EQUIPMENT AND CLEANROOMS

BioPharm: What type of equipment is typically used for aseptic processing?

O'Connor: The major piece of equipment, so to speak, is a cleanroom. Cleanrooms contain laminar airflow hoods, isolators or restricted access barrier systems (RABS), filling lines, sterilizing filters, autoclaves for sterilizing the equipment, depyrogenation tunnels for removing any endotoxins, as well as other equipment. Cleanrooms also have automated cleaning systems for reducing any low levels of contaminants prior to sterilizing, and isolators that have filling lines installed in them. These units are totally enclosed and have a localized area with what's called "Grade-A air" inside of them; this is where the filling line fills the product into final containers such as vials, syringes or bags.

BioPharm: Can you provide more details about cleanrooms and the garments that are required?

O'Connor: There are a number of different standards around cleanrooms, but the International Organization for Standardization (ISO) 14644-1 defines a cleanroom as a room in which the concentration of airborne particles is controlled and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the room and which other relevant parameters (e.g., temperature, humidity, and pressure) are controlled as necessary.

Within the cleanroom, the critical components include high-efficiency particulate air filters on the ceilings that filter all the air coming into the room, as well as exhaust vents at the floor level. These vents ensure that laminar airflow and effective removal of air so that there are many air changes per hour, typically from 5 to 100. There should not be any drains inside an aseptic processing area in a cleanroom. Airlocks are important to facilitate the movement of people and equipment from one cleanroom into another.

It's important that cleanrooms are designed appropriately to ensure seamless and rounded floor-to-wall junctions to prevent buildup of any contamination or water. Floors and walls and ceilings must be constructed of smooth, hard surfaces that can be easily cleaned. One should limit the amount of fixtures and fittings on the walls to facilitate the ease of cleaning of walls, and layout of equipment must be optimized for the comfort, and movement of people.

In addition to ISO 14644, in Europe, cleanroom classifications are divided into Class A, B, C, and D, where A is the most stringent and D is the least exacting. In the US, room classifications are referred to as Class 100, Class 1000, Class 10,000, and Class 100,000. The ISO standards then would be 5, 6, 7, and 8. The standards in general apply to particle sizes in the range of 0.5 microns to 5 microns.

The standards are used interchangeably, depending on where your site is located and where you're being regulated. So, if your site is regulated by FDA, it would use the Class 100, 10,000 100,000 standards. Similarly, if your site follows the European standard, that means using Class A, B, C, and D. A Class-A air area would be used to perform a high-risk operation such as filling or making aseptic connections. A Grade-B area is typically used for aseptic preparation and as a backround environment for traditional filling operation. Grade C is used for preparation of solutions and equipment.

Microbial monitoring is also required to demonstrate the cleanliness of the cleanroom during production. The recommended limits are specific for the each room classification. Cleanrooms should have settle plates where air is allowed to settle to support the growth of bacteria. Staff can then see how much bacteria might be in the environment. Contact plates can be put up against walls and surfaces, and gloveprints can be used in Grade A and B areas. Gloveprints are where people actually place their gloved fingers to see whether there is any contamination present.

With each area, there are standardized limits. In a Grade-B room, for example, one can have no more than 10 colony forming units. It's important to trend these results, otherwise one cannot determine whether the room is under control. If there is no control, the product is at risk.