One of the most difficult and critical areas in designing a pharmaceutical facility is establishing the clean room. The clean room is not merely a controlled area but rather a specifically engineered environment to reduce the chance of contamination and ensure that all of the environmental conditions like air quality, humidity, temperature and pressure within it are maintained consistently.
All types of cleanrooms, regardless of whether their purpose is for producing sterile products, developing formulations or conducting microbiology tests, must conform to regulatory requirements including EU GMP Annex 1, US FDA cGMP and ISO 14644 standards.
This post defines the steps to properly design and construct a cleanroom according to the operational requirements and regulatory expectations for a pharmaceutical company.
The classification of cleanrooms is dependent on the number of airborne particles in the cleanroom environment. Cleanroom classes are the primary classification systems of cleanrooms, which are ISO 14644-1 and EU GMP. Both of these guidelines categorize cleanrooms as per to the airborne particle concentration present in the area.
ISO 14644-1 categorizes cleanrooms classes from ISO 1 through ISO 9.
EU GMP categorizes sterile cleanrooms into four grades A, B, C and D.
Establishing the proper cleanroom classification early in the design process, helps ensure the other aspects of cleanroom design are consistent with air cleanliness levels, gown requirements and environmental monitoring procedures.
The cleanroom layout should take into consideration how personnel and materials flow through the facility; therefore, a cleanroom should have both a unidirectional personnel flow and a unidirectional material flow, which will allow clean and dirty activities to be kept separate from one another and eliminate the possibility of materials being backtracked through a cleanroom after entering.
Some important principles of cleanroom layout:
Recommended construction materials are:
Wall & Ceiling: Epoxy coated or stainless steel panels
Floor: Seamless Epoxy or polyurethane floor with coved edges
Door & Window: Flush mounted with smooth surface
Lighting: Flush mounted sealed lighting fixtures to prevent dust
Never use materials like wood or gypsum as they produce or retain particulates. All joints should be sealed with silicone for a complete seal and protection from air infiltration resulting in area contamination.
Characteristics of cleanroom HVAC systems include:
A. Air Filtration - High efficiency particulate air (HEPA) filters help to remove 0.3 microns sized particles greater than or equal to 99.97% efficiency.
B. Air Changes (ACH) per Hour - Ranges from 20 air changes per hour for lower-class clean rooms to over 600 air changes per hour for higher-class clean rooms.
C. Pressure Differential - Pressurized areas of cleanrooms have positive pressure in comparison to surrounding areas which helps control openings to keep contaminants out of the area.
D. Temperature and Humidity Control - Specific target values include 20 - 22 degrees Celcius and 40 to 60 percent relative humidity.
F. Air Flow Patterns - Aseptic clean rooms must have airflow patterns that keep the contaminants away from critical areas.
Regularly conduct preventive maintenance along with testing for filter integrity (through either DOP or PAO testing) to maintain the maximum operational capacity.
In general, the air pressure in the cleanroom area is greatest at the point of highest cleanliness and decreases as you move farther into the area of the least critical cleanliness; i.e., there are fewer opportunities for air to be contaminated.
Some examples of the use of pressure differential between cleanroom areas can include:
Class A: +30 Pa
Class B: +20 Pa
Class C: +10 Pa
Class D: 0 Pa
Airlocks and gowning areas are two typical transition areas, so each area must have its own defined level of pressure control. It is recommended to have the appropriate type of differential pressure gauge or magnehelic gauge at the connections between the cleanroom and the surrounding environment, such as outside the building.
Personnel Flow Steps:
- Entering the Change Room → Removal of street clothes + Shoes
- Thoroughly wash and sanitize hands
- Wear Cleanroom Garments including: Coveralls, Gloves, Masks, Shoe Covers.
- Through airlock to the Controlled Area.
Material Flow Steps:
- Material Airlocks must be equipped with interlocking doors.
- Disinfect all surfaces before entering.
- Separate Equipment should be used for Entry/Exit to Prevent Cross Contamination.
Ensure Unidirectional Flow = No Backflow of Materials or Personnel.
Utilities, for example, purified water (PW), clean steam, compressed air and nitrogen, must meet pharmaceutical grade quality specifications. The pipe systems must be made of stainless steel (SS 316L) and should have an orbital weld and sloped drains preventing stagnation.
Critical utilities will need to be validated for microbial quality and chemicals according to the requirements established by USP <1231> and ISO.
The cleanroom’s qualification is performed in 4 incremental stages:
1) Design Qualification DQ): Determines whether or not the cleanroom has been designed in accordance with defined requirements and relevant regulations;
2) Installation Qualification (IQ): Ensures that every part of the cleanroom has been installed properly;
3) Operational Qualification (OQ): Checks to see if the cleanroom is functioning correctly. This includes testing; i.e., airflow, HEPA filter integrity, pressure and temperature control; and
4) Performance Qualification (PQ): Establishes that the cleanroom will consistently operate as specified under normal working conditions.
Depending upon the maximum dimension and/or the intended use of the cleanroom, requalification should be done in every 6 -12 month to maintain compliance with current standards.
The following are typically all important environmental factors:
- Airborne particulate counts, according to ISO 14644-1.
- Viable air and surface monitoring, using settle plates or swabs.
- Temperature, humidity and pressure differentials.
The effectiveness or frequency of cleaning and disinfecting procedures should be validated. If applicable, use rotation of disinfectants (e.g. alcohol + sporicidals) and document everything when cleaning.
- Basics of Good Manufacturing Practice (GMP) and sanitation.
- Proper way to get into and observe inside a cleanroom.
- Methods to clean, verify effectiveness of dirty rooms and keep records on everything.
Compliance with these requirements will occur through the execution of regular internal audits, responding to any deviations and the creation of periodic/recurrent training programs.
Establishing a pharmaceutical cleanroom is a complex process that combines engineering, microbiology, & regulatory compliance. A properly designed & managed cleanroom creates an environment free of contamination; therefore, the cleanroom's air pressure, material transfer, surface finish & material validation must all work together to ensure the cleanroom's efficacy.
Developing & maintaining the cleanroom will ensure the safety, efficacy & compliance of all pharmaceutical products produced in it with Good Manufacturing Practices (GMPs). Therefore, a pharmaceutical cleanroom's upfront investment of time spent on planning, documentation & training creates operational excellence & provides for a solid foundation upon which to build future success.
All types of cleanrooms, regardless of whether their purpose is for producing sterile products, developing formulations or conducting microbiology tests, must conform to regulatory requirements including EU GMP Annex 1, US FDA cGMP and ISO 14644 standards.
1. Define the Purpose and Classification
To establish a cleanroom facility, first thing to do is to clarify the purpose of the cleanroom. Define the use of proposed cleanroom, utilized for sterile processing, non-sterile production or microbiological testing. The functions of a cleanroom are directly related to its classification or cleanliness level and associated design criteria.The classification of cleanrooms is dependent on the number of airborne particles in the cleanroom environment. Cleanroom classes are the primary classification systems of cleanrooms, which are ISO 14644-1 and EU GMP. Both of these guidelines categorize cleanrooms as per to the airborne particle concentration present in the area.
ISO 14644-1 categorizes cleanrooms classes from ISO 1 through ISO 9.
EU GMP categorizes sterile cleanrooms into four grades A, B, C and D.
Establishing the proper cleanroom classification early in the design process, helps ensure the other aspects of cleanroom design are consistent with air cleanliness levels, gown requirements and environmental monitoring procedures.
2. Determine the Cleanroom Mechanism and Flow
A cleanroom's layout has an impact on its overall effectiveness. If the layout is designed poorly, cross-contamination, backflow of unfiltered air and personnel errors are likely to occur.The cleanroom layout should take into consideration how personnel and materials flow through the facility; therefore, a cleanroom should have both a unidirectional personnel flow and a unidirectional material flow, which will allow clean and dirty activities to be kept separate from one another and eliminate the possibility of materials being backtracked through a cleanroom after entering.
Some important principles of cleanroom layout:
- Locate personnel and materials that enter and exit from separate airlocks.
- Keep all gowning, preparation and operation areas clearly defined.
- Differentiate between rooms of different cleanliness levels using pressure differentials of 10 to 15 Pa.
- Maintain a logical flow of material through the cleanroom area to minimize cross contamination. All materials should go through material entry → processing → packaging → waste removal.
3. Select Construction Materials Carefully
Construction materials used for cleanroom should be smooth, non-porous that are easy to clean and resistant against disinfectant. Gaps and holes can allow microorganisms to grow and they must be avoided.Recommended construction materials are:
Wall & Ceiling: Epoxy coated or stainless steel panels
Floor: Seamless Epoxy or polyurethane floor with coved edges
Door & Window: Flush mounted with smooth surface
Lighting: Flush mounted sealed lighting fixtures to prevent dust
Never use materials like wood or gypsum as they produce or retain particulates. All joints should be sealed with silicone for a complete seal and protection from air infiltration resulting in area contamination.
4. HVAC System Design (Air Handling Unit)
HVAC systems are vital to the performance of cleanrooms; they provide the mechanisms necessary to sustain proper air cleanliness, temperature, humidity and relative pressure within cleanrooms.Characteristics of cleanroom HVAC systems include:
A. Air Filtration - High efficiency particulate air (HEPA) filters help to remove 0.3 microns sized particles greater than or equal to 99.97% efficiency.
B. Air Changes (ACH) per Hour - Ranges from 20 air changes per hour for lower-class clean rooms to over 600 air changes per hour for higher-class clean rooms.
C. Pressure Differential - Pressurized areas of cleanrooms have positive pressure in comparison to surrounding areas which helps control openings to keep contaminants out of the area.
D. Temperature and Humidity Control - Specific target values include 20 - 22 degrees Celcius and 40 to 60 percent relative humidity.
F. Air Flow Patterns - Aseptic clean rooms must have airflow patterns that keep the contaminants away from critical areas.
Regularly conduct preventive maintenance along with testing for filter integrity (through either DOP or PAO testing) to maintain the maximum operational capacity.
5. Create Zoning and Pressure Cascade for Cleanroom Areas
Cleanroom areas are developed as an area of increasing cleanliness through the use of a pressure cascade.In general, the air pressure in the cleanroom area is greatest at the point of highest cleanliness and decreases as you move farther into the area of the least critical cleanliness; i.e., there are fewer opportunities for air to be contaminated.
Some examples of the use of pressure differential between cleanroom areas can include:
Class A: +30 Pa
Class B: +20 Pa
Class C: +10 Pa
Class D: 0 Pa
Airlocks and gowning areas are two typical transition areas, so each area must have its own defined level of pressure control. It is recommended to have the appropriate type of differential pressure gauge or magnehelic gauge at the connections between the cleanroom and the surrounding environment, such as outside the building.
6. Define Personnel and Material Flow Procedures
The largest source of contamination to a cleanroom is from human personnel. By implementing strict movement and gowning protocols, the risk of contamination is minimized.Personnel Flow Steps:
- Entering the Change Room → Removal of street clothes + Shoes
- Thoroughly wash and sanitize hands
- Wear Cleanroom Garments including: Coveralls, Gloves, Masks, Shoe Covers.
- Through airlock to the Controlled Area.
Material Flow Steps:
- Material Airlocks must be equipped with interlocking doors.
- Disinfect all surfaces before entering.
- Separate Equipment should be used for Entry/Exit to Prevent Cross Contamination.
Ensure Unidirectional Flow = No Backflow of Materials or Personnel.
7. Test and Install Cleanroom Utilities and Equipment
Equipment within the building should be constructed on materials that can be easily cleaned, should be corrosion resistant and should produce the least amount of particles possible.Utilities, for example, purified water (PW), clean steam, compressed air and nitrogen, must meet pharmaceutical grade quality specifications. The pipe systems must be made of stainless steel (SS 316L) and should have an orbital weld and sloped drains preventing stagnation.
Critical utilities will need to be validated for microbial quality and chemicals according to the requirements established by USP <1231> and ISO.
8. Perform Qualification and Validation
The cleanroom should be thoroughly qualified before actual manufacture to ensure it meets its designed specifications.The cleanroom’s qualification is performed in 4 incremental stages:
1) Design Qualification DQ): Determines whether or not the cleanroom has been designed in accordance with defined requirements and relevant regulations;
2) Installation Qualification (IQ): Ensures that every part of the cleanroom has been installed properly;
3) Operational Qualification (OQ): Checks to see if the cleanroom is functioning correctly. This includes testing; i.e., airflow, HEPA filter integrity, pressure and temperature control; and
4) Performance Qualification (PQ): Establishes that the cleanroom will consistently operate as specified under normal working conditions.
Depending upon the maximum dimension and/or the intended use of the cleanroom, requalification should be done in every 6 -12 month to maintain compliance with current standards.
9. Implement Environmental Monitoring and Cleaning Programs
When a cleanroom is operating successfully, the environmental conditions must be monitored at all times.The following are typically all important environmental factors:
- Airborne particulate counts, according to ISO 14644-1.
- Viable air and surface monitoring, using settle plates or swabs.
- Temperature, humidity and pressure differentials.
The effectiveness or frequency of cleaning and disinfecting procedures should be validated. If applicable, use rotation of disinfectants (e.g. alcohol + sporicidals) and document everything when cleaning.
10. Train Personnel and Maintain Compliance
Personnel need to be properly trained in order for a cleanroom to be effective. Training should consist of the following areas:- Basics of Good Manufacturing Practice (GMP) and sanitation.
- Proper way to get into and observe inside a cleanroom.
- Methods to clean, verify effectiveness of dirty rooms and keep records on everything.
Compliance with these requirements will occur through the execution of regular internal audits, responding to any deviations and the creation of periodic/recurrent training programs.
Establishing a pharmaceutical cleanroom is a complex process that combines engineering, microbiology, & regulatory compliance. A properly designed & managed cleanroom creates an environment free of contamination; therefore, the cleanroom's air pressure, material transfer, surface finish & material validation must all work together to ensure the cleanroom's efficacy.
Developing & maintaining the cleanroom will ensure the safety, efficacy & compliance of all pharmaceutical products produced in it with Good Manufacturing Practices (GMPs). Therefore, a pharmaceutical cleanroom's upfront investment of time spent on planning, documentation & training creates operational excellence & provides for a solid foundation upon which to build future success.
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