Perhaps the single most important development affecting contami-nation control technology and practices in life sciences facilitiesduring the past decade has been the increased usage of barrier iso-

lation technology to meet safety, codes, and regulatory compliance. Forexample, in validated sterility testing, the implementation of isolationtechnology has completely displaced the construction of new clean-rooms. Carmen Wagner and Jennifer Raynor reported on and identifiedover 193 isolator-based sterility testing systems in a recent article [1].We expect this same substitution paradigm to occur for all new hospitalpharmacy aseptic and potent compounding applications as well.

What is new and exciting today is that even in a small single line facil-ity, IF the facility is designed properly to take advantage of the benefitsof barrier isolation processing, the single line facility will be less expen-sive on a first cost basis than a conventional aseptic processing (ISOClass 5, EU Gr. A/B) [2] cleanroom suite, and there will be a paybackfrom operating cost savings as well! Isolators provide qualitative bene-fits by removing the operators from the process, and every biotech andpharmaceutical facilities engineer should evaluate the “best availabletechnology,” and if appropriate, recommend and incorporate isolatorand barrier technology in new projects. Proper implementation of barri-er isolation technology requires a great deal of “front-end” earlyinvolvement by facilities, process, QA and validation personnel. Theenclosed system must be fully engineered and integrated with theprocess equipment in order to adequately address critical servicerequirements.

The overall net footprint for a new, greenfield commercial manufac-turing facility based on isolator technology will be smaller than a con-ventional cleanroom suite, and the number of rooms required willdecrease when all process steps are contained in barriers. There willalways be a facility of some sort, as in addition to VHP cycle validationbeing dependent upon good ambient temperature stability, cGMP’s willalways require a dedicated space in order to achieve good access controland proper functional flows (people, process, equipment, product, mate-rials, waste, etc.).

As the isolator based fill line is somewhat less flexible than a conven-tional line should re-configuration be required, it is not usually favoredin process development applications, unless one is dealing with highlytoxic or potent compounds (more and more aseptically produced compounds are being developed that have Operator Exposure Levels inthe Category 3 and 4 high to extreme potency range). Isolator valida-tion has typically cost more than validation for a conventional fill line, and taken longer, although the differential seems to be decreasingwith increasing industry and regulatory experience and familiarity. It is critical to start Validation Master Planning early in the project, espe-cially so when isolation technology emerges as an integral part of theBasis of Design (see Figure 1).

21 CR 211 cGMP Issues21 CR 211 cGMP IssuesBy and large, regulatory agencies recognize that many aspects of the

manufacture of pharmaceutical products will be improved by a proper-ly implemented barrier isolation installation. The regulatory agenciesappear to be most comfortable with hard wall construction, positivepressure, high transfer integrity, chemically disinfected designs, espe-cially when combined with good ergonomics and a well planned andstrictly enforced operator training program.

The two most highly debated subjects remain the classification of theroom surrounding the barrier isolator, and the issue of turbulent vs.“laminar” flow within the isolator (assuming that ”laminar flow” – cor-rectly referred to only as “unidirectional flow” - is even feasible toachieve within the physical constraints of the isolator itself). In gener-al, classifications for surrounding room areas have trended over time torelax and currently most designs appear to be based on “Class 100,000”(European Grade “D”), rather than the Class 10,000 (or even substan-tially better!) that the earliest installations utilized. It is absolutely crit-ical to note that when discussing room classifications with designers andsuppliers, discussions are meaningless if one does not reference the clas-sification to an occupancy state, typically either “at rest” (“unmanned”),or “operational” (“manned”).

The marked exceptions are of course containment applications, wherehazardous materials such as highly active cytotoxics or even radioactivematerials are being filled. Here concerns relative to the ingress of viablecontaminants into negative pressure barrier isolators leads us to higherroom background classifications, typically Class 10,000 in operation orEuropean Class “B” in order to keep background microbial levelsacceptably low (Tables 1-4).

Certainly there is a cost advantage to new facilities when designedspecifically for barrier isolator technology “from the ground up.” Roomlayouts become far simpler and much of the space traditionally devoted

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Barrier Isolation TechnologyCan Improve Life SciencesCleanroom ApplicationsScott E. Mackler Cleanroom Consulting, LLC

FIGURE 1: VALIDATION MASTER PLAN [4]

• Defines 100% of the project Validation requirements• Lists all facilities, equipment and utilities to be challenged

or qualified• Identifies all required protocols and SOP’s• Assigns responsibilities and resources required to accom-

plish Validation• Provides a comprehensive schedule for Validation activities

to unidirectional corridors, gowning, and segregated processing roomscan be eliminated. For example, one initial design [5] for production ofclinical materials called for construction of 2,500 square feet of clean-room. The cost of this space exceeded the project budget. An analysiswas carried out to assess the feasibility of separating operations by timeand protocol and the original philosophy of separation of operations byroom was abandoned in favor of isolation technology. In the new gen-eral layout, cell banking (working), seed preparation, cell culture, andcell separation are carried out in the same room, each within a dedicat-ed barrier isolator unit. The complete cGMP space was resized and re-integrated with the needs of the revised processing scheme, and therequired area was eventually reduced to 1,500 square feet. This requiresteamwork, and an unambiguous understanding of the process and theprocessing methods to be used [6].

As far as turbulent vs. unidirectional airflow inside of Class 100 iso-lators, Class 100 conditions can easily be demonstrated utilizing turbu-lent flow, but convention will continue to dictate for the foreseeablefuture that certain processes, such as aseptic filling, will be performedalmost entirely under unidirectional downflow conditions. The localregulatory authorities should be consulted early-on if one plans toimplement a less conventional approach and obviously the criticality ofthe process to be performed, the materials being manipulated and the

inherent particle producing nature of the operation inside the isolatorwill all contribute to the final configuration and selection of an internalflow (be it air or inert gas) regime. The long awaited FDA cGMP asep-tic processing guidelines update will hopefully shed additional light onwhat field investigators expect to see from industry in the application of“good science.”

PPharmaceutical Isolator Tharmaceutical Isolator TrendsrendsEurope is presently ahead of the U.S. on roughly a 2:1 basis in the

deployment of barrier isolation technology for aseptic fill lines. Today,the leading early adopters of barrier isolation – having multiple installa-tions - are basically the major pharmaceutical companies, includingBaxter, Pharm-acia, Aventis, Novartis, Johnson & Johnson (Cilag), EliLilly, Merck, and Pfizer [8]. The growth trend in barrier isolation seems to be quite real and causal

variables driving this most likely include [9] - • Hazard Containment requirements are growing as drug compounds

become more highly active• Safety risks and litigation potential require companies to make greater

use of effective containment systems• Inert atmospheres are increasingly required for stability and safety of

newer drug products• Frequency of clean formulation and aseptically processed bulk appli-

cations are increasing• Reduction in validation time as systems become more common• The FDA considers barrier isolators a “potential” technology improve-

ment over cleanrooms – and this opinion is supported by Validationdata!

Isolator users are reported to desire –

• Reduction in decontamination cycle (dehumid-ification, conditioning, sterilization and aera-tion) times

• Guidance on environmental monitoring pro-grams

• Better availability of accessories • More effective regulatory guidance

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TABLE 1: EUROPEAN CGMP GUIDLINE

CLASSIFICATIONS [2]

AT REST IN OPERATIONMax permitted Max permitted

Number of Number ofParticles/m3, > Particles/m3, >

Room Grade 0.5 µm 5 µm 0.5 µm 5 µmA 3500 0 3500 0B 3500 0 350000 2000C 350000 2000 3500000 20000D 3500000 20000 N/A N/A

TABLE 2: EUROPEAN CGMP GUIDLINE

MICROBIAL LIMITS INOPERATION [2]

90MM 55MM GLOVESETTLE CONTACT PRINT, PLATE, PLATE, CFU/

GRADE AIR, CFU/M3 CFU/4HRS CFU/PL GLOVEA <1 <1 <1 <1B 10 5 5 5C 100 50 25 -D 200 100 50 -

TABLE 3: AIR CLEANLINESS CLASSIFICATION COMPARISON - AT REST [7]

GRADE 0.5 µm 5 µm FS209E US ISO BS5295 ISPEImperial 14644-1

A 3500 0 M3.5 100 5 E CriticalB 3500 0 M3.5 100 5 F CleanC 350000 2000 M5.5 10000 7 J ControlledD 3500000 20000 M6.5 100,000 8 K Pharmaceutical

TABLE 4: AIRBORNE ENVIRONMENTAL

REQUIREMENTS [10]

AUTHORITY CONTROLLED CLEAN CRITICALFDA CDERJune 1987Aseptic ProcessingGuidelinescfu/10ft3 25 - <1

Draft USP (1116)February 1997“Microbiology”cfu/ft3 <2.5 <0.5 <0.1(cfu/m3) (<100) (<20) (<3)

EC Annex 1, 1997Cfu/m3 100 10 <1(cfu/10ft3) (30) (3) (0.3)

• Better half suit & glove quality• Improvement in technology transfer (including Factory Acceptance

Testing and VHP cycle development under load and more completeTurn Over Package documentation)

Hospital and Medical Applications Hospital and Medical Applications Barrier isolation is a very cost-effective alternative to a cleanroom for

the preparation of sterile products at ASHP-defined risk levels 2 and 3,and for cytotoxic and other hazardous compounds (such compoundsrequire, at a minimum, the use of a Class II vented BSC). The recentASHP “Guidelines on Quality Assurance for Pharmacy-Prepared SterileProducts” (Am J Health-Syst Pharm 2000; 57:1150-69) more closelyreflect pharmaceutical industry-standard accepted practice than pastversions.

Barrier isolator technology is more expensive than a simple laminarflow hood, but other than for ASHP risk level 1, the LFH is required tobe located inside a cleanroom. There will also be ongoing operating andmaintenance costs advantages that accrue to the barrier isolator versusan aseptic cleanroom (Am J Health-Syst Pharm 1999; 56:1433-6). Thebarrier isolator installation must still consider appropriate controlledaccess, some level of gowning, and SOPs for sanitization and disinfec-tion (Figure 2).

ConclusionsConclusionsThe use of barrier isolation does not absolve the user from following

strict cGMPs, especially with regard to operator training and aseptictechnique. A barrier isolator is not a substitute for terminal sterilization.Each application should be evaluated on its own merits, and the benefits

made explicit. For example, depending on thelength of time a process may run, the volumeof compound to be handled and the frequencyof loading vs. the need to decontaminate, insome cases users have found that the retrofit ofa barrier isolator line into an existing conven-tional installation will result in increasedthroughput. The improved safety and confi-dence levels, and the ability to run a continous,multi-shift line, vs. batch operation, have beenthe drivers for such improvements [10].

Over 170 barrier isolation-based semi-auto-mated or automated fill/finish operations arenow on-site in various pharmaceutical andbiotechnology facilities around the globe, andthis level of adoption and acceptance certainlyimplies that there are concrete benefits (Photos3 & 4). Filling machines are now being(re)designed to integrate with the isolator forimproved cleanability, maintenance, and tosupport unidirectional flow criteria, something

that we were never able to actually achieve when filling machines wereinstalled into unidirectional flow cleanrooms! Barrier isolator applica-tions include biopharmaceuticals, clinical materials, potent drug asepticfilling and prepackaged syringes.

Documentation is an area that needs more work with regard to stan-dardization. Full traceability, such as is found in ISO 9000 standards, isrequired, from manufacturing through actual installation, fit-up, qualifi-cation and on-going operations. It is critical to state early-on in thedevelopment of your user requirements document what your expecta-tions are for Factory Acceptance Testing (FAT), e.g., VHP cycle devel-opment and validation under load for sterility test isolators, SiteAcceptance Testing (SAT) and vendor documentation (Figure 3). �

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HOSPITAL AND MEDICAL ISOLATOR

CLASS 100 MODULAR CLEANROOM WITH

CONTAINMENT ISOLATOR FOR POWDER

FILLING/WIPEDOWN APPLICATION - PROJECT IS INSTALLED AND FDA VALIDATED

RESTRICTED ACCESS BARRIER

Photos 1 & 2 Courtesy of IsoTech Design,Montreal, Quebec, Canada

Photo Courtesy of Servicor CPI and Carlisle Barrier Systems Photo Courtesy of Baker Company

PHARMACEUTICAL ISOLATOR

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FIGURE 2: ASHP DEFINITIONS

Risk Level 1 Risk Level 2 Risk Level 3

Risk Level 1 Risk Level 2 Risk Level 3

Risk Level 1 Risk Level 2 Risk Level 3

Products that are (1) stored at room temper-ature and completely administered within28 hours from preparation, (2) unpreservedand sterile and prepared for administrationto one patient, or batch prepared for admin-istration to more than one patient and con-tain suitable preservatives, and (3) preparedby closed-sys-tem aseptic transfer of sterile,non-pyrogenic, finished pharmaceuticalsobtained from licensed manufacturers intosterile final containers obtained fromlicensed manufacturers.

Products that are (1) administered beyond 28hours after preparation and storage at room tem-perature, (2) batch prepared without preserva-tives and intended for use by more than onepatient, or (3) compounded by complex ornumerous manipulations of sterile ingredientsobtained from licensed manufacturers in a ster-ile container obtained from a licensed manufac-turer by using closed-system, aseptic transfer.

Products that are (1) compounded fromnonsterile ingredients or with nonster-ile components, containers, or equip-ment before terminal sterilization or (2)prepared by combining multiple ingre-dients (sterile or nonsterile) by usingan open-system transfer or open reser-voir before terminal sterilization

Definition of Products by Risk Level

Examples of Sterile Products by Risk Level

Single-patient admixtureSingle-patient ophthalmic, preservedSingle-patient syringes without preserva-tives used in 28 hoursBatch-prefilled syringes with

preservativesTotal parenteral nutrient (TPN)

solution made by gravitytransfer of carbohydrate and amino acidsinto an empty container with the addition ofsterile additives with a syringe and needle

Injections for use in portable pump or reservoirover multiple daysBatch-reconstituted antibiotics without preser-vativesBatch-prefilled syringes without preservativesTPN solutions mixed with an automatic com-pounding device

Alum bladder irrigationMorphine injection made from powderor tabletsTPN solutions made from dry amino acidsTPN solutions sterilized by final filtrationAutoclaved i.v. solutions

Figure 2 – ASHP DefinitionsIsolator (or barrier isolator): A closed system made up of four solid walls, an air-handling system, and transfer and interactiondevices. The walls are constructed so as to provide surfaces that are cleanable with coving between wall junctures. The air-han-dling system provides HEPA filtration of both inlet and exhaust air. Transfer of materials is accomplished through air locks, gloverings, or ports. Transfers are designed to minimize the entry of contamination. Manipulations can take place through either gloveports or half-suits.

Facilities and Equipment

The controlled area should be separated fromother operations to minimize unnecessary flowof materials and personnel through the area. Thecontrolled area must be clean, well lighted, andof sufficient size for sterile compounding.A sink with hot and cold water should be near,but not in, the controlled area. The controlledarea and inside equipment must be cleaned anddisinfected regularly. Sterile products must beprepared in a class100 environment (the critical area), such aswithin a horizontal or vertical-laminar-airflowworkbench or barrier isolator. Computer entry,order processing, label generation, and recordkeeping should be performed outside the criticalarea. The critical area must be disinfected peri-odically. A workbench should be recertifiedevery six months or when it is moved; prefiltersshould be changed periodically. Pumps shouldbe recalibrated according to procedure.

In addition to risk level 1 guidelines, the fol-lowing are recommended for risk level 2 prod-ucts: controlled areamust meet class 10,000 cleanroomstandards; cleaning supplies shouldbe selected to meet cleanroom standards; criti-cal-area work surface must be cleaned betweenbatches; floors should be disinfected daily,equipment surfaces weekly, and walls monthly;and there should be environmental monitoringof airand surfaces. An anteroom of highcleanliness is desirable. Automatedcompounding devices must be calibrated andverified as to accuracy, according to procedure.A properly maintained barrier isolator providesa Class 100 environment for product prepara-tion. Therefore the isolator itself can be in aseparate area of the pharmacy but need notactually be in a cleanroom.

Products must be prepared in a class 100work-bench in a class 10,000 cleanroom, ina class 100 cleanroom, or in a suitable bar-rier isolator. Access to the cleanroom mustbe limited to those preparing the productswho are in appropriate garb. Methods areneeded for cleaning, preparing, sterilizing,calibrating, and documenting the use of allequipment. Walls and ceilings should bedisinfected weekly. All nonsterile equip-ment that is to come in contact with thesterilized final product should be sterilizedbefore introduction into the cleanroom. Ananteroom of high cleanliness (i.e., class100,000) should be provided. Appropriatecleaning and disinfection of the environ-ment and equipment are required.

SIDEBAR [3]SIDEBAR [3]

Definitions:Barrier - an engineered system that provides a method of separating a process from the surrounding environment. In the simplest example,no environmental control is provided, and the barrier assures that theoperator can view the process while ensuring that nothing impedes theflow of “first air” from the cleanroom ceiling downward over theprocess. Any attempt by the operator to intercede or intervene with theprocess will result in a shutdown immediately upon defeat or breach ofthe barrier.Microenvironment - an engineered enclosure system used to maintain alow particulate environment around a production process (most often insemiconductor production). Control may be provided for temperature,(over)pressure, relative humidity, make-up air and recirculation air.Processes inside the microenvironment may represent a hazard of onetype or another to the operator.Barrier Isolator - an engineered enclosure system used to create andmaintain an aseptic, low-particulate environment around a pharmaceuti-cal production process. Temperature, (over)pressure, relative humidity,airflow, dynamic mousehole conditions and make-up air balance areprecisely controlled to assure aseptic processing conditions. Interfacesare designed to validatibly maintain the required aseptic conditions andsterility assurance during transfer of materials, components, product,waste and services. IQ/OQ protocols, integrated CIP/SIP systems/chem-ical sterilant generation and comprehensive factory acceptance testing isstandardly provided by the manufacturers.Containment Isolator - an engineered enclosure system used to containpotent, hazardous, toxic or biologically active compounds. Complexityof these systems varies depending on the level of hazard that must becontained. The enclosure is maintained at a negative pressure withrespect to the surrounding environment. Airtight rapid transfer andequipment interfaces, bag/in-bag/out HEPA or even ULPA filtration,DIP systems, reliable glove interchanges, battery back-up systems fortransfer isolators and emergency systems designed to overcome a sud-den pressure breach are required.

RReferenceseferences1. Carmen Wagner, PhD., and Jennifer Raynor Pharmaceutical

Engineering, The Journal of the ISPE March/April 2001, “IndustrySurvey on Sterility Testing Isolators: Current Status and Trends.”

2. MCA (Medicines Control Agency) Rules and Guidance forPharmaceutical Manufacturers and Distributors 1997.

3. Eliot J. Cook, President & CEO Absolute Control Systems “BarrierIsolators and Microenvironments for Cleanroom Applications”Presented at “Cleanrooms’ East”, Baltimore, MD March 1998.

4. Scott E. Mackler Project Planning & Basis of Design for cGMPCleanrooms, Parts 1&2, A2C2, The Journal of MicrocontaminationDetection & Control May/June 1998.

5. Stephen W. Fitzpatrick and Scott E. Mackler Clinical ProductionFacilities – Delivery, Design, Operating, and RegulatoryConsiderations Pharmaceutical Technology, September 1995,pages 118-126.

6. Tim Coles “Isolation Technology: A Practical Guide” InterpharmPress, Inc., 1998.

7. ISPE, Baseline Pharmaceutical Engineering Guide Volume 3,Sterile Manufacturing Facilities First Edition/January 1999.

8. Jack Lysfjord and Michael Porter Pharmaceutical Engineering, TheJournal of the ISPE March/April 2001, “Barrier Isolation Historyand Trends, a Millennium Update.”

9. Carlisle Barrier Systems – Conference for Advanced BarrierIsolation Technology – April 25-26, 2000.

10. Scott E. Mackler Barrier Isolation Technology: Facilities UpdatePharmaceutical Technology, February 2000.

11. Scott E. Mackler The Practical Integration of Barrier Isolation A2C2,The Journal of Microcontamination Detection & Control, October2001.

Acknowledgement: Reprinted with permission from the October 2001 issue ofA2C2, the Journal of Advancing Applications in Contamination Control, published by Vicon Publishing, 62 Rte. 101A, Ste. 3, Amherst, NH 03031; 603-672-9997; info@a2c2.com; www.a2c2.com.

Scott E. Mackler’s experience in the clean-room industry includes project planning andbasis of design development, commercializa-tion of new cleanroom construction products,applications for process isolation and mini-environments, construction claims arbitra-tion, vendor/contractor identification andqualification, RFP/RFQ preparation, projectfinancial justification, site selection servicesand third party design reviews. Mr. Macklerperforms due diligence of cleanroom products

companies on behalf of the investment banking community andfacilities evaluation and assessment on behalf of real estate devel-opment firms. Mr. Mackler is founder and principal of CleanroomConsulting, LLC, a firm specializing in contamination controlindustry services. Mr. Mackler holds a BSME from RensselaerPolytechnic Institute and the MBA degree from the University ofHouston. Mr. Mackler can be contacted at sem@cleanroom-con-sulting.com

FIGURE 3: BASIC ELEMENTS OF THE

TURN OVER PACKAGE (TOP) [4]

• Manufacturer’s Quality Assurance program• Engineering Specifications• Engineering Drawings incl. P&ID’s• Instrument/Component Information• Fabrication Records• Software Documentation• Certifications, Inspections, Testing Records• Complete Installation Instructions• Sequence of Start-up & Shut Down Procedures• Multiple Sets of Operating & Maintenance manuals incl.

SOP’s• Spare Parts List(s) including Replacement Parts,

Consumables, & Recommended Lubricants• Documented Vendor-provided On-Site Training for

Operators• Installation Qualification (IQ), Operational Qualification

(OQ), & Performance Qualification (PQ) Protocols• Proposed FAT & SAT criteria

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