The document provides an overview of aseptic processing and contamination control. It defines aseptic processing and compares it to terminal sterilization. Sources of contamination during aseptic processing are discussed, including personnel, air, and equipment. Methods to control contamination are outlined, including quality risk management, contamination control strategies, cleaning and disinfection procedures, environmental monitoring programs, media fills, and quality control testing.
2. Contents
• Introduction to aseptic processing,
Aseptic Processing vs. Terminal
Sterilization
• Contamination:
Sources and control
• Microbial environmental monitoring
• Media Fill
• Quality Control
• References
3. Aseptic Processing
Aseptic processing is defined as “handling of
sterile product, containers, and/or devices in
a controlled environment, in which the air
supply, materials, equipment, and personnel
are regulated to maintain sterility”
(ISO 13408-1, 2008)
4. Producing Drug Products By
Terminal sterilization
• Product containers are filled and sealed under
high-quality environmental conditions
designed to minimize contamination, but not
to guarantee sterility.
• Product in its final container is subject to a
sterilization process such as heat or
irradiation.
Aseptic processing
• Drug product, container, and closure are
subject to sterilization separately, and then
brought together.
• Because there is no process to sterilize the
product in its final container, it is critical
that containers be filled and sealed in an
extremely high –quality environment.
7. Bacteria, virus, fungi and other viable microbes
Bacterial spores and endotoxins
Non viable Particles like dust, fibers, glass and other
visible and sub-visible particulates suspended in the air
and may contaminate product.
Contaminating Agents
8. Sources of Contamination
• Personnel born contaminants
• Poor or improper Sanitization: Procedures deficient, or poorly
executed
• Air born contaminants.
• Inadequate HEPA seal (over 90% vials contaminated)
• Velocity through HEPA Filters: Variable velocities between
filters. Inadequate laminar flow resulted. Low or undetectable
velocity at work surface.
• Mechanical failure of filling tank; main pump failure; cooling
system leaks at joints.
9. Control
Quality risk management (QRM)
Holistic Contamination Control Strategy (CCS) focused on minimizing
contamination control with respect to sterile manufacturing
Reduce the risk of contamination through
10. Quality Risk Management (QRM)
Processes, equipment, facilities and manufacturing activities
should be managed in accordance with QRM principles to ensure
Prevention of microbial, particulate and pyrogen contamination in
the final product.
Proactive use of risk management
Regular review of risk assessment
Use of effective root cause and CAPA
Employing staff with expertise to undertake risk assessment
Risk assessment should not simply confined to manufacturing, it
needs to extend to packaging and to the distribution of the
finished medicinal product, thereby embracing the requirements
of Good Distribution Practice (GDP)
11. Contamination Control Strategy
(CCS)
A formal, holistic CCS which reflects the site-wide strategy
to define all critical control points and assess the
effectiveness of all the controls (design, procedural,
technical and organisational) and monitoring measures
employed to manage risks associated with contamination
respect to sterile manufacturing.
13. Premises
• Airlock for personnel
• Airlock for equipment and materials
• Technical and operational separation measures for component
preparation, product preparation and filling
• Wider use of barrier technology such as Restricted Access
Barriers Systems (RABS) or isolators
• Smooth, impervious and unbroken surfaces to minimize the
contamination and to permit proper cleaning and disinfection
• Floor drains designed to prevent back flow
14. Premises
• Maintain Pressure differentials minimum 10 pascals
• Indicators of pressure differences and warning system for failure
• Permit observation of production activities from outside the
Grade A zone and Grade B area
• No ingress of airflow from lower grade to higher grade areas
demonstrated by Airflow patterns visualization
• Clean Air and Clean Air Equipment Qualification
• Cleaning and Disinfection
15. Clean Air and Clean Air Equipment
Qualification
Qualification of cleanrooms and clean air equipment should
include
• Installed filter leakage and integrity testing
• Airflow measurement - Volume and velocity
• Air pressure difference measurement
• Airflow direction and visualization
• Microbial airborne and surface contamination
• Temperature measurement
• Relative humidity measurement
• Recovery testing
• Containment leak testing
16. Cleaning and Disinfection
Cleaning :
The process of removing product residues and contaminants such as
dirt, dust, grease from the surface. Cleaning is the first step for
sanitation
●Contaminants can be – Physical, - Microbiological, - Biological, -
Chemical agents
Disinfection:
The process by which the reduction of the number of microorganisms is
achieved by the irreversible action of a product on their structure or
metabolism, to a level judged to be appropriate for a defined purpose
• Sporicidal agent – An agent that destroys bacterial and fungal spores
when used in sufficient concentration for specified contact time
17. ISOPROPYLALCOHOL (70%)
• Powerful disinfectant
• Effectively kills bacteria and fungi
• Mode of action: denatures proteins, dissolves lipids
and can lead to cell membrane disintegration.
• But does not inactivate spores!
e.g., phenols, Alcohols, Aldehydes etc.,
Disinfectant
19. Cleaning and Disinfection
• More than one disinfectants by rotation
including one Sporicidal
• Facility independent disinfectant efficacy
testing
• Validated disinfection process covering expiry
period
• Sterile disinfectants for Grade A/B
• Assessment of microbial contamination for In
House disinfectants
• Effectively removal of disinfectant residues
20. Personnel
• Sufficient appropriate personnel
• Minimum number of personnel permitted to enter cleanroom
• Gowning Qualification for entering Grade A zone and Grade
B areas
• Minimum basic training
-Personnel Hygiene
-Gowning
-Cleanroom practices
-Contamination control
-Aseptic techniques
-Effect on patients due to loss of sterility
22. Personnel Hygiene
Personal hygiene procedures including wearing
protective clothing apply to all persons entering into
production areas:
● Full-time employees
● Temporary workers
● Contractor's employees
● Visitors
● Inspectors
23. Personnel Hygiene
Illness or open lesions:
●May affect the quality of products
●Should not handle starting materials, intermediates or finished
products, etc.
●Instruction and encouragement to report to supervisors
Direct contact between product and operator:
●Should be avoided
●Starting materials, primary packaging materials, intermediate
and bulk product
24. Personnel Hygiene
Protection of product from contamination:
●Clean clothes appropriate to personnel activities
●Including hair covering (e.g. caps)
Check change rooms/changing facilities:
●Hand washing, signs, drying of hands
●Used clothing stored in separate closed containers while
awaiting cleaning
●Laundering of clean area clothing according to an SOP and in
an appropriate facility
●Procedure for disinfecting and sterilizing when required
Activities To Be Done
25. Personnel Hygiene
●Smoking, eating and drinking not allowed in production areas,
laboratories and storage areas
●No chewing (e.g. gum), or keeping food or drinks allowed
●No plants kept inside these areas
●Rest and refreshment areas should be separate from
manufacturing and control areas
Other Activities
26. Clean Room Behaviour
• Good practice:
• gowns/PPE changed if damaged, wet or used for
long durations
• check yours and others regularly
• target max duration = 4 hours
Time
Avoid rapid movements
– creates particles
– disturbs air flows
Avoid aerosol production
personnel = contamination
https://www.youtube.com/watch?
v=yuc6cNBrbxM
28. Clean Room Behaviour
Aseptic technique must always be used wherever applicable
Fresh sterilised gloves must be worn immediately before a critical
activity and regularly sanitised
● but do not use disinfectant spray near product, components,
raw materials or env. mon. equipment
29. Clean Room Behaviour
Minimise spread of contamination during critical
activities:
● avoid touching your person or other people
● avoid touching human contact sites such as:
♦ pens bin handles
♦ keyboards paperwork
♦ keypads desks
♦ doors plugs/switches
♦ chairs any unclean equipment
♦ telephones containers (disinfectant cans?!)
●if you do make contact - sanitise gloves
30. Environmental Monitoring
The goal of the environmental monitoring program is to
provide meaningful information on the quality of the
aseptic processing environment during production as well
as environmental trends.
31. Environmental Monitoring
Non-viable count
-Particle Count
Viable Count
Active Air monitoring
- Settle Plate
Passive Air Monitoring
-Active Air plate
Surface monitoring
-Contact plate
-Swab
Personnel monitoring
-Contact Plate (Gloves and Gown)
33. Aseptic Process Simulation (APS)/
Media Fill
A simulation of the entire aseptic formulation and filling process in
order to determine the capability of the process to assure product
sterility
Used to validate the aseptic process
34. Media Fill
Use microbial growth media instead of drug product-any
contamination will result in microbial growth.
It doesn’t provide a direct relation for sterility but gives
an adequate evaluation for operational processing steps
Accessed Prefilled time as part of media fill
Accessed time limit for aseptic assembly
Maximum exposure time of Sterilized containers to
closures
35. Product Inspection
• Inspection for particulate matter
• Container Closure integrity (CCIT):
• CCIT – Needs to consider impact of transportation -GDP
• Microbial Ingress test to determine acceptable stopper height
displacement
36. Quality Control
• Examination of Raw materials based on required microbial quality
as defined in contamination control strategy .
• Strengthen sterility testing
• Sampling from the beginning middle and end of batch , plus
following any significant intervention
• Endotoxin Testing
37. Extremely heat stable – recommended conditions for
inactivation are 180 0 C for 3 hours.
Endotoxin: a pyrogenic (fever inducing) substance (e.g. lipopolysaccharide)
present in the bacterial cell wall. Endotoxin reactions range from fever to death.
Endotoxin Testing
LAL Assay (Limulus amoebocyte lysate)
ENDOTOXIN LIMIT FOR WFI IS
0.25 EU/ml
Quality Control
