Untitled Quiz

Aseptic Process Simulation (Media Fill)

• Aseptic Process Simulation (APS) is a tool used to evaluate the capability of aseptic processing activities.
• It uses microbiological growth-promoting media instead of actual product.
• APS simulates the entire aseptic process, from product/component sterilization to final container sealing.
• Media contacts all product-contact surfaces during simulated processing.
• Media is incubated to check for microbial growth.
• This evaluation helps determine potential product contamination during aseptic processing.

Origin of Media Fill Tests

• Health Canada Guideline GUI-0119, clauses 66, 67, 68, and 69, require process validation that includes process simulation testing using nutrient media (media fill).
• The nutrient medium should be selected based on product dosage form, selectivity, clarity, concentration, and suitability for sterilization.

Process Simulation Test Requirements (Clauses 67 & 68)

• Clause 67: The simulation test should mimic the aseptic manufacturing process, including critical subsequent steps and all known production interventions (normal and worst-case).
• Clause 68: Initial validation requires three consecutive satisfactory simulation tests per shift. Repetition is needed after any major process changes. Re-testing is often required every six months.

Number and Frequency of APS

• The number and type of APS depends on a risk assessment of the aseptic process.
• They're required during qualification/validation of new facilities or production processes. Minimum of three APS are a regulatory expectation.
• Semi-annual APS is a regulatory expectation for qualified lines/processes.
• Any major process changes require a risk assessment to determine if, and how many, APS are needed.

Risk Assessment and Worst-Case Scenarios

• Risk assessment identifies hazards and their likelihood of harming patients, focusing on sterility assurance loss in aseptic processing.
• The process defines worst-case scenarios for manufacturing, including personnel, interventions, container closure types/sizes, line speed, and batch size.

Study Design

• APS study/program should incorporate risk factors and assess process control.
• It should simulate worst-case activities, conditions, and operations identified during risk assessment.
• Aseptic compounding should be simulated entirely, possibly integrated with other processes like filling.
• Longest durations and both routine and corrective interventions should be assessed.
• Aseptic assembly-line set up should be considered for simulation.

Additional Considerations

• Number of personnel, duration, and shift changes are essential factors
• Number and type of aseptic additions and transfers.
• Connections/disconnections.
• Critical steps: Lyophilization, line speed, volumes, container closure types/systems, and inert gassing are crucial.
• Frequency, and number of runs. -3 consecutive runs

Documentation

• Extensive documentation of every APS step, rationale, performance, acceptance criteria, results, and deviations is vital.
• A comprehensive protocol outlining requirements and rationale for studies should be prepared.

Protocol

• An approved APS protocol should be in place before starting the study.
• Protocol elements should include responsible execution groups, worst-case scenario rationale, room/line/equipment identification, container closure types, volume, minimum number of units to be filled, processing speed, and media type.

Incubation Conditions, Acceptance Criteria

• Incubation conditions should be appropriate for bioburden/environmental isolate recovery (range 20-35°C depending on the media and typically for at least 14 days).
• Prior to incubation, all units need to be appropriately inverted to allow media to reach all surfaces.
• Acceptance criteria for APS studies aim for zero contaminated units.
• Different criteria apply for different production batch sizes. -If there's one contaminated unit for batches less than 5,000, a new validation is needed.

Interventions

• Activities in the aseptic filling area are categorized as routine (inherent) or non-routine (corrective).
• Specific examples of both categories should be detailed.
• The list should be re-evaluated periodically or when unusual events occur, with documentation of interventions and frequency.

Personnel Training

• Comprehensive training is crucial.
• This includes gowning, cleanroom behavior, GMP, procedures, successful APS participation, periodic qualification, and documented procedures.

Pre-incubation and Post-incubation Inspection

• Pre-incubation inspection focuses on identifying and removing non-integral units. These may have cracks, misaligned components, etc.
• Post-incubation inspection focuses on visual verification of growth, counts of units are needed.
• Personnel trained to recognize different growth types should perform inspection.

Process Qualification for Lyophilized Products

• APS should capture loading, lyophilization process, unloading steps for lyophilization chambers.
• Either a shortened hold time and partial vacuum or a simulated full cycle under sterile air are both options for testing.