVENTIONS:

11.1 Routine  Interventions:

• Aseptic assembling of Machine Parts  
• Initial Volume Adjustment
• Machine speed adjustment
• Compressed air pressure adjustment
• Periodic Fill Volume Checking and Verification.
• Run the filling machine on optimum speed for 5 min
• Environmental monitoring during operation:
• After 45min. lunch break
• No. of Persons increased in Filling and Sealing area for 15 minutes during filling.
• Change of operator for approx. 20 minutes.
• Shift change over
• Tea break
• Remove the broken Ampoule from the filling line 25 min
• Break for Dinner
• Handling of  Ampoule
• Gloves replacement

11.2 Non-Routine intervention:

• Sensor adjustment or Replacement
• Aseptic Manipulations
• Conveyor or guide rail adjustment
• Run the filling machine on minimum speed for 5 min.
• Run the filling machine on maximum speed for 5 min.
• Machine break down for 15 min (Minor).
• Use of single pair sterile gloves/torn gloves for 5 minute.
• Machine break down activity for 60 min (Major).
• AHU of Filling Area OFF for 05 min.
• Power Failure for 05 min.
• Open the safety panels on the filling M/C keep the panels open for 10 minutes during the M/C stoppage.
• LAF of Filling Area OFF for 05 min.

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1.0 OBJECTIVE

The objective of this study protocol is:

• Identification of all aseptic manufacturing interventions (routine as well as non-routine)
• To perform risk assessment of each intervention, specifically with respect to the potential microbial contamination risk to the product
• Classification of each intervention, based on the risk assessment

2.0 PURPOSE

Purpose of this study is to address, relevant issues associated with the aseptic manufacturing intervention and establish a basic understanding. This includes the following:

• Identification of aseptic manufacturing interventions
• Risk assessment of each intervention with respect to its product contamination potential
• Risk based categorization for process simulation interventions.

This document and comprehensive review of the aseptic manufacturing interventions will become basis and a framework for development of a SOP for management of aseptic manufacturing intervention and for the risk assessment of any new interventions that if reported during a routine production batch manufacturing. This is a requirement as per the USFDA Guidance for Industry, “Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, Sep. 2004”.

3.0 BACKGROUND

Performing an aseptic process almost always requires operators to manipulate sterile or sterilized products and components. These activities are considered as potential opportunities to offer the introduction of viable/ non-viable contamination to the product. That potential has been recognized in the recent FDA inspection and then also in the subsequent Warning Letter.

4.0 INTRODUCTION

Interventions in aseptic processing operations fall into two main categories: routine and non-routine.

Routine interventions (Inherent Interventions) are activities that are inherent parts of the aseptic process and integral parts of every batch. Typical routine interventions include but not limited to:

• Aseptic assembly of the production equipment before use
• Initial product connection or introduction
• Start-up component supply or introduction
• Initial fill weight or volume adjustment
• Periodic component replenishment
• Periodic fill weight or volume checking and verification
• Environmental monitoring
• Stopper/seal track blockage and clearance
• Speed adjustment
• Empty toppled vial/fallen/broken vial removal
• Operator breaks and meals
• Operator shift changes
• Product container replacement
• Any other interventional activity which is an integral part of the process.

Non-routine interventions are activities that are predominantly corrective and may not be a part of every batch. Although in theory, non-routine interventions may not be necessary during the aseptic process, in practice such interventions are almost always required to correct some anomaly. Some common non-routine interventions involve:

• Filling needle adjustment/ replacement
• Filling pump adjustment/ replacement
• Perform Filling with single piston & needle
• Load cell alignment adjustment
• Any other line malfunction requiring manual correction

5.0 OVERVIEW

5.1       Aseptic Manufacturing Process Steps

5.1.1 General Procedure

The aseptic manufacturing is performed using Isolator Technology. The entire aseptic manufacturing process is divided into four parts:

• Compounding in the compounding isolator and transfer in closed condition into the integrated vessel
• Depyrogenation of vials and sterilization of equipment/ accessories, compounding/ filtration vessels, closures and overseals
• Decontamination of the Filling System Isolators using Vaporized Hydrogen Peroxide.
• Sterilizing grade filtration at point of fill and aseptic filling process

1.0 Overview:

Manufacturing of sterile products by aseptic processing involves assembly of the sterilized materials/articles under aseptic conditions. Since the sterile active substance, sterilized containers and closures are exposed to the aseptic environment, there is a likely chance of one or more units becoming non-sterile. It is for this reason process simulation study is performed employing media fill to assess the sterility assurance level of the aseptic processing area and the process overall

• The aseptic processing operation is validated using a microbiological growth medium in place of the product. This Process Simulation, also known as a Media Fill, normally includes exposing the microbiological growth medium to product contact surfaces of equipment, container closure systems, critical environments, and process manipulations to closely simulate the same exposure that the product itself will undergo.
• The sealed containers filled with the medium are then incubated to detect microbial contamination. Results are then interpreted to assess the potential for a unit of drug product to become contaminated during actual operations (e.g., start-up, sterile ingredient additions, and aseptic connections, filling, and closing). Environmental monitoring data from the process simulation can also provide useful information for the processing line evaluation.

2.0 Objective

The objective of this protocol is to provide a written guideline for the validation of the aseptic process and practices to confirm its acceptability in protecting the aseptically filled product from microbial contamination for Process Simulation by media fill study in a Dry Powder Injection (Powder in Glass Vials) manufacturing facility.

3.0 Purpose

The purpose of this protocol is to ensure that the sterile products manufacturing process is simulated as closely as possible with the possible worst-case scenarios and aseptic interventions to demonstrate by Media Fill study that the sterilization processes, the aseptic processing, the aseptic processing conditions and the aseptic environment are suitable enough to provide a high degree of sterility assurance level (SAL).

4.0 Scope:

The scope of this protocol is limited to the “Process Simulation by Media Fill Study” in sterile drug product manufacturing facility for powder in glass vials.

5.0 Training

The validation team members shall be trained on the execution of process simulation study and report compilation. The training record shall be attached with final report. (Format No.XXXXXXX).

6.0 Process details and Methodology:

6.1 Process description and design:

As a part of the Process Simulation Study and to provide assurance on the sterility of products to be manufactured, the following operations shall be validated.

Filling and sealing process shall be done under aseptic conditions.

1. During process simulation Study, the aseptic filling operations shall be carried out, using Sterile Soybean Casein Digest Medium as a microbiological growth promoting medium and Sterile Mannitol as a placebo product, in place of the drug substance.
2. Sterile Mannitol shall be used to recover the microorganisms, if present on the product contact surfaces of the manufacturing equipment and encountered during aseptic operations.
3. Soybean Casein Digest Medium shall be used to promote the growth of the microorganisms using sterile mannitol as product simulation for filling of vials.
4. This process simulation (also known as a Media fill) shall include exposing sterile mannitol to the product contact surfaces of manufacturing equipment, container closure systems, critical environments and process manipulations, to closely simulate the same exposure that the product undergoes, during routine manufacturing.
5. Any process parameter of the manufacturing process, which may inhibit the growth of the micro-organism, shall not be simulated, e.g. very high or very low temperature, Nitrogen gas for purging, inhibitory concentration of the placebo (sterile mannitol), etc.   
6. Since manufacturing operations are generally performed in A shift, General shift and B shift therefore process simulation runs shall be conducted with at least one run daily, such that each critical aseptic step can be simulated in the shift.
7. The extension of shift shall be done up to 24 hours and shift change over shall be simulated during media fill runs.
8. Process simulation is carried out by filling sterile Mannitol through dosing disk and Soybean Casein Digest Medium through separate assembly fixed on the filling machine.
9. To exactly simulate aseptic filling process, the volume / quantity and period of occupancy of equipment shall be kept as per the routine contact volume/quantity and equipment occupancy for all critical processing steps.
10. After completion of filling and bunging operation, vials are transferred to sealing area through a conveyor for sealing. The sealing of vials shall be done under laminar air flow.
    1. Sealed vials shall be transferred to optical inspection room through conveyor and shall be subjected for 100 percent visual inspection as per the SOP.
    2. After completion of optical inspection segregate the good and rejected vials separately. “Rejected vials” such as mould defects, sealing defects (flip-off open, not properly sealed, broken flip-off  seal, no flip-off on seal, black spots on flip-off  seal, wrinkled crimping) which is integral shall be considered as cosmetic defects & same shall be incubated separately.
    3. All integral units should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected.
11. Transfer the optical tested vials for incubation as per the protocol.
12. These sealed vials (good and rejected) shall be incubated at 22.5 ± 2.5°C for 7 days (Inverted position) and at 32.5 ±2.5°C for further 7 days (upright position). These vials shall be observed for any growth / turbidity after 7 days & 14 days of incubation by trained microbiologist.
13. If turbidity or any microbial growth is observed in the vials, take a picture of these vials and identification of microorganisms shall be done at species level.

An investigation shall be conducted in order to ascertain the source of microbiological contamination and the investigation report shall be prepared for the corrective and preventive action, to reduce the microbiological contamination in the aseptic processing area as per SOP.

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PROTOCOL FOR STERILIZING GRADE MEMBRANE FILTRATION VALIDATION STUDY|FILTER VALIDATION STUDY|0.22 MICRON FILTER VALIDATION

1.0      OBJECTIVE:

The objective of this study is to validate the performance, safety, and reliability of the filtration process used for the sterilization of solutions. This validation ensures that the selected filter is suitable for its intended use, maintains product integrity, and complies with regulatory requirements. The study will evaluate critical aspects of filter performance, including:

1. Adsorption – Assessing potential loss of active ingredients or critical Excipients due to adsorption onto the filter membrane.

2. Extractables – Identifying and quantifying any potential leachable substances released from the filter that may impact product quality or patient safety.

3. Integrity Testing – Confirming the filter’s integrity before and after filtration to ensure sterility assurance.

4. Viability Testing – Verifying that the filtration process effectively retains microorganisms, ensuring sterility of the final product.

Additionally, the study will assess Critical Process Parameters (CPPs) to define the operational limits and ensure process consistency. These parameters include:

• Maximum Filtration Time – The longest duration for which the filter can be effectively used without compromising performance.

• Total Contact Time – The total time the filter remains in contact with the solution during processing.

• Maximum Operating Pressure – The highest allowable pressure applied during filtration to ensure filter integrity and performance.

• Flow Rate – The acceptable range of solution flow through the filter, ensuring efficiency and effectiveness.

• Maximum Filtration Volume – The total volume of solution that can be filtered without compromising filter performance or product sterility.

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

2.0      SCOPE:

The scope of this protocol is limited to the validation of Filtration process by using 0.22 Micron Membrane filter (Diameter 293 mm) made up of Nylon and Supplied by Micro Separations 

3.0 FILTER VALIDATION TEST PLAN

3.1Validation test shall include following test:

3.1.1Validation Test Matrix

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