Containment Technology

The historical development of the isolator technology is shown in [1] and [3]. Isolators are now a part of the pharmaceutical industry [6], which cannot be imagined without. Since its beginnings in the nuclear industry, many isolator applications are new to the chemical and pharmaceutical industries and are used to separate the user, product, and environment consistently from each other. For the pharmaceutical industry of the twenty-first century, containment systems for aseptic processes and the handling of API's have become more important. A modern isolator as it is used in the pharmaceutical industry of today can be designed for the product and process protection and/or for the protection of operators and the environment. Additional safety features and operating costs savings versus conventional clean room approaches are driving the change to containment solutions. Containments can be glove boxes, isolators, or restricted access barrier systems (RABS) . Isolators have captured a firm position in the pharmaceutical industry during the past few years.

Personnel protection isolators are increasingly replacing the personnel protection clothing, which is needed to enter process plants that are classified hazardous for operators. Full protective suits have the disadvantage that they are expensive in purchase and reconditioning, and time-consuming changes for the operator are necessary. Furthermore, the environment cannot be effectively protected from the release of problematic chemicals. The protection of the environment, the employees and the products can be done much easier with the use of tight isolators in which the process takes place. The active ingredients in the form of dust particles of different sizes can't escape and do not reach the skin and respiratory tract of the operators and the surrounding room. If there are minor leaks, the concentration of the hazardous substances is markedly reduced.

Product protection isolators are used for the protection of the processed product from particular or microbial contamination. But not only the product also the process like testing pharmaceutical samples for sterility or aseptic filling of vials and syringes can be protected from microbial and particular contamination. There are several methods with different levels of protection, starting from simple laminar flow units with PVC curtains up to open or closed Restricted Access Barrier System(RABS) and barrier isolator technology.

In the described RABS and isolators a variety of filter systems are used. There are different filter systems available to make up the air as well as to filter the exhaust air for the aeration of containments. The design and the efficiency of the filter system depends highly on the targets, which are defined by the OEL level (Operators Exposure Level) of the material, the amount of dust created in the process and the SAL (Sterility Assurance Level), which has to be achieved for the product and the process

Access devices are used to handle processes, products or tools, within an isolator. This is often done manually with gloves through glove ports or if heavy loads are to be moved over a half-man suit. For safe handling of radioactive substances in isolators, there are manipulators (see Sect. 5.3) of varying type in use. For choosing the right manipulation procedure for the process, one follows the results of the project-related ergonomics study (see Sect. 1.2) and the requirements of the processes to be executed. An overview of access devices is in the ISO 14644-7 in this chapter and ISO 14644-7 Annex C to see. Robots are nowadays used in pharmaceutical isolators or cRABS for filling and sealing of vials and syringes only sporadically but, in the future there will be more solutions based on robots [1].

An isolator or cRABS is a closed system, which can only work, if material liquid or solid can be transferred into or out of the isolator [10]. The transfer of goods and tools in and out of containment is an important process step and a critical procedure in the containment technology. During the past years a lot of efforts have been made from the industry to improve and develop transfer systems into containment isolators for different applications like product protection, operator, and environment protection or a combination of both. As important as the transfer in the containment, is the transfer out of the containment. The transfer can either be continuous or batch wise. Figure 6.1 shows the different transfer devices typically used with isolators for aseptic processes.

The main factors of the impurity in isolators, where people work with toxic powders are dust of auxiliary materials and additives, as well as active compound materials. In isolators, in which bottles, ampoules, or cartridges are filled, broken glass and liquid or powdered product is the main source of pollution. Avoiding cross-contamination, material carryover and the protection of the environment and the operators are essential aspects of a thorough cleaning. Isolators with complex internal installations can be a problem for the user in this regard.

The FDA “Guidance for Industry” requires that all product contact surfaces inside the isolator before the start of each aseptic process are sterilized. Here is the method of choice the heat sterilization with steam (SIP). All plant parts or accessories which do not withstand the temperatures to be achieved for successful steam sterilisation, must be fumigated with a decontamination procedure, which makes the surfaces in the work area free of living organisms. It must be demonstrated a germ reduction of 6 log-levels with a suitable biological indicator.

In aseptic operating production, the master plan for monitoring of the isolator provides meaningful information about the quality of the direct status of the aseptic manufacturing environment. Over a longer period of time, (trends) a consistent monitoring program allows to detect changes in the status “free of germs” of the isolator. The monitoring of the isolator helps to identify possible routes of contamination quickly and allows taking appropriate corrective action.

For plants in the pharmaceutical environment, the general structure of the documentation according to the GAMP 5.0 model is advantageous, see also [1]. It describes how to define the basis of the user data, lists the individual documents in a system of planning. Then planning documents are refined, written in construction plans and specifications, according to which the isolator system is built. In the last section of the isolator construction these documents are consulted again to illustrate in the qualification, that there is a ready-made system that meets the customer requirements.

In the pharmaceutical industry, more products are coming to production from biotechnological research. Their market volume increases disproportionately, which is also reflected in the dimensions and capacity of the isolator units required for fill-finish production steps. These products usually react very sensitive to external influences and cannot be terminally sterilized, therefore an aseptic preparation method with controlled environment is required. The isolator provides for it over the classical method of preparation in the clean room or with a simple barrier system such as open RABS, advanced technology options. Due to the strict physical separation of process and product on the one hand and the operator on the other hand, many atmospheric conditions are created and maintained. As an example, very low O₂ concentrations or low humidity for the processing of oxygen-sensitive or moisture-sensitive products are mentioned.