Manufacturing

The industrial manufacturing of injectable drug products presents very different and difficult challengeswhen compared with other industrial manufacturingapplications. In order to enhance patient safety and ensure product quality, the pharmaceutical industry hasbeen implementing advanced aseptic processing (AAP)systems that utilise advanced forms of automation,robotics, machine vision and separative devices in an effort to protect the pharmaceutical product fromcontamination. These separative devices fall into twocategories: restricted access barrier systems (RABS) andisolators. Although driven by different reasons, isolator-barrier systems and ANSI/RIA R15.06 (‘Safetyrequirements for industrial robots and robot systems’)have the same objective: to restrict operator access to themost critical areas of the machinery. A RABS or isolator-based robot system, when properly implementedaccording to ANSI/RIA R15.06 and current GoodManufacturing Practices (cGMPs), will provide a robotcell that meets the requirements for AAP.

ADVANCED ASEPTIC PROCESSINGThe Parenteral Drug Association (PDA) describes an asepticprocess as: “The process for manufacturing sterile products

by which microbiological contaminationis eliminated from the product andproduct contact surfaces protecting theproduct from sources of contamination”(1). The challenge for pharmaceuticalmanufacturers is to ensure that theproducts they manufacture are made in amanner that precludes microbiologicalcontamination. This is especiallyimportant for injectable or parenteral

drugs; these products carry the highest risk as the injectionbypasses all the barriers that nature has provided for the patient.

Traditionally, an operator within an open, ISO 5cleanroom environment performs sterile drugmanufacturing using automated or semi-automated

machinery, or is even done by manual operation.Although operators within the cleanroom environmentwear sterile cleanroom garments, they remain the greatestcontributor to cleanroom and product contamination. Astudy by Whyte (2) showed how activity by peoplewearing cleanroom gowning affected particle generationrates for particles 0.5µm in size:

� Sitting motionless: 500,000 particles per minute� Sitting with head, arms and body movement:

1,000,000 particles per minute� Walking at two mph: 5,000,000 particles

per minute

The study clearly illustrates that the removal of people fromthe manufacturing process is essential to minimise the riskto product sterility.

Advanced aseptic processing is the utilisation ofautomated technologies – such as robotics and physical barriers – to eliminate operator interventionwith regard to the process, open product containers and exposed product contact surfaces. The key to AAP operation is maintaining absolute control of contamination sources through physical andaerodynamic means against contaminant migration intothe sterile environment.

ISOLATORS & RESTRICTED ACCESS BARRIER SYSTEMSIsolators and RABS are rigid-wall mini-environmentsthat provide a physical and aerodynamic barrierbetween the operator and the sterile drugmanufacturing process enclosed within the interiorenvironment. Both isolators and RABS, when operatedproperly, will provide an ISO 5 cleanroom environmentmeeting the regulatory requirements for particulate andmicrobiological concentrations. Although the internalrequirements are the same for RABS and isolators, there are several key design features that differentiatethe two systems.

The aim of advanced aseptic processing is the elimination and absolutecontrol of all sources of contaminants – most importantly, human-generated contamination. Robotics and isolator-barrier systems will be the core technologies to advance this initiative further.

88 Innovations in Pharmaceutical Technology

By Joshua Russell atAutomated Systems of Tacoma (AST)

Robotics and Isolator-Barrier Systems: The Perfect Combination for Advanced Aseptic Processing

Figure 1: Aseptic isolatorwith a Stäubli Stericlean,six-axis robot arm that iscompatible with vapourphase hydrogen peroxidesterilisation

Source: Stäubli Robotics

IPT 34 2010 26/8/10 15:26 Page 88

Isolator AttributesAn isolator is a totally enclosed and sealed stainless steelglove box type system. The isolator has an air handlingsystem that provides high efficiency particulate air(HEPA) filtered air to the interior in a unidirectionaldown flow pattern. The air handling system can bedesigned to provide the isolator interior with positive ornegative pressure. A positive pressure isolator is used toprotect the interior environment from ingress of anycontaminants from the background cleanroom. Negativepressure isolators are used for containment of biologicalor chemical products that are highly toxic and hazardousto the operator. Since the interior of the isolator is sealed off from the background cleanroom, the operatorcan access the interior through glove ports or half suits. Sterile containers, stopper components andenvironmental monitoring materials are brought in toand out of the isolator through air locks, mouse holes and devices known as rapid transfer ports (RTPs)(see Figure 1).

One of the major advantages that isolators have overRABS-type systems is that the interior can be bio-decontaminated through an automated process, whichusually uses hydrogen peroxide vapour (H2O2). This automated bio-decontamination process allows for a repeatable and consistent high-level bio-decontamination of the interior, thus the sterilityassurance level (SAL) is improved significantly overconventional cleanroom manufacturing.

RABS AttributesRABS also offer a high level of product protection andcontamination control. Unlike isolators, they use acombination of physical and aerodynamic barriers toprevent ingress of contaminants into the interiorenvironment. The physical barrier is similar to machineguarding, equipped with glass or polycarbonate doorswith stainless steel walls that totally enclose themachinery and with an air handler supplying HEPAfiltered, unidirectional airflow providing an ISO 5 environment.

RABS operate with a positive pressure and a high airexchange rate relative to the background cleanroom.They are typically unsealed barriers, having the HEPAfiltered air supplied to the RABS interior and exhaustedthrough a gap between the RABS walls and theequipment. Those that exhaust to the backgroundenvironment are referred to as open RABS. An openactive RABS has the air handler integrated into thebarrier system. A passive open RABS is a barrier systemthat is built around equipment installed below airhandlers in the background cleanroom, which providethe ISO 5 environment. Closed RABS offer another

option and are, by design, sealedisolators that can be underpositive or negative pressure, butare manually cleaned and bio-decontaminated rather thanutilising an automated bio-decontamination process, as istypical of isolators. Likeisolators, the introduction andexit of materials is done throughmouse holes, rapid transfer ports(RTPs) and pass throughs. Glove ports and half suits arealso used to further separate an operator from the sterileinterior of the RABS (see Figure 2).

In the early implementation of the RABS concept by the pharmaceutical industry, many companiesconsidered any enclosure around a process to be a RABS,claiming that it provided enhanced sterility protectionover conventional cleanroom manufacturing. But inmany cases, operators would continually open the RABSdoors to access areas within the critical zone to performan intervention – thereby defeating the purpose of theRABS, and creating an unpredictable level ofcontamination. Ultimately, RABS can meet therequirements of advanced aseptic processing if it is usedas intended – that is, with the operator separate from theprocess. RABS can only achieve this criterion when anyand all open door interventions are prohibited.

ROBOTICS IN ASEPTIC PROCESSINGAseptic manufacturing in general is a very repetitive activitythat requires a high degree of reproducibility in order tocreate a high-quality product. Robots are the ideal platformto provide the highly accurate and repeatable operationdemanded by aseptic processing. Additionally, robots can operate in environments where humans cannot. Thisbecomes particularly important in applications that requirecontainment of highly active and potent compounds.Robots can also be safely integrated into critical asepticareas, because they generate extremely low non-viable andviable particulate levels that are compatible with ISO 5environments. To further advance the compatibility ofrobotics with isolators andadvanced aseptic processing, robotmanufacturers such as StäubliRobotics have developed the TXseries Stericlean and HE 6-axisrobot arms, which are compatiblewith sanitising using IPA(Isopropyl Alcohol) and bio-decontamination with sporicidalagents and vapour phase hydrogenperoxide (VPHP) (see Figure 3).

89www.iptonline.com

Figure 3: AseptiCellrobotic aseptic fillingsystem utilises two vision-guided Stäubli Stericleanor HE robots

Source: Automated Systems of Tacoma

Figure 2: Restrictedaccess barrier systemencloses a vial filling line, and helps to ensurethe aseptic environment

Source: Telstar North America

IPT 34 2010 26/8/10 15:26 Page 89

Isolated robotics in aseptic manufacturinghas one particular advantage overtraditional aseptic machinery – flexibility.Robots are completely adaptable and can change with the product or process. If the current application or thecontainer format has changed, the robotsystem can be reprogrammed for anothermanufacturing process with minimal

investment. To adapt the robot to another application itwould only require new or modified end-of-arm tooling,processing fixtures, programming and possibly someadditional utilities like vacuum and sterile air. The turn-around time and resources required to reconfigure a robotare considerably less than the investment in a new,dedicated machine or filling line.

Robot tool changer technology is widely used byother industrial manufacturing sectors to maximise theflexibility of robot systems, but remains untapped inpharmaceutical applications. Tool changers allow therobot to quickly couple and decouple the end-of-armtooling to perform other manufacturing operations thatcannot be performed with a single tool. It is conceivablethat a single aseptic filling line could be designed formultiple container types (syringes, IV bags, vials and soon) where the operator would only have to provide theproper tool to the robot for the particular container type,thereby providing a manufacturing line with superiorflexibility and rapid changeover.

ROBOT SAFETY EQUALS PRODUCT SAFETYIn typical industrial applications, a robot cell is enclosedwith a safety fence having a combination of light curtains,laser area scanners, electronically interlocked doors andawareness signalling to safeguard the operator from the‘restricted operating space’ of the robot. ANSI/RIAR15.06, ‘Safety requirements for industrial robots androbot systems’, provides the designer and integrator of therobot system with standard methods for assessing risk tooperator safety; defines the requirements for protectingpersonnel interacting with or near the robot system; andassists with devising strategies to mitigate the level ofassessed risk (see Figure 4).

The combination of isolator-barrier technology with robotsafety requirements ensures that protection of the criticalzone is maintained during aseptic production. Withisolator-integrated robots, the isolator walls become thesafety fence encircling the robot. Light curtains detectoperator presence at the glove port(s), and the access door(s)are electrically interlocked, mechanically prohibiting thedoor(s) from being opened. The electrical outputs fromthese safety devices can be recorded and attached to theproduct batch record. Additionally, quality controlpersonnel can verify that the recorded interventions werevalidated per media fill and follow the process standardoperating procedures (SOPs).

In a RABS application, the designer of the controlsystem can utilise these safety devices to their advantage bydeveloping a systematic approach through the machinecontrol architecture to mitigate contamination risk duringan open door intervention. This strategy would not allowinterventions to take place or manufacturing to resumeunless certain conditions were met. This reducescontamination risks when an intervention is absolutelynecessary by having the control system walk the operatorthrough a defined validated process. For example, the robotcould be programmed to move the tool to the farthest pointaway from and above the intervention location (near thesupply HEPA filter, for example) prior to the door beingelectronically unlocked, thus minimising the contaminationrisk to the product contacting elements of the robot tool.

CONCLUSIONThe aim of advanced aseptic processing is the eliminationand absolute control of all sources of contaminants – mostimportantly, human-generated contamination. Roboticsand isolator-barrier systems will be the core technologiesthat further this initiative. A properly integrated robotsystem that is compliant with ANSI/RIA safetyrequirements, combined with a properly designed andimplemented isolator-barrier system, offers a flexible roboticcell that is compatible with the strictest of regulatorystandards. Ultimately, the many layers of operator andproduct protection provided by isolated robotics offersuperior control over ingress of contamination whencompared with traditional cleanroom manufacturing –thereby protecting product quality and minimising risk topatient safety.

References

1. Parenteral Drug Association (2008b) Technical Report

No 44, Quality Risk Management for Aseptic

Processes, PDA Journal of Pharmaceutical Science

and Technology, Supplement, Vol 62, No S-1, 2008

2. Whyte W, Disciplines Required Within a Cleanroom,

Cleanrooms, Supplement, ppS10-S14, December 1998

90 Innovations in Pharmaceutical Technology

Joshua Russell is Principal Engineer for the life sciences businesssegment at Automated Systems of Tacoma (AST) in Tacoma,Washington. As Principal Engineer he provides technical guidanceassisting customers by developing automated solutions forpharmaceutical and biotechnology manufacturing applications, andsupports the development of new products for AST’s life sciences

business segment. He has a BS in Mechanical Engineering from Saint Martin’sUniversity and is a member of the International Society of PharmaceuticalEngineers (ISPE). Email: jrussell@ast-inc.com

Figure 4: ANSI/RIAR15.06-1999 robotsafety compliant RABSunit that protects theoperator from the robotsystem and protectsthe product fromcontaminationoriginating from theoperator

Source: AutomatedSystems of Tacoma

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