Pharmaceutical manufacturing has aseptic production as one of its toughest processes because the end product has to stay sterile without the need of terminal sterilization after filling. This implies that the process must include control of microorganisms and the contamination due to particles at every manufacturing step, starting with the preparation of the components, through the actual filling and stopping of containers and transferring them afterwards.
The challenge of maintaining an appropriate cleanroom is not the only one concerning the aseptic processing. The process itself is an overall system that involves the design of the manufacturing facility, staff practices, sterilization of equipment, material transfer, monitoring of environment, implementation of process control, and prevention of contamination.
An optimized aseptic process assumes that contamination occurs at many different points of the process and presumes the implementation of multiple independent systems limiting it.
Aseptic manufacturing is different from terminal sterilization in that terminal sterilization involves the use of validated processes for sterilizing sealed products. Aseptic processing relies on controlling the environment in which the production takes place.
Some common products that involve aseptic processing are:
- Parenteral injections
- Ophthalmic medicines
- Sterile biological drugs
- Some vaccines
- Sterile solutions
- Certain cell and gene therapy products
The method must be very well controlled because once the sterile parts have been in the aseptic conditions, there can be no way to sterilize them again.
- Clean room and facility design
- HVAC system and proper air flow
- Personnel gowning
- Equipment sterilization
- Component preparation
- Transferring the materials
- Aseptic filling process
- Monitoring the environment
- Cleaning and disinfecting
- Ensuring the integrity of the container
- Process simulation
If any aspect fails, the whole sterilization goes down.
The most high-risk operations that involve unprotected sterile product filling are carried out under the most demanding conditions. Grade A conditions according to EU GMP Annex 1 are normally applied for aseptic activities carried out under strict conditions and are supported by an appropriate outside condition, depending on the technology and process.
Air flow pattern is crucial in this respect. Unidirectional airflow or other properly designed air flow system has to provide protection of unprotected sterile product and critical surfaces against contamination.
Qualification of cleanrooms usually involves evaluation of such parameters:
Prior to entering any classified area, staff members must comply with an approved gowning procedure which suits the class and operation of the cleanroom.
Such procedures may include:
- Hygiene of hands
- Head and beard cover
- Face mask
- Cleanroom suit
- Sterile gown
- Sterile shoes
- Sterile gloves
However, wearing the proper gown alone is not enough. Staff members need to know about aseptic behavior.
Unjustified movement, talking, touching equipment, incorrect usage of gloves and poor methods of making interventions can increase contamination risk.
That is why all personnel should be properly trained and certified before starting their operations.
According to the kind of material and the technique used, some examples of rafters are:
- Steam sterilization
- Dry heat sterilization
- Radiation process
- Sterilization using gas
- Use of filtration process to sterilize liquids
The chosen method must be shown to be valid and to ensure that the sterilization is performed without side effects on the component.
There are many possibilities for input contamination caused by materials being moved to sterile areas.
Thus, special techniques have to be developed for transferring. Some examples include:
- Pass-through chambers
- Airlocks
- Validated disinfection
- Decontamination techniques
- Double-door sterilization equipment
- Getting rid of all the contaminants
Such techniques allow avoiding that dirtiest part of the process come in contact with the purest one. It is rather important to pay attention to surface points of containers because the outer part may be quite polluted despite the purity of inner substance.
Generally, the process embraces:
Where possible, implementing barrier technologies like RABS and isolators allows minimizing the people’s impact on the critical areas.
The program can include monitoring:
As opposed to pharmaceutical fluids, a suitable sterile microbiological medium is used to imitate the aseptic process.
All types of conditions occurring during the actual manufacturing of products should be simulated. In some cases, specific conditions can be simulated too:
Contamination control strategy consists of:
- Unjustified manual actions
- Poor practices of dressing
- Unsatisfactory disinfection practices
- Weak monitoring system
- Bad design of materials transfer procedures
- Unqualified personnel
- No airflow studies backed with monitoring of airflow
- Ignorance of recurring contamination trends
- Inadequate monitoring of sterilization process
These weaknesses can be easily identified as soon as the results of monitoring and assessment start deteriorating.
The strongest aseptic processes are centered on contamination prevention rather than substantial reliance on the tests conducted for the product at the end of the process. The usage of modern barrier technologies, automation, effective environmental monitoring and scientifically sound contamination control principles increases the number of benefits and reduces the threats connected with human interference.
Its main goal seems to lie in the safeguarding of the sterile product from all the places where contamination is able to occur.
An optimized aseptic process assumes that contamination occurs at many different points of the process and presumes the implementation of multiple independent systems limiting it.
What is Aseptic Manufacturing?
Aseptic manufacturing refers to the method of producing and filling sterile pharmaceutical products in isolated conditions and controlling the environment to avoid contamination.Aseptic manufacturing is different from terminal sterilization in that terminal sterilization involves the use of validated processes for sterilizing sealed products. Aseptic processing relies on controlling the environment in which the production takes place.
Some common products that involve aseptic processing are:
- Parenteral injections
- Ophthalmic medicines
- Sterile biological drugs
- Some vaccines
- Sterile solutions
- Certain cell and gene therapy products
The method must be very well controlled because once the sterile parts have been in the aseptic conditions, there can be no way to sterilize them again.
Core Elements of an Aseptic Process
When talking about aseptic manufacturing, it is better to think of it as a set of processes that work together instead of one single operation. These main components include:- Clean room and facility design
- HVAC system and proper air flow
- Personnel gowning
- Equipment sterilization
- Component preparation
- Transferring the materials
- Aseptic filling process
- Monitoring the environment
- Cleaning and disinfecting
- Ensuring the integrity of the container
- Process simulation
If any aspect fails, the whole sterilization goes down.
Facility and Cleanroom Requirements
Aseptic processes are carried out in controlled cleanrooms with specified air cleanliness levels.The most high-risk operations that involve unprotected sterile product filling are carried out under the most demanding conditions. Grade A conditions according to EU GMP Annex 1 are normally applied for aseptic activities carried out under strict conditions and are supported by an appropriate outside condition, depending on the technology and process.
Air flow pattern is crucial in this respect. Unidirectional airflow or other properly designed air flow system has to provide protection of unprotected sterile product and critical surfaces against contamination.
Qualification of cleanrooms usually involves evaluation of such parameters:
- Presence of particles in the air
- Air flow rate
- Difference in pressure
- Temperature
- Humidity
- Recovery capabilities
- Integrity of HEPA filters
Personnel Gowning and Behavior
Staff members are considered to be one of the most major sources of potential contamination.Prior to entering any classified area, staff members must comply with an approved gowning procedure which suits the class and operation of the cleanroom.
Such procedures may include:
- Hygiene of hands
- Head and beard cover
- Face mask
- Cleanroom suit
- Sterile gown
- Sterile shoes
- Sterile gloves
However, wearing the proper gown alone is not enough. Staff members need to know about aseptic behavior.
Unjustified movement, talking, touching equipment, incorrect usage of gloves and poor methods of making interventions can increase contamination risk.
That is why all personnel should be properly trained and certified before starting their operations.
Preparation and Sterilization of Components
The preparation and sterilizing process of components must be done correctly. All components that will be utilized in contact with sterile materials should be properly sterilized.According to the kind of material and the technique used, some examples of rafters are:
- Steam sterilization
- Dry heat sterilization
- Radiation process
- Sterilization using gas
- Use of filtration process to sterilize liquids
The chosen method must be shown to be valid and to ensure that the sterilization is performed without side effects on the component.
Material Transfer Into the Aseptic Area
The containers, closures, filling machinery, tubing and different parts used in the process have to be fully controlled.There are many possibilities for input contamination caused by materials being moved to sterile areas.
Thus, special techniques have to be developed for transferring. Some examples include:
- Pass-through chambers
- Airlocks
- Validated disinfection
- Decontamination techniques
- Double-door sterilization equipment
- Getting rid of all the contaminants
Such techniques allow avoiding that dirtiest part of the process come in contact with the purest one. It is rather important to pay attention to surface points of containers because the outer part may be quite polluted despite the purity of inner substance.
Aseptic Filling Process
The aseptic filling method is the main activity in which the following combine: sterile product, packaging, sealing, apparatus and surroundings.Generally, the process embraces:
- Preparation of sterilized bulk solution
- Sterilization or filtering of the substance
- Transference to the filling apparatus
- Preparation of sterilized packages and seals
- Aseptic filling
- Partial or full stopping
- Final sealing of a package
- Examination of the package and following treatment
Where possible, implementing barrier technologies like RABS and isolators allows minimizing the people’s impact on the critical areas.
Environmental Monitoring
Environmental monitoring provides proof that aseptic environment is kept under control.The program can include monitoring:
- Non-viable airborne particles
- Viable airborne microorganisms
- The contaminations of the surfaces
- The contaminations of the personnel
- Pressure differential
- Temperature and humidity according to the relevance
Media Fill or Aseptic Process Simulation
The Aseptic Process Simulation (APS) or Media Fill is of great significance when it comes to the qualification of a sterile or aseptic processes.As opposed to pharmaceutical fluids, a suitable sterile microbiological medium is used to imitate the aseptic process.
All types of conditions occurring during the actual manufacturing of products should be simulated. In some cases, specific conditions can be simulated too:
- Operator interventions
- Adjusting equipment to another mode of operation
- Vacuuming the line
- Changing shifts
- Maximum time period of the operation
- Number of personnel like operators
- Influences on the containers
Contamination Control Strategy
The aseptic production process should be controlled by a rigorous Plan for Contaminant Control (CCS).Contamination control strategy consists of:
- Design of the production building
- Regulations regarding the staff
- Disinfection and cleaning
- Clearing equipment from harmful bugs
- Transfer of materials
- Environmental monitoring
- Design of processes
- Provision of utilities
- Maintenance
- Controls of suppliers
- Interventions during aseptic production
Common Weaknesses in Aseptic Manufacturing
Several problems can make aseptic production inefficient:- Unjustified manual actions
- Poor practices of dressing
- Unsatisfactory disinfection practices
- Weak monitoring system
- Bad design of materials transfer procedures
- Unqualified personnel
- No airflow studies backed with monitoring of airflow
- Ignorance of recurring contamination trends
- Inadequate monitoring of sterilization process
These weaknesses can be easily identified as soon as the results of monitoring and assessment start deteriorating.
The strongest aseptic processes are centered on contamination prevention rather than substantial reliance on the tests conducted for the product at the end of the process. The usage of modern barrier technologies, automation, effective environmental monitoring and scientifically sound contamination control principles increases the number of benefits and reduces the threats connected with human interference.
Its main goal seems to lie in the safeguarding of the sterile product from all the places where contamination is able to occur.
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