Clean room and aseptic processing

Unlike the conventional pharmaceuticals, radiopharmaceuticals are often not heat sterilized prior to patient use. Application of aseptic processing is, therefore, of primary importance for microbiological purity of the radiopharmaceutical preparation. This is achieved through production in clean room environment where airborne particles are controlled to reduce the possibility of contaminant particles entering the product, and ultimately the patient. ISO 14644-1 defines the clean room as “a room in which the concentration of airborne particles is controlled, and which is constructed and TABLE 5.3. SAFETY PRECAUTIONS FOR EQUIPMENT AND

MATERIALS (ADAPTED FROM REF. [5.2])

Chemical type Consideration

General Solvent resistant coved flooring.

Possibly needs ventilated storage.

Solid, sturdy shelving for storage.

Space for chemical waste storage.

Plumbed, conspicuously labelled eye wash and safety shower within 30 m or 10 s travelling distance.

Fire extinguishers mounted near entrance of work or storage area and conspicuously labelled.

Flammable liquids More than 40 L in a laboratory needs flammable liquid storage cabinet.

Storage not allowed below grade.

Corrosives Storage in low cabinets or shelves.

Radioactive material Physically separated eating and drinking areas.

Separate radioactive material areas from other areas.

Space for radioactive waste storage.

Biological agents Hand washing sinks with electronic controls.

Space for medical waste storage.

Highly toxic chemicals Hand washing sinks with electronic controls.

Highly toxic gases Vented gas cabinet.

Coaxial tubing.

Vapour sensors with alarms.

used in a manner to minimize the introduction, generation and retention of particles inside the room, and in which other relevant parameters, for example, temperature, humidity, and pressure are controlled as necessary.” Therefore, the facility must provide clean rooms with specified air quality for production of radiopharmaceuticals.

Typically, production areas where the vial or product is exposed to atmosphere (critical site) must be a class 100 (class a) laminar flow cabinet, which is enveloped in a Class 10 000 (Class C) room (supporting clean areas).

Entrance to the main clean room area is usually through anterooms of Class 10 000 (Class C), and is interlocked. The facility should be designed and engineered to achieve the required cleanliness. The critical components in design are: HEPA filters for incoming air; more than 20 air changes per hour (>20); and a pressure differential between rooms of different classes of 10-15 Pa. The pressure differential between classified and non-classified rooms should be 12.5 Pa (the pressure should be higher in the cleaner area).

5.4.1. Air purity

In clean rooms, the entire room should have overall positive pressure in relation to the adjacent room. An access to the aseptic areas should be through anterooms with airlocks, pass-through windows, and interlocking doors with appropriate pressure gradients if possible. Typically, the room would be of air Class 10 000 (Class C) and the production area within this room where the product is exposed to air would be of Class 100 (Class A). The local regulations should be used as the guiding principle while planning the clean rooms.

Classifying the entire room as Class A would ensure product purity but is not necessary and will become too expensive.

5.4.2. Personnel ingress and egress

There should be a single means of ingress and egress. This entrance should be as far as possible from the laminar flow hood or area where the sterile preparations are occurring, to avoid stray air currents from interfering with the air flow inside the hood. It should also be as far as possible from the front faces of the hot cells. This will reduce the chance that rapidly opening the door will cause some contamination in the hot cells from being sucked into the room if the cell door is open.

5.4.3. Room surfaces

The selection of proper materials for the walls and floors, and the care of the scientific instruments, is an important concern as they can affect the safety and efficiency of the workplace.

Walls. The walls should be covered with a seamless material or painted with a smooth surface paint which will not catch dust. The surfaces should be washable with a disinfectant solution.

Floors. Likewise, the floors should also be covered with seamless vinyl or other material which can be washed and does not offer any cracks or crevices for the accumulation of dirt particles.

Pipes, tubing, etc. All exposed tubing and pipes should be covered when possible to avoid the buildup of dirt on the surfaces or between tubes. This is particularly true for overhead pipes where they are not in clear view and dust may accumulate on the top of the pipes. A good practice is to place some type of covering over the pipes which can be easily cleaned. Materials used in production should be introduced into the clean room in a controlled manner to reduce the bioburden. The use of pass-through windows is usually the best means of maintaining a clean environment within the clean room. Provision should be made for gowning in an anteroom prior to entering the clean room.

5.4.4. Aseptic processing hoods

There are a large number of commercially available aseptic processing hoods on the market. They should provide an environment of Class 100 (Class A) for the sterile preparation of the vials.

There are a number of considerations which should be in place for clean aseptic processing areas. Table 5.4 provides a checklist for clean areas of differing classes.

5.4.5. Monitoring

The clean room should be monitored round the clock for pressure differential, temperature and humidity. Also, the air quality within the rooms should be monitored for compliance at a regular interval (typically, semi-annually). Regular monitoring will prevent the HEPA filters becoming clogged over a period of time. There should be audible alarms if there is an air handling system failure and the pressure differentials are not maintained.

TABLE 5.4. CLEAN ROOMS AND ASEPTIC PROCESSING LEVELS (ADAPTED FROM REF. [5.3])

Open Class C Class A Laboratory location and access

 Anteroom located between the processing area and the

outside.

 Outside door and inner door interlocked so only one can be

opened at a time.

 Interlocked doors have manual overrides for emergency exit.

 Clothing change area located in anteroom.

   Doors, frames, casework and bench tops to be non-absorptive

(use of organics should be avoided if possible).

   Surfaces are scratch, stain, moisture, chemical and heat

resistant.

  Surfaces should be continuous (no seams).

  Drawers to be of one piece construction.

  Reagent shelving to be equipped with lips to contain spills.

  100% outside air supplied.

 Benches, doors, drawers, door handles, etc., have rounded rims and corners.

 Visual pressure differential monitoring devices at doorway to

room.

  Audible and visual alarms for air system failure.

  Supply air to be HEPA filtered.

  Supply air system interlocked with exhaust to prevent

overpressure.

  Exhaust air to be HEPA filtered.

  Supply and exhaust systems outside radioactive areas for ease

of maintenance.

   Mixed hazardous waste disposal system in place.

  All penetrations sealed with non-shrinking sealant at the

containment barrier.

  All conduits and wiring sealed with non-shrinking sealant at

the containment barrier.

  Windows do not open to the outside.

Radiopharmaceutical production related materials including chemicals and supplies should be stored according to the storage conditions required for specific products. GMP guidelines are very clear on segregation of materials which have been qualified for use in pharmaceuticals production. Most of these supplies and chemicals are to be controlled in terms of inventory and usage.

5.5. QUALITY CONTROL AREA