Pharmaceutical Technology_ The Advantages of Restricted-Access Barrier Systems.pdf

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10/30/13 Pharmaceutical Technology: The Advantages of Restricted-Access Barrier Systems

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Figure 1: Equipmen t in a

cleanroom. Curtains mounted tohe sterile air manifol d or a

safety partition separate the

aseptic area from the

cleanroom. The machine often

will have its own fil tration.

March 2, 2007

The Advantages of Restricted-Access Barrier SystemsBy Johannes Raus chnabel

Filling machines often are installed in sterile rooms and separated by isolators to preventcontamination. These methods have certain drawbacks, including making interventions more

difficult. Restricted-access barrier systems are an alternative that ensures sterility and facilitates

interventions.

Patient safety often requires that drug products be filled and packaged in sterile conditions.Sterile cleanrooms and isolators prevent contamination during the filling process. The useof cleanrooms is well established, and isolators are gaining increased acceptance. Eachmethod, however, has its drawbacks such as making process interventions more difficult. Incertain applications, restricted-access barrier systems (RABS), which can provide a level ofaseptic quality near that of isolators, offer an efficient alternative and more processflexibility.

Sterile rooms. The aseptic processing of parenteral drugs andother sterile products such as opthalmic medicines and inhalersrequires sterile handling to prevent the product from coming intocontact with particulate and microbial impurities. For this reason, processing usually isperformed in sterile rooms (see Figure 1).

Production equipment such as filling machines must have a hygienic design and must besanitized regularly. In addition, operators cannot enter the sterile room until they changetheir clothing and are disinfected. Despite the precautions, experience with this methodologhas shown that the major contamination source for the product continues to be the

operators themselves. Incomplete disinfections, inappropriate operator actions, andproblematic machinery that requires frequent manual interventions can cause viablecontamination. Any biological contamination of a processing line and its associated drugsmay pose a risk to patients receiving the product.

To prevent such risk, the production areas, production machinery, and processes must bevalidated for aseptic quality. For example, operators must work according to precise, certified standard operatingprocedures (SOPs), which require special training programs. In addition, the production technology must functionreliably to minimize operator interventions. The sanitation procedures must ensure the maximum removal of microbimpurities. Complete sterilization (the removal of all divisible organisms) of the entire machine and the entire area ishard to achieve with open-cleanroom methodology (1).

The pros and cons of isolator technology. Products with higher standards and greater security
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Figure 2: Equipment i n aisolator. Air is prepared a

recirculated in the i solato

through double-window

systems or return-air ducts

Tabl e I: A comparison o

cleanrooms, restricted-

access barrier systems

(RABS), and isolators.

Figure 3: Vial-filli ng li ne with a passive

requirements necessitate the use of isolator technology, which completely encloses the asepticworking area (see Figure 2).

The high air-purity cleanroom (ISO class 5) inside an isolator is limited to the space above themachine's baseplate (2). The surrounding external area can have a lower air quality (aminimum of class 8) as long as the physical separation is maintained (35). This separation canbe achieved using:

a separation wall between the aseptic area and the surrounding area ( e.g.,a plasticcurtain [soft wall] or a metal partition with glass windows [hard wall]);

gloveports in the separation wall for manual interventions such as materials handling formicrobiological monitoring or for responding to process disruptions;sterile-transfer mechanisms for moving production components, tools, and monitoringmaterial (double-door transfer systems are common);mouseholes with format-specific parts to minimize the space around incoming and outgoing containers;positive interior pressure relative to the surrounding room.

Another important aspect of isolator technology is that it requires the biodecontamination of all machinery andisolator surfaces in the aseptic-process area before each production run. Biodecontamination is necessary becausthe isolator typically is opened for maintenance, format changes, cleaning, and product changeover. Opening theisolator removes the physical separation of the cleanroom and the potentially contaminated surrounding area. Themost common biodecontamination systems for isolators use H 2O 2vapor. In the conditioning phase, H 2O 2vapor

introduced into the sealed isolator until it reaches a specified concentration. Next, H2O

2is held at this

concentration for a specific duration. Finally, during the aeration phase, the H 2O 2vapor is removed by purging th

isolator with fresh, filtered air. This process can take 310 h, depending on the biodecontamination system, isolatosize, surface areas, and air-filter size. During this period, the process line cannot be used, although otherprocedures such as cleaning and steaming in place of the filling system can be performed during aeration.

The long duration of a biodecontamination cycle reduces operational flexibility when working withan isolator. This procedure, however, does guarantee that each production run begins with abiodecontaminated system, which is nearly sterile (demonstrating a 6-log inactivation ofbiodecontaminants).

Manual operations within the aseptic area are more difficult with isolators. Gloveports must beused in place of direct operator access. This technique requires greater reliability and

automation for process machinery inside an isolator than is required in a traditional cleanroom.All interfaces, gloveports, mouseholes, and transfer ports must be integrated into the physicalbarrier because they separate the clean process area from the potentially contaminated exteriorareas.

Isolators always have their own air-handling system to maintain production conditions andachieve the optimal conditions for the biodecontamination cycle.

RABS: an alternative. The restricted-access barrier system (RABS) can be an alternative to isolators andcleanrooms. The RABS concept entails a physical barrier between operators and production areas, but the barrier limited. A limited barrier is acceptable because RABS always must be set up in high-class cleanrooms (at least ISO7). Thus, RABS do not require their own biodecontamination system (6).

Guidelines and standards for RABS

To date, no specific standards or regulations for RABS have been developed.Manufacturers should follow existing norms and regulations for the basic processingof sterile pharmaceutical products. Operators can consult ISO Standard 14644, Par7 for guidance when using RABS as a protective solution (5). Appendix A of Part 7features a diagram that shows the reliability of a separation versusthe separationmethod. It demonstrates that RABS can be considered an aerodynamic measure thhas a high physical separation. The system's interior atmosphere can be controlledbut pressure control is limited. In contrast, the diagram shows that isolator solutionshave a small leak rate and appropriate positive or negative pressure control.

The US Food and Drug Administration is the first authority to offer preliminary


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RABS.

Figure 4: Machine in an

active RABS. The RABS

has its own air-handling

system that draws air from

the area and through

openings below the prod

transport.

Figure 5: Machine in a

passive closed RABS. Air i s

recycled from the room air-

handling system. A prefilter

also is used, which helps

prevent contamination of

he air-handling system. Figure 6: Aseptic powder-filli ng li ne inpassive closed RABS.

definitions of the approximately 75 existing RABS installations worldwide (6). Aworking group of industrial experts drafted a definition of RABS and guidelines forRABS operation for FDA. This draft emphasizes that:

"RABS can operate as 'doors closed' for processing with very low risk of contamination similar to isolators, or permitrare 'open door interventions' provided appropriate measures are taken (7)."

Opening the main doors during production is permissible and only requires in-depth documentation in exceptionalcases. The same is not true for the transfer doors because the physical and aerodynamic barrier to the externalarea is only guaranteed when the doors are closed. Sometimes, industrial safety concerns prohibit the opening of

RABS doors during production, regardless of aseptic considerations.

Appropriate guidelines, manuals, and drafts for isolators are available in the three major pharmaceutical markets:the United States, Europe, and Japan. The recently rewritten FDA guidelines, Annex 1 of the European Union goodmanufacturing practice guidelines, and the detailed PIC/S recommendations are helpful for the planning and use ofan isolator (3, 4, 8). The Japanese admission authority also is presently working on an appropriate document.

Classifications of RABS

RABS are more than just a safety covering for production machines. Incoming air passesthrough suspended high-efficiency (of at least HEPA Class H14) filters and is distributed evenlyby a sterile manifold. The doors of the RABS are locked, and the gloveports are the only meansof access. Users must transfer materials and components by means of special aseptic transfer

systems. Air flows out of RABS the same way it does with simple barriers: through openingsunderneath the doors or through holes in the lower sections of the doors. The air returns to thesame room from which it came. In a closed RABS, air is prefiltered and recirculated throughducts.

RABS can be classified as either active or passive systems. Apassive RABS does not have itsown air recirculation, filtering, or conditioning. Its high-purity air supply comes from thecleanroom. Air flows downward from the ceiling and returns to the surrounding room throughopenings under the doors. The air from the room returns through air ducts to the room air-handling unit (see Figures 3 and 4).

An active RABS typically has an air-handling unit directly attached to it.This unit always contains a HEPA filter and provides even air-flow distribution with the help of

sterile air manifold. A cooling system also can be integrated for temperature-critical products.Air-conditioning expenditure is limited because fresh air is drawn from the cleanroom (seeFigure 4).

A closed RABS is different. ClosedRABS also may be passivesystems that use the cleanroom's ventilation system and filterceiling. The air does not return to the surrounding area, itpasses through prefilters and ducts into the room'sairconditioning system (see Figure 5). Because closed RABSconcepts are used with toxic and dusty product applications,operators must pay special attention to cleaning the return airducts and changing the prefilters without contaminating them(see Figure 6).

Active closed RABS have air-filtration and air-conditioning systems (see Figure 7),which are needed to keep conditions constant within the aseptic area, especiallywhen air cooling is required.

Closed RABS can be operated with positive or negativepressure, which requires good sealing and pressurecontrol. In these applications, a closed RABS is similarto an isolator (see Figure 8).

The next level of aseptic operation and productionsafety is not attainable with RABS because of the lack ofa biodecontamination system and the reduced air


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Figure 7: Machine in active closedRABS. The RABS has its own ai r-

handling unit. If necessary,

recirculating air is prefiltered over

mechanisms that permit a

contamination-free filter change.

Figure 8 : Active cl osed RABS with pressure-

zone control.

sealing. Closed RABS, as opposed to isolators, alsorequire additional expenditures that must be considered( e.g.,the surrounding area must be an ISO class 7cleanroom). Each RABS installation balancespharmaceutical security, industrial safety, buildingsupport systems, operational flexibility, and the moneyinvested in the system.

If the RABS is operated according to the guidelines, thecomponent-transfer techniques, sanitation processes,

format-change procedures, and maintenanceprocedures required are different from those of acleanroom installation.

Operating a RABS

Glove integrity. Before the beginning of a production run, the integrity of the barrier must be guaranteed. Inparticular, the gloves must be tested for leakage and damage regularly. To reduce dependence on SOPs, a regulaphysical testing method should be used in addition to the visual examination of the gloves. Two options forexamination are:

testing the gloves before mounting them on the RABS and sterilizing them;testing the gloves in the mounted position.

Both options have advantages and disadvantages. When the gloves are mounted, the entire glove assembly,including the mounting ring, can be tested. When the glove is tested before mounting, the isolator can be preparedfor production, thereby reducing setup time. The sterile installation of the gloves is a challenge in each case. Thegloves must be pre-sterilized, transferred into the cleanroom, and installed to the mounting ring in a sterile manner

Glove sterilization can occur in an autoclave bag. The material of the glove is a keyfactor for sterilization. Common glove materials such as chlorosulphonatedpolyethylene (Hypalon) will physically change after 810 cycles in an autoclave.More-stable materials such as ethylene propylene diene monomer, however, arestable for a nearly unlimited number of cycles in an autoclave. Assembling thegloves at the glove-mounting rings in a sterile way is difficult and requiresexperienced operators. Reversing the mounting ring can facilitate this operation byallowing the glove to be mounted from outside the isolator, rather than from insideThis arrangement reduces the length of the glove, however, so longer gloves maybe necessary.

Sterile transfer. Components, tools, and growth media for monitoring the microbiological state of the air in the RABSmust be transferred in a sterile manner. A RABS can incorporate systems such as double-door transfer and steamsterilizers. A transfer chamber or simple transfer door also can be used. Transfer chambers possess inner and outedoors that are interlocked so that only one door can be opened. The interior of the transfer container, from whichcomponents such as stoppers are taken out of bags and introduced into the production process, should be ISOcategory 5. Simple transfer doors should be installed below the process level to reduce the influence of ambient airon the aseptic area. Opening the main doors to transfer components is not permissible, according to FDA's draftdefinition, because a RABS has no positive-pressure plan that could prevent outside air from entering the system.

Closed RABS can be operated with positive pressure, but opening the doors during operation is not permitted forindustrial-safety reasons.

Product-contact parts. The sterile assembly of filling-machine product-contact parts, including containers andcomponent-holding parts, is difficult, especially when the component size is considered. For example, after aproduction run, a stopper sorting bowl was cleaned, dried, packed into a sterile bag, and autoclaved ( e.g.,in thematerial lock). Afterwards, the packaged bowl was taken from the air lock. The bowl was unpacked outside thesanitized RABS because of its physical dimensions. The heavy and bulky sorting bowl subsequently had to beinstalled into the aseptic area through an open RABS door. The draft of the RABS definition states:

"Sterilization-in-place (SIP) is preferred for contact parts such as fluid pathways. Where this cannot be achieved,such parts should be sterilized in an autoclave, transferred to the RABS viaa suitable procedure and asepticallyassembled before processing (6)."


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Figure 9: Mousehole i n

active closed RABS.

Disinfection. The sanitation of a RABS is substantially more complex than that of a machine with no barrier system.More surfaces and larger surfaces must be sanitized, and some surfaces are harder to reach because of the barrieOperators try to achieve aseptic conditions with a RABS, which is impossible with open production systems.

The draft RABS definition refers to a "'high-level disinfection' of all nonproduct contact surfaces within the RABS witan appropriate sporicidal agent before batch manufacture" (6). The draft defines high-level disinfectionas amicrobiological disinfection that increases product security and is a precondition for long production runs. A partitiobetween operators and aseptic production areas is insufficient for better product security. The correct interfacesolutions and the correct handling are highly significant. RABS allow long production runs, but impose morerestrictions than isolation systems. The definition draft carefully states:

"In certain circumstances, multiple day operations are possible depending on design, appropriate disinfection plan,risk mitigation steps, early regulatory review ( i.e.,pre-operational review is recommended), and a subsequentongoing evaluation of process control data (6)."

To avoid an open-door intervention, the machine function should be highly automated and as reliable as possible.Each intervention risks contact contamination or the ingress of low-quality outside air. For this reason, a RABSshould have an automatic clean-in-placesteam-in-place (CIPSIP) system as an isolator does. This systemprevents manual handling of product-contact parts such as pumps and filling needles. The draft RABS definitionsupports this in the following passage:

"Design to prevent door openings can be achieved by a number of measures which include Clean-In-Place/SterilizeIn-Place (CIP/SIP) to the point of fill for liquid filling operations, remote or automated sampling for in process control

testing (IPC) including monitoring for viable and non-viable particles, and the use of enclosed transfer systems whicoffer greater protection during introduction of components and pre-sterilized equipment (6)."

Closed RABS

Closed RABS are a special case because they take both aseptic requirements and industrialsafety into account. The draft RABS definition states, "There are occasions where containmenof toxic materials is required and special closed or containment RABS may be used" (6).Recirculating air must be prefiltered in a closed RABS before it returns to the air-recyclingsystem. Prefilter changes must occur either under full protection or through a contamination-free procedure ( i.e.,bag-inbag-out). Pressure-isolation zones, or pressure buffers, canprotect upstream and downstream equipment from filling-area contamination. Implementingpressure zones, however, requires sealing the closed RABS sufficiently and separating thepressure zones with mouseholes (see Figure 9).

The leak tightness of a closed RABS depends on the industrial safety requirements and theoccupational exposure limit value of the product being handled (10). A RABS must be sealedtighter for products with lower personnel exposure limits and for which personnel protection isreduced or limited. As sealing requirements increase, the cost of a RABS approaches the costof an isolator. In addition, flexibility is reduced because simple transfer systems are no longersufficient to achieve good tightness. Postproduction system cleaning also has cost implicationsThe higher the expectations of an automated cleaning system ( e.g.,a washing-in-placesystem), the higher the expenditure for the process systems. The cost of the RABS systemtherefore can approach that of an isolator.

Conclusion

Restricted-access barrier systems are more than just a physical barrier. The systems also require careful handlingof interfaces, interventions, and material transfers. Processes surrounding the isolator and sanitation must beadapted and consistently observed to take full advantage of RABS. Special aseptic-transfer techniques andsolutions can be used with RABS, and they provide much operational flexibility. Sanitation processes are morecomplex in a RABS system than in a traditional sterile area. In addition, just as in isolation systems, glove handlingand assembly at the gloveports in RABS are more complicated because of sterility requirements.

RABS also have a critical disadvantage compared with an isolator installation. Cost savings cannot be achieved byreclassifying working spaces because the minimum requirement for the RABS operation area must still be classifiedISO class 7. For this reason, a RABS is always a compromise. If operators accept numerous restrictions, they canenjoy increased flexibility and reduced validation and revalidation expenditure compared with the isolator, resulting


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improved production quality in existing pure areas.

Johannes Rauschnabelis a director of process engineering and a coordinator for barrier systems and thePharmaLab at Bosch Packaging Technology, Pharma Liquid, Crailsheim, Germany, tel. 149 7951 402 452,

[email protected]

.

Submitted: June 29, 2006. Accepted: Aug. 23, 2006.Keywords: aseptic processing, barrier systems, cleanrooms, isolators

References

1. K.H. Wallhuser, Praxis der Sterilisation, DesinfektionKonservierung; KeimidentifizierungBetriebshygiene,(Thieme Verlag, Stuttgart, Germany, 5. vllig berarbeitete Auflage, 1995), S. 388.

2. International Organization for Standardization (ISO), EN/ISO 14644, Clean Rooms and Associated ControlledEnvironments Part 1: Classification of Air Cleanliness (ISO, Geneva, Switzerland, 1999).

3. US Food and Drug Administration, Guidance for Industry, Sterile Drug Products Produced by Aseptic ProcessingCurrent Good Manufacturing Practice(FDA, Rockville, MD, 2004).

4. European Commission (EC), EC Guide to Good Manufacturing PracticeRevision to Annex 1: Manufacture ofSterile Medicinal Products(EC, Brussels, Belgium, 2003).

5. ISO, EN/ISO 14644, Clean Rooms and Associated Controlled EnvironmentsPart 7: SD-Module (ISO, Geneva,Switzerland, 2005).

6. J. Lysfjord and M. Porter, "RABS Survey Data," paper presented at the ISPE 14th Annual Barrier IsolationTechnology Forum, Arlington, VA, 2005.

7. International Society for Pharmaceutical Engineering, "Restricted Access Barrier Systems (RABS) for AsepticProcessing: ISPE Definition," http:// www.ispe.org/galleries/reg-new-gallery/RABS_Definition_8-16-2005.pdf

8. Pharmaceutical Inspection Cooperation Scheme (PIC/S), Isolators Used for Aseptic Processing and SterilityTesting(PIC/S, Geneva, Switzerland, July 2004).

9. ISO, EN/ISO 14644, Clean Rooms and Associated Controlled EnvironmentsPart 7, Appendix C7: Sleeves andGloves (ISO, Geneva, Switzerland, January 2005).

10. Berufsgenossenschaft der chemischen Industrie [Professional Association of the Chemical Industry], Merkblatt 057, "Sicherer Umgang mit Gefahrstoffen in der pharmazeutischen Industrie" [instruction sheet M 057, "SafeHandling of Hazardous Materials in the Pharmaceutical Industry"], Dr. Otto Pfeffer, Ed. (Jedermann Verlag,Heidelberg, Germany, 1999).


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Figure 1: Equipm ent in a cleanroom. Curtains mounted to the sterile air manifold or a safety partition separate the aseptic area from

the cleanroom. The machine often will have its own filtration.

Figure 2: Equipment in an isolator. Air is prepared and recirculated in the isolator through double-window systems or return-air ducts

Figure 7: Machine in active closed RABS. The RABS has its own air-handl ing uni t. If necessary, recirculating air is prefiltered over

mechanisms that permit a contamination-free filter change.


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Table I: A comparison of cleanrooms, restricted-access barrier systems (RABS), and isolators.

Figure 3: Vial-filling line with a passive RABS.

Figure 4: Machine in an active RABS. The RABS has its own air-handling system that draws air from the area and through openings

below the product transport.

Figure 5: Machine in a pass ive closed RABS. Air is recycled from the room air-handl ing system. A prefilter also is used, which helps

prevent contamination of the air-handling system.

Figure 6: Aseptic powder-filling line in pass ive closed RABS.

Figure 8: Active clos ed RABS with press ure-zone control.

Figure 9: Mousehole in active clos ed RABS.

References

1. [email protected]
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