Risks in high-potency manufacturing

The use of a production line for manufacturing injectable, high-potency drugs in asepsis has risks. It is important to determine the risk levels of the critical aspects of the processing. The principal areas that should be taken into consideration when evaluating risk areas and modalities to control are as follows:

• Management of chemical contamination
• Management of cross-contamination
• Management of aseptic processing
• Management of the environmental impact
• Comparison of different aseptic techniques used in manufacturing high-potency drugs.

Isolators (ALL FIGURES AND IMAGES ARE COURTESY OF THE AUTHOR.)

The intermediate phases of the production process do not pose significant risk because the liquid product is confined inside the isolators or the distributor system (tanks, transfer tubes, and needles). From a containment perspective, it is much easier to manage liquid solutions than powder because of the following:

• Liquids have more limited characteristics of dispersion and diffusion
• Solutions are significantly more diluted than an active principle in powder
• The principal risks to diffuse contamination are tied to dispersion in air and are present when liquids are in an aerosol phase.

The risky points of the production process are:

• Preparation of the solution (i.e., the handling of high-active powders)
• Product vials (i.e., the potential that a solution drops on the surface of sealed vials or vials break inside the freeze-dryer)
• Washing of soiled process components (e.g., tanks, tubes, needles, and the freeze-dryer)
• Transfer of various materials potentially contaminated on their surface.

The approaches to mitigate risk in each of these areas are detailed below.

Preparation of the solution. Adoption of isolators that operate with negative-pressure conditions and the integrity control of the isolators, particularly the gloves, shield operators from exposure to powders. The direct transfer of the powders to the predissolution tank, integrated in the isolator, avoids any risk of environmental dispersion. The cleaning of the closed isolator and the gathering of washing water in such a tank guarantee that the product of manufacturing remains confined, in liquid form, inside the tank. The periodical substitution of the filters, mainly exhaust ones, is executed by a trained staff, which is aware of the risks, and through a system of high containment (i.e., bag-in/bag-out).

Product vials. The last phase of the production process involves the external washing and drying of the sealed vials, which eliminate eventual traces of contamination by the product solution. The unloading of the vials from the freeze-dryer is another extremely risky point for the operators' exposure to the powder because the product is turning to its solid state. Because of the high incidence of vials breaking in the freeze-dryer, this phase is conducted within isolators both during loading and unloading. These operations further use an automatic system (i.e., pusher) and an adequate condition of loading (i.e., "pizza door"), which noticeably reduce human intervention during the process and favor the maintenance of aseptic conditions.

Washing of soiled process components. The cleaning procedures are mainly handled automatically. Where manual intervention is necessary, however, gloves are used. All manual washing activities are conducted on soiled solution components and never on powder ones.

Transfer of various materials. Because of previous handling (e.g., the supplier's container that holds the API, the container holding the API that is returned from production to the warehouse, and samples of material), all materials potentially contaminated by traces of high-active powders on their surfaces are handled with protective gloves and individual protective equipment such as masks and glasses. As a precautionary measure, all containers are wrapped in new plastic covers that collect traces of powder and avoid dispersion into the environment. All critical manipulations are performed under the safety hood or inside the isolators by trained personnel who are aware of and trained to control the risk.