Isolator System Technology
An isolator is defined as a decontaminated unit meeting Grade 5 conditions that provides uncompromised, continuous, isolation of its interior from the surrounding environment. (ISPE, 2011, p.134). 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, p.152). Isolators can be either “open” or “closed” depending upon their operational state and may operate at positive, neutral, or negative pressures with respect to the surrounding environment. When “closed,” isolators may exchange air with the surrounding environment only through microbially retentive filters. When “open,” isolators may transfer air directly to the surrounding environment through openings (e.g., “mouseholes”) that preclude the ingress of bio-contamination (ISPE, 2011, p.134)
As a member of the Validation team in the Multinational Pharmaceutical Manufacturing Company producing sterile products I would recommend the use of Closed System Aseptic Processing by use of six stage research and development Isolator. This isolator, ideal for research and development and is designed to provide the maximum protection for the operator during the manipulation operations and to ensure the separation between the external environment and the interior of the isolator itself (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, p.12). When compared to traditional open processing, the room and facility requirements may be reduced when using uncompromised barrier technology. The room air classification, zoning, and monitoring requirements reduce to the extent that the HVAC system may no longer be regarded as critical. The gowning level requirements reduce as a result of the closed process and the room classification reduction. Personnel gowning areas and material airlock areas are reduced in number. The level or extent of room cleaning is reduced. Sanitized walls are not included in the product protection equation for isolator systems. The room finish and detailing requirements are reduced. Coved corners at the floor, wall, and ceiling intersection may not be required. Coved corners facilitate room cleaning and may be a factor in product protection in “open” processes, but not in isolator protected open processes. (They may, however, be “discretionary upgrades,” along with other features critical to open processing). ISPE (2011, p.69)
The 6-stages isolator is divided into the following glove box chambers which include Chamber A where the reactor is provided with tubes that connect to synthesis chamber C; Chamber B which is the Material inlet prechamber; Chamber C where Synthesis 1 takes place; Chamber D with Drying Systems made of vacuum dryer and is connected on the rear side ; Chamber E where Synthesis 2 takes place and is equipped with MT analytical balance; and Chamber F which is the material outlet prechamber equipped with barrier sack system.
The top priority of its design is the safety of personnel, and hence the features in the isolator are for safe operation. These features include 6 working areas, turbulent flow with nitrogen, oxygen monitoring, negative pressure in respect with laboratory environment, fully PLC controlled and fully washable. As per ISPE guidelines(2011, p. 25), Isolators are decontaminated internally typically using an automated system such as vapor-phase hydrogen peroxide (VPHP) and no access is permitted to inside the isolator, other than for materials movements via controlled alpha-beta docking ports. When tested using micronized lactose isolators the isolator has 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, p.13)
According to Samuel (2012, p.234) Operation of the Isolator involves introduction of materials into the isolator through Chamber B they are then conveyed to Chamber C where Synthesis 1 takes place. The reactor material is then provided via Chamber A and after reaction has occurred the products are moved to Chamber E where Synthesis 2 takes place and lastly conveyed to Chamber D for Drying.
Six stage research and development isolator have a HEPA filtration system used to condition entering and exiting air and to remove primary particles and 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, p.89)
The Isolator system has a number of advantages over the existing non barrier systems:
The 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 (Brian, 2004, p.90).The reduction in operating costs cover the leasing costs of the isolation system with no additional expenditure. The isolator 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, p.21). The use of isolators can reduce room classification requirements, leading to smaller and lower cost HVAC systems (ISPE 2011, P. 91)
Due to the use of HEPA filtration in totally enclosed environment, the isolator no longer requires 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, p.1137)
Isolators have the highest levels of separation effectiveness amongst the three environmental contamination control approaches recognized in the ISPE guidelines (2011, P.22.) 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. It allows dimensional alterations, change of transfer devices and mechanisms, incorporation of machinery and equipment, addition of several chambers and compatibility with particular cleanrooms.
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. According to ISPE(2011, p.90) The use of isolators minimizes or eliminates interaction of the Grade 5 zone with the surrounding environment, thereby significantly reducing this risk hence enhancing efficiency and safety.
The major disadvantage with this isolator like any other barrier method is inevitable degree of leaking. Despite the best-laid containment or isolation designs, six stage research and development isolator inevitably leaks 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.
According to ISPE Baseline Pharmaceutical Engineering Guide Sterile Manufacturing a number of validation considerations should be followed to ensure that the design, construction, commissioning and qualification of the isolator meet the standard guidelines for production of sterile products. These 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, p.20)
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). it should is also important to considered that the adoption of barrier or isolator technology in new and renovated facilities can significantly impact material flow and personnel movement in the area compared with traditional open aseptic processing set-ups and this should be thoroughly considered at design outset. ISPE (2011, p.76). The ISPE baseline guidelines on Facility design approaches recommend that in an isolator set-up, the surrounding room environment does not come in contact with the product and its immediate process environment at any period during processing, and it is, therefore, not part of the product protection equation, although control of the surrounding room is still a regulatory requirement. This allows the general level of finish of the room to be reduced as well as reducing the HVAC area classifications in the room. (ISPE, 2011, p. 67)
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 isolator’s 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). The selection, training, and motivation of personnel are vital to Good Manufacturing Practice. Exclusive reliance on the enclosure to preserve the aseptic processing environment will not be enough and may give a false sense of security. Operators should be given a thorough understanding of how to operate the control system and perform the aseptic operation within it. The operator is required to have knowledge of the transfer devices and decontamination. (ISPE, 2011, p 151)
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 results to a competitive advantage of our company over others.
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