In this article, three specialists from Litek focus on the field of primary containment that can be achieved with a suitable design of the process under isolator.
Written by Javier Alonso Gómez, Alex García and Gastón Ariel Estruch
Containment in the use and handling of high potent products has several aspects that must be analysed. Containment is not absolute. The different levels of containment that can be obtained will depend on the system and technical solutions applied.
The evaluation and verification of the containment level must be in accordance with the analysis and detection capacity. The development of new and more active pharmaceutical ingredients and with lower therapeutic doses, it forces extreme containment measures and ultimately also forces the use of more sophisticated analytical detection techniques.
A drug production project with a highly potent active ingredient requires a detailed study from concept to validation. In this article we want to focus on the field of primary containment that we can achieve with a suitable design of the process under isolator. We will analyse a product weighing process.
The phases of a project for the weighing of a high potent product require the following steps to be carried out in an orderly manner.
User requirements analysis
Study case - user requirements analysis
In this article, we study a weighing case with the following starting data:
Before initiating the risk analysis, it will be necessary to establish a basis for proper management.
It is necessary to name a person in charge, and to create a multidisciplinary team to analyse and approach the analysis from all perspectives. In this case the project team consists of:
Another important point is to determine the toxicity of the product to be handled. In many cases, a detailed characterisation of a product is not available. As there is no universal and unique system for categorising exposure control bands, pharmaceutical companies themselves often define values based on their knowledge of the product, therapeutic compounds, work environment, equipment, controls, and other factors.
Chart 1: Results of the risk analysis
A common example might be “Occupational Exposure Band 1” (OEB 1) (>1000 μg/m3), OEB 2 (10 to 1000 μg/m3), OEB 3A (1 to 10 μg/m3), OEB 3B (0.01 to 1 μg/m3), OEB 4 (<0.01 μg/m3).
Each category will have a corresponding OEL. These categories are set based on a detailed toxicological evaluation of all possible adverse effects.
Figure 1: Typical Risk Management Process
The final determination of the product category does not depend on a single factor, such as the therapeutic dose. The total toxicological profile will be fixed when the category is finalised.
Containment strategy - Regarding the primary barrier, the risk analysis, and in accordance with the applicable regulations, the isolator should be selected as the containment strategy.
In this phase, the laboratory must draft the URS document, as detailed as possible, the most important aspects of the isolator from the end-user's perspective.
From a conceptual design point of view, we propose an isolator with the following characteristics:
At this stage, the FDS (Functional Design Specification) document must be drafted, which covers the functional aspects of the isolator design.
Inlet: Air Lock for entry of materials and tools. Two gloves to allow unpacking tasks. DRUM elevator, prepared for different sizes, and sealed with inflatable gasket seals during operation.
Outlet: Split butterfly valve port, to plastic bag or metal bottle (figure 2).
Waste port, a continuous liner, with inflatable seal port or RTP.
Figure 2: 3D modelling of the proposed solution
Figure 3: Drum loading at the base of the isolator and Outlet of heavy product through split butterfly valve
Manual cleaning with a spray gun in the air lock, and spray balls and spray gun in the main chamber.
The cleaning of the main chamber, where the products will be handled by the operator, will require detailed study.
Spray balls connected to the CIP circuit will clean most of the product dispersed along the isolator.
The control system is based on an Industrial PLC connected to the sensors and detectors of the isolator for its correct operation.
This software has an electronic register that can be validated according to GAMP 5.
The control system can be integrated with the laboratory's MES system.
Figure 4: Control system architecture
An interface solution based on mixed reality technology is integrated, where the isolator operator will have real-time access to all the necessary information for its correct use. For example, he has real-time access to the standard operating procedures, being able to review each step of the process through the mixed reality system and avoid errors during the process.
The operator himself, through the mixed reality system, will be able to inform the system of the progress of the process, having total traceability and electronic registration of the process.
The ventilation and filtration system consists of a compact ventilation module with separate supply and exhaust EC fans. The classification obtained inside the chamber is ISO 8 according to ISO14644.
An identical system of components with the same functionalities is foreseen in both the airlock and the isolation chamber. A HEPA H-14 filtration in the supply air and a double HEPA H-14 filter in the exhaust air of both the airlock and the main chamber are foreseen.
The filters are PUSH-PUSH so that they can be changed from inside the isolator, allowing a safe filter change.
The manufacture of a mock-up of the isolator in disposable material (wood or cardboard) on a scale of 1:1 is highly recommended for ergonomically studying the isolator. Hence, the user can evaluate the functionality of the isolator for the specific processes defined and it can be modified and finally approved before the construction of the definitive model in stainless steel.
It is necessary to build a multidisciplinary team to tackle the project with the highest level of knowledge and to carry out a thorough risk analysis. When it is decided to establish the isolator as the primary barrier, it will be necessary to carry out a specific project, including all the details that ensure the manufacture of a suitable isolator for the defined application, and complying with all the established requirements.