Pharmaceutical products that directly enter the bloodstream need to be prepared in an aseptic environment where the facility and equipment are design to keep microbiological contaminants at a minimum. Sterile products are defined as those that are injected using a syringe or intravenous catheter, medical devices that are inserted into the body, and inhaled products such as those used for asthma. These cleanrooms are purpose-built facilities developed to bring treatments to patients faster without compromising safety and quality.

Recommended Gowning Requirements for Sterile Product Cleanrooms

At each cleanliness level, a change in operator gowning is required. The basic process for entering a sterile product cleanroom is:

When an operator enters a controlled not classified (CNC) space, they are required to change from street clothes into a facility uniform. After changing, they enter an ISO 8 Class 100,000 space which requires hair and shoe covers or dedicated plant shoes. The next level, ISO 7 Class 10,000, requires sterile gowning. This is put on in an ISO 7 gowning room before entering the ISO 7 Class 10,000 aseptic core. Skin cannot be exposed so the operator must have a hood, facemask, and goggles. A laminar-airflow ISO 5 Class 100 environment created by supplying air filtered through high-efficiency particulate air (HEPA) filters from directly above the machine is provided within ISO 7 Class 10,000 process suite where product or product containers are exposed.  

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Classifications and Specifications of Support Zones in a Sterile Product Cleanroom

Each support zone is designed to reduce the chance of contamination of the product being developed. For the GMP warehouse, where sampling and weighing operations are being performed, follow the same environmental conditions as those for GMP products being made. Once the raw materials enter the processing areas, a higher level of environmental control is required. The cleanrooms and corridors are designed to be of higher classification until the aseptic core is reached. Each level is designed to protect the next level to prevent contamination of the product.

A manufacturing support zone designed to make sterile products usually composes of an ISO 8 Class 100,000 area and includes

• Formulation - where a bulk material received from an API facility is added to a liquid that is to be transferred into a container
• Component preparation - where packaging materials that will come into direct contact with the product are washed as the first step in the cleaning process
• Equipment preparation - where equipment parts that come into direct contact with the product or components that are in direct contact are prepared for sterilizing

Design Considerations of the Filling Suite in a Sterile Product Cleanroom

The filling suite is composed of multiple rooms that include areas for gowning, air locks to separate each operation and to maintain room pressurization, and the filling room.  Gowning rooms comprise of a transition zone from ISO 8 Class 100,000 to ISO 7 Class 10,000 and are usually designed to create an ISO 7 Class 10,000 environment. 

The filling suite can be set up in several ways. One option is for operators to directly access the filler. A second way is to use a restricted access barrier system (RABS) which is a glove box that separates the operator and the room environment from the open product. 

The filling suite is typically ISO 7 Class 10,000, and within the suite the filling equipment is protected by unidirectional airflow from above. The aseptic core needs to be designed and maintained to be the cleanest room in the operation. This room also has the highest differential pressure. Therefore, when doors are opened to the surrounding air locks, the direction of the airflow should flow out of the filling room and into the air lock. 

What are some critical parameters you need to consider?

Some critical parameters you need to take in a count are temperature, humidity, pressure, and space cleanliness level. These parameters need to be defined by the requirements of the products. Note that humidity can increase and decrease the HVAC operational cost based on the season and location of the facility. Space temperature is usually maintained between 62 degrees Fahrenheit and 66 degrees Fahrenheit.  While determining space temperature and humidity levels, operator comfort should be considered along with the product requirements. In aseptic core areas, the airflow rate is considerably higher than in the support areas. A common practice is to use recirculated air because it reduces the HVAC energy consumption.  

Air that is flowing to aseptic areas need to be filtered by a ceiling mounted terminal HEPA filters at minimum 99.99% most penetrating particle size (MPPS) efficiency. Return air should be located strategically to avoid any recirculation zones and provide a good sweep of the airflow within the room. Utilizing computational fluid dynamics (CFD) method provides a good visual representation of the airflow within the space. 

A key to protection of products and personnel are air locks. The cascading air lock is generally considered for use in aseptic operations. The primary objective of an air lock is to segregate the clean space from surrounding areas. This is accomplished by maintaining a pressure differential where the aseptic suite has the higher pressure. This will cause the direction of airflow to go into the air lock when the air lock door is opened. Air recirculation should be maintained 24/7 in aseptic areas. 

So, what’s next?

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