ASEPTIC PROCESS SIMULATION (MEDIA FILL)
Aseptic Process Simulation: Process simulation test, which is also synonymously known as media fill, is the aseptic process, where a microbiological growth medium is substituted to the product, which is manipulated and exposed in a similar way to that of the product.
PURPOSE Of ASEPTIC PROCESS SIMULATION :
To define the procedure to be followed for validation of Aseptic Processes by process simulation study through a media fill.
It describes methods and procedures for conducting the process simulation run to validate or revalidate the aseptic processing lines involved in the manufacturing of sterile drug products.
Process simulation study provides a way.
To demonstrate the capability of the aseptic process to produce sterile drug products consistently.
• To evaluate and qualify the personnel practices while participating in the aseptic drug product manufacturing process.
• To evaluate the impact of the changes made to aseptic processing lines.
• To demonstrate that the environmental -controls are adequate to meet the basic requirement necessary to produce a sterile drug by aseptic processing.
SCOPE:
This procedure applies to all aseptic processing lines involved in the manufacturing of sterile drug products.
This procedure is not applicable for drug substances, terminally sterilized products, and products other than sterile dosage forms.
Applicable for process line where both terminal sterilized and aseptic filling process is carried out.
RESPONSIBILITY:
The manufacturing department shall be responsible for:
Preparation, review, and approval of master BMR of Media Fill.
Review of media fills protocol and report.
Review and interpretation of executed media fill BMR.
To provide the required information to the validation department for developing a media fill matrix.
Ensure the prerequisites of media fill.
Execution of manufacturing & filling, sealing, visual inspection, and incubation, etc., and recording in relevant documents as part of protocol/SOP.
Ensuring media fill participation of personnel involved in aseptic operations.
Responsible for verification of compliance with the media fill procedures.
Participation in media,:-fill failure investigation (if any).
QC (microbiology) department shall be responsible for:
Review of media fill protocol and report.
The preparation of media fills the participation list of personnel involved in the aseptic operation.
GPT testing of sterilized media and post-incubation of media-filled containers.
Conducting environmental and personnel monitoring in aseptic areas as per schedule.
Visual inspection of media-filled containers for microbial growth post-incubation.
Issuance of sterilized dehydrated medium to the production department for media preparation and record the same.
Detect the growth of organisms in unit/container and identify up to the species level.
Participation in media-fill failure investigation (if any).
To perform the CCIT test of the filled unit/container.
The engineering department shall be responsible for:
To provide all required utilities throughout the process
Ensuring media participation of the engineering personnel involved in maintenance activities of the aseptic area.
Simulation of maintenance activity during media fill run.
Qualification & Validation Department (Q & V):
Preparation & review of media fill protocol & report; media fill planner, report, & periodic summary report. Execution of the media fills as per the Validation Master Plan (VMP).
Prepare media fill summary after completion of each media fill.
QA department shall be responsible for:
Review and approval of master BMR of media fill.
Review and approval of media fill protocol and report.
Verifying the prerequisites of media fill activities.
Collection of samples as per protocol
Ensuring media fill participation of personnel involved in aseptic operations
Carrying out In-process testing during media fill.
Review of line clearance at all stages of manufacturing.
Monitoring of overall media fill activity.
Review of executed media fills BMR.
Participation in failure investigation (if any).
To ensure compliance with the protocol
DEFINITIONS:
Process Simulation: Process simulation test, which is also synonymously known as media fill, is the aseptic process, where a microbiological growth medium is substituted to the product, which is manipulated and exposed in a similar way to that of the product.
Aseptic Processing: Handling of sterile materials in a controlled environment, in which the air supply, materials, equipment, and personnel are regulated to control the microbial and particulate contamination to acceptable levels.
Growth Promotion Test: This test is performed to demonstrate that media will support microbial growth.
Intervention: Intervention are the events on aseptic processing lines that can be either planned for routine activities like fill weight adjustment or unplanned activities like container breakage and stopper jams.
Aseptic Processing Facility: A building containing clean rooms in which air supply, materials, and equipment are regulated to control microbial and particulate contamination.
Bio-burden: Total number of microorganisms associated with a specific item before sterilization.
Clean Area: An area with defined particulate and microbiological cleanliness standards (e.g., Class 1000, Class 10,000 or Class 100,000).
Clean room: A room designed, maintained, and controlled to prevent particulate and microbiological contamination of drug products. Such rooms are assigned and reproducibly meet an appropriate air cleanliness classification. A room is used in such a way as to reduce the introduction,generation and retention of contaminants within the area.
Colony Forming Unit (CFU): A microbiological term that describes the formation of a single macroscopic colony after the introduction of one (or more) microorganism(s) to microbiological growth media. One colony-forming unit is expressed as 1 CFU.
Critical areas: Areas designed to maintain the sterility of sterile materials, Sterilized products, containers/closures, and equipment may be exposed in critical areas.
Critical surfaces: Surfaces that may come into contact with or directly impact sterilized products or containers/closures. Critical surfaces are rendered sterile before the start of the manufacturing operation and sterility is maintained throughout processing.
Decontamination: A process that eliminates viable bio-burden via the use of sporicidal chemical agents.
Depyrogenation: A process used to destroy or remove pyrogens (e.g., endotoxin).
Gowning Qualification: A program that establishes, both initially and periodically, the capability of an individual to do the complete sterile gown in an aseptic manner.
Terminal sterilization: The application of a lethal agent to sealed, finished drug products to achieve a predetermined sterility assurance level (SAL) of usually less than 10-6 (i.e., a probability of a non-sterile unit of
greater than one in a million).
Validation: Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.
Aseptic filling assembly: Aseptic filling assembly is a process of assembling a pre-sterilized filling pump and filling needles aseptically for filling drug products in critical areas.
Aseptic technique: Aseptic technique is a set of specific practices and procedures performed carefully in controlled conditions to prevent any kind of viable and non-viable contamination during aseptic manipulations [E.g. Aseptic connections] of sterile materials.
Component: Any article intended for use in the manufacture of a drug product, including those that may not appear in the final drug product.
Corrective Intervention: The interventions that are performed to correct or
adjust an aseptic process during its execution are called Corrective interventions. Ex: Sensor adjustment, replacing equipment components, and breakdown activity.
Inherent Intervention: The interventions that are an integral part of the aseptic process and are required for set up or routine operations and/ or monitoring are called Inherent interventions. Ex: Aseptic assembly,
environmental sampling etc.
Integral containers: Containers which are having its integrity/intact and there should be no leakage from the container/unit.
Non-Integral containers: Leaking cracked or damaged media-filled containers where the integrity of containers is compromised.
Isolation systems: The system separates the external clean room environment from the aseptic processing line and avoids exposure from personnel.
Isolator: A decontaminated unit, supplied with higher air quality that provides uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding cleanroom air and personnel).
Media fill abort/invalid: A simulation run may be aborted/ invalidated under any circumstances and the commercial lots/routine production batches are equally handled for similar situations (as applicable).
Worst Case simulation: A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions).
Product containers. and closures system: The container closure system is the science, art & technology of enclosing or protecting products for distribution, storage, sale, and use. Example (Vial, PFS, LOPE bottle, BFS, FFS, ampoule & cartridges, etc.
Procedure:
Process simulation concepts and Principles:
Media fill Principle:
Media fill run is carried out to provide an overall assessment of the microbiological acceptability of the aseptic processing activities. The outcome of the media fill run shall be used to detect and identify any process or procedural defects, which can lead to microbiological contamination of the product.
Media fill run is carried out using pre-sterilized Soyabean casein digest medium (SCDM) / Alternative thioglycolate medium (ATM) (for anaerobic condition) to simulate the product solution during manufacturing and filling.
Media fill run is carried out with the same procedure, processes and environmental conditions used for the actual product by substituting the product with microbiological nutrient medium within the aseptic process boundary.
Media fill shall be carried out on each aseptically processed filling line.
If line is used for manufacturing of both aseptically manufactured product as well as terminally sterilized product, then media fill is required for only those products which are manufactured aseptically.
Pre-requisites:
Check the growth promotion test of the sterile dehydrated SCDM / Tryptic Soya Broth /ATM before manufacturing a media batch as per the quality control specifications.
If the media fill simulation is part of new facility/Line then check the history of environmental monitoring.
All the steps intended for aseptic manufacturing shall be reproduced in media fill, including aseptic sampling and aseptic filling dilution of the final product (if any).
Following activities are required to be successfully completed / implemented before conducting media fill runs (but not limited to):
Equipment qualification and Instrument calibration.
Facility cleaning & sanitization programmed qualification.
Facility environmental monitoring system qualification.
Implementation of environmental decontamination procedures.
Personnel training and gowning certification.
Qualification of area/ HVAC system/ WFI/Pure steam.
Qualification of required utilities.
Validation of sterilization processes.
Environmental monitoring shall demonstrate that the new facility is under desired state of control.
Applicable SOPs for process/practice/equipment.
Note:
In case of new facility/Line, Introduction of any new container size, prior to media fill, pre assessment shall be performed for the identification and
evaluation of the intervention, through the WFI trial with speed or any placebo in case of dry powder facility.
The date, timing and type of media fill shall be agreed upon by production, quality assurance and quality control based on the schedule of media fill run.
The approved BMR and protocol shall be made available to the production.
Media:
Soybean Casein Digest Medium (Gamma irradiated) shall be used for process simulation test.
The characteristics of the media are following:
Low selectivity of media i.e. it is a broad spectrum medium which supports the growth of wide range of aerobic organisms including bacteria and fungi.
Filterability: Soya bean casein digest medium is easily filterable.
Soya bean casein digest medium (SCDM) is easily soluble in water for injection.
Clarity of the media when dissolved in water for injection, it allows for easy observation of turbidity, if present.
In case of Opaque/Translucent container, coloured SCDM media can be used for easy detection of any growth/turbidity.
3% SCDM shall be used for aseptic process simulation.
Dehydrated Media prior to use, to be checked for the growth promotion quality against the gram positive, gram negative bacteria, yeast, mould, and
appropriate environmental isolates when inoculated with < 100 CFU challenge.
Released media (pass the growth promotion test) shall be used for aseptic process simulation.
Rationale for the selection of the media i.e. SCDM or Alternative thioglycolate medium (ATM) shall be incorporated for the first media fill run on any new
lines.
Alternative thioglycolate media (ATM) shall be used for process simulation test for anaerobic condition.
2.9 % ATM shall be used.
Media fill schedule:
Validation department shall prepare and maintain an annual media fill schedule and matrix of worst case simulation for conducting periodic qualification in each filling line.
The schedule shall contain details of media fill along with the due date for next media fill run on each line. Schedule shall be included in the Validation Master Plan.
Schedule for the employee covered in media fill shall be prepared and maintained by QA department.
Periodic media fill run schedule shall be prepared and approved at the end of every year i.e. December (minus one month)
Strategy for scheduled media fill run is as follows:
| Types of batches | Strategy for scheduled media fill run |
| Scale up and engineering batches | Scheduled media fill run is not mandatory. |
| Exhibit and PPQ batches | Prior to execution, media fill run shall be executed. |
| Commercial batches | Media fill run shall be executed as per approved schedule. |
Number and Frequency of media fill runs:
Initial Media Fill (New Facility/ Process):
For new facility or production process, minimum three consecutive successful media fill run shall be performed to release the facility/ line for intended purpose.
Initial media fill run are generally conducted after completion of following activities (but not limited to).
1. Equipment qualification
2. Facility environmental system qualification
3. Implementation of environmental decontamination procedures
4. Personnel training and Gowning certification
5. Environmental monitoring shall demonstrate that the new facility is under desired state of control.
6. Qualification of Area/Equipment/air handling unit’s (HVAC system)/Water system and Utility system.
7. Validation of sterilization processes
8. All Standard operating procedures shall be available
9. All instruments shall be calibrated, all preventive maintenance and other maintenance requirements shall be completed as per the schedule.
Note: All the measure and precautions are to be taken as per the routine production.
Re-validation
Risk assessment shall be performed for consideration of media fill run in various circumstances, such as; (but not limited to)
Production shut down and start up
Change in the process /steps
Major modifications to any equipment which is directly in contact with the sterile product, product containers / closures (inter changing standard parts
does not constitute a major equipment modification).
Modification to equipment or facilities, which potentially affects the air quality or air flow in the aseptic environment.
Increase in production personnel in processing area, introduction of additional shift.
When data from a media fill indicates that the process is not in a state of control, when indicated by corrective actions within an investigation.
Continuous excursion observed in critical area environmental monitoring results which are above the action levels.
An increased incidence of product sterility test failures and breach of asepsis in the aseptic processing area.
Major modification to HVAC system of aseptic area
Product sterility failure investigation confirming a contaminated product
Changes in the line configuration/container size or shape/batch size.
Change in the vendor of material based on assessment in case change in the dimension.
Following criteria to be considered for frequency of media fill run on each filling line; (but not limited to)
- Media fill run per process line- Semiannually.
- Media fill run per shift- Semiannually.
- Media fill run per worst case that is smallest vial size with highest speed Annually
- Media fill run per worst case that is largest vial size with slowest Speed Annually.
- Media fill for the assessment of Anaerobic condition – Once in 3 Year.
- Highest Duration of Intervention -Annually.
- Highest Frequency of Intervention -Annually.
- Personnel Qualification-Annually.
Periodic: When there are no major changes to a validated status of aseptic manufacturing and filling with respect to area, processes and systems, a
single successful media fill run shall be taken on each filling line every six monthly from the date of filling of previous media fill run preferably (minus 30
days). Line can be utilized for production after scheduled Media fill run before receiving the result but release of such batches shall be based on successful
results of media fill run.
For periodic run, when there are multiple container sizes available on single line using the same process, the bracketing approach can be utilized.
For bracketing approach: – Consider the batch size, fill volume, filling speed, neck size, height, mouth diameter, largest container with widest neck
diameter (rationale: Maximum opening: prolonged exposure due to slow speed and higher filling time). Smallest container (rationale: handling difficulty
leading to interventions)
Container size to execute the initial media fill as well as periodic media fills. If one/ two container closure are planned, initially, minimum three successful
media fill runs shall be performed by using one/ both container size(s) at frequency of once in a year alternatively on six monthly bases.
If more than two container closure are planned, then bracketing approach shall be considered. In such cases, initial media fill shall be performed with
three consecutive run and one run each during periodic media fill shall be performed with identified worst-case container sizes (Preferably minimum
and maximum container size) at frequency of once in a year alternatively on six monthly basis and one media fill run with remaining each container(s)
shall be covered in a period of 3 years.
Circumstances basis (unscheduled), but not limited to;
For introduction of new product:
Risk assessment to be carried out for the process flow, which may include new processes, additional aseptic connections (interventions), new aseptic
technique etc. Through the risk assessment it required to decide whether it trigger media fill for that particular product.
Introduction of any new container;
Any new container introduction, then bracketing approach shall be considered based on the evaluation. If new container falls in between the
worst case container sizes i.e. minimum and maximum container sizes, only one successful media fill run is required and if the container size is outside
the worst case set, three consecutive successful runs are required and the matrix will be extended to the newly introduced container.
Different closure sizes shall be included in matrix, number and frequency of media fill run shall be carried out based on worst case.
Size (number of units to be filled) and duration of Run:
Number of units filled in routine manufacturing varies from product to product, based on the quantity of batch and market/registration requirement of the
product considering the maximum intended commercial batch size for respective containers.
Size of run is sufficient enough to cover all interventions (inherent and corrective).
Number of units filled shall be in between 5000 to 10000 for production batch sizes is between 5000 to 10000 units. Whereas for the batch sizes fewer than
5000 units, the number of media filled units shall be at least equal the maximum batch size.
If the product batch size is more than 10000 units then the media fill batch size should be at least equal to10000 units or more.
To determine the appropriate filling duration of the media fill run, following criteria shall be considered:
The filling duration of media fill shall be no less than the length of the actual manufacturing process.
Simulation of all inherent and corrective interventions shall be done including the consideration of their frequency of occurrence, so that the interventions
are equal to or more than expected interventions during actual production operations.
Normal operations such as, operator gown changes, change of operators, lunch/dinner break and operator shift change should be simulated.
Number of shifts to be in operation on the filling line as the media fill involve all three shifts.
Number of personnel required to participate in the media fill shall be considered while deciding filling duration.
The number of containers shall be targeting in such a way that, minimum of above for respective size is submitted for incubation after inspection.
Note: Media fill run should be performed on different days and hours during the week and not only at the beginning of a work day.
Container and closure:
The container and closure used for aseptic process simulation (media fill) run shall be similar to the actual product with respect to size and shape. In case similar container closure not available as per commercial production, comparison of the container and closure shall be attached which shall include comparison of dimension e.g. Neck diameter of vial, seal diameter and rubber
Stopper diameter.
Clear container of identical configuration shall be substituted for opaque and amber containers of same size and shape of original container with similar MOC, to aid in detecting contamination.
Colored SCDM media can substituted with normal SCDM media for easy detectability of contamination based on assessment in case of opaque/Translucent container.
Line speed and Fill volume:
The filling speed shall be set at the optimum range that is operated during normal production for that container size. Higher speed can be justified if it is known to result into more interventions.
Conduct each media fill run with a single line speed, In case speed vary shall be justified.
Minimum speed in case of larger/higher pack size (for maximum exposure),
Optimum Speed in case of the optimal container size (for covering the remaining container within the bracketing approach).
Maximum speed in case of lower pack size (for increased interventions) as per protocol.
There shall be enough quantity of medium in the container to contact all the container closure surface, when the container is inverted and swirled, and shall be enough to permit the detection of microbial growth.
A volume of the media shall be at least greater than 50% of the total volume of the container.
A technique used to wet all the surfaces must be defined in a protocol. E.g. inverting containers to wet surfaces. The containers shall be inverted before and during incubation. E.g. at least before starting incubation and 7 days of incubation.
Regardless of the accurate fill volume, the process simulation test shall include a fill weight adjustment following similar method as that of normal production, any weight adjustment container shall not be discarded.
To reduce or nullify the un-stoppered vial/ container rejections due to low/high fill volume, disable the “check Net weight “option in the Filling machine HMI (if applicable). Fill volume to be widened in the system from (zero) 0 to maximum filling capacity as per container size format as calculated in the protocol.
Personnel qualification and Considerations:
All the personnel who are authorized to enter the aseptic area during manufacturing, including production operator, supervisor, IPQA, microbiologist and maintenance personnel, shall participate in a media fill at least once a year. Schedule shall be maintained.
Person must successfully complete the gowning qualification before participation in media fill run. They should have all relevant training but not limited to cGMP training, procedure training, gowning practices, clean room practices, training in basic microbiology, clean room operation and procedure for intervention (Smoke study video recording should be referred). The initial gowning qualification only authorize the personnel to enter up to Grade B area and allowed to performed non-critical activities such as cleaning and sanitization of area etc.
Note: – In case any personnel enter into the Aseptic area (Grade-A) in non-operational condition, personnel are allowed to performed activity under grade A based on the assessment.
After gowning qualification, the person shall be trained on job with respect person’s function in aseptic area, for e.g. for machine operator, practical demonstration shall be imparted within the aseptic area for operation, assembling and handling of intervention. These activities are then performed by the operator which shall be evaluated by supervisor/qualified operator.
This entire activity shall be driven by applicable site specific procedure for qualification of personnel.
Participation shall be consistent with the nature of each operator’s duty included in any one of the following critical aseptic operation in the media fill run.
Unloading of sterilized components from sterilizer in cool zone area.
Handling of sterile rubber stopper bags in cool zone.
Transfer the sterilized components, filling assembly from unloading LAF to mobile LAF to filling line.
Transfer of ready to use components from dynamic pass box to mobile LAF to filling line to filling area through LAF trolley.
Opening of rubber stopper bags, bottles, Nozzle, caps- in case of 3-piece line and charging of rubber stoppers, bottle, nozzle, caps into respective Hopper.
Assembling of machine parts, setting of machine for liquid media filling.
Aseptic connections i.e. Outlet of Storage vessels to filling line.
Unloading of sterilized garments.
Handling of sterilized media in the filling room for filling into unit/container
Microbiological monitoring.
Maintenance work and support of operations.
Demonstration part of on job training shall be performed before the cleaning schedule of next batch, when there is no activity associated with product manufacturing.
After completion of on job training, person shall be allowed to participate in media fill run. On successful completion of media fill run, qualified person is allowed to participate in routine batch manufacturing activities.
The participants in a media fill run are required to sign the appropriated section of the batch record to ensure their participation. Once the media fill and final protocol has been signed off, the approved list of participation will be updated, and the certification for aseptic handling will be provided.
Visual Inspector shall be, qualified for the visual inspection of the media fill unit as per the visual inspection procedure.
Environment and Personnel monitoring:
Environment monitoring shall be performed as per respective SOP to cover entire media fill run. The frequency of monitoring shall be same as for routine production.
Monitoring shall be performed by settle plate, air sampling, surface monitoring, personnel monitoring, non-viable monitoring.
All the product contact surfaces such as filling needles, tubing, vibratory bowls and chute, but not limited to shall be monitored at the end of every media fill run.
Worst case simulation:
Hold time of room (maximum time after completion of sanitization i.e. clean hold time), sterile bulk, sterilized equipment, sterilized garments, container closures as applicable shall be simulated during process simulation test by maintaining them for a defined extended period of time before use. Hold time study once performed during initial qualification, shall be once in two years.
If any filtered inert gas being used during aseptic processing, same shall be replaced with filtered compressed air, whereas for anaerobic media use of inert gas shall be considered.
Holding of the 0.2 micron filtered media bulk in respective holding vessels after filtration and prior to filling.
Maximum number of personnel allowed during normal production shall be simulated during process simulation test at least once in a year.
Worst case intervention during the media fill process shall be performed as per the respective plant and process specific interventions defined in the procedure (BMR/Protocol): However, media fill run should not be used to justify practices that pose 1unnecessary contamination risks.
For worst case simula1ion, schedule to be prepared as per the VMP.
