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MEDIA FILL

(VALIDATION OF ASEPTIC
PROCESSES)
REFERENCES

 Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-


operation Scheme PI-007-06

 Media Fills for Validation of Aseptic Preparations FDA Guidance


document.
TRAINING TOPICS

 Introduction.
 Importance of Media Fill.
 Process Simulation Test Procedures.
 Process Simulation Test Conditions.
 Interpretation of Data.
 Environmental and Personnel Monitoring.
 Staff Training.
 Important Factors in Validation of Aseptic Manufacturing.
What is Media Fill

 Definition: A “media fill” (also known as a “process


simulation”) is the performance of an aseptic
manufacturing procedure using a sterile microbiological
growth medium in place of the drug solution.
Microbiological growth medium is used in place of the drug
solution during media fills to test whether the aseptic
procedures are adequate to prevent contamination during
actual drug production. A media fill is one part of the
validation of an aseptic manufacturing process.
IMPORTANCE OF
MEDIA FILL
How do we make sterile
products ?
There are two main approaches used in our industry

 Terminal sterilization – where the final filled product is


sterilized (e.g. in an autoclave) Media Fill is not required.
Option not available for biologics.

 Aseptic Processing – where all materials, packaging and


solution are sterilized separately then assembled aseptically
to give final product. This requires media fill validation.
Sterility Assurance
 Sterility Test is limited – does not provide sufficient sterility
assurance –
 Media Fills will provide assurance of all of the
processes/systems:
 Aseptic Operators Technique and Interventions
 Sterilization Systems
 HVAC Systems
 Product filtration programs
 Cleanroom / Facility / Pressure etc.
 Cleaning and sanitation program
 Movement of materials into Grade B and Grade A
Sterile Products and Risk

 With terminal sterilization, provided the bioburden is not too


high, the final product will be sterile. The risk of having an
unsterile product is very low. Very very few sterility based
recall are from terminally sterilized product.

 With aseptic processing even if all components and solution


are sterile poor technique by an operator can introduce
microbial contamination and make the product unsterile.

 The more manual the aseptic process, the higher the risk.
Minimizing contamination
Items What we do to prevent microbial contamination
Vials Sterilized and depyrogenated with dry heat oven or tunnel
Rubber Closures / Caps Sterilized by autoclave
Chemicals Tested to be sure microbial contamination is within specification.
Water for Injection Held at high or low temperature and ozonated
miscellaneous small Sterilized by autoclave / Hot Air Oven
items (scissors, scoops.
Tweezers, etc)
Air Supply Air is especially filtered to reduce chances of microbial problems.
HEPA filters are tested regularly to verify efficiency.

Operators Trained so they understand aseptic technique. Technique verified by


media fill challenge
Garments We use sterile garments to protect product
Production We sample and test to verify absence of microbes
environment
Bulk Tanks Cleaned and sanitised – we test to show they are clean
Sterilising Filters Are supplied sterile or sterilized in house
Industry Trend (Regulator Preference)

 Controlling contamination is always better than monitoring it


 Minimise / eliminate hand filling operations
 Minimise machine interventions – relies upon well tuned and reliable
equipment.
 Separate operators from the exposed product
 Semi closed Restricted Access Barrier Systems (RABS)
 Fully closed RABS
 Isolator Technology
Grade A
Critical Space and Critical Surfaces
Critical Space – Grade A / ISO 5
A critical space is one in which the sterilized drug product,
containers, and closures are exposed to environmental conditions
that must be designed to maintain product sterility.

Critical Surfaces within Critical Space Not all


Grade A space is a critical surface.
Surfaces that may come into contact with or directly affect a
sterilized product or its containers or closures.

Critical surfaces are rendered sterile prior to the start of the


manufacturing operation, and sterility is maintained throughout
processing. Generally monitored post processing.
Air Visualization in Grade A Space

 Looks for turbulence in Grade A


 Looks for entrainment B to A
 Identifies worst case locations for EM monitoring
 Must do in “at rest” state
 Must do in simulated “dynamic state” near interventions
 Must do whenever a major change to Grade A occurs
 Should repeat periodically – e.g every 3 years
 Must have a protocol and visualisation report prepared by
QC/QA Microbiology
 Can use videos as training tools for aseptic operators
PROCESS
SIMULATION TEST
PROCEDURE
GROWTH MEDIA
 The most commonly used growth medium is
soybean casein digest medium (SCDM), which is
commercially available under various names such as
Trypticase Soy Broth.
 Reason: capable of supporting a wide range of
microorganisms.
 Concentration of media: Recommendations of the
supplier should be followed unless alternative
concentrations are validated to deliver equal results.
Personnel
capability
Aseptic
Sterilization technique
processes

Room and
HVAC Environmental
integrity Controls

“Aseptic
Processing and
Sterility Assurance"

Incident Processing
responsiveness Line
Integrity

Sanitation Product
Procedures Filtration
Media Fill
Validation
People & Aseptic Processing
 People continuously shed microbes & particles into their
surroundings; cleanroom garments do not contain all of the
organisms present on human skin.

 People represent the main risk for non-sterile products

 The presence of contaminating microorganisms during


aseptic interventions is largely unavoidable.

 The transfer of those organisms to the critical space is


avoidable.

 Try to manage and control the level of unplanned


interventions.
Aseptic Personnel Qualification Program

 Demonstrate an understanding of applicable Standard Operating Procedures (SOPs)


 Demonstrate an understanding of Basic Microbiology
 Demonstrate an understanding of Aseptic Practice Theory and Cleanroom behavior
 Demonstrate gowning proficiency by actually completing three consecutively successful
gownings.
 Successfully complete a “Media Transfer Evaluation” within a Grade A hood in a
laboratory environment demonstrating successful aseptic technique simulating
interventions.
 Successfully participate in a process simulation (media fills) annually – covering
interventions
Other Personnel Management Rules

 Cannot be in Grade A until fully


qualified – assistant in Grade B
 Frequent glove/gown
surveillance – if failing must
have re-training and re-
qualification. Maintain a table of
results
 Dis-qualified if cannot meet
standards
 Any positive on Grade A gloves
is a problem – must be
investigated
Media Fill Validation
 Evaluates the entire process
 Must occur every 6 months per process line per shift
 Must include all aseptic operators over time eg.
annually
 Must include “ancillary” staff who have to enter the
room
 Must be “worst case” challenge to the process:
 Routine and non-routine interventions by each operator
 Different container – closure combinations
 Maximum # personnel in the room
 Changeovers and sterile hold times for equipment
 100% inspection process
 Run size: 5000 or maximum # processed on lien for the container

Combination. Pass = NIL positives


Acceptance Criteria

When filling fewer than 5000 units, no contaminated


units should be detected.
 When filling 5,000 to 10,000 units:
a) One (1) contaminated unit should result in an
investigation,
including consideration of a repeat media fill;
b) Two (2) contaminated units are considered
cause for revalidation, following investigation.
 When filling more than 10,000 units:
a) One (1) contaminated unit should result in an
investigation;
b) Two (2) contaminated units are considered
cause for revalidation, following investigation.
In an ideal (risk free) world
every potential risk would be covered in the media fill
 Every sterile bulk hold period would be simulated for the maximum hold
period
 Aerobic and anaerobic media would be used
 Simulation of the maximum permitted bulk hold time and maximum filling
time
 Every possible intervention, stoppage, process, procedure or worst case
situation would be simulated
 Every possible container/closure combination would be tested
 Every aseptic operator would perform every intervention 3 times
 > 10,000 container per run and would be zero positives
Process Interventions

 Principle:
 Avoid interventions,
 Where they are unavoidable, minimize their
impact.

 Routine interventions are activities that are


inherent parts of the aseptic process and
integral parts of every batch.

 Non-routine interventions are activities that


are predominantly corrective and may not be a
part of every batch.
Routine Interventions

Routine interventions are interventions that are normal parts of


aseptic processing. These may be:
 Aseptic assembly of equipment before use (stopper bowl, cap bowl etc.
 Adjustment of the machine tracks
 Initial product connections (i.e. to filler or to filter)
 Siliconing of the vial turntable
 Fill weight checks
 Bubble point testing of filters
 Component additions (vials, stoppers, caps)
 Environmental monitoring
 Any other intervention that is part of the normal process
 Stoppages due to meal or rest breaks
Non-­Routine Interventions

Non-routine interventions are any interventions that are corrective


and are or should be uncommon. Examples are:

 In process adjustment of the machine tracks


 Removing defective seals on containers
 Removing vials from the line that have jammed the machine
 Removing vials from the line that have fallen over
 Product filter change (initial bubble point failure ?)
 Replacement of filling needle or hose
 Product spillage or leakage
 Poorly fitting stoppers that require more manual manipulation
 Any other problem that requires manual correction
Risk Rating of Interventions

Risk Intervention Activity Potential Frequency of Glove


Rating
Contamination inclusion in monitoring
Risk media fill post
intervention

Critical Surface or
5 aseptic connection Very High Every Fill Yes

Proximity to an open
4 container High Every Fill Yes

Remote to an open Medium Once per year No


3 container/closure

2 Post Capping Low Once per year No

1 Grade B activity Very Low Once per 2 No


years
Grade A Intervention Rules
 Make sure the machine is stopped first
 ALWAYS sanitise hands thoroughly before going into Grade A space
 Keep as much of your body as possible out of the cabinet
 NEVER lean over to top of an open vial, stopper/cap bowl or the filling
needle.
 Use sterile forceps to retrieve or remove upturned vials
 Do not intervene to remove stoppers, vials, caps that are not interfering
with processing – clean up at the end
 Sample gloves post intervention
 Practice good aseptic technique EVERY TIME!
Process Validation - Media Fills

 The Media Fill Trial is a simulation of the filtration and aseptic


filling process, which substitutes a microbiological growth
medium for a sterile product.

 The Media Fill Trial provides to evaluate aseptic processing


operations that may affect the sterility of the final product, and
the performance of aseptic filling personnel under operational
conditions.
Pre-requisites to Process Validations
 Critical area are qualified and HVAC HEPA filters certified
 Environmental monitoring procedures are qualified
 Environmental monitoring media is approved for use
 Equipment and component sterilisations steps are validated
 Sterile filtration of bulk products is validated
 Media used in simulations is qualified
 Staff involved in the media fill are qualified in aseptic gowning
 Staff entering the filling area are trained in aseptic technique.
 Media fill inspectors are trained to detect turbidity
Elements of Aseptic Process Validation
 Media Fill Conditions / worst case situation / What are the risk factors ?
 Frequency and Number of Runs
 Duration of Run
 Size of Run
 Line Speed
 Environmental Conditions
 Media
 Incubation and Examination of Media-Filled Units
 Interpretation of Results
Number of Runs

 Principle:
 Minimum: three (3) to qualify the line initially
 Maximum: Enough to ensure that results are
consistent and meaningful.
 Routine re-validation: each processing line every 6
months.
 All personnel who are authorized to enter the aseptic
processing room during manufacturing should
participate at least once a year.
 Participation should be consistent with the nature of
each operator’s duties during routine production.
Duration of a Media Fill?
 The duration of the run should:
 Simulate the expected maximum time for routine
manufacture
 Include all production shifts.
 Be dictated by the time needed to fill the required
number of units
 Ensure that the necessary number of units and
activities are included.
 The validated maximum run tome should be included in
batch records
Simulation Conditions - Media

 Principle:
 Optimize detection of any microbiological contamination.
 Soybean casein digest medium (SCDM), should be used as it
promotes growth of gram-.positive and gram- negative bacteria,
and yeast and mold
 Consider inclusion of anaerobic growth media (e.g., fluid
thioglycollate medium) if there is a relevant risk factor.
 Need to consider production related isolates (use own
isolates).
 Media must contact all of each unit (container and closure)
Incubation of Media-Filled Units
 Principle:

 Media units should be incubated under conditions adequate


to detect microorganisms that might otherwise be difficult to
culture.
 Incubation temperature should be:
 Suitable for recovery of bioburden and environmental isolates
and should at no time be outside the range of 20-35oC.
 maintained within +2.5oC of the target temperature.
 Incubation time should not be less than 14 days.
 If two temperatures are used for the incubation of the media filled
units, the units should be incubated for at least 7 days at each
temperature (starting with the lower temperature).**

** controversial (PICs recommends 2 temperatures)


Simulation Conditions - Media

 Principle:
 Optimize detection of any microbiological
contamination.
 Soybean casein digest medium (SCDM), should be
used as it promotes growth of gram-.positive and
gram- negative bacteria, and yeast and mold
 Consider inclusion of anaerobic growth media
(e.g., fluid thioglycollate medium) if there is a
relevant risk factor.
 Need to consider production related isolates (use
own isolates).
 Media must contact all of each unit (container
and closure)
Examination of Media-Filled Units

 Each media-filled unit should be examined for contamination by


personnel with appropriate education, training, and experience
 QC Microbiology oversight throughout any such examination.
 All suspect units identified during the examination should be
brought to the immediate attention of the QC microbiologist.
 Use clear containers (with otherwise identical physical
properties) for amber or other opaque containers.
 When a firm performs a final product inspection of units
immediately following the media fill run, all integral units should
proceed to incubation. (Non-integral units should be separately
incubated.)
100% Inspection of Filled Units

 GMPs require 100% visual inspection of filled units


 This can be by automated (camera), semi automated
(mechanical presentation to a viewing station) or manual
inspection.
 All the above have advantages and disadvantages
 Must have an SOP and a Record of inspection
 Where people are used to inspect they must:
 Be trained in inspection

 Be tested to be able to accurately select a range


of different defects
 Be rotated out so they do not get tired
 Be eye tested annually
Acceptance Criteria and Responses
 The target is zero positives.
 Any positive unit indicates a potential sterility
assurance problem, regardless of run size.
 All positive units should be identified (speciated) and should
result in a thorough, documented investigation by
microbiology and production
Additional media fills may be required in response to the following:
 Where routine shutdown of a dispensing line has occurred to perform
maintenance or engineering project activities.

 Non-routine maintenance or engineering project activities are performed


that require significant modification of the Dispensing Line or HVAC
system in a dispensing line. The requirements for a media fill will be
determined via project related risk assessments.
 A dispensing line is decommissioned permanently or for a significant
period of time (greater than 6 months).
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