Isolator system technology
Isolator is a structure that is sealed or supplied with air through a microbial retention filtration system and can be decontaminated. It uses decontaminated interfaces only or Rapid Transfer Ports for transfer of materials when closed. It however, allows for the entrance and egress of materials through distinct outlets that have been designed and certified to prevent the transfer of contamination when open. Isolator systems are designed to meet the thorough clean and restricted environmental needs of Pharmaceutical, Biotechnology, Medical devices, Radiopharmaceutical and Nuclear industries. (Alison, 2006 p152)
The device provides a physical barrier between the operator and a work process. They are designed to maintain an internal condition and for the provision of an isolation of a process. The device operates at negative, positive, or ambient differential pressure. Isolators provide product, personnel and environmental protection. (Antoine Al-Achi, 2013 p24) In the pharmaceutical industry, people are the major source of contamination in aseptic manufacturing of drugs therefore; reducing personnel intervention into the process zone has significant impact on the efficacy of the final drug product. (Jane, 2011 p12)
The twin chamber, reactor charging isolator is built-in with an integral pneumatic drum tipper and used for charging catalyst powder into a reactor vessel. The top priority of its design is the safety of personnel, and hence the features in the isolator are for safe operation. When tested using micronized lactose isolators have an Operator Exposure Level (OEL) of less than 0.01μg/m3.The isolation workstation is a closed environment which uses solid stainless steel walls to create a critical zone for handling of products. To enable viewing of operations by personnel a hard clear plastic wall is used. The area offers protection to both the product and the pharmacist since it is completely contained. (Troy, 2007 p13)
According to Samuel ( 2012 p 234) Operation of the Isolator involves the drum being fixed onto the tipper and the lid is removed and the safety gate is closed afterwards. In order to make sure that the does not let the tipper function, pneumatic circuit is interlocked. After that the drum is raised, tipped and docked with the isolator. The drum dock system seals the outer liner and the drum rim to the isolator. The system uses compression seal and inflatable seal technology for the sealing process.
The bagged powder from the drum is moved into the transfer chamber, from there into the charging chamber through the transfer door. With the safety knife, the bag is opened and charged into the reactor placed below. The discharge hopper is provided with a grid to prevent objects and the bag from falling into the vessel underneath. Continuous liner bag out port system is used in the removal of the waste materials. (Brian, 2004 p 90)
A HEPA filtration system is used to condition entering and exiting air and to remove primary particles those that may be generated by the supplies being used in the unit. The air is recycled within the unit with a small quantity of air being discharged as a measure of sustaining a pressure differential between the environment in which it is located and the interior of the unit. The pressure differential is crucial in providing a back-up when there is a breach of the system’s security. (Tim, 2004 p89)
Isolator systems have a number of advantages over the existing non barrier systems:
Isolation technology offers a cost-effective method of achieving sterility of products. The capital costs and operating costs of isolator systems are less than those of a clean room. The reduction in operating costs covers the leasing costs of the isolation system with no additional expenditure. The technology offers an alternative to laminar flow technology that is cost-effective. They have reduced investment in disposable supplies such as personnel protective clothing, and have controlled expansion. The system can be turned off when not in operation hence, operating costs are also reduced significantly. (Michael, 2002, p21)
Due to the use of HEPA filtration in totally enclosed environment, isolators no longer require large volumes of air, hence reduced size of the mechanical air systems. This creates less noise and heat than laminar flow technology because the air filtration system of the unit is not being used to provide a barrier hence high velocity is not needed. (Seymour, 2001 p1137)
Integrity of the product can be increased because compounding personnel are moved from the critical zone and are only able to manipulate the product through glove ports. The requirement of procedures of a “set back” is eliminated by the solid barriers. The materials are placed in the work zone in a manner that has no effect on the laminar air flow. (Bill, 2003, P.429)
The isolator approach allows for growth of the facilities without disrupting existing operations. Based on volume and mix of product, providers control start-up and constant expenses by increasing the number of workstations with increasing demand. The equipment allows expansion to meet demand as the lead times for equipment are as short as six weeks. In addition, certification and installation can be accomplished within a matter of hours. This also offers the advantage of flexibility of location
The technology offers workflow efficiency whereby organization and transfer of materials into the workstation is by use of a tray system. Efficiency and safety is also enhanced by the internal disposal systems for sharp objects and packaging materials. There is freedom of placement of materials which allows more efficient work flow and productivity.
The major disadvantage with isolators like any other barrier method is inevitable degree of leaking. Despite the best-laid containment or isolation designs, isolators inevitably leak to some degree. It is important for users to ask themselves ‘what leak rate can I tolerate?’ It however doesn’t matter as long as the system leaks in the direction that protects workers and product, as appropriate.
Other processes used as a means of achieving an aseptic environment in pharmaceutical industry are laminar flow technology and clean room construction technology. A clean room is a contained space where stipulations are made to reduce contamination and control other environmental parameters such as humidity, temperature and pressure. High Efficiency Particulate Air (HEPA) filter is the key component that is used to trap particles. All air delivered to a clean room passes through HEPA filters. Ultra Low Particulate Air (ULPA) filters can also be used and in some clean rooms where stringent cleanliness performance is required. It is recommended that personnel that work in clean rooms should undergo general training in contamination control theory. They should enter and exit the clean room through airlocks, air showers and gowning rooms. They must also wear special clothing designed to trap contaminants that are naturally generated by skin and the body.
The laminar flow technology allows containment of infectious splashes generated by microbiological procedures hence provides an aseptic work area. It protects the working environment from airborne contaminants by maintenance of a constant, unidirectional flow of HEPA-filtered air over the work area. It provides protection to the culture or to the user depending on the design. It is recommended that personnel be adequately to ensure proper use of the technology.
The Validation considerations of isolator systems are important because validation helps to verify that the isolator system and all associated equipment are suitable for sterility tests and is performed in three phases: installation qualification, operational qualification and performance qualification. (James, 2013, p.3)
Akers (1978, p 5) states that the Installation Qualification phase will include a full description of the physical features of the system, such as the size, internal design, and materials of construction. The unit outline will be diagrammed with interfaces and relocation systems dimensionally indicated. Compliance with design specifications for utility services, such as external exhaust, air supply, temperature, vacuum and humidity control, must be verified. Other equipment used together with the isolator system will also be described. Equipment manuals and copies must be catalogued and stored in a place that they can be recovered and reviewed. Conformity of drawings to design specifications should also be verified.
Possible process-control or equipment problems that might cause system failure in the course of operation should also be identified and documented in failure-mode analysis and hazard analysis. The system can be modified to minimize the risk of failure and critical control point methods established. (Jerold , 2012, p20)
The Installation Qualification should document in details about the equipment, Construction Materials, Instruments, Utility Specifications, Filter Certification and Computer Software associated with the isolator system.
The Operational Qualification phase is used to verify that the isolator system is operating in conformance to functional specifications. It involves operational performance check which will be used to verify that all alert and alarm functions conform to their functional stipulations. Isolator Integrity Check will test whether the integrity of the isolator is sustained in normal operating environment. A leak test will be performed to verify conformity to functional specifications and to ensure safety. A sterilization cycle can be performed to verify that all actual values conform to cycle steps and set points. Sterilization Cycle Development will be performed when the Operation Qualification phase is completed to establish the parameters necessary for process control during routine sterilization cycles.(FDA, 2004 p 8)
The Performance Qualifications phase verifies that the system is working in compliance with its operator requirement specifications. It involves Cleaning Verification to avoid the effect of products such as aggressive antimicrobial agents as residual products such as interference with the ability of subsequent tests to detect low levels of contamination in a new product. Sterilization Validation will also be performed to verify the isolators efficiency in production of sterile drugs. All Performance Qualification data will be adequately summarized, reviewed, and archived. (Attia , 2004 p. 3)
According to Parenteral Drug Association( 2000 p 34 ),Environmental monitoring is a staple in manned clean room process control. Environmental monitoring methods in isolators have been imported from clean room with only minor modification. Contamination in isolators according to sterility testing is always considerably less than manned clean rooms.
Glove tears, separations or pinhole leaks give the greatest risk of contamination in isolators. To reduce contamination from glove tears there was a switch from the Neoprene gloves to Hypalon gloves. In addition there has been the use of a sterilized under glove and single piece glove/sleeve systems to eliminate separations of the glove, sleeve and the wrist. (Agalloco,2006, p. 60)
My recommendations for integration of isolator systems into new facilities are:
Operators should be trained in procedures specific to the isolator. All training sessions and the evaluation of the operator’s performance should be documented in the individual’s training record. It is important to train all personnel in the appropriate safety procedures necessary for the operation and maintenance of the isolation system Personnel safety in the use of a sterilizing agent must be assessed. (Katayama, 2008, p. 235)
Sigwart (2005, p. 30) states that material Safety Data Sheets or equivalent documents should be available in the immediate area where the sterilizing agent is being used. All storage and safety precautions should be followed.
An operational readiness inspection of the safety of the isolator and all associated equipment should be performed and documented prior to placing the unit in service. (Jason, 2005, p.3)
According to Parenteral Drug Association (2001, p22) Maintenance of aseptic environment of the isolator system throughout the defined operational period must be validated. In addition, implementation of a microbiological monitoring program is paramount to discover malfunctions of the isolator system or the occurrence of adventitious contamination in the isolator. This involves a routine sampling program, such as sampling after sterilization on the first day of operation and sampling on the expiry day of the estimated maintenance of asepsis period. To demonstrate maintenance of asepsis, Intermediate sampling is performed within the isolator. The surfaces of the isolator can also be monitored using swabs for surfaces that are irregular or contact plates for surfaces that are flat. (Sandle, 2003, p. 43)
Isolator system technology is cost-effective, creates less noise and heat, increases integrity of the product, allows for growth of the facilities and improves workflow efficiency hence resulting a competitive advantage of our company over others.
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