The pharmaceutical industry holds its sterile drug products, including injectables, of the highest degree of cleanliness and prevention from contamination. A number of sterile drugs do not have an option for being subjected to terminal sterilization. Because of this, the process for producing these sterile products through aseptic processing has great importance.
To preserve the sterility of sterile rooms, it must be done in such a way as to protect against the possible introduction of microbial, particulate and/or pyrogen contamination. The U.S. FDA (Food and Drug Administration), EMA (European Medicines Agency) and the WHO (World Health Organisation) specifically and strictly enforce good manufacturing practice (GMP) requirements under their own respective regulations and EU Annex 1.
The article seeks to describe in detail all measures taken to protect the aseptic manufacturing process of sterile products in pharmaceutical sterile manufacturing areas.
In the manufacture of pharmaceutical products, aseptic conditions are created by:
- Grade A - Critical zones (i.e. fill area)
- Grade B - Background environment to Grade A
- Grade C & D - Lower critical stages
The following are critical design features for the cleanroom:
- Smooth, non-shedding surface materials
- Sealed wall/ceiling areas
- Minimal particle generation
- Controlled access via airlocks
A properly designed cleanroom is the basis for maintaining an aseptic environment.
The following are essential factors related to the HVAC system:
- High-Efficiency Particulate Air (HEPA) filtration which captures particulate contaminants and microbial contamination from the air
- Use of laminar airflow design within the critical areas
- Using pressure differentials to control the ingress of contamination in an area of Grade A and higher (pressurized), versus lower pressurized areas.
- Use of controlled temperature and humidity
Unidirectional airflow is used to move clean air from the clean air supply, while clearing contaminated air from the clean area of the cleanroom.
Completion of strict gowning procedures is critical to the development of successfully managing contamination.
The gowning requirements include the following:
- Sterile gowning products (coverall, gloves, masks and goggles)
- Proper gowning procedures to follow
- Ongoing training and certification of all personnel for proper use of gowning materials
The following are examples of good hygiene practices:
- Hand sanitization
- No jewelry or cosmetics
- Limiting movement in a cleanroom
If personnel do not gown correctly, it can compromise the entire sterile environment.
There are many ways to monitor the environment.
Examples of ways to monitor the environment include:
- Counting particles in the air
- Microbial monitoring (including settled plates and air samplers)
- Surface monitoring
- Monitoring personnel
The data generated from environmental monitoring helps identify trends and prevents contamination.
The following key practices should be followed:
- Only using validated disinfectants
- Rotate the disinfectants used to avoid developing resistance
- Establishing and following cleaning schedules and establishing standard operating procedures for cleaning
- Verifying that the cleaning process is effective through verifying cleaning validation
All surfaces and equipment and floors will be regularly cleaned.
The following methods can be used to accomplish sterilization:
- Autoclaving (using steam heat)
- Dry heat sterilization
- Filtering solutions to sterilize them
- Chemical sterilization
In order to ensure that the sterilization method chosen will be effective, the chosen method must be validated.
Some of the top ways to maintain good practice include:
- Making as few interventions as possible
- Performing as few excess movements as possible
- Keeping correct hand position
- Correct use of sterile tools and equipment
Any lapse of technique on the operator's part could lead to contamination.
Media fill studies are conducted, which simulate the actual manufacturing of product by using microbiological growth media.
Media fill studies are designed to:
- Determine the performance of the aseptic process
- Identify possible contamination points
- Verify the aseptic techniques being practiced by operators
The success of media fill studies is an indication that the aseptic environment is being maintained.
The following are examples of good practices when designing flow:
- Separate entry points for materials and personnel
- Use of airlocks and pass through boxes
- Unidirectional flow of materials
By maintaining controlled movement, the risk of contamination can be significantly reduced.
The following types of equipment should be maintained and calibrated:
- HVAC systems
- Sterilization equipment
- Monitoring devices
Ongoing maintenance will help ensure consistent performance.
Main sources of contamination are:
There are guidelines, such as GMP and EU GMP Annex 1, that address:
Aseptic manufacturing is one of the most important areas in drug production as various facility designs, standard operating procedures, trained personnel and continuous monitoring are necessary to maintain an aseptic condition in a sterile area.
If a pharmaceutical company has good contamination control practices, validates its processes and follows regulatory agency requirements, it can produce safe and aseptic pharmaceutical products.
In sterile manufacturing, there is no margin for error. Each step of the process must be controlled for the protection of the patient and the quality of the product.
The article seeks to describe in detail all measures taken to protect the aseptic manufacturing process of sterile products in pharmaceutical sterile manufacturing areas.
What are Aseptic Conditions?
An aseptic environment is one with no living microorganisms ("viable microorganisms") or particles such as dust and dirt that may cause contamination of a product and, therefore, a loss of sterility.In the manufacture of pharmaceutical products, aseptic conditions are created by:
- Controlled cleanroom environment
- Following strict gowning procedures
- Using only validated sterilization methods
- Having continuous environmental monitors during manufacture
Importance of Maintaining Aseptic Conditions
Creating aseptic conditions and maintaining sterility is critical because:- Sterile products are inserted directly into patients
- Contaminated products may lead to serious infections or even death of a patient
- Regulatory agencies require compliance with aseptic manufacturing processes
- Recalls of contaminated product(s) can be very costly and damaging
Key Elements for Maintaining Aseptic Conditions
1. Cleanroom Design and Classification
The classification of cleanrooms are important to the process of sterile manufacture. There are three grades for cleanrooms as per EU GMP Annex 1:- Grade A - Critical zones (i.e. fill area)
- Grade B - Background environment to Grade A
- Grade C & D - Lower critical stages
The following are critical design features for the cleanroom:
- Smooth, non-shedding surface materials
- Sealed wall/ceiling areas
- Minimal particle generation
- Controlled access via airlocks
A properly designed cleanroom is the basis for maintaining an aseptic environment.
2. HVAC System and Airflow Control
The Heating, Ventilation and Air Conditioning (HVAC) systems support the cleanroom environment in the control of contamination.The following are essential factors related to the HVAC system:
- High-Efficiency Particulate Air (HEPA) filtration which captures particulate contaminants and microbial contamination from the air
- Use of laminar airflow design within the critical areas
- Using pressure differentials to control the ingress of contamination in an area of Grade A and higher (pressurized), versus lower pressurized areas.
- Use of controlled temperature and humidity
Unidirectional airflow is used to move clean air from the clean air supply, while clearing contaminated air from the clean area of the cleanroom.
3. Personnel Gowning and Hygiene
The biggest contributor to contamination in sterile areas is the personnel working in those areas.Completion of strict gowning procedures is critical to the development of successfully managing contamination.
The gowning requirements include the following:
- Sterile gowning products (coverall, gloves, masks and goggles)
- Proper gowning procedures to follow
- Ongoing training and certification of all personnel for proper use of gowning materials
The following are examples of good hygiene practices:
- Hand sanitization
- No jewelry or cosmetics
- Limiting movement in a cleanroom
If personnel do not gown correctly, it can compromise the entire sterile environment.
4. Environmental Monitoring
By monitoring the environment continuously, the conditions of the cleanroom will be kept within limits.There are many ways to monitor the environment.
Examples of ways to monitor the environment include:
- Counting particles in the air
- Microbial monitoring (including settled plates and air samplers)
- Surface monitoring
- Monitoring personnel
The data generated from environmental monitoring helps identify trends and prevents contamination.
5. Cleaning and Disinfection
Regular cleaning and disinfection are a critical component of maintaining sterile environments.The following key practices should be followed:
- Only using validated disinfectants
- Rotate the disinfectants used to avoid developing resistance
- Establishing and following cleaning schedules and establishing standard operating procedures for cleaning
- Verifying that the cleaning process is effective through verifying cleaning validation
All surfaces and equipment and floors will be regularly cleaned.
6. Sterilization of Equipment and Materials
All equipment that is coming into sterile areas must be sterilized beforehand.The following methods can be used to accomplish sterilization:
- Autoclaving (using steam heat)
- Dry heat sterilization
- Filtering solutions to sterilize them
- Chemical sterilization
In order to ensure that the sterilization method chosen will be effective, the chosen method must be validated.
7. Aseptic Techniques and Operator Practices
Operators must employ appropriate aseptic techniques during manufacturing.Some of the top ways to maintain good practice include:
- Making as few interventions as possible
- Performing as few excess movements as possible
- Keeping correct hand position
- Correct use of sterile tools and equipment
Any lapse of technique on the operator's part could lead to contamination.
8. Media Fills and Process Validation
To prove the reliability of an aseptic process, validation must occur.Media fill studies are conducted, which simulate the actual manufacturing of product by using microbiological growth media.
Media fill studies are designed to:
- Determine the performance of the aseptic process
- Identify possible contamination points
- Verify the aseptic techniques being practiced by operators
The success of media fill studies is an indication that the aseptic environment is being maintained.
9. Material and Personnel Flow
In order to avoid cross contamination, it is important to properly design the flow of materials and personnel.The following are examples of good practices when designing flow:
- Separate entry points for materials and personnel
- Use of airlocks and pass through boxes
- Unidirectional flow of materials
By maintaining controlled movement, the risk of contamination can be significantly reduced.
10. Maintenance and Calibration
All equipment located in sterile environments must be regularly maintained and calibrated.The following types of equipment should be maintained and calibrated:
- HVAC systems
- Sterilization equipment
- Monitoring devices
Ongoing maintenance will help ensure consistent performance.
Common Sources of Contamination
By knowing where contamination comes from, we've started to manage against those sources.Main sources of contamination are:
- Operators (skin, hair and clothes)
- Airborne materials
- Equipment surfaces
- Raw material
Challenges in Maintaining Aseptic Conditions
There are many difficulties in maintaining aseptic conditions because of:- Human involvement
- Very complicated equipment
- Changes in the environment
- Following very strict laws
Regulatory Expectations
Regulatory bodies have established very specific requirements in sterile manufacturing.There are guidelines, such as GMP and EU GMP Annex 1, that address:
- Contamination Control Strategy (CCS)
- Environmental Monitoring
- Staff Qualifications
- Validation of Processes
Best Practices for Maintaining Aseptic Conditions
1. Create a Contamination Control Plan (CCP)
A Contamination Control Plan integrates all levels of controls into one comprehensive system of controls.2. Minimize Human Intervention
Automation or isolators greatly reduce contamination risk from human contact.3. Conduct Regular Training
Ongoing education allows for ongoing compliance by personnel performing aseptic procedures.4. Conduct Routine Audits
Internal audits allow for identifying any gaps between current practice and required practices and assisting in identifying areas for improvement.5. Implement New Technology
Isolators and Restricted Access Barrier Systems (RABS) provide enhanced protection from contamination through use of advanced technologies.Future Trends in Sterile Manufacturing
The sterile manufacturing process is undergoing a transformation with the introduction of the following technologies:- Automation & robotics
- Real-time monitoring of the environment
- Barrier/advanced barrier technologies
- Digital quality management systems
Aseptic manufacturing is one of the most important areas in drug production as various facility designs, standard operating procedures, trained personnel and continuous monitoring are necessary to maintain an aseptic condition in a sterile area.
If a pharmaceutical company has good contamination control practices, validates its processes and follows regulatory agency requirements, it can produce safe and aseptic pharmaceutical products.
In sterile manufacturing, there is no margin for error. Each step of the process must be controlled for the protection of the patient and the quality of the product.
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