Aseptic Process

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Simulation
 Aseptic Process Simulation (APS)
➢ Aseptic Process Simulation (APS), also known as a
media fill, is a critical validation method used in the
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pharmaceutical industry to assess the aseptic processing

environment.
➢ It simulates the actual manufacturing process by
substituting the product with a sterile growth medium,
which can support the growth of microorganisms.
➢ This method ensures that the aseptic processes,
equipment, and personnel can produce sterile products
without contamination.
 Key Components of
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Aseptic Process
Simulation
 Media Selection
➢ The growth medium, typically tryptic soy broth
(TSB), is selected for its ability to support
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microbial growth.
➢ The medium should be sterile, and its ability to
support growth should be validated.
 Simulation of Actual Conditions
➢ The APS must simulate actual processing
conditions as closely as possible.
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➢ This includes the same equipment, personnel,

and environmental conditions used in routine
production.
 Filling Process
➢ The medium is filled into containers (such as
vials, ampoules, or syringes) using the same
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equipment and procedures used for actual

product filling.
➢ The process should cover all possible
interventions and worst-case scenarios.
 Incubation
➢ After filling, the containers are incubated under
conditions that allow for the detection of any
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microbial growth.
➢ Typically, this involves incubating at two
different temperatures: 20-25°C and 30-35°C
for a period of 14 days.
 Inspection
➢ After incubation, the filled containers are
inspected for signs of microbial growth.
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➢ Any growth indicates a breach in the aseptic

process.
 Documentation and Evaluation
➢ The results are documented and evaluated.
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➢ A successful simulation demonstrates the

aseptic process's ability to consistently produce
sterile products.
 Frequency of APS
➢ Regulatory guidelines typically require periodic
aseptic process simulations, often performed
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semi-annually, or more frequently if there are

significant changes in the process or
equipment.
 Performing an
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Aseptic Process
Simulation (APS)
 Planning and Preparation
➢ Define the Scope: Identify the specific processes, equipment,
and personnel that will be involved in the simulation.
Include all critical aseptic operations such as filling, capping,
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and sealing.
➢ Select Growth Medium: Choose a growth medium like
Tryptic Soy Broth (TSB) that supports a broad spectrum of
microbial growth. Ensure the medium has been validated for
sterility and growth promotion.
➢ Develop a Protocol: Create a detailed protocol outlining the
procedures, environmental conditions, and acceptance
criteria for the simulation. This should include the number of
containers to be filled, the volume of medium per container,
and the duration of incubation.
 Simulate Production Conditions
➢ Set Up Equipment: Use the same equipment, components,
and materials as in the actual production process. Ensure
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all equipment is sterilized according to standard operating

procedures (SOPs).
➢ Personnel Preparation: Involve the same personnel who
perform the actual production operations. Ensure they
follow the same gowning and aseptic techniques used in
production.
➢ Environmental Monitoring: Conduct environmental
monitoring of the cleanroom or aseptic area during the
simulation. This includes monitoring air quality, surfaces,
and personnel.
 Perform the Media Fill
➢ Start the Fill Process: Begin filling the containers (e.g., vials,
ampoules, syringes) with the sterile growth medium under
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aseptic conditions. Use the same filling speed, volume, and

sequence as in actual production.
➢ Simulate Interventions: Introduce routine and non-routine
interventions that might occur during production, such as
equipment adjustments, operator interventions, and
component changes. This helps assess the process's ability
to remain aseptic under worst-case conditions.
➢ Seal Containers: Once filled, seal the containers using the
same capping or sealing process used in production. This
step should also be performed under aseptic conditions.
 Incubation and Monitoring
➢ Incubate the Containers: After sealing, incubate
the containers at two different temperatures
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(typically 20-25°C and 30-35°C) to detect

microbial growth. The incubation period is usually
14 days.
➢ Monitor and Inspect: Regularly monitor the
incubation process and inspect the containers for
any signs of contamination (e.g., turbidity, color
change). Inspections should be done visually, and
the results recorded meticulously.
 Data Collection and Evaluation
➢ Document Results: Record all observations, including any
contamination events, the type of intervention performed,
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and the results of environmental monitoring.

➢ Analyze Data: Compare the results against the predefined
acceptance criteria. Typically, the absence of growth in all
containers is required to pass the simulation. However, if
contamination is detected, a root cause analysis must be
conducted.
➢ Review Environmental Data: Analyze the environmental
monitoring data to ensure that the aseptic conditions were
maintained throughout the simulation.
 Reporting and Documentation
➢ Prepare a Report: Summarize the study in a detailed
report that includes the objectives, methods, results,
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and conclusions. The report should also document any

deviations from the protocol and the corrective actions
taken.
➢ Review by QA/QC: The Quality Assurance/Quality
Control (QA/QC) department should review and
approve the report to ensure that all regulatory and
internal requirements are met.
➢ Archive the Report: Store the report and all related
documentation securely for future reference and
regulatory inspections.
 Follow-Up Actions
➢ Address Failures: If the simulation fails (i.e., if
contamination is detected), identify and correct
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the root cause before repeating the simulation.

➢ Continuous Improvement: Use the findings
from the media fill to improve aseptic
processes, equipment design, and operator
training.
 Regulatory Compliance
➢ Ensure Compliance: Verify that the media fill
complies with regulatory guidelines, such as those
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from the FDA, EMA, and WHO. These guidelines

often specify the frequency of media fills and the
conditions under which they must be performed.
➢ Ongoing Validation: APS should be conducted
periodically (e.g., semi-annually) and whenever
significant changes are made to the process,
equipment, or facility.
 Key Interventions
to Cover in an
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Aseptic Process
Simulation
 Operator Interventions
➢ Gowning and Gloving: Simulate the replacement of gloves
or gowning parts if they are suspected of contamination or
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if they become torn.

➢ Aseptic Connections: Making aseptic connections, such as
connecting sterile tubing or components, which could
introduce contamination if not performed correctly.
➢ Stopping and Restarting the Line: Stopping the filling line
and then restarting it. This might be necessary for
equipment adjustments or resolving issues and presents a
contamination risk.
 Equipment Interventions
➢ Changing Filters or Components: Replace filters,
seals, or other critical components during the
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process, which could introduce a risk of

contamination.
➢ Adjusting Equipment: Making adjustments to the
filling or capping equipment, such as changing fill
volume settings or replacing filling needles, which
requires breaching the aseptic area.
➢ Cleaning of Equipment: Performing cleaning
operations on equipment within the aseptic area that
is in contact with sterile product or components.
 Material and Component Interventions
➢ Component Replenishment: Replenishing sterile
components (e.g., stoppers, vials) in the filling
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area, which may require opening sterile packaging

or containers.
➢ Loading and Unloading: Loading empty
containers (vials, syringes) into the filling machine
and unloading filled containers. This can introduce
contamination if not handled properly.
 Environmental Monitoring Interventions
➢ Routine Monitoring: Conducting routine
environmental monitoring activities, such as
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air and surface sampling, during the

simulation. These activities require operators
to enter the aseptic area and can introduce
contamination.
 Aseptic Assembly and Packaging
Interventions
➢ Assembly of Equipment: Assembling
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equipment within the aseptic area, such as

connecting sterile tubing to pumps or filling
machines.
➢ Packaging Activities: Conducting packaging
operations, such as sealing vials or syringes,
under aseptic conditions.
 Atypical or Non-Routine Interventions
➢ Corrective Actions: Simulating corrective actions that
might be required during the process, such as removing
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and replacing a defective component or correcting a

filling error.
➢ Operator Entry/Exit: Simulating the entry and exit of
operators into and out of the cleanroom or aseptic area,
which is a potential contamination source.
➢ Simulated Power Failure: Performing a simulation of
power failure or equipment shutdown, followed by a
restart, to assess the response to unexpected
disruptions.
 Key Considerations
➢ Multiple Runs: Regulatory agencies often require
multiple media fill runs (typically three consecutive
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successful runs) to validate the aseptic process.

➢ Interventions: All potential interventions that could
occur during a production run should be included in the
media fill to challenge the process under worst-case
conditions.
➢ Worst-Case Scenario: The number of vials filled and the
duration should represent the worst-case production
scenario, including maximum batch sizes and extended
operations.
 Thank You
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➢Starlin

➢Ph. No. +91 8220217354

➢Email:
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