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ISOLATOR
Sterilization Validation of an Isolator System
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Manufacturers who use vapor phase hydrogen peroxide–sterilized isolators need to take a comprehensive, ongoing systems approach to validation.
Isolation technology has been developing rapidly in recent years.
Implemented in the pharmaceutical industry to raise the sterility assurance levels of aseptically manufactured products, the technology is also finding a niche in the medical device industry. Isolators can be custom designed and built to segregate a specific process, allowing aseptic manipulation of products without human intervention. Isolators meet predetermined performance criteria, including a sterility assurance level (SAL) of 10–3 to 10–6, depending on the application.
One method used to sterilize an isolator is vapor phase hydrogen peroxide. There are four phases in the sterilization process. The process begins with dehumidification of the air in the isolator chamber. In the second phase, conditioning, hydrogen peroxide (H2O2) from a generator is vaporized and injected into the isolator at a high flow rate. The isolator is usually at atmospheric pressure, but may be operated under a vacuum. The dispersion efficiency and vapor uniformity of the H2O2 are critical to efficient sterilization, which is the next phase of the process. When sterilization is complete, an aeration process removes all traces of H2O2 from the isolator.
It is essential that all isolator systems are validated before use. Validation studies should include a qualification of the isolator and all associated equipment, including the H2O2 generator, which is separate from the isolator itself. The validation of the system should be documented by protocol and contain the same elements as the validation of any process: installation qualification, operational qualification, and performance qualification.
INSTALLATION QUALIFICATION
The installation qualification phase of the validation program consists of an engineering evaluation of all equipment. It should include detailed documentation of the isolator system, complete with dimensions, internal configuration, and all materials used in construction. Comparable documentation of the H2O2 generator should be done separately. In both cases, the description should include a diagram of the unit layout, with interface and transfer systems clearly indicated and their dimensions given. The following items should be included in the documentation:
•Equipment description.
•Manufacturer specifications.
•Construction materials.
•Instruments (including calibration status).
•Utility specifications.
•HEPA filter certifications.
•Computer software.
OPERATIONAL QUALIFICATION
For the system to be fully validated, both the isolator and generator systems must operate as intended, which is the purpose of the operational qualification. During this phase of the validation process, all sensors, indicators, and other critical components are tested to ensure that they are operational and properly calibrated. In systems where more than one isolator is used, each isolator should be checked independently. Data should be collected on all critical operational parameters that affect operation. During operational qualification, users should:
•Perform a mock run to check all cycle alarms and alerts in both the isolator and generator.
•Perform an integrity test to check for leaks, especially around transfer ports, gloves, and half-suit connections.
•Conduct a pressure test to ensure that positive pressure can be maintained in the isolator.
•Establish preventive maintenance procedures.
•Test for proper air exchanges.
•Verify cleaning procedures.
•Ensure that the piping system properly connects the generator to the isolator and the isolator to outside exhaust.
Operational considerations for the H2O2 generator should include an evaluation of each phase of the sterilization cycle—dehumidification, conditioning, sterilization, and aeration—and establish the reliability of the following systems:
•HEPA filter integrity.
•Computer alerts and alarms.
•Drier capacity and status.
•Sterilization cycle verification.
•Temperature distribution and mapping in the isolator.
•Uniform sterilant distribution using chemical indicators.
PERFORMANCE QUALIFICATION
The actual operation of the isolator system is initiated in the performance qualification phase, during which several initial steps should be performed to ensure success. To begin with, a determination must be made of the appropriate cycle parameters given the isolator configuration, room temperature, and loading. Isolator systems need not be installed in a controlled environment, but because most isolators are influenced by their environment, they should be located in a room maintained at constant temperature and relative humidity. Access to the system should be limited to trained operators.
Because the half-life of the H2O2 gas decreases as the mass of the material in the load increases, operators need to determine the maximum fixed-load requirements for their specific system before validating the isolator. Fixed-load configurations will vary depending on isolator size and specific functional requirements. In a sterility test system, for example, the isolator would contain sterility test supplies appropriate for the number of tests to be performed each day. Operators should fill each isolator with the identified items while ensuring that the loading does not interfere with gas distribution. Items should be placed on stainless-steel shelving and separated to allow the maximum diffusion of H2O2. The most effective sterilization occurs on the surfaces of unwrapped items, such as glass and metal, but surfaces of wrapped items can be sterilized when packaged in Tyvek. Paper or plastic bags should be avoided.
After the load configuration is determined, temperature mapping should be performed to determine heat distribution. This is conducted during the dehumidification phase (when the isolator air is circulated through a drier). Thermocouples are placed throughout the isolator and among the items. Heat-distribution analysis identifies any cold spots within the isolator, enabling operators to calculate the maximum safe concentration of H2O2 that can be used without causing condensation. H2O2 concentration is dependent upon the temperature of both the room and the isolator. A dehumidification setting of 20% should be established. In some climates, achieving set points lower than 20% can add considerable time to the total sterilization cycle.
Figure 1. Chemical indicator color-change range. Cumulative numbers of chemical indicators
showing change.
During temperature mapping, chemical indicators (CIs) should be placed adjacent to thermocouples to evaluate gas distribution. The color change from white to gray-violet, which indicates increasing H2O2 concentration, is gradual but should be complete within 25 minutes (Figure 1). CIs should be placed under the gloves, in folds of half-suits, within the load, and in the corners. Uniform gas distribution can be enhanced using fans mounted within the isolator.
Figure 2. Vapor phase hydrogen peroxide (VPHP) and water concentration (milligrams per liter)
versus time in minutes, with fans on (top) and off (bottom). Scale for VPHP measurements is on the left vertical axis of each graph; the water measurements are on the right vertical axes.
During these initial runs, the isolator should be closely observed for the formation of condensate. Condensation occurs when the gas concentration exceeds its saturation point at a given temperature. Condensation of H2O2 vapor indicates a gas concentration that is too high for the temperature within the isolator. Condensate can also indicate a situation similar to that seen when fans are not used: a less-uniform gas concentration in some areas causes the concentration to be too great for the isolator's temperature (Figure 2).
CYCLE DEVELOPMENT
Most generator manufacturers supply standard tables to aid in determining the proper H2O2 concentration. These tables indicate the maximum allowable concentrations for isolators of various sizes and take into account temperature, relative humidity, load mass, and flow rate. Using the tables, operators can select the proper cycle parameters for the dehumidification, conditioning, and sterilization phases.
Figure 3. D-value vs. steady-state hydrogen peroxide gas concentration.
In sterilization, the time in minutes required to reduce a microbial population by 90% is referred to as the D-value. Approximate D-values for different cycle parameters are available to isolator operators to help in the selection of appropriate injection rates and exposure times of H2O2. The D-value in most isolators falls between 2 and 5 minutes (Figure 3).
Once the proper cycle parameters have been determined, initial fractional H2O2 sterilization cycles can be run using biological indicators (BIs). The sterilization of all internal surfaces of the isolator, in addition to the external surfaces of the items placed inside, are validated as for any sterilization method, using resistant BIs. Bacillus stearothermophilus has been identified as the most resistant organism to H2O2 vapor sterilization. To validate to a SAL of 10–6, BIs with a spore population of 106 are used. It is possible that the carrier material for the BIs could absorb the H2O2; to prevent this from occurring, the spores should be inoculated onto stainless-steel coupons and packaged in Tyvek pouches. Also, the population of the indicators should be verified before validation.
At this point, operators are ready to determine the appropriate half cycle for H2O2 sterilization. One of two approaches can be used to accomplish this: users can perform sequential fractional cycles, increasing the gas-exposure time for each cycle, which is commonly practiced in EtO validation; alternatively, users can test exposed BIs in duplicate at intervals during a single gas exposure cycle. In the first approach, where all cycle parameters remain constant and only the gas-exposure time changes, the sterility of the BIs is tested after exposure to each fractional cycle; the gas-exposure time that yields a total kill of all the BIs is deemed the appropriate half cycle. In the second approach, users place media tubes and pairs of BIs in the isolator's worst-case location. At the start of gas inject and every 2 minutes thereafter, the BIs are placed in the media tubes. Meanwhile, controls are also exposed to assess the effect of the gas on the growth of the BIs. The time which produces total kill of all BIs is then selected as the half cycle gas-exposure time.
STERILIZATION VALIDATION
Once the half cycle gas-exposure time has been determined, three consecutive cycles should be run using BIs and thermocouples. Sterility testing should yield all negatives (no surviving BIs) to successfully validate the selected cycle parameters. The appropriate BI growth controls should all be negative and media growth promotion tests should be positive.
After acceptable sterility levels are achieved, a full cycle should be run to determine the time required to completely aerate the isolator. The goal during aeration is to reduce H2O2 gas to an acceptable level, typically 1.0 ppm or less. When injection of the gas ceases, the generator's catalytic converter breaks down the H2O2 gas into water vapor and oxygen. The aeration time depends on the isolator volume, the mass of adsorptive material, and the rate of outgassing from the materials. Creating higher air-exchange rates by using the generator fan can optimize aeration rates. Aeration efficiency can be routinely monitored in the sterilant return lines using a semiquantitative Drager gas detection tube capable of detecting H2O2 gas between 0.1 and 21 ppm.
Several times during the validation process, regeneration cycles may be required to remove humidity from the drying agent. This phase takes approximately 18 hours and should be performed overnight so as not to interfere with the scheduled cycle runs. The lower the drier capacity, the longer the dehumidification phase will be.
OTHER VALIDATION ISSUES
Several additional tests must be performed to demonstrate that the gas does not penetrate product containers, supplies, environmental samples, etc. Wrapping items in metal foil or placing them in a sealed container will prevent contact with the sterilizing agent, but note that wrapped items must be previously sterilized by other means since the H2O2 gas cannot reach the product. Both sterility test media and environmental control media must pass growth-promotion testing. It is essential to demonstrate that exposing the test articles to H2O2 sterilization does not interfere with the ability of the sterility test to detect low levels of organisms.
The maintenance of isolator sterility over time should be established and continually monitored. Monitoring should involve a schedule of routine sampling. For example, sampling could occur on the first day after isolator sterilization, on each subsequent day of use, and on the last day of operation. Surfaces can be sampled using premoistened swabs and with settling plates placed within the isolator during operation. It is always advisable to check the fingers of gloves and all transfer ports. Periodic inspection of gaskets, ports, and gloves to detect imperfections are also an important part of maintenance. Worst-case situation tests, including loss of power to the isolator or the transfer of additional supplies, also should be performed during routine sampling tests. And finally, since the primary route of contamination within the isolator is through the addition of supplies, special precautions must always be taken to ensure that only sterile items are added to the isolator.
BIBLIOGRAPHY
Akers, James E, James P Agalloco, and Colleen Kennedy. "Experience in the Design and Use of Barrier Isolator Systems for Sterility Testing" (paper presented at the PDA International Symposium, Basel, Switzerland, February 1994).
Amsco/Steris. VHP 1000 Biodecontamination System Cycle Development Guide. Mentor, OH: Amsco/Steris, 1991.
The Design and Monitoring of Isolators. Regional Quality Control Subcommittee of Regional Pharmaceutical Officers, September 1993.
Fritz, Claire, Don Eddington, and Dennis Cantoni, "Real-time Monitoring of Vapor Phase Hydrogen Peroxide for Cycle Development," American Glovebox Society Publication 11, no. 1 (1998).
Nieskes, Rick. "Validation of a Hydrogen Peroxide Gas Decontamination System for Isolators." The Booth Validator 2, no. 5 (1995).
Rickloff, James R and Joseph P Dalmasso. "Hydrogen Peroxide Gas Steril-ization: A Review of Validation Test Methods." Apex, NC: Amsco Sterilizer Co.
Rickloff, James R and Leslie M Edwards. "Modern Trends in Isolator Sterilization." In Isolator Technology. Eds. Carmen Wagner and James Akers. Buffalo Grove, IL: Interpharm Press, 1995.
Sintim-Damoa Kwame. "Other Gaseous Sterilization Methods." In Sterilization Technology: A Practical Guide for Manufacturers and Users of Health Care Products. Ed. Robert F Morrissey and G Briggs Phillips. New York: Van Nostrand Reinhold, 1993, 335—347.
United States Pharmacopeia. "Sterility Testing—Validation of Isolator Systems." In USP XXIII Informational Chapter 1208, Pharmacopeial Forum 23 no. 6, (1997).
Anne F. Booth is the principal consultant in her own firm, Booth Scientific Inc., a company that provides GMP and sterilization consultation for medical device manufacturers. She holds a master's degree from the University of Michigan and is an active participant in numerous industry organizations.
Photos courtesy of Steris Corp. (Erie, PA).
Reference: http://www.mddionline.com/article/sterilization-validation-isolator-system. Accessed in December 26,2010
ISOLATOR
Daragh D. Byrne, Ph.D.
Wyeth Biopharma
Introduction
The sterility test is one of the most fundamental tests performed within the sterile manufacturing pharmaceutical industry. It is a method to establish the presence or absence of viable microorganisms (bacteria and fungi) using defined culturing methods and is applied to all substances, preparations or articles which, according to the Pharmacopoeias, are required to be, or purporting to be, sterile [1- 3]. This includes products manufactured under aseptic conditions or terminally sterilized.
Due to the exacting nature of the test and the serious consequences that could result from a positive sterility result (i.e. batch rejection), the test is required to be performed under carefully controlled aseptic conditions. Traditionally, sterility testing was performed by personnel within a class A laminar airflow located within a class B clean room. Yet there are problems inherent with this type of set-up, e.g. unfiltered air can be exchanged with the surrounding environment, the work area can only be manually disinfected, and the test area is directly accessed by gowned personnel [4]. In recent years, however, isolator technology has emerged as a valuable alternative for the preparation and testing of sterile materials. An isolator can be defined as a containment device that utilizes barrier technology for the enclosure of a controlled workspace. Isolators offer advantages over clean rooms, the main ones being that they can be relatively easily decontaminated and they prevent the introduction of personnel borne contamination into the isolator [4].
However, isolators do present their own challenges and they require a very careful and rigorous validation program in order to meet the strict requirements of the regulatory authorities. The validation of a sterility test isolator suite is an intensive process that can take anywhere from 6 to 24 months to complete, depending on the complexity of the systems. Figure 1 gives an overview of the many stages of a typical isolator validation program. As the figure shows, even before delivery of the systems, a large amount of planning and preparation must be done. The remainder of this article will discuss in greater detail the various steps involved, and will hopefully provide some guidance to those embarking on an isolator validation program.
User Requirement Specification (URS)
In essence, the URS is a document that details what the user wants or expects the isolator(s) to do. It is written at the very outset of a project and it is of critical importance to the success of the validation program, as acceptance criteria of subsequent testing, such as the PQ, should be based on details set out in the URS. It is wise to be as precise as possible in the description, as this will also minimize the risk of subsequent misinterpretation.
There are many isolator manufacturers in the market today, each with their own slant on isolator design and configuration. The isolator should be designed to meet your specific requirements, and the URS is valuable as the basis for the tendering process. The following is a list of just some of the items that should be specified in the URS:
• Soft-wall vs. Hard-wall envelope. The majority of the isolators used for sterility testing use a soft-wall/flexible (PVC) film to form the workspace envelope, as it is relatively inexpensive and yet quite durable. For handling of cytotoxic or radio-pharmaceutical materials, where personnel protection is of primary concern, hard-wall/rigid plastic should be considered.
• Gloves vs. Half-suit. Half-suits may offer more flexibility, reach and range of movement than simple glove ports. Other ergonomic requirements or limitations (e.g. height) need also to be stated.
• Positive vs. Negative pressure. Generally for sterility testing, isolators will operate at positive pressure (at least +10Pa to surrounding environment [5]) in order to keep contaminating particles out, but in some circumstances (e.g. cytotoxics and radio-pharmaceuticals) it may be required to operate the isolators at negative pressure to protect personnel and the environment.
• The type of transfer devices for movement of materials in and out of, and between, isolators. The most common transfer device is known as the Rapid Transfer Port (RTP) and allows immediate transfer between isolators or containers without break of containment.
• Internal air quality requirements. For sterility testing, an EC GMP Grade A / US Class 100 (Iso Class 5) environment for viable organisms is a must (i.e. zero viable organisms allowed). The requirements for inlet and outlet HEPA filters (either single or double (recommended)), along with the intended air flow regime (turbulent or uni-directional, air-change rates etc.) must also be considered.
Reference:http://americanpharmaceuticalreview.com/ViewArticle.aspx?ContentID=202. Accessed in December 26,2010
ISOLATOR
Isolator Quest
By Robert Gardino and Kevin Jones
© PHOTOGRAPHY: MICHAEL MCCLOSKEY, KONSTANTIN ANDROSOV AGENCY: DREAMSTIME.COM
Perseverance necessary to find the right fit
The pursuit of a good sterility test isolator is an adventure that involves deciding the rationale for its use, selecting the equipment, justifying the capital expense, and installing and validating the unit.
We embarked on a mission to study isolators for sterility testing, though many of the issues also apply to aseptic processing.
We navigated a variety of road-blocks to realize the efficiency these isolators provide.
THE RATIONALE
Despite concerns about regulations and compliance, the clearest rationale for using isolators is enhanced product protection. During sterility testing of sealed vials, the risk of contamination from extraneous sources is minimal. Testing formats that require the container to be opened present significantly greater risk of extraneous contamination.
The risks cannot be completely eliminated. Removing the operator/analyst from the environment and ensuring that exposure of product and test material only occurs within a sealed, decontaminated environment greatly enhance the process, however. Aside from the obvious regulatory expectations and interests, other issues, such as analyst comfort and the cost of disposables for clean room operation (e.g., gowning, preparation time, sanitization, and clean room monitoring) make the use of isolators enticing.
Isolators with automated decontamination cycles allow for unattended preparation of the working space and test materials. Once all test items are loaded, the cycle can be initiated and decontamination and aeration accomplished without further human intervention. This is a clear advantage over clean room sanitization and rinsing, which involve the manual de-contamination of materials required during sterility testing in a clean room. Isolators with an automatic decontamination cycle allow you to prepare the chambers for use, run the cycle overnight, and commence testing the following morning. This functionality saves both time and money.
THE EQUIPMENT
When deciding which vendor to work with, you must choose either glove box or half suit and either hard wall or soft wall isolators. Height restrictions and the taller profile of half suit isolators led us to pick glove box isolators. To shorten the decontamination/aeration cycle, we chose the hard wall models.
In considering which vaporized hydrogen peroxide (VHP) vendor to use, you will immediately get caught up in the wet versus dry process dispute. Both processes work, but they have different cycle times; the dry process requires higher peroxide levels and a longer aeration period. We strongly recommend that you visit sites using the equipment under consideration and talk with users before deciding on the isolator and VHP generator. Of particular importance are the challenges inherent to validation, routine maintenance of the equipment, and associated down time. This research is the best investment of time and resources that you can make during the decision-making process.
After evaluating vendors of both the isolator and VHP generator equipment, we became aware of an isolator system manufactured by Skan AG (Allschwil, Switzerland) with a fully integrated VHP generation system. This product offers several advantages:
Each isolator has its own generator, providing redundancy (if more than one isolator is purchased) that can minimize down time;
It costs about 25% as much as the stand-alone models;
The design is simple;
The generator is validated as an integral part of the system; and
There is no need to regenerate desiccant because the process is wet and desiccant is not used.
After additional discussions with Skan AG isolator customers, we decided to purchase their unit.
THE JUSTIFICATION
Sterility isolator technology is a significant investment for any company. If you're a project manager or owner, you must be prepared to justify the purchase.
The benefits of sterility test isolator technology can be tangible (efficiency, greater throughput for samples, and use of fewer consumables) or intangible (reduced fatigue and employee burnout).
Key criteria to focus on when preparing the operational justification include:
Significant reduction in the risk of false-positive results and the corresponding savings for investigations and product release delays;
Increased capacity for sample analysis;
Enhancement of compliance with domestic and international guidelines and expectations;
Reduced employee fatigue and attrition due to harsh conditions in clean room technology environment;
Decreased expenditures for consumables (about $20,000 per year, including reduced cost for gowning supplies, disinfectants, and related supplies); and
Portability (sterility test isolators can be relocated).
In our example, isolators can save 745 work hours, which can be used for other activities such as batch release or testing. You can do more with the same number of employees-or fewer. There will also be greater flexibility in scheduling personnel, which will increase capacity.
Clean room technology may require two employees to work in tandem to pass through needed materials or for safety purposes. The isolator equipment allows the analyst to leave the lab for supplies or other reasons. Carefully planned de-contamination cycles in a sterility test isolator can allow for faster turnaround on test scheduling when compared with that required for a clean room environment. Planning allows for greater sample throughput, expedited product release, and greater capacity.
Clean room technology frequently requires annual shutdowns for maintenance, such as repairing epoxy paint and disinfectant-induced corrosion.
Sanitizing and monitoring to recommission the clean room can add two weeks to the down time. Isolators minimize this time, ensuring more efficiency and sample volume for the lab.
Though it is difficult to calculate because it varies with time and conditions, there will be a reduction in the organism isolate identification related to environmental excursions and positive sterility test investigations. Additionally, the costs associated with subcontracted DNA-sequence identification of isolates will be reduced because the isolator technology should reduce or eliminate the environmental effects of clean room technology.
Financial decision-making criteria are weighted differently from company to company and industry to industry, but key indicators for any investment are net present value, internal rate of return, and return on investment. These will factor into any company's decision to buy sterility test isolators.
THE INSTALLATION
Perhaps the next biggest hurdle is deciding where to install the isolators. This is especially problematic if you have an older laboratory space that was not designed with isolators in mind.
An isolator may be the largest piece of equipment purchased for a microbiology lab. The footprint must allow ample space on all sides for work and maintenance. When height restrictions are an issue, choose a unit with maintenance access on the front of the unit rather than on the top.
To meet height requirements, we constructed a lab. We installed dedicated HVAC to meet the requirements of an ISO Class 8 clean room. FDA advises that an aseptic processing isolator should not be located in an unclassified room. While no such requirement exists for sterility test isolators, it is prudent to plan for ISO 8 even if the environment is not classified. Providing a clean, controlled-access environment helps to ensure safety.
Isolators are typically custom-built, even when a standard unit is available. Knowing how the isolators will be used and documenting user requirements are vital parts of the process. At AAIPharma, a supplier of product development and support services to the pharmaceutical, biotechnology, and medical device industries, we purchased two Skan ARIS isolators, which are a standard design for sterility testing purposes.
For our use, we determined that we wanted the isolators directly linked with pass-through doors. As a contract lab, we see many product formats, ranging from aqueous injectables and ophthalmic and otic solutions to sterile powders and implantable combination products and devices, to name a few. Each format has unique test parameters. Our worst-case scenario, from a material-needs point of view, requires in excess of 80 one-liter bottles of media plus samples, as well as all associated testing materials and controls. To set up one test requires the space available in both isolators; thus, we needed the units to be joined in some fashion. For simplicity, we opted for a pass-through setup rather than a rapid transfer port. The isolators may be used as a single-test environment or as independent clean zones for testing. We have essentially doubled our capacity from a single ISO Class 5 clean room to two side-by-side isolator units.
Other design considerations include the isolator's working height, which affects analyst comfort, and the accommodation of an integral membrane filtration unit. The choice of vendors for the filtration unit was important because a design modification became necessary for the unit chosen. The two most widely marketed devices are the Millipore Steritest Equinox (Millipore, Billerica, Mass.) and the Sartorius Sterisart (Sartorius Stedim Biotech, Aubagne, France). The Equinox has a higher profile inside the isolator, while the Sterisart has a greater profile beneath the isolator chamber, requiring the door to the electrical panel beneath the work surface to be redesigned to accommodate the pump unit.
Figure 1. Isolator Technology Versus Traditional Clean Room
© PHOTOGRAPHY: GRAHAM KLOTZ, BRUCE GRUBBS AGENCY: DREAMSTIME.COM
Once we established our design requirements, we scheduled the manufacture of the isolators. With the exception of the review of design documents, the build process was rather seamless. Most of the lab's preparation during this time was focused on facilities and utilities issues. This required diligence from all parties involved, including company engineering and facilities maintenance departments, contractors, equipment vendors, and the isolator company. The HVAC system components required perhaps the longest lead times. Each isolator/VHP generator has particular temperature and relative humidity (RH) range requirements.
It's important to ensure that the HVAC unit can deliver the appropriate environment consistently. Ensuring proper ventilation and isolator exhaust required continued discussions. The exhaust component was particularly troublesome. To decrease the aeration time, which is the key to a shorter decontamination cycle, unrestricted exhaust is critical. The ARIS isolators have unidirectional airflow.
No fans are required to disperse the VHP. Exhaust is accomplished through an air return in the back of the unit that is driven, by a blower, through a HEPA filter and up the exhaust flume.
An additional consideration for the location of the isolators is their exhaust needs. A short, straight, unrestricted exhaust flume greatly enhances the aeration rate. No auxiliary exhaust blower is necessary as long as the length of the exhaust duct is less than 10 meters, there are no right angle bends, and the diameter of the HVAC ducts is as large as the exhaust coupling on the isolator.
Because cycle time is critical to turnaround time between testing, we sought to maximize the efficiency of this component of the system. We achieved all parameters necessary to minimize the aeration times by carefully selecting the location of the isolator lab, the location of the isolators within the lab, and the components of the exhaust system, and by ensuring proper installation. The exhaust system was made of surgical welded stainless steel and run straight through the roof.
Prior to construction, we planned the location of the isolators in the room. During construction, lighting fixtures were installed that we later found to be directly in line with the exhaust couplings of the isolators. Once the isolators were installed in the optimal location in the room, we decided that it would be wiser to relocate the lighting fixtures rather than to bend the exhaust system around the lighting fixtures. Though it seems like a simple item-and something that could have been avoided during the lab design phase-it was not obvious, until the isolators were installed, precisely where the exhaust ducts would need to go. The exact location of the isolator exhaust coupling, the angle at which the isolator chamber was mounted on the stand, and the location of the ceiling joists were all important considerations in deciding the final exhaust location.
While installing the isolators in new construction, we became aware that the final electrical inspection was going to be performed after the isolators were installed. The isolators were labeled with European electrical certification rather than a UL-listed one as required in the U.S. This was discovered during the electrical inspection and further delayed implementation of the isolators. The equipment had to be retrofitted on site before the in-field UL labeling could be accomplished. While waiting for the retrofit and UL labeling-roughly a two-month process- we proceeded with installation and operational qualification (IO/Q), some of which had to be repeated after UL labeling.
THE VALIDATION
Because we had no experience validating isolators, we contracted with a third party for validation services.
In our travels to visit the users of various isolators, we had learned how time-consuming and difficult validation can be. We spoke to individuals who had been trying to validate their isolators for more than a year. This problem has a lot to do with isolator design and features, but it's also related to the level of experience of those performing the validation. Hiring individuals with a proven track record is money well spent. Though they are few, they are easy to find: Just ask an isolator vendor or most users. Aside from the IO/Q mentioned above, the steps involved include D-value testing of biological indicators in the isolators, decontamination/aeration cycle development, the formal load-dependent performance qualification (PQ) studies, and sterilant intrusion and residue effects (false-negative studies).
Document preparation alone justifies the cost of validation services; the nuances of isolator validation, together with the tricks of the trade, will truly make you glad that you did not "try this at home."
An isolator may be the largest piece of equipment purchased for a microbiology lab. The footprint must allow ample space on all sides for work and maintenance. When height restrictions are an issue, choose a unit with maintenance access on the front of the unit rather than the top.
Also, the advice given by validation vendors regarding the materials and supplies needed up front, as well as applicable vendors of the same, may save a great deal of time. Speaking of materials, one critical parameter for validation is the proper selection of test samples for cycle development and PQ loads and for sterilant intrusion studies. Those companies who have one or more products to test with the same format, such as sealed glass vials, have the advantage of simply including all products in validation studies.
We already mentioned the variety of product formats that we test as a contract lab. These come in all sizes and shapes-not to mention the various construction materials used for containers and closures. Add to that the particular seal strengths used during processing, and you are left with quite a selection.
Now imagine that you don't have samples available because they all belong to other companies. Careful planning and a good relationship with your clients are both critical to sourcing the samples needed for validation. Fortunately, the benefits for the client companies during sterility testing in an isolator should make most of them willing participants in your validation activities. �
Robert Guardino is director of microbiology for AAIPharma Inc. (Wilmington, N.C.). Reach him via e-mail at robert.guardino@aaipharma.com. Kevin Jones is director of compendial testing services for AAIPharma Inc. Reach him via email at kevin.jones@aaipharma.com.
RESOURCES
1. Fisher J, Caputo RA. Comparing and contrasting barrier isolator decontami-nation systems. Pharm Technol. 2004;28:68-82.
2. Food and Drug Administration. Guidance for industry: sterile drug products produced by aseptic processing-current good manufacturing practice. Food and Drug Administration. Rockville, Maryland. 2004. Available at www.fda.gov/cber/gdlns/steraseptic.pdf. Accessed July 23, 2007.
http://pharmaceuticalvalidation.blogspot.com/2010/01/isolator-quest.html. Accessed December 26,2010