pharm pro mar 2011

INTERPHEX2011™Official Media Sponsor of

®

2011 FACILITY OF THE YEAR AWARDS

7 Category Winners Profiled

WWW.PHARMPRO.COM

NEW TECHNOLOGY FOR THE BIOPHARM/PHARMACEUTICAL PROFESSIONAL MARCH 2011

RISK-BASED VALIDATION

ELIMINATING SINGLE-USE GUESSWORK

■ Roche ■ MedImmune ■ Merck■ Novartis ■ Pfizer Health AB

■ Pfizer Manufacturing Deutschland■ Shire Human Genetic Therapies

CLINICAL TRIAL MATERIAL PRODUCTION & TESTING

INSTRUMENTATION GOES MULTI-FUNCTIONAL

INTERPHEX 2011 SHOW ISSUE

pp1103_cover_online.indd 1pp1103_cover_online.indd 1 3/4/2011 10:44:31 AM3/4/2011 10:44:31 AM

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Volume 26, Number 00GROUP PUBLISHER

TOM LYNCH [email protected]

PUBLISHER MIKE KELLY, 973-920-7751

[email protected]

MICHAEL AUERBACH, [email protected]

ASSOCIATE EDITORLUKE SIMPSON, 973-920-7763

[email protected] MANAGER

SUSAN FRANK, [email protected]

ART DIRECTORBEVERLY BLAKE, 973-920-7116

[email protected] ASSISTANT

ALYSSA McCARTHY, [email protected]

WEB PRODUCTION SPECIALIST BRENT TOMASINO, 973-920-7479

[email protected] DEVELOPMENT

GAIL KIRBERGER, [email protected]

EDITORIAL ADVISORY BOARDMichael J. Beier,

Senior Vice President of OperationsTITAN PHARMACEUTICALS, INC.

Dr. James V. Blackwell, PhD, ConsultantBIOPROCESS TECHNOLOGY CONSULTANTS, INC.

Ronald C. Branning, Vice President Global Quality

GENENTECH INC.Robert F. Dream, Vice President

H.D.R. COMPANY LTD.Johanna Carmel Egan,

VGP Project ManagementELI LILLY

Girish Malhotra, PresidentEPCOT INTERNATIONAL

Allan F. Pfitzenmaier, PresidentVECTECH PHARMA CONSULTANTS INC.

Susan Polizzotto, Manager, R&D QA GMP Compliance

US SANOFI PASTEURCarlos Villalobos, Sr. Dir. Global Engineering

BRISTOL-MYERS SQUIBBRichard G. Whitfield, Senior Director

PFIZERPatrick Wong, Director of Global Engineering

BRISTOL-MYERS SQUIBB (BMS)

■ IN THIS ISSUE

■ P H A R M P R O . C O M

■ 4 MARCH 2011 | PHARMACEUTICAL PROCESSING

CORPORATE OFFICE: 100 Enterprise DriveSuite 600, Box 912

Rockaway, NJ 07866-0912973-920-7000

CHIEF EXECUTIVE OFFICER, RICH REIFFPRESIDENT, GEORGE FOX

CHIEF FINANCIAL OFFICER, TERRY FREEBURGVICE PRESIDENT, HUMAN RESOURCES

SUSANNE FOULDS

Official Media Sponsor of theINTERPHEX Show

Volume 26, Number 2GROUP PUBLISHER

TOM LYNCH [email protected]

PUBLISHER MIKE KELLY, 973-920-7751

[email protected]

MICHAEL AUERBACH, [email protected]

ASSOCIATE EDITORLUKE SIMPSON, 973-920-7763

[email protected] MANAGER

SUSAN FRANK, [email protected]

ART DIRECTORBEVERLY BLAKE, 973-920-7116

[email protected] ASSISTANT

ALYSSA McCARTHY, [email protected]

WEB PRODUCTION SPECIALIST BRENT TOMASINO, 973-920-7479

[email protected] DEVELOPMENT

GAIL KIRBERGER, [email protected]

EDITORIAL ADVISORY BOARDMichael J. Beier,

Senior Vice President of OperationsTITAN PHARMACEUTICALS, INC.

Dr. James V. Blackwell, PhD, ConsultantBIOPROCESS TECHNOLOGY CONSULTANTS, INC.

Ronald C. Branning, Vice President Global Quality

GENENTECH INC.Robert F. Dream, Vice President

H.D.R. COMPANY LTD.Johanna Carmel Egan,

VGP Project ManagementELI LILLY

Girish Malhotra, PresidentEPCOT INTERNATIONAL

Allan F. Pfitzenmaier, PresidentVECTECH PHARMA CONSULTANTS INC.

Susan Polizzotto, Manager, R&D QA GMP Compliance

US SANOFI PASTEURCarlos Villalobos, Sr. Dir. Global Engineering

BRISTOL-MYERS SQUIBBRichard G. Whitfield, Senior Director

PFIZERPatrick Wong, Director of Global Engineering

BRISTOL-MYERS SQUIBB (BMS)

8 Roche - PROCESS INNOVATION

10 MedImmune - PROJECT EXECUTION

14 Merck - FACILITY INTEGRATION

18 Novartis - EQUIPMENT INNOVATION

20 Pfizer Health AB - OP EXCELLENCE

22 Pfizer Manufacturing Deutschland - SUSTAINABILITY

24 Shire Human Genetic Therapies - HONORABLE MENTION

30 INTERPHEX 2011 Highlights

48 A Risk-Based Approach to Validation Focusing on the much overlooked validation governance.

54 Instrumentation Goes Multi-Functional Instrumentation technologies driven by validation costs.

56 Clinical Trial Material Production and Testing

What your CMO is not telling you.

60 Reduce the Impact of Contamination Events

The quicker you detect a problem, the faster you can fix it.

■ COVER STORY

2011 FACILITY OF THE YEAR AWARD

CATEGORY WINNERS

page 55

page 46

page 28

■ DEPARTMENTS

6 From The Editor

28 What’s Hot

INNOVATIONS46 Indicators, Monitors, Controllers51 Control and Automation Systems55 Regulators, Gauges, Actuators

On the Cover: Roche's MyDose proj-ect was developed to manufacture the MyDose Vartridge, a single-use infusion device that enables subcutaneous admin-istration of large quantities of liquid medication.

Facility of the Year AwardCATEGORY WINNERS

page 31

pp1103_toc.indd 4pp1103_toc.indd 4 3/1/2011 1:11:50 PM3/1/2011 1:11:50 PM

I“Innovation distinguishes between a leader and a follower.” Steve

Jobs said that and who could really argue with him. Apple has been at the cutting edge, and perhaps the bleeding edge of technology in-novations for so long it has almost become expected of them to intro-duce game changing technologies and products every few years.

Some might say that the pharmaceutical industry has been lacking in innovation recently. You might also say that it's not really fair of me to make comparisons between the consumer electronics industry and the highly regulated pharmaceutical industry in terms of innova-

tive products and thinking, but I’m here to tell you that inno-

vation is alive, well and thriving in the pharmaceutical industry.Just take a look within the pages of this issue and our profiles of

the seven winners in the 2011 Facility of the Year Award competition. Each of these pharmaceutical companies have pushed the envelope and impressed a panel of judges with their innovations, resourceful-ness, and team-approach in designing and building what many would argue are the most complex manufacturing facilities in the world.

While I was reading through the award submission packages for each of these facilities I was struck by the passion these companies have for building facilities that ultimately will produce a product that will hopefully affect someone’s life. You could also sense their strong desire to tell the story behind the facilities – the teamwork involved, the challenges met and overcome, and the satisfaction that comes with building something you know will continue to provide inspira-tion and innovation for years to come.

I hope as you read through our profiles you get the same sense of innovation and passion that I did. Also, if you happen to be at INTERPHEX 2011 in New York City this year be sure to visit the Facility of the Year Award display. There you will be able to meet and talk to the people behind these award-winning facilities.

■ FROM THE EDITOR


Innovation Evident

Have a comment or question about Pharmaceutical Processing? My E-mail is: [email protected]

Some might say that the pharmaceutical

industry has been lacking in innovation

recently. But I’m here to tell you that

innovation is alive, well and thriving in

the pharmaceutical industry …

■ Michael Auerbach, Editor in Chief

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Headquartered in Basel, Switzerland, Roche is widely rec-ognized as a leader in research-focused healthcare and biotech-

nology, with proven in-vitro products, tis-sue-based cancer diagnostics and diabetes management offerings. A key element of the company’s continued position atop the pharmaceuticals marketplace has been in the development of new and more efficient ways to bring their products to market.

This would be vital for one of Roche’s newest offerings – the MyDose Vartridge. MyDose being the trade name for a single use infusion device that enables the subcutaneous adminis-tration of large quantities of liquid medication. The medicine contained in this particular product allows for the delivery of a new formulation of drugs containing various monoclonal anti-bodies, such as Herceptin, MabThera and Actemra. MyDose’s main functional component is the Vartridge – a hybrid con-tainer combining the features of glass vials and cartridges.

The patient puts the Vartridge on their stomach where an adhesive patch keeps it in place. A button is pressed and a sterile needle penetrates the abdominal wall and the necessary medication is injected. The Vartridge uses a fluid path con-tainer set in motion by a battery-powered, motorized drive that depresses a conic-shaped piston. This ensures the Vartridge is completely empty when the piston is compressed.

Over 40 steps are needed to assemble the 83-component device, which is produced at Roche’s Kaiseraugst site along the Rhine valley, approximately 10 miles east of the compa-ny’s global headquarters. Annually, this facility produces 120 million packages of medication used in 130 countries.

In getting the Vartridge to market as quickly as possible, Roche needed to upgrade the Kaiseraugst facility with state-of-the-art process modules that would be tailored specifi-cally to the production of the MyDose device, including a high degree of flexibility to allow for producing various de-vice sizes and active substances.

In addition to customizing processing equipment and investing in new technologies, a key element of this proj-ect was Roche’s establishment of a Cross Functional Team (CFT), their traditional approach to these fast-tracked proj-ects. The company feels these teams ensure direct commu-

nication and faster decisions. The uniqueness of this CFT was that peo-

ple from product development and project management worked together to achieve a common goal. This would be vital, as the development of the device had not been fin-ished when the project was initiated, so the

team needed their plans to stay on schedule. A NEW BONDING EXPERIENCE

The production process for the MyDose device is unique to Roche, as no other product in their galenical manu-facturing approach (also known as formulation, or the manufacturing process by which all active pharmaceutical ingredients produced chemically or by biotechnology are transformed into application forms suitable to treat pa-tients) demands many state-of-the-art production steps.

The challenges associated with developing/designing the device were vastly outweighed by the challenges of produc-ing the correct, optimized manufacturing process layout in a relatively small space, and still meet all timelines. Vartridge required the modification of standard machines for production steps such as washing, siliconization and filling, yet strict temperature control requirements had to be maintained during the whole production process, due to temperature sensitivities.

Uwe Bank, Head of Process Technologies, explains. “The familiar processes of washing and siliconization turned out to be challenging since the new primary container is open on both sides. So we had to develop a new spraying needle and a new spraying sequence for this kind of shape.

“The difference between the bigger and smaller vial di-ameters also forced us to develop new washing cycles,” he continues. “An ordinary vial has a bottom and generates a back pressure and therefore a mechanical force which helps to clean a vial more efficiently.

“Another challenge was the machine noise. Only with the special design of some parts and changes in the construc-tion could we achieve the required 78 dBA.”

The Zoning Concepts were also extremely strict. The product requires Zone Grade C (ISO 8) with Grade A (ISO 5) air supply for the filled Vartridge from the inspection step

Customized Production Delivers Personalized MedicineRoche’s MyDose project wins Process Innovation category in the ISPE/INTERPHEX/Pharmaceutical Processing Facility of the Year Awards.■ By Jeff Reinke, Editorial Director


■ P H A R M P R O . C O M ■■ PROCESS INNOVATION

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Facility of the Year AwardPROCESS INNOVATION

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the cartridge holder, had to be demonstrated and there is no procedure at all to execute such a test.

“So, Roche developed a test method, based on the proofed concept of a helium leakage test. The final challenge was devel-oping welding parameters during project execution. The welding actually hap-pens trough the trans-parent cartridge holder, introducing heat at the ‘black part’ (transfer unit). Since the product is temperature sensitive, we had to make sure that the welding temperature would not harm the product, and demonstrate this to the authorities and our internal quality department. Therefore, we had to record continuously the welding tempera-ture and define a boundary with upper and lower limits.”

Additionally, process equipment for this project was designed and built as packaged units, including all instru-mentation. They were brought into finished, empty halls and connected to their corresponding media, energy supply and IT. Roche felt one of the main advantages with such an approach was a higher quality installation due to assembly under factory clean conditions.

The production process underwent several major changes, as the design of the devices developed and the full implications of the production process were understood (i.e. laser welding of the fluid path components under clean room conditions).

However, regardless of all these potential obstacles, by July 1, 2010 the design, construction, installation and quali-fication of equipment in an environment Zone Grade A (ISO 5) of an existing clinical supply unit was complete.

Roche had handed the design and production of the Vartridge to their Global Engineering Department, and they responded with a project completed in 13 months (four months ahead of schedule) and at a total project cost that was 1.3 percent under budget. ■

Designing the production process of the Vartridge (top left) encompassed a number of challenges, ranging from clean-room certifications and approvals to implementing assembly and special-ized welding operations in a limited footprint of an existing facility.

e


until welding. The unique integration of a laser welding pro-cess under clean room conditions also represented a poten-tial bottleneck in production that had to be adjusted.

Production of the device involves many more steps and components than a “normal” auto injector device, which Roche grouped in to four major segments.1. Vartridges are delivered to the production line in trays, fol-

lowed by careful washing, siliconizing, depyrogenization, sterile filling and closing of the Vartridge to provide for the core characteristic of the product.

2. Manual quality inspection.3. Assembly and welding of the fluid path components

(Vartridge, cartridge holder and transfer unit) to produce the finished fluid path. This would prove to be the most complex step, as it called for implementing assembly and welding processes under clean room conditions.

4. Further assembly, including base plate, housing, fluid path and plaster before country-specific labeling and packaging.During step three, trays and tubs are delivered manually to

the assembly and welding machine. A clean room validated ro-bot picks the three components (transfer unit, filled Vartridge, and cartridge holder) one after another and assembles them. The laser welding process, under controlled conditions, follows to seal the transfer unit with the cartridge holder. Once in this state, this new component is called a fluid path, and must be air tight to guarantee sterility.

The welding process posed a big challenge for Roche’s vali-dation team. Sophisticated measurements were developed to prove the stability and reliability of the process, with several testing methods, such as a helium leakage test, developed to validate the quality of the laser welding seam.

Roche worked with two companies, Leister and Insys, for the laser technology. “Introducing this kind of technology into the pharmaceutical industry in a clean room environment was a very challenging task because of three factors; the compound of the plastic parts, the guarantee of sterility, and the develop-ment of welding parameters,” offers Bank.

“The compound of the plastic parts is crucial for the welding success,” he continues. “A slight variation of carbon black par-ticles would fail the laser welding process.

"That means that the supplier of the plastic components to be welded together had to implement validated processes to guarantee the right percentage of carbon black particles. Proof of tightness, to guarantee sterility in the inner room of

PHARMACEUTICAL PROCESSING | MARCH 2011 9 ■

■ P H A R M P R O . C O M■ PROCESS INNOVATION

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The dedicated operator training lab where instructors used a pared-down verison of the PCS to simulate production scenarios.

The complexity of the Frederick Manufacturing Center (FMC) Expansion construction project undertaken by MedImmune

made being on time and on budget a chal-lenge from the very beginning. Aggressive timelines and phase overlaps meant that the project team had to think outside the box in order to meet the company’s goals - developing extraordinary solu-tions from ordinary tools was one of the project themes.

The project team drew on the military background of some of its members to develop thorough and efficient operator train-ing and risk-management techniques. Additionally, MedImmune called on experience gained from previous projects in order to fine tune project management methodologies. But it was the unwavering attention to safety that really impressed the Facility of the Year Award (FOYA) judges, helping the FMC Expansion project get over the line in the Project Execution category.

SAFETY FIRST To have no lost-time accidents during 2,300,000 man-

hours is an amazing feat, and impossible if project manag-ers don’t take ownership of safety.

“An owner has to drive safety. There are a lot of firms that somehow believe that it is the responsibility of the prime construction manager; we simply have a position that a lost time incident is an unacceptable event,” explains Andy Skibo, Senior Vice President of Global Engineering and Facilities at MedImmune.

“You have to engage a [construc-tion] firm that can manage that way. They will perform better for an owner who has that drive than they will for an owner that says

‘you guys go mange that,’” adds Skibo.Progress meetings provided Skibo with

a platform to reemphasize the priorities to team members.

“When we report project progress, we don’t report cost or schedule first, we report con-struction safety first. Only when that data is

available do we go into cost and schedule - it’s known that there are no gold stars handed out for good cost and schedule performance if the construction safety is not up to snuff.”

But the real key to such an outstanding safety record, ac-cording to Skibo, is the workers themselves.

“We don’t hand out construction safety incentives to our prime contractors, but we do hand out incentives to the ac-tual workers. If the workers themselves don’t want to work in a safe environment, there’s no way of achieving two mil-lion work hours without a lost-time incident.”

Skibo also had a deeper, more ideological incentive for safety on this project: “It’s inconsistent to deliver pharma-ceutical products for human health and not worry about the people that work for you.”

THE PROBLEM: TRAINING & RISK MANAGEMENT MedImmune had over 100 staff members that needed de-

tailed training on the use of the new process control system (PCS). Switching from a small-scale, semi-automatic facility to a fully-automated, multi-product facility meant that the job functions for a large number of employees would be altered

significantly.Skibo was acutely

aware of the prob-lems that can come from a lack of staff training and transi-tion planning.

“MedImmune had experience with a pilot plant facility - a brilliant physical project, on time and on budget, and a bril-

Military Precision, Flawless Safety MedImmune proved that aggressive construction and validation timelines can be achieved without sacrificing worker safety .■ By Luke Simpson, Associate Editor

■ P H A R M P R O . C O M■ PROJECT EXECUTION

Facility of the Year AwardPROJECT EXECUTION


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The 2,300,000 man-hour construction project was com-pleted without a lost time accident.

liant technical facility when it was done, but there was a difficult transition for our development team moving from a labora-tory, bench-scale environment to a fully-in-tegrated, two-story development facility.

“So for the FMC expansion project, when we were still a year away from mechanical completion, we wanted to take advantage of that experience and focus on training of the entire team to ensure that the baton wasn’t

improve project execution.The project called for a “vertical cliff of

startup” between construction and manu-facturing operations, not a smooth transi-tion over many months. Figuring out how to design the startup, according to Skibo, is only half of the battle. The more important question was how to undertake a failure-mode analysis and failure response when things do not go as planned.

dropped between the physical completion of the project and the start up of the manu-facturing environment,” says Skibo.

THE SOLUTION: A MILITARY APPROACH

Working with Skibo was Patricia Rader, Executive Vice President at Raland Technologies, and Brent Hill, Director of Automation Global Engineering. Rader and Hill had military backgrounds and saw sev-eral opportunities to use this experience to



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to the sequential process where we commis-sion first, then start installation qualification (IQ), then operational qualification (OQ) and finally performance qualification (PQ).”

“ICQ overlaps a lot of commissioning and the IQ stage in particular, and it over-laps some of the OQ. The goal is not only to overlap the schedule, but to not do the

Rader and Hill immediately recognized this situation as a civilian version of ad-vanced mission planning.

“Much of mission planning is figuring out how to workaround problems and not just ‘how do I do it if everything goes perfectly.’ That’s where the military training came into it,” explains Skibo.

The military training methodology con-sisted of a four-tiered approach:• Concept training.• Review of operational standard operating

procedures (SOPs).• Hands-on, instructor-led training.• On the job training.

During the third phase, trainees used a complete, isolated replica of the PCS to not only familiarize themselves with the soft-ware, but also to prepare for problem sce-narios that may arise. The system was built using Rockwell’s SoftLogix software package and allowed training and validation activi-ties to be performed simultaneously.

“We knew, given the complexity of the plant, that once you’ve qualified an area, if you have something in the area that needs to be changed, the process is very demanding. You have to manage the change. It doesn’t leave you any room to run through 15 ‘what-ifs’ to figure out what needs to be changed. This is where many startups like this run into time delays. The solution isn’t obvious, and the only way to figure it out is to play with the equipment. If you’re in a validated state, that can set you back a month or two.

“From day one we said we were going to have a training room with two full PCS simulators that look, to the operator, just like the real thing. It was a completely off-line computer system backed up with training modules that could run a synthetic batch or problem - the operator could put in a prob-lem and try various solutions.” says Skibo.

MASTERING PHASE OVERLAPS If there was any room for improvement on

this project, Skibo sees the potential for a deeper understanding of the non-sequential integrated commissioning and qualification (ICQ) process.

“The area that we think could be improved upon is making sure that we have, through-out the company, a clear understanding of what the ICQ process is. It’s much different

same task twice. That has to be understood top to bottom by the engineering, construc-tion, manufacturing, quality and qualifica-tion groups,” explains Skibo.

Recognizing the need for continuous im-provement is the first step towards another best-in-class facility construction project for Skibo and MedImmune. ■



~ Since 1983 ~

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MedImmune on winning the 2011 Facility of the Year Award for Project

Execution.

ACC is proud to have been the Automation

and Information System Integrator on the

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Automated Control Concepts, Inc. (ACC) is an independent systems integration firm specializing in process automation and information technology solutions. ACC provides services and solutions from initial specification development and system design through the implementation, commissioning and qualification of plant-wide automation and manufacturing execution systems.

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Three different views of equipment in the modular built manufac-turing area. Below: Bottle filling line. Center: View of the mainte-nance room with access to the 60” tablet coater. Right: The second level fluid bed dryer.

The desire to expand and improve core drug development capa-bilities and to meet the strategic need to increase productivity

and efficiently manage a significant increase in clinical trial patient demand led Merck to embark on an ambitious expansion of its Global Clinical Supplies Manufacturing, Packaging and Warehouse in Summit, New Jersey.

The integration of the new facility and renovation of an existing facility on-site has resulted in the project winning the Facility Integration Award in the Annual Facility of the Year Award program jointly sponsored by ISPE, INTERPHEX and Pharmaceutical Processing.

A GROWING NEED Merck’s Global Clinical Supply groups were located in

Kenilworth and Union, New Jersey with limited space, equip-ment capability and scale. The mix of potential compounds in the pipeline indicated a need for a flexible, multi-product solution to manufacture, fill, package, and distribute clinical supplies. The elimination of third party organizations within the clinical manufacturing process was also a priority. The new Global Clinical Supply facility was designed and built to support drug development in the stage be-tween discovery and commercializa-

tion. There tablets, capsules, liquids and inhalation products for clinical trials are manufactured along with the new technolo-gies developed for transfer to commercial production facilities.

An existing building in Summit, New Jersey, was selected as the location to sup-

port Merck’s drug development activities in the stage be-tween discovery and commercialization. In order to sustain on-time delivery of clinical supplies, the new consolidated facility was required to integrate with other pharmaceutical development functions, achieve compliance with cGMP and regulatory requirements and address the needs for flexible, multi-product manufacturing.

CONSOLIDATION AND EXPANSION The project consolidated several cGMP clinical manufactur-

ing, packaging and warehouse areas within a single state-of-the-art facility in Summit, New Jersey. An existing decommissioned production building, S6, was partially demolished, renovated and expanded for improved clinical manufacturing and develop-ment capabilities, increasing productivity and efficiency, and enabling Merck to better manage a projected significant in-

crease in clinical trial patient load. The expansion project included utilization of modular building construction for primary manufacturing operations and adaptive reuse of a former pharmaceuti-cal warehouse. Speaking to the benefits of using a modular approach, Michael D. Cirello, Clinical Supplies Director,

Expansion Through ConsolidationMerck's new global clinical supplies facility expands to meet market needs■ By Mike Auerbach, Editor In Chief

■ 14

■ P H A R M P R O . C O M■FACILITY INTEGRATION

Facility of the Year AwardFACILILTY INTEGRATION

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GPC Operations said, “The modular con-struction was very valuable in achieving the overall success of the project. The major components that led to the suc-cess were:1) The 3-D model which allowed for

a complete review of the facility prior to any fabrication being initiated. This significantly contributed to minimal field changes. It also allowed for a very clean layout in the mechanical spaces.

2) Standardization of building equipment and finishes. This allowed the user to have a complete knowledge of the type and quality of building finishes and equipment (HVAC, lighting,) the building would have.

3) Schedule. The flexibility that comes with sequencing the fabrication of the modules allowed for problems encountered with some of the equipment deliveries”.The combination of a modular approach

along with adaptive re-use and renovation helped Merck to achieve the project’s aggres-sive deadline with minimal site disruption and maximized utilization of existing infra-structure. The project also included integra-tion of sustainable design throughout the de-sign process, culminating in a new, premium efficiency Operational Support Building. The completed clinical manufacturing facility has the capability to scale-up and deliver a variety of products simultaneously, including oral solid dosage, liquid, dry powder inhala-tion products for clinical manufacturing, fill-ing, packaging and process development.

THE HYBRID APPROACH The clinical manufacturing facility was

constructed by Pharmadule modular fabri-cation in Sweden. Related equipment and utilities were installed during fabrication and integrated into each module, thereby reduc-ing time and enabling concurrent engineering project completion in Sweden. At the same time in New Jersey, demolition, excavation and foundation work was ongoing. When the modules arrived, they were set, assembled and “hooked” up. A critical element of the project was aligning the new manufactur-ing modules to the existing structure on two sides. Commenting on the integration of

Early front-end planning, timely com-munication and well coordinated se-quencing of concurrent, complex and phased activities between geographi-cally dispersed team members were also key factors in successful project completion. With the capacity and ca-pability to scale-up and deliver a vari-ety of products simultaneously, Merck

has increased productivity, technology, com-pliance and innovation to meet current and future drug development pipeline needs.

THE DETAILS OF FLOW As mentioned, one of the project goals

was a seamless integration of new and reno-vated space. Also important to the facility was the efficient flow of people. When asked about his favorite features and details of the facility, Cirello says, “The facility layout pro-vides for the efficient flow of people, materi-als and equipment both within and external to the various integrated business units operating within the facility. This complex functionality was effectively engineered into an esthetically appealing yet practical facil-ity. I’m also very happy with the contiguous technical space providing for ease of access for mechanical service without having to enter the GMP space. This was consistent with the goal of keeping the majority of serviceable utilities and process equipment components in the technical space.”

JUDGES RESPONSE Cirello feels that there were several factors

that contributed to the Facility of the Year Award judges selecting his facility. “The fac-tors include all the technical challenges and flexibility requirements associated with the design of a development facility. In this case the primary driver for the engineering design is not a product with well defined process re-quirements, but a series of platform technolo-gies and varying scales that may be needed based on the development product attributes. In addition, the project included a combina-tion of selective demolition, new construction, renovation using both conventional stick built and modular construction technology. In addition, the project was able to adapt to a significant change in user requirements, the de-scoping of sterile manufacturing at 90% of BOD, resulting in only minimal impact to the project timelines.” ■

■ P H A R M P R O . C O M■FACILITY INTEGRATION


modular and stick-built construction, Cirello says, “The biggest limitation was the distance in both time and miles between the design teams for the modular and stick-built. It was important to us to have a seamless design so that someone moving from one part of the facility to the other would not see any ap-preciable difference. This was made more dif-ficult because the construction materials and techniques in each country had some small variations. In order to help overcome this lim-itation several methods were employed. First, situating an engineer from the company per-forming the "Stick Built" part of the project in the offices of Pharmadule during the design phase helped us to understand and com-municate issues between the different teams. Second, the use of a Project Information Management System (PIMS) served as a cen-tralized repository for both the project/design documentation and provided a forum for ini-tiating, approving and communication of vari-ous 'design decisions' to the project team.”

MODULAR DETAILS The structure consisted of 82 modules

fabricated in Sweden from frame to fit-out, including utility hook-ups, to completion in 24 months. Co-located project teams (3 sites in Sweden/4 sites in the US) consisted of two design teams, the teams were sepa-rated not by functional areas, but by the different design approaches required. The project teams utilized web-based Project Information Management System (PIMS) to develop, review, monitor, control, document and archive key aspects of the design, con-struction, qualification,schedule and costs. By utilizing a web-based Project Information Management System (PIMS), Merck achieved successful project management/execution to develop, review, monitor, control, document and archive key aspects of the design, con-struction, qualification,schedule and costs. The entire team was able to work within a single system with a single set of data monitoring project performance in real-time.

The maintenance mezzanine in the "stick built" portion of the facility

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Novartis Vaccines provides more than 20 vaccines to prevent viral and bacterial diseases and is dedicated to

delivering on its promise of prevention through the research, development and production of innovative, safe and effective vaccines. The company’s new MARS (Marburg Site) facility in Marburg, Germany was designed and built to be the company’s “Center of Excellence” for mod-ern vaccine produc-tion.

The company’s efforts to design and build a flexible vac-cine manufacturing facility incorporating a state-of-the-art laser egg opening machine has resulted in the facility win-ning the Equipment Innovation award in the 2011 Facility of the Year award competition jointly sponsored by ISPE, INTERPHEX and Pharmaceutical Processing magazine.

MARS - A COMPLETED INTEGRATED SITE The MARS Project integrated on to one site the manufac-

ture of existing vaccine concentrates and the production of media, buffer and adjuvant products.

The project also integrated support functions, such as equipment cleaning and sterilizing, by centralizing the fa-cilities at the Marburg site. Other accomplishment of the MARS Project included a new Quality Control building that consolidates the analytical and quality control functions for the Marburg sites. In the process of designing and building a state-of-the art vaccine facility, the company also seized upon the opportunity to enhance lean manufacturing tech-niques, to innovate processes and improve equipment de-sign and operation, to ensure that the new buildings meet

the latest sustainability trends and to create an excellent working environment for operations and QC staff with open views from all operating rooms to the country-side around the site.

CAPABILITIES The production facility is

capable of manufacturing 20 million doses per year of rabies vaccine or 40 million doses per year of tick-born encephalitis

vaccine or any combi-nation of the two, uti-lizing two interchange-able production lines. The media, adjuvants and buffer production

at the site supports all of the 20 vaccines within

the Novartis portfolio.The QC facility performs 35,000 to 40,000 analytical tests and more than 100,000 environmental and utility monitoring samples per year.

The warehouse serves an integral part of the production facility ensuring lean raw ma-terial and final product movement via a connecting spine. It has a capacity of 4,000 pallet spaces with chilled and ambi-ent temperature storage.

FULL FACILITY FLEXIBILITY The design leverages the revised requirements for live

vaccine processing issued by the FDA in October 2007 and made effective in July 2008. The design and operating con-cept allows concurrent manufacturing of two different live vaccines on two segregated manufacturing lines in the same production area. The changeover procedure allows the facil-ity to switch manufacturing from one vaccine to the other and also enables the facility to manufacture two vaccines either concurrently or in campaign.

This inherent flexibility allows the facility to respond

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The Incredible Egg Opening MachineCreating a center of "eggs"ellence for modern vaccine production■ By Mike Auerbach, Editor In Chief

■ P H A R M P R O . C O M ■■EQUIPMENT INNOVATION

Facility of the Year AwardEQUIPMENT INNOVATION


■

The LEO system handles pre-disinfected eggs on trays with a capacity of 84 eggs per hour with a future potential to accommodate 3000 eggs per hour.

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Left: The process of opening of the eggs is performed using an industrial-scale laser process under strict clean room conditions. The laser egg opener automatically opens eggs in parallel while maintaining aseptic conditions. Transportation of the eggs through the egg opener is by means of a conveyor belt system controlled by optical sensors.Above: The facility design and operating concept allows concurrent manufacturing of two dif-ferent live vaccines on two segregated manufacturing lines in the same production area.

the production flow. In the new MARS facility the process of opening of the eggs is performed using an industrial scale laser process under strict clean room conditions. The laser egg opener (LEO) automatically opens eggs in parallel while maintaining aseptic conditions. Within the new LEO han-dling system in the MARS facility, the pre-disinfected eggs are handled on trays with a capacity of 84 eggs with the potential to accommodate 3000 eggs/ hour. The trays are manipulated by the operator at the “front end” of the laser egg opener within a laminar flow tent. Transportation of the eggs through the egg opener is by means of a conveyor belt system controlled by optical sensors. These can detect tray position and occupation. This ensures that the laser is only distributed to the eggs present and not to the empty spaces. The layout of the trays and the conveyor system allows the opening of 4 eggs in parallel using 4 individual laser beams. The benefits of the LEO are: the elimination of cross con-tamination and increase process throughput contributing to the overall 10-fold productivity of the facility.

The opening of the eggs in the past was performed manu-ally with the help of an “egg puncher” which operated pneu-matically. The operator needed to manually open every single egg with this device. This older method is carried out under clean room classification and increases the risk of cross-con-tamination due to the contact and damage to the eggs.

JUDGES IMPRESSED In their selection of the Marburg site as a category win-

ner, the judges mentioned several key factors that influ-enced their decision. Among them was the quick project execution of only 26 months, the impressive safety record of a 1.7 million manhours with no lost-time incidents; and finally the innovative use and integration of the laser egg opening system which eliminated cross-contamination and increased processing efficiency. ■

quickly to health and market needs and reduces the cost of running dedicated facilities.

PROCESSING STEPS At the Marburg site a new process flow was implemented

that enabled the facility to achieve a 10-fold increase in pro-ductivity. The basics of the process include:

Cell preparation: The upstream of the process is based on the infection of a suspension of chicken embryos fibroblasts with live virus. The cells and the viruses are incubated at controlled temperature for 5 days in single use cell factories and the virus suspension is harvested into a fixed stainless steel vessel.

Virus propagation: The harvest is then filtered in a sec-ond vessel in which the inactivation agent is added to the harvest and mixed. To complete the inactivation, a matura-tion step takes place in a third vessel.

Inactivation: A purification/concentration step by ultra-centrifugation on sucrose gradients completes the process. The transfer between vessels and to the ultracentrifuges is with stainless steel lines.

From the harvest vessel to the ultracentrifuge, the bio-safety and the sterility of the product is ensured by a closed system. All transfers are driven by the automation system. Transfer lines and vessels are sterilized with clean steam (SIP), cleaning in place (CIP) by units dedicated to each of the two manufacturing lines.

THE HEART OF THE FACILITY It might seem odd and a bit old-fashioned in this modern

age to consider that the manufacture of vaccines is still primarily based on eggs. But this is still the case in many facilities around the world. At the Marburg site the key to the dramatic production increase was the installation of a highly automated laser egg opening machine.

As mentioned above the production of TBE/rabies vaccine consists of three major production steps: preparation of the cell suspension; virus propagation and concentration of the inactivated virus.

In the first step of production, SPF (specific pathogen-free) eggs are used to produce cells for the next steps in



■ P H A R M P R O . C O M■EQUIPMENT INNOVATION

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Prior to 2010, Pfizer Health AB produced its legacy products Genotropin® and Somavert® in separate facilities. Somavert

was sourced from a contract manufacturer while Gentropin was manufactured at a Pfizer facility in Strängnäs, Sweden.

The two drugs have opposite effects on the human physi-ology - Genotropin is used to treat growth hormone defi-ciency and Somavert is a growth hormone antagonist - but the proteins used in each are very similar. Pfizer’s develop-

ment scientists saw an opportunity to exploit this similarity to develop almost identical unit operations that could be used for both products within the same facility.

The project - dubbed Project Pegasus - had two fundamental ground rules: The new Bio 7 facil-ity would not require an increased head count and a two-shift pattern would be sufficient to produce two batches per week. To achieve this, the project team went back to the drawing board and re-evaluated a

number of steps in the manufacturing pro-cess, including some thought to be standard in pharmaceutical processing.

Today, the Bio 7 facility is able to produce the two products much more efficiently - ex-ceeding the goal of two batches per week with 3.5 batches per week - and is recognized

in this year’s Facility of the Year Awards (FOYA) as the winner of the Operational Excellence category. Here’s how Pfizer made it happen.

TIME IS MONEY The FOYA judging panel recognized the effort that Pfizer

put into reducing equipment turnaround times. A major focus of the de-bottlenecking projects was to optimize the clean-in-place (CIP) and steam-in-place (SIP) procedures.

Four CIP skids are used to provide dedicated cleaning functions to the various processing areas. Skids 1, 2 and 3 are used to clean equipment, vessels and lines that have been exposed to proteinaceous material, and require both chemical make-up and water rinse tanks. The cool water pre-rinse is executed at the same time as the hot chemical solution is prepared, creating a seamless CIP sequence.

CIP time is further reduced by eliminating the puri-fied water pre-rinse compressed air blowdown sequence.

Culturing Excellence Pfizer Health AB’s Project Pegasus team created an environment where operational improvements and innovation are encouraged and applied. ■ By Luke Simpson, Associate Editor


■ P H A R M P R O . C O M ■■ O P - E X C E L L E N C E

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Facility of the Year AwardOPERATIONAL EXCELLENCE

Multi-Batch Stock Buffers Using high-concentration stock buf-

fers that are in-line diluted allows

the use of buffers across multiple

batches without the need for large

vessels. This reduces the number

of preparations per batch, which in

turn reduces the number of CIP runs.

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Pfizer Health AB's Bio 7 facility in Strängnäs,

Sweden, where the legacy drugs Genotropin®

and Somavert® are produced.

Left to Right: Buffer hold skids in the buffer hold area; The fermenter super skid, assembled at a vendor workshop prior to factory acceptance testing; A chromatography skid and column in the downstream processing area.

- chromatography gels and some TFF membranes, for example.

The Project Pegasus team found that the added value from SIPing ves-sels and lines was questionable, and in some instances may in fact hide a cleaning problem. The decision to eliminate downstream SIP made a significant contribution to the reduc-tion in equipment turnaround times and increased facility capacity.

PHARMACEUTICAL COUNTERCULTURE The ability to improve efficiency by questioning and

changing processes that many think are standard in bio-pharmaceutical processing requires an environment where operational improvements and innovation are encouraged and applied.

“Every voice and idea counts no matter where it comes from. Everyone on the team is continuously encour-aged to contribute ideas,” explains Kim Sandell, receiving project manager for the Bio 7 facility and Pfizer Health AB’s director of Operational Excellence.

“We also communicated that not everything could be implemented di-rectly, but we track proposals so that we can pick them up as the facility evolution continues. I like to think of a process and a facility as a journey, and that by finalizing the project we have just left the station; we need to im-prove and get better as we move along over the years,” adds Sandell.

Risk-based approaches helped Sandell’s team challenge “common practice” with scientifically sound ar-guments.

“We used risk-assessment technolo-gies such as failure mode and effects analysis (FMEA) to ensure that we focused on the important stuff.”

And what is Sandell most proud of?“We built Bio 7 in a platform technology - I like to com-

pare it to the car industry’s way of building many different models on one common platform. This makes it simpler to introduce new processes in the future.” ■

■ P H A R M P R O . C O M■ O P - E X C E L L E N C E

Inline conductivity measurements conducted at the facility showed that air blowdown was not required to remove re-sidual pre-rinse water from the object prior to preparing the cleaning solution.

Further tests found that the manual removal and rein-stallation of vent filters before and after vessel CIP was unnecessary. As a result, the vent filter housings at the Bio 7 facility are designed so that the vent line can be cleaned without removing the filter element or housing. This also eliminated delays and potential accidents caused by fittings that are not secured properly.

SIP REALITIES Conventional wisdom suggests that SIP functionality

should be allowed for in downstream processing areas. SIP was included in the original downstream design specifica-tions, but the functionality was removed when the project team determined that materials with the highest risk of re-taining contaminating microbes cannot be steamed-in-place



A Clean Solution It is common for facilities to use

NaOH cleaning solutions that also

contain surfactants. When a surfac-

tant is used, the required rinse con-

ductivity requirement is much more

strict (< 5 µS/cm). During cleaning

validation at the Bio 7 facility, it was

shown that a relatively low con-

centration of NaOH was sufficient

to clean all product contact equip-

ment. By avoiding a surfactant in

the cleaning solution, the final rinse

conductivity for certain parts of the

process can be much higher (< 200

µS/cm to 5 µS/cm), saving a consider-

able amount of water and time.

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Left to right: Solar panels produce green electricity at the Pfizer Freiburg site; Lab areas now fea-ture adiabatic cooling; Steam generator for the wood pellet boiler; Tablet coating manufacturing area with air conditioning generated by the wood pellet boiler; Wood pellets are produced from dried, untreated residue wood (sawdust, shavings, residue wood from the forest, etc.)

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Pfizer’s Freiburg, Germany plant is the company’s largest packaging facility and a strategic manu-facturing site. In 2008, 8 billion

tablets and capsules were packaged into 230 million packs comprising medicines to treat a variety of diseases.

The site’s SPRING-E MAP (Strategic Plant Restructuring Energy Master Plan) was designed and implemented to opti-mize the manufacturing and packaging operations on the site and prove that cost savings and sustainability were not mutu-ally exclusive.

The success of the project and its implementation of cut-ting edge technologies resulted in the facility winning the 2011 Facility of the Year Award for Sustainability, jointly sponsored by ISPE, INTERPHEX and Pharmaceutical Processing magazine.

SUSTAINABILITY: THE GOAL FROM THE START The team at Pfizer’s Freiburg plant held the strong belief and

philosophy that cost-savings and environmental responsibil-ity could go hand in hand. To determine how best to do this at Freiburg, the team put together a plan that eventually led to five major projects and more than 200 smaller projects all aimed to implement cost and energy efficient technologies.

The main technologies implemented at Freiburg include:

• Geothermal heating and cooling of office buildings• Biomass steam for pharmaceutical manufac-turing and packaging• Biomass absorption cooling for pharmaceu-tical manufacturing and packaging

• Adiabatic cooling for laboratories and high efficiency manufacturing areas

• Photovoltaic for electricity generation GREEN ACHIEVEMENTS

The result of implementing a wide array of green tech-nologies has led to some remarkable achievements. For ex-ample, the site’s greenhouse gas emissions were cut by 80%. Considering that European Union provisions on reducing gas emissions target a 20% reduction by the year 2020 you can see how impressive this achievement really is. In addition, the change to renewable energy sources means that 91% of the site’s primary energy is generated from these sources.

While the results are certainly impressive, perhaps more noteworthy is the fact that these achievements were accom-plished by making renovations and improvements to an exist-ing facility. When asked about the challenges of renovating a facility to meet sustainability goals in comparison to working from a clean sheet and designing them into a new facility, Michael Becker, Director of Engineering at Freiburg commented, “Here you have to separate two cases, first - the technology and second - the green strategy. It was clear that we could not use every technology because the buildings and environment

Going Green In The Black Forest Pfizer's Freiberg SPRING-E MAP Plan proves cost savings and sustainability are not mutually exclusive ■ By Mike Auerbach, Editor in Chief


■ P H A R M P R O . C O M ■

■SUSTAINABILITY■

Facility of the Year AwardSUSTAINABILITY

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For an industry that is usually reluctant to change, the use of the wood pellet boiler was a daring choice. “The technol-ogy was not solely designed for pharmaceutical facilities,” say Becker, “but we designed it for use in our facility.” Becker con-tinues, “The boiler is embedded into our building monitoring system to provide the necessary reliability for pharmaceutical processes and GMP s. It is fully automated and its operation is fully embedded in our highly automated facility. One example of this is that the wood pellets can be automatically trans-ported into the boiler via pneumatic hoppers which is much cleaner and eliminates manual handling.”

LOCAL EXPERTISE With such advanced technologies implemented, you might

think the Freiburg team had to scour the globe looking for experts, but in fact the expertise needed was found locally, as Becker explains, “Freiburg is know as the "Green City" of Germany meaning there are a lot of companies with expertise in "Green Technologies" and we used that benefit to work with different vendors and the (local) university. In this case we had a very agile partner on site and all the systems we installed were "Right First Time". That meant timelines were met, targets were achieved and very importantly; continuous improvement processes could be adapted to increase efficiencies.”

JUDGES REACTION The Facility of the Year Award judges were obviously im-

pressed with Pfizer’s accomplishments at Freiburg. In fact, in their comments the judges said that in their opinion this proj-ect is truly what sustainability is all about. Adding that they were most impressed with how Freiburg engineered a long term sustainability program that is unparalleled in pharmaceu-tical manufacturing.

The facility has received a lot attention both from within Pfizer and from other pharmaceutical companies. “Freiburg is seen as a ‘Green Lighthouse’ within Pfizer,” says Becker. “We have a lot of visitors looking at the technologies - from within and also external companies. We try to help them with our experience.” ■

were given and we had to integrate the technologies into that environment. But we had a clear strategy in our "Energy and Resource Conservation Master Plan" which was the basis for the design so that helped us to achieve the green targets.”

With a project of this size and scope one of the inevitable questions is when does all this green technology start paying dividends. According to Becker, in some instances this has already occurred. “The majority of projects had a break even point approximately 2.5 years from implementation and, de-pending on the actual installation time, some of the projects have already achieved this. By implementing these technolo-gies we were able to show that we could combine ‘economical and ecological” targets. We proved that getting Freiburg more competitive and ‘healthier’ were complementary goals.”

EUROPE’S LARGEST WOOD-PELLET BOILER At Freiburg, the boiler house has been switched over to bio-

mass fuel, resulting in Pfizer installing and operating Europe’s largest wood pellet boiler. By modernizing the facility this way the company saves the environment 5,500 tons of carbon diox-ide annually as well as six-figures in heating costs.

The wood pellet steam boiler system replaces two of four ex-isting boiler systems which were built in 1962, and provide ap-proximately 85% of the heat and steam required at the location.

Wood pellets are produced from dried, untreated residue wood (sawdust, shavings, residue wood from the forest) with a diameter of approximately 6 - 8 mm and a length of 5 - 45 mm. They are compressed under high pressure without add-ing chemical binding agents, and have a heat value of around 5 kWh/kg. The energy content of one kilogram of pellets corre-sponds to about half a liter of heating oil.

In an integrated and sustainable fuel cycle, sawmills from Buchenbach and Kehl in the nearby Black Forest supply the biomass fuel for the wood pellet steam boiler. With an annual production capacity of over 200,000 tons, the works have suf-ficient capacity to supply Pfizer GmbH with their annual re-quirement of around 5,000 tons. The proximity between pellet production and combustion further improves the ecological balance sheet thanks to the short transport distances.

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■ P H A R M P R O . C O M■SUSTAINABILITY



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Going inside Shire's Atlas project provides a look at some of the single-use technolo-gies it implemented, including customized bioreactor equipment and aseptic bags.

All Photos: Erin Chrusciel, erinchrusciel.com

One of the world’s leading bio-pharmaceutical companies, Shire Human Genetic Therapies (HGT) focuses their work on life-short-

ening, neuro-muscular conditions such as Fabry disease, Gaucher disease and Hunter syndrome. These diseases are treated by enzyme replacement therapies that are now being produced in one of the company’s newest and most unique facilities.

Project Atlas, in Lexington, MA is Shire’s third cell culture facility and one of four buildings on the Lexington Technology Park (LTP) campus – the global center for Shire’s HGT division. The Atlas facility supports the manufacture of Replagal® (for Fabry disease) and VPRIV® (for type 1 Gaucher disease).

While a number of features make Project Atlas stand out, perhaps the most intriguing is Shire’s first-ever imple-

mentation of extensive single-use technologies at commercial scale. And at the heart of this ambitious project are a number of unique and customized processing solu-

tions that were developed during design and construction.

PIONEERING SINGLE USE In its 200,000 square feet of production space,

Atlas provides multi-product upstream and downstream operations for two simultaneous

production runs. This is complimented by three completely ster-ile trains; two 2,000 L and one 500 L perfusion cell culture bio-reactors, with the 500 L reactor capable of being upgraded to a 2,000 L reactor without layout modifications or utility upgrades.

With speed to market as the primary driver in combating such vicious diseases, Shire researched and analyzed the use of single-use technology versus stainless steel. The main challenge was that single-use process technology had yet to be proven at the 2,000 L scale. However, CRB, the project’s design and engineering firm, helped discover a number of benefits that fortified the company’s decision to make Atlas a single-use facility:• Single-use led to a significantly shorter construction time. • The disposable nature of the system meant nearly all CIP and

SIP considerations were eliminated, cutting additional costs and saving time.

• Aseptic bags, a closed process, and single use bioreactors and tubing help reduce the potential for contamination.

• Production schedules can be compressed since there is no

Multiple Benefits From Single Use Project Shire Human Genetic Therapies’ Atlas Project recognized with Honorable Mention in ISPE/INTERPHEX/Pharmaceutical Processing Facility of the Year Award. ■ By Jeff Reinke, Editorial Director


■ P H A R M P R O . C O M■HONORABLE MENTION

Facility of the Year AwardHONORABLE MENTION

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■ P H A R M P R O . C O M■HONORABLE MENTION


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need to clean vessels. The savings real-ized by reducing the number of media and harvest hold vessels was approximately $350,000 per bioreactor, and since no vessel would ever be out of use for cleaning, Shire was able to eliminate three 3,000 L vessels per bioreactor, saving roughly $1 million.Also, although it is counterintuitive to

believe that technology utilizing single-use plastic bags is better for the environment, it proved to offer some very green benefits:• The use of caustic cleaning materials is de-

creased by 95 percent.• Bags can be reused at certain points along

the sterile train, such as in media hold.• 87 percent less water is consumed.• Facility footprint was shrunk by 38 percent.• Single-use translates to 30 percent less en-

ergy being needed for process equipment and 29 percent less energy for HVAC.

• 25.5 percent less CO2 is emitted. Additional benefits for Shire in imple-

menting this approach included:• Improved safety. In the event of instrument

malfunction, the operator can see what’s go-ing on and react more quickly.

• Culturing new products is made easier by the uniformity of instrument connectivity and in-terface. Single-use equipment will always be the same in all facets of production. To take a product from the lab to clinical or from clinical to commercial, one need only define a small number of scaling parameters.

• Flexible, single-use tubing allows for piping modifications that would be more difficult with stainless steel.

• An operator can change out one bioreac-tor bag or centrifugal insert more quickly than it would take to clean stainless steel piping and vessels. So Atlas can switch production focus in a couple of shifts, rather than days or weeks.

• Due to the closed nature of the technol-ogy, clean room space is optimized by moving some systems out of classified space and into controlled non-classified space. This cuts costs while improving maintenance access. When asked about lessons learned in

implementing a single-use approach, Jerry Justin, Shire Plant Manager offered the fol-lowing advice:• "Fluid mixing and temperature control are

important considerations as the scale of the operation increases.

• "Be open to working with vendors in seeing what type(s) of new technology is available or been successful.

• "Understand the impact that leachables and extractables will have on your process.

• "While initial capital costs may be lower with disposables, also pay attention to how on-go-ing operating costs may be more expensive."

AN INDUSTRY FIRST During facility design, no single-use 2,000

L bioreactors were in use anywhere in the world because of the difficulties with agita-tion in a bag so large. Shire’s design team worked with Xcellerex to design a system that would provide mixing at the top and sides of the bag without creating shear around the impeller. The solution was a sin-gle-use, bottom-mounted, magnetic impeller pre-packaged with the 2,000 L bio-bags and driven by an external motor.

Another significant equipment innovation was the highly integrated control system spearheaded by Honeywell. The single-use bioreactors were packaged with their own control software for consistency and ease of use, but Shire felt it important to have a uni-form interface across all their skids. A unique element on the Shire project was the construc-tion of a full, mock working system that was built by Xcellerex and supported by Honeywell in working out any issues of the single-use sys-tem in advance of the actual implementation.

Custom designing the software would per-mit Shire to control the centrifuge and biore-actor as a single unit. This came at significant cost - approximately $750,000, but according to the company, the result was a uniform interface that will reduce errors and training time, while permitting seamless data integra-tion and collection.

The automation control system also ex-ecutes batches in a controller, rather than a server-batch application. This eliminates extra hardware costs and time spent on infrastruc-ture development by reducing the number of components required to implement the auto-mation. Additional benefits include:• Functionality can be better distributed be-

tween the batch procedural levels, so there’s a series of standalone subsystems that can run for several weeks without intervention.

• The user does not have to take the entire batch management system out of service to make configuration changes—only the

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PHARMACEUTICAL PROCESSING | MARCH 2011

affected areas. • Fewer communication points that could

be connected by mobile laptops outside washdown areas, which use a wireless mesh network, simplified the overall auto-mation system.Additional equipment-based production

benefits realized from the implementation of the single-use system included:• A disposable tangential flow filtration (TFF)

system was selected for easing scalability and changeover between multiple batch sizes.

• A risk-based assessment led to the de-termination that a purified water system had no direct impact on product quality. So Shire switched control of the purified water to a less demanding system that is faster and less expensive to operate.

• 162 limit switches were eliminated after the design team determined they were not necessary on GMP (good manufactur-ing practices) utility valves, saving Shire another $350,000.

• A final component of Shire’s strategy was based upon the concept of “briefly ex-posed.” For example, the media and buffer preparation operations are open processes that require powder additions. Since the process is open, the room environment is typically classified and the solution is filtered. The Atlas facility locates the prepa-ration vessels in classified space, but con-siders the process closed as the material is delivered to the transfer panel. At the trans-fer panel, a connection is made between the media hold bag and the transfer panel that is “briefly exposed” (i.e. the clean outlet port of the valve is exposed briefly to the room environment in order to make the connection). Assessment led to declas-sifying the entire media and harvest hold room. The team was able to declassify over 7,000 square feet, saving time and money.While no one element can be given all the

credit, the portions of the design and engi-neering plan detailed here all played a cru-cial role in the successful completion of the Atlas project. In addition to getting life-saving medication to their customers more quickly, Atlas opened five months ahead of schedule and $10 million under budget. While single-use may not be the best approach for every facility, Shire credits it with taking the Atlas project to greater level of success. ■

Your new plant. Ready when you need it and under budget.Conventional biologics manufacturing facilities take years to build, with

budgets that can easily exceed $100 million. Building such a facility is risky,

especially when your drug is still awaiting clinical approvals. Meanwhile, the

pressure is on to have capacity ready to meet production requirements.

FlexFactory is a proven, modular biomanufacturing platform that requires a

much simpler facility for deployment. This means your new facility can be

built and commissioned in less than a year, and at a fraction of the cost of a

conventional plant. Don’t break ground until you’ve taken a closer look.

For a free FlexFactory Greenfield Paper, visit:

www.xcellerex.com/build1.866.Xcellerex [email protected]

Visit us at INTERPHEX Booth No. 1542


Redesigned Dry Vibrating Magnetic Filters Handle Pharmaceutical and Food Powders � Dry Vibrating Magnetic Filter (DVMF) features a stainless steel construction option that makes it an ideal choice for handling food and pharmaceutical powders. The DVMF features a high intensity, high gradient magnetic field generated in the bore of a solenoid coil encased in steel housing. Filter elements are provided by a matrix system that consists of a series of stainless steel metal discs. The matrix amplifies the externally applied magnetic field, produces regions of extremely high gradient and pro-vides collection sites for the capture of ferrous contaminants. ■ Eriez, Erie, PA 16506. www.eriez.com or call 888-300-3743

� Stainless Steel Flow Cell for Ultrasonic Processes with Small Volumes The flow cell fc2clampk fits the

company’s industrial ultrasonic processors UIP500hd (20kHz, 500W),

UIP1000hd (20kHz, 1kW), UIP1500hd (20kHz, 1,5kW) and 2000hd (20kHz, 2kW).

Its high energy input into the liquid process-ing medium and its small volume make the unit

ideal for the nano, pharma and biotech indus-tries. The ultrasonic reactor features a cooling jacket

that allows temperature control during high energy input. The flow cell is made of stainless steel, has simple geometries and can easily be disassembled and wiped out. ■ Hielscher Ultrasonics GmbH, Germany. www.hielscher.com or call +49 (0)3328 437 428

■ W H AT ' S H OT■ P H A R M P R O . C O M

■ 28 MARCH 2011 | PHARMACEUTICAL PROCESSING P

� Mini-Dispense Pump Provides Economical Liquid Dosing Solution The Furon® Mini-Dispense Pump provide an economical and efficient solution for accurately dispensing small amounts of liquids. Designed with a 100% fluoropolymer wetted flow path, Furon® Mini-Dispense Pumps are suitable for use with highly corrosive media, or in applica-tions where ultra-high purity media is a must. Furon® Mini-Dispense Pumps are pneumatically driven. When pilot air is applied to the actuator, the pump dispenses the desired volume. Manual adjust-ment knobs allow for easy setting of dispense volume (shot size) and dispense speed. Patented PTFE rolling diaphragm technology assures high dispense accuracy and repeatability. Compact and efficient design makes Furon® Mini-Dispense pumps an ideal solution for dosing of liq-uids in semiconductor or biopharmaceutical batch processes, accurate dispensing of liquids into containers or vials (filling line equipment), or any other application requiring accurate dispensing of small doses of liquid. ■ Saint-Gobain Performance Plastics, Garden Grove, CA 92841. www.furon.com or call 714-238-1360

WHAT’S HOT


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r

■ P H A R M P R O .C O M


SAMSON CONTROLS INC.

USA · Internet: www.samson-usa.com Phone: (281) 383-3677 · Fax: (281) 383-3690

CANADA · Internet: www.samsoncontrols.com Phone: (905) 474-0354 · Fax: (905) 474-0998

MEXICO · Internet: www.samson.com.mxPhone: (728) 285-2001 · Fax: (728) 285-2028A

0110

5EN

Rugged.Modular. Easy.

The SAMSON Type 3241 Globe Valve is ruggedly designed and built to handle the most demanding con-ditions of any processes involving the fl ow of liquids, gases and vapors. Its modular design gives the user the fl exibility to incorporate a variety of features to meet their applications. The SAMSON TYPE 3241 truly gives you many advantages:

� EASY to change trim

� EASY to add bellows

� EASY to change packing

� EASY to change actuator fail-sale position

� EASY to set up and calibrate without an expensive hand held device

Call or visit our website to see how easy it can be to make all of your control valve problems disappear.

� Full Stroke PTFE Diaphragms For AODD Pumps Full Stroke PTFE (Teflon®) Diaphragms are now available for use on all of the company’s AODD pump lines. The full-stroke design of these new diaphragms results in improved pump performance. This is the result of increased product displacement per stroke, translating into greater flow rates and higher efficiencies than are found in pumps that operate with reduced-stroke PTFE diaphragms. The diaphragms also use the same shaft and piston combinations as the company’s stan-dard rubber and TPE (thermoplastic elastomer) diaphragms, mean-ing they are easily retrofittable to existing pumps without the need for any extra components. The new Full Stroke PTFE Diaphragms are available on 1-, 1.5-, 2-, and 3-inch pumps. The Full Stroke PTFE Dia-phragms (pictured on left) provide increased product displacement per stroke versus older, lower flowing models (pictured on right). ■ Wilden Pump & Engineering Company, Grand Terrace, CA 92313. www.wildenpump.com or call 909-422-1730

� Heat Transfer Oil Systems Control

Process Temperatures Up To 350°F The HTF 350 Series heat transfer fluid systems now offer both heating and combined heat-ing/cooling units with capacities ranging from three to 24 kW. The HTF 350 Series offers users a wide range of heating capacities

for controlling process temperatures up to 350°F. The HTF 350 Series features a small

footprint and design, ideal for process applications where space is limited and continuous temperature control is required. Three system configura-tions are available, each available with five and 10 GPM flow rates:Heating only - provides up to 24 kW of heating capacity and will heat

your process automatically upon demand.Cooling only - includes a heat exchanger that matches the amount of

heat to be systematically removed from your process.Heating and Cooling - combines both heating and cooling for total

temperature control of your process.Standard features include a high-efficiency gear pump; insulated,

energy-efficient heater manifold; microprocessor-based controller; NEMA-rated electrical enclosure with safety door disconnect switch; expansion/fill tank; UL 508A labeled electrical sub-panel; and NFPA 79 electrical safety standards. ■ Mokon, Buffalo, NY 14207. www.mokon.com or call 716-876-9951

pp1103_whatshot.indd 29pp1103_whatshot.indd 29 2/28/2011 1:46:05 PM2/28/2011 1:46:05 PM

Weldable, Sealable, Moldable Tubing Free of Silicone Oils AdvantaFlex™ biopharmaceuti-cal tubing outlasts similar tubing tested in peristaltic pumps by 6 to 10 times. It’s ideal for aseptic tubing welds and is heat sealable. Advan-taFlex is free of silicone oils and animal-derived ingredients. It offers fewer extractables and is available as molded assemblies and BioClo-sure™ container closures. The material complies with USP Class VI, ISO, EP, and FDA standards. Made in USA. ■ AdvantaPure®, Southamp-ton, PA 18966. www.advantapure.com or call 888-755-4370 INTERPHEX 2011 Booth No. 3032


H I G H L I G H T S

INTERPHEX2011™

3297

Easy on the EyesGet instant, precise results from an easy-to-read digital display—at an economical price

L/S ® Precision Variable-Speed Pumps

800-323-4340 Masterfl ex.com/8307

®

MANUFACTURED BY 123c

888-595-5560 • [email protected] • www.advantapure.com/pp

Single Use Systems

■ Molded silicone or AdvantaFlex® TPE

■ Class 7, ISO-certified clean roommanufactured & assembled

■ Single use/disposable moldedcomponents attach to bags, filters, bottles, BioClosure™ container closures & more

■ Animal derived ingredient free

■ Validation & extractablestest portfolios available

■ Contact us today or seeus at Interphex Booth 3032

for batch filling & sampling

AdvantaFlex®, BioClosure™, NewAge Industries AdvantaPure®,and NewAge® are trademarks of NewAge® Industries, Inc.

Vertical Vibratory Tablet Deduster The KD6010 is the next generation of the E92 with many advanced features including the patented counterweight vibration system, and C820 controller. The KD6015 is the combina-tion version with a metal detector integrated with the deduster on a single stand. Features and benefits include; upward conveying range 250 - 750 mm; conveying of tablets of 3 - 20 mm diameter, and capsules; acrylic glass housing (PMMA); stainless steel drive; constructed according to GMP specifications; for cleaning, the deduster can be disassembled easily and without tools by a single person. ■ Kraemer US, LLC, Allendale, NJ 07401. www.kraemerus.com or call 201-962-8200 INTERPHEX 2001 Booth No. 2620

Diaphragm Pumps Ideal For High-Purity Containment Applications BIOCOR diaphragm pumps are ideal for applica-tions with the highest purity, containment and cleanability requirements. Built to emulate and be placed in the same applications as dia-phragm valves, the BIOCOR pumps are able to assure sterility and handle products contain-ing protein solutions, cellular structures, and other shear-sensitive products. With no me-chanical seals, rotors, or stators, the BIOCOR offers free passage for thorough cleaning and sterilization. Diaphragm pumps are ideal for applications that require negative suction lift, self priming and dead head capability. The fluid contact materials are only low ferrite <1% 316L Basel Norm stainless steel that is polished to R.A. of 15µ-inch and USP class VI PTFE. ■ Almatec, Dover Corporation Pump Solutions Group, Downers Grove, IL 60515. www.pumpsg.com or call 630-487-2240 INTERPHEX 2011 Booth No. 3173



pp1103_InterphexHighlights1.indd30 30pp1103_InterphexHighlights1.indd30 30 2/28/2011 2:27:01 PM2/28/2011 2:27:01 PM

Gravimetric Feeder Designed For Free-Flowing To Hard Flowing Powders The KT20 is a twin-screw pharmaceutical feeder that offers gravimetric feeding of free flowing to very hard flowing powders. The feeder offers interchangeable feed screws that are tailored to the material being fed. All parts in contact with the material being fed are stainless steel and unit is easy to disas-semble. The horizontal agitator prevents bridging and moves material to the discharge screws. ■ K-Tron Process Group, Pitman, NJ 08071. www.ktron.com or call 856-256-3265 INTERPHEX 2011 Booth No. 3637



H I G H L I G H T S

INTERPHEX2011™

Pumping System Uses Precision Stepper Motors The PDS-100 uses precision stepper motors to control a variety of the company’s patented valveless piston pumps. The PDS-100 has a range from 500 nanoliters per dispense to 2 liters per minute continuous flow. It will ac-commodate all FMI pump sizes in both fixed and adjustable displacement configurations. The pump heads are integrally mounted to the control unit which is housed in rugged anodized aluminum enclosure. ■ Fluid Metering, Inc. Syosset, NY 11791. www.fmipump.com or call 800-223-3388 INTERPHEX 2011 Booth No. 3070

Sanitary Pressure Transmitter Complies with CIP and SIP Procedures The SA-11 sanitary pressure transmitter is capable of measuring down to inches of water column, full span of 40” H20 minimum. This permanently sealed sens-ing system includes food grade (FDA approved) system fill fluid, and is designed for com-pliance with “clean in place” (CIP) and “sterilize in place” (SIP) procedures. With a 0.25% accuracy (B.F.S.L.), rugged 316L SS wetted construction and a wide operating temperature rating, the SA-11 meets 3A and EHEDG sanitary criteria for pressure and level measurement in the food, pharmaceutical, cosmetic, and bever-age industries. This pressure transmitter is temperature compensated to provide a stable output signal when exposed to variations in temperature. The SA-11 features an integral cooling extension between the sanitary connection and transmitter pressure sensor allowing a maximum permissible process temperature to 300°F. ■ WIKA Instrument Corporation, Lawrenceville, GA 30043. www.wika.com or call 888-945-2872 INTERPHEX 2011 Booth No. 3809


Allendale, New Jersey

Tablet de-dusting solutions from the Global Leader

For 35 YEARS the pharmaceutical industry has relied upon to de-dust, de-burr and convey tablets with the highest efficiency.

To learn more about how to

the EFFICIENCY of your tableting lines contact Kraemer U.S.



H I G H L I G H T S

INTERPHEX2011™

Containment Systems Bring Drugs To The Market Place Faster Company partners with core pharmaceutical equipment suppliers, including Capsugel and Sturtevant to provide full containment systems to the world’s pharm/biopharm, sterile, chemi-cal and lab industries. PSL and Capsugel have collaborated in the design and manufacture of the Xceloprotect™ isolator which provides high operator protection when filling potent compounds on Capsugel’s Xcelodose® preci-sion powder micro-dosing system. ■ Powder Systems Limited (PSL), Boise, ID 83713. www.powdersystems.com or call 208-376-7008 INTERPHEX 2011 Booth No. 1827

Moisture Analyzer Can Test A Variety Of Samples Company has developed the Relative Humid-ity (RH) Sensor method of moisture analysis and designed an instrument designed to meet the needs of the pharmaceutical industry. Computrac moisture analyzers are capable of testing a variety of samples using differ-ent size vials with a current sensitivity able to accurately and reliably detect moisture as low as 100ppm. No solvent and no material processing for lyophilized pharmaceuticals are necessary for analysis, making it an ideal alternative to Karl Fischer titration. ■ Ari-zona Instrument, Chandler, AZ 85224. www.azic.com or call 800-528-7411 INTERPHEX 2011 Booth No. 2777

HVAC System Cools, Dehumidifies and Cleans Air Based on liquid desiccant technology systems deliver 40%+ energy cost savings, precisely control humidity without overcool-ing and can be powered by renewable energy sources such as solar thermal or waste heat. Unit is available as a retrofit or new installa-tion. Product used by many pharmaceutical leaders such as GlaxoSmithKline, TEVA and Glenmark. ■ Advantix, North Miami Beach, FL 33160. www.advantixsystems.com or call 888-818-5171 INTERPHEX 2011 Booth No. 1783

Visit us at INTERPHEX Booth No. 2662 Visit us at INTERPHEX Booth No. 2620


Vacuum Conveyors Designed For Free- And Non-Flowing Powders Vacuum conveying equipment and systems range in convey rates from 500 pounds per hour to 5,000 pounds per hour and beyond. Designed for free and non free flowing powders they can be equipped for use with any application such as loading tablet press machines, mix tanks, and blenders. ■ VAC-U-MAX, Belleville, NJ 07109. www.vac-u-max.com or call 973-759-4600 INTERPHEX 2011 Booth No. 2882

Agitators Specifically Designed For Pharmaceutical

Applications PharMix 1000, 3000, 4000, and D-Series top-entering agitators are specifically designed for demanding pharmaceutical and biotechnical mixing applications. Features include all stainless steel drives and versatile drive motor mounting con-figurations. Product contact material is

T316LSS (S31600/S31603) standard or is available in any higher alloy. Unlimited

impeller availability includes custom designs. Mechanically polished finishes and final electro-polishing is available. A wide range of hygienic shaft seals are available to meet any application. The units have robust shaft designs. In-vessel hygienic couplings are avail-able for use with extended shafts and large diameter impellers, and facilitate maintenance accessibility. ■ DCI, Inc., St Cloud, MN 56303. www.dciinc.com or call 320-252-8200 INTERPHEX 2011 Booth No. 3605

UNIQUE SENSING

INTELLIGENCE.

Tel. 631-427-3898 • Fax. 631-427-3902 • [email protected]

HygroClip2 – Innovation in Humidity and Temperature Measurement

Innovation is the key for the All-New HygroClip2 and AirChip3000 from Rotronic. The latest development from ROTRONIC raises humidity and temperature measurementto new heights of performance.

A few of the key innovations include:• Accurate to ±0.8%RH & ±0.1˚C• Sensor self-diagnostic and auto correction with alarm feature• New sensor design to speed humidity/temperature response and improve accuracy

For a complete view of all the innovative features of the HygroClip2 visit our website:www.rotronic-usa.com or call us today.

135 Engineers Road • Hauppauge, NY 11788



H I G H L I G H T S

INTERPHEX2011™

Lyophilization Cart Offers Class 100 Environment Lyophilization cart features:• ISO Class 5/IEST Class 100 environment• Proper space to load, unload and manipulate• Laminar flow, positive air pressure• High quality, cleanable surfaces• Custom designs• Replaceable racks for different height vials■ Custom Powder Systems, Springfield, MO

65803. www.custom-powder.com or call 417-868-8002

INTERPHEX 2011 Booth No. 2479



Hygienic Pumps Offer Ultra-Pure Design The Hygienic Series (HS) pumps offer high flow rates (230 gpm) and ultra-pure/cleanable design for biopharma-ceutical processes. These pumps are specifically designed for applications that require negative suction lift or self-priming capability, compat-ibility and full containment with hazardous products. Also, the dead head capability of the HS pumps offers unique simplified solutions to filter or filler feeds that have limited inlet pressure tolerances. The HS pumps include the documentation and meet the highest standard for validation purposes. Materials of construc-tion include fully traceable 316L stainless polished, electropolished, and passivated to 15µ-inch. ■ Wilden Pump & Engineering, LLC, Grand Terrace, CA 92313. www.wildenpump.com or call 909-422-1730 INTERPHEX 2011 Booth No. 3173

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H I G H L I G H T S

INTERPHEX2011™

Stainless Steel Bottles for Stability Studies STB Bottles are available in sizes from 1 mL to 750 mL. They have a 10 Ra or better finish and traceability/certifications are available for the 316L stainless steel lots used in their manufacture. The radiused interior facilitates cleaning and optional fill, vent tubes may be added to the end cap. ■ Eagle Stainless, Warminster, PA 18974. www.eaglestainless.com or call 215-957-9333 INTERPHEX 2011 Booth No. 2132

Vacuum Pump For Difficult Pharmaceutical And Chemical Applications COBRA NC 630 single-stage, direct-driven ro-tary screw dry vacuum pumps are designed for difficult applications in pharmaceutical and chemical processing industries. They have a continuously variable pitch screw design that operates more efficiently, has a higher CFM to horsepower ratio, and lower operating temperatures than traditional dry screw pumps. With vacuum down to .0075 Torr and pumping speeds to 370 ACFM, they will operate at atmospheric to ultimate pres-sure. ■ Busch USA, Virginia Beach, VA 23452. www.buschusa.com or call 757-463-7800 INTERPHEX 2011 Booth No. 2236


Tablet Coater Available For Testing Users can test the Bohle Tablet Coater (BTC) before they buy it at the company’s Service Center in Warminster, PA. The BTC reduces processing times up to 35% percent com-pared to conventional tablet coating systems, yielding significant cost savings and im-proved campaign efficiency. Working with the company’s staff in the 2,000-square-foot Ser-vice Center, pharmaceutical companies can also train their personnel on the following in an environment meeting cGMP guidelines: Process development and optimization; dem-onstration of latest software; containment application demos; blending (lab and produc-tion scale); and milling (cone mill or hammer mill). ■ L.B. Bohle LLC, Warminster, PA 18974. www.lbbohle.de or call 215-957-1240 INTERPHEX 2011 Booth No. 2617

Custom Core-Tableting Press With Interchangeable Turret Design The Hata CVX Core Press of-fers special mechanical fea-tures to allow for precision core alignment and an added feature of multi-layer core-tableting. This is a custom mechanical assembly specific to the user’s core tablet size and core tablet shape, and is added to Hata’s Three-Layer Tablet-ing Press System. The CVX-Series is ideal for multi-layer and custom core-tableting technology. The Hata CVX Press is equipped with a press control kiosk that is portable for space-savings and flexibility. The new press control design is user-friendly with touch screen capability for ease of operation. The press design is easy to disassemble both interior press parts as well as complete turret removal. ■ Elizabeth-Hata International, North Huntingdon, PA 15642. www.eliz.com or call 412-829-7700 INTERPHEX 2011 Booth No.2253



H I G H L I G H T S

INTERPHEX2011™

Contract Manufacturer Adds Clinical/Commercial Vial And Syringe Lines The company, which has a bulk drug sub-stance track record with > 5,000L of cell-culture capacity and over three years of cGMP manufacturing experience, now offers parenteral drug product cGMP manufactur-ing capabilities. The syringe filling line can produce 70M units/year and the vial line, with filling, lyophilization and capping all under barrier isolation, can produce 15M units/year. ■ Cook Pharmica, Bloomington, IN 47403. www.cookpharmica.com or call 877-312-2665 INTERPHEX 2011 Booth No. 1265


Biocontainer Offered In 50 mL Configuration The TepoFlex® line of biocontainers has been expanded to include new 50 mL biocontainer standards. These biocontainers are the smallest standard size offered, providing end users an option for small volume sampling applications. Engineered for maximum product recovery, the 50 mL TepoFlex® biocontainer provides unpar-alleled fluid integrity when used in applications where long term storage is required. Three stan-dard configurations of the 50 mL biocontainer assembly are available. Additionally, the biocon-tainer is configurable with a maximum of three ports for integration into custom assemblies tailored to end user’s specific process require-ments. ■ Meissner Filtration Products, Inc., Camarillo, CA 93012. www.meissner.com or call 805-388-9911 INTERPHEX 2011 Booth No. 2611

Sliding Door Ideal For Sterile Filling Areas The Rytec® Pharma-Vision™ slide door offers the benefits of maximum visibility in addition to the ability to contain and separate different en-vironments. Maximum visibility is attained using a frameless, flush glazed tempered glass panel. The intrinsically hygienic tempered glass panel is top-hung, eliminating cumbersome end-caps, framing brackets and tracks on the floor. Along with this easy to clean glass panel, the Pharma-Vision™ features an all stainless steel round track and trolley assembly that eliminates dirt and debris collection points. All door compo-nents have been engineered for accessibility and easy cleaning. The high efficiency ¼ HP AC drive motor offers wear-free operation utilizing soft starting and soft stopping technology while achieving operating speeds up to 40" per sec-ond. ■ Rytec Corporation, Jackson, WI 53037. www.rytecdoors.com or call 888-467-9832 INTERPHEX 2011 Booth No. 1759

We makepharmaceutical

feeding processes work

PureFeed® Pharmaceutical Feeders

For pharmaceutical feeding solutions, call:(800) 558-0184

www.accuratefeeders.com

C O N T I N U O U S M I X I N G

H O T M E L T E X T R U S I O N

C O N T I N U O U S G R A N U L A T I O N

F E E D I N G E X P E R I E N C E I N :

Product Line Features:• Feed rate range from .02 kg/hr to 150 kg/hr.• Easy disassembly and cleaning in minutes.• 316L stainless steel.• Ceramic feed disc delivers pulse-free metering.• Disposable, flexible hopper speeds cleaning

and eliminates cross contamination.



H I G H L I G H T S

INTERPHEX2011™

Polymer Pallet With Intermittent Perimeter Lip The PROTECH® 4048 heavy duty plastic pallet is now available with a half inch tall (0.5 inch) intermittent perimeter lip. The pallet is a one-piece molded design that eliminates trapped water and cross contamination during sanita-tion. The distinct advantages of the PROTECH 4048 over wood pallets include its resistance to mold, bacteria, odor and insect infestation. It features true four-way pallet jack entry, larger fork lift pockets tapered for easy entry plus thicker legs to help minimize impact damage. ■ TMF Corporation, Havertown, PA 19083. www.tmfitzgerald.com or call 610-853-2008 INTERPHEX 2011 Booth No. 2059

PTFE Lined Hoses Company offers a line of PTFE lined flexible hoses including the Bioflex range of smooth-bore PTFE flexible hoses that feature a pat-ented liner design. Bioflex offers the advan-tages of a smooth bore hose, combined with the essential aspects of a convoluted design. Corroflon is a convoluted PTFE hose, offering flexibility and kink resistance. ■ Aflex Hose USA, LLC, Pipersville, PA 18947. www.aflex-hose.com or call 215-766-1455 INTERPHEX 2011 Booth No. 2341



Printer Enables High-Speed Coding For Complex Applications The Wolke m600® advanced small character thermal ink jet (TIJ) printer from is ideal for complex coding requirements often found in the pharmaceutical industry. The printer enables high-speed coding of serial-ized data and many types of bar codes, including GS1 DataMatrix, to be compatible with track-and-trace applications. Four printhead models facilitate integration into packaging lines by enabling printing from above or laterally, with print heights ranging from ½ inch to 2 inches. Uptime performance is enhanced through a range of features includ-ing quick ink cartridge replacement and Wolke Universal Black ink, a genuine Hewlett-Packard® ink. Universal Black ink delivers an optimal combination of long decap time — which keeps ink fluid — and short drying time, making it an ideal ink for varnish-free surfaces on folded chipboard boxes and other paper substrates. ■ Videojet Technologies Inc., Wood Dale, IL 60191. www.videojet.com or call 800-843-3610 INTERPHEX Booth No. 3505


H I G H L I G H T S

INTERPHEX2011™

Tablet Laser Drilling And Marking Systems Pharmaceutical tablet laser drilling and laser marking system offers “on-the-fly” tracking of tablets producing superior aperture quality over the full range of aperture sizes. The bowl feeder and handling system offer a superior handling environment for a smoother transi-tion and reduced chance of tablet breakage and lost yield. This design allows for a large range of tablet dimensions to be drilled with little to no changeover between sizes. Software package provides process vali-dation and is provided with software for compliance to CFR 21 part 11. System provides for 100% vision inspection of the tablets and also provides the support and documentation for the IQ, OQ, and PQ tests.

Control Micro Systems, Winter Park, FL 32792. www.cmslaser.com or call 407-679-9716 INTERPHEX 2011 Booth No. 1967

■


The Smartest DistanceBetween Two Points.

VAC-U-MAX is a premier manufacturer of custom pneumatic systems and supportequipment for conveying, batching, andweighing materials.

Count on us for:• Decades of engineering and conveying

expertise. • Customized solutions that meet your

specific needs. Because our systems arenot “off the shelf,” they are always onthe mark.

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Pneumatic Conveying Systems from VAC-U-MAX.



H I G H L I G H T S

INTERPHEX2011™

Pressure Transmitter With Flexible Calibration The Mercoid® Series 3100 Smart Pressure Transmitter is a microprocessor-based high performance transmitter, which has flexible pressure calibration, push button con-figuration, and programmable using HART® Communication. The Series 3100 is capable of being configured for differential pressure or level applications with the zero and span buttons. A field calibrator is not required for configuration. The transmitter software compensates for thermal effects, improving performance. EEPROM stores configuration settings and stores sensor correction coef-ficients in the event of shutdowns or power loss. The Series 3100 is FM approved for use in hazardous (classified) locations. The 100:1 rangeability allows the smart transmitter to be configured to fit any application. ■ Dwyer Instruments, Michigan City, IN 46361. www.dwyer-inst.com or call 219-879-8868 INTERPHEX 2011 Booth No. 2937

Sterile Clean Room Wipes Validated sterile cleanroom wipes are gamma irradiated with Cobalt-60 to a sterility assurance level of 10-6 in accordance with procedures outlined in Standard AAMI/ISO 11137-Method 1. Each delivery is lot-traceable and accompanied by a Certificate of Processing and a Certificate of Sterility. Linear-tear packaging is designed with ease of use with gloved hand. ■ Lymtech Scientific, Chicopee, MA 01014. www.lymtech.com or call 800-628-8606 INTERPHEX 2011 Booth No. 2272

Visit us at INTERPHEX Booth No.2882


Secure Connection Service For Inspection Systems The Symetix Secure Connection (SSC), us a service for VeriSym® and OptyxSG® inspec-tion systems. SSC allows Symetix engineers to have network access to the installed vision system and enables them to perform remote diagnostics using data, images, and other in-formation that is not possible with telephone support. With this direct connection, services can be provided at any hour of the day, which reduces downtime while saving customers time and money. SSC gives both the user and Symetix engineers the ability to make a simple and secure network connection to the inspection system, even when the inspection system is behind a network firewall. With SSC, users may back-up logs and setups to a secure archive and move logs and batch records to any computer with a network con-nection. When permitted, Symetix engineers may also be allowed access to the machine user interface, data, images, and logs. SSC allows machine logs, product setups, images, and other information relating to the status and performance of the inspection system to be shared in a controlled and secure manner for purposes of remote diagnostics, customer assistance, and secure batch log storage. ■ Symetix, Walla Walla, WA 99362. www.symetix.com or call 509-394-3524 INTERPHEX 2011 Booth No. 2789

s Intrinsically safe (air-operated diaphragm pump)

s Engineered for maximum containment

s CIP and SIP capables Drainable by magnetically lifting

of the valve balls from the outside (B20/B32 only)

s SS316L stainless steel (Basel Stan-dard II, ferrite content < 1%) wetted path polished to 0.4μ-m (16μ-in)

s Maximum fl ow rates: - B20: 58 lpm (15 gpm) - B32: 125 lpm (33 gpm) - B40: 280 lpm (61 gpm)s Self primings Dry-run capable

Certifications:

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Contact Our Expert:�4EL�� s�&AX�� 6AN�"UREN�3T��s�'RAND�4ERRACE��#!��53!#ARL &RIEDRICH 'AU� 3TR��s��+AMP ,INTFORT��'ERMANY4EL�� s�&AX�� s�INFO ALMATEC�DE�s�WWW�ALMATEC�DE



H I G H L I G H T S

INTERPHEX2011™

Pressure Sensors For Sanitary Environments Sanitary pressure instruments are specifically designed for the unique requirements of phar-maceutical, biotech and food processing applications. Constructed with a welded, electropol-ished diaphragm media isolator, these devices mate to industry standard Tri-Clamp® sanitary connections. Rugged stainless steel sealed gauge housings allow Ashcroft® sanitary instru-ments to withstand the most severe cleaning methods, including chemical wash-down and high-temperature decontamination. ■ Ashcroft Inc., Stratford, CT 06614. www.ashcroft.com or call 800-328-8258 INTERPHEX 2011 Booth No. 1945



Bausch + Stroebel Machine Company, Inc.21 Commerce DriveP.O. Box 206North Branford, CT 06471 USA

� +1 203 484 9933Fax +1 203 484 [email protected]

March 29 - 31, 2011

Jacob K. Javits Convention Center

New York, NY

Booth # 3209

TOP-NOTCH PRECISION:

The BAUSCH+STROEBEL product range specializes in machines for pharmaceutical primary packaging, including equipment for washing, sterilizing / depyrogenating, fi lling, closing and labeling of containers such as ampoules, cartridges, disposable syringes, vials and bottles of all kinds. Our systems are designed to comply with the latest FDA and GMP requirements and are available for all capacity ranges, starting from laboratory testing and clinical batches to fully integrated commercial production.

more than 40 years

experience and high quality

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H I G H L I G H T S

INTERPHEX2011™

Floor System Offers A Long-Lasting Finish The Stonres NVL floor system cures to a hard, durable, long lasting finish, eliminating the need for routine, costly repairs, and its smooth, seamless surface ensures a safe and easy to clean floor. Stonres NVL, a urethane-based system, is designed for superior ergonomic support, resiliency and long-lasting performance, offering classic designs for open space projects. It is a poured-in-place floor that never needs to be removed, providing a sustainable floor solution. Stonres NVL is ideal for clean rooms, labs and corridors and is offered in eight standard colors and a broad range of custom color blends. ■ Stonhard, Maple Shade, NJ 08052. www.stonhard.com or call 856-321-7538 INTERPHEX 2011 Booth No. 1040

Dry Powder Inhaler Stores APIs on a Microstructured Carrier Tape The Taper Dry Powder Inhaler stores active pharmaceutical ingredients (API) on a micro-structured carrier tape, enabling it to provide up to 120 pre-metered doses. The Taper DPI uses 3M microreplication and extrusion technol-ogy to create a “dimpled” tape upon which one or more APIs are coated. This dimple design allows the use of API only, virtually eliminating the need for lactose or complex powder formu-lations. Upon opening the mouthpiece, a dose is ready for use. The airflow of the patient’s inhalation releases an impactor that strikes the tape and releases API into the air stream further deagglomerating API particles as they pass through the device. A visual ready indicator, au-dible click to signal dose delivery, dose counter and its breath-actuated delivery helps ensure ef-fectiveness and makes the device patient-friend-ly and accurate. ■ 3M Drug Delivery Systems, St. Paul, MN 55144. www.3M.com/dds or call 800-643-8086 INTERPHEX 2011 Booth No. 3620




H I G H L I G H T S

INTERPHEX2011™

Diaphragm Valves Available In Fractional Sizes The Bio-Flow fractional hygienic diaphragm valve product line provides a complete program of manual or pneumatically actuated diaphragm valves in fractional sizes optimally designed for use in pharmaceutical applications. Valves are comprised of forged 316L stainless steel bodies and avail-able with weld or clamp ends in 1/4”, 3/8” or 1/2”. The fractional assemblies are available with TFM and EPDM diaphragms which meet FDA, USP and ASME-BPE compliance. The product line is ideal for applications including neutral gases and liquids, high-purity, sterile, aggressive or abrasive fluids. ■ Burkert Fluid Control Systems, Irvine, CA 92614. www.burkert-usa.com or call 800-325-1405 INTERPHEX 2011 Booth No. 3833

Powder Feeder Operates At 20 grams/hr The PureFeed® DP-4 is a highly innovative gravimetric feeder that can accurately feed dry pharmaceutical and nutraceutical pow-ders at feed rates as low as 20 grams/hour. A speed controlled, inert ceramic feed disc sep-arates the material supply from the discharge point assuring no material compaction or flooding. ■ Schenck AccuRate, Whitewater, WI 53190. www.accuratefeeders.com or call 888-232-4837 INTERPHEX 2011 Booth No. 2660



H I G H L I G H T S

INTERPHEX2011™

Multi-Layered Sintered Mesh Filter Media Porostar® is a sintered, multi-layered woven wire cloth laminate that allows migration-free filtration from less than 1 to 200 microns. Porostar can be designed to specific charac-teristics, including pore size, pore distribution, porosity, and permeability. Pressure drop is often less than other comparable media designs. A new HYPERFLO Porostar® sintered mesh laminate offers up to 50% increased permeability versus traditional mesh laminates. As a result, pressure differentials are significantly reduced. HYPERFLO Porostar® can be custom fabricated for applications requiring micron ratings of 25 and larger. The stainless steel construction provides extended filtration media life, with simple cleanup. Porostar® Filter plates and elements are engineered to customer specifications for durability and a long wear life. Stainless steel, Hastelloy, Alloy 20, and other corrosion resistant alloys provide extended filtration media life with simple cleanup. ■ W.S. Tyler, Mentor, OH 44060. www.wstyler.com or call 800-321-6188 INTERPHEX 2011 Booth No. 2057

Process Development And Small Batch Production System System is designed for process development, clinical studies or for simply producing smaller batches and is based upon the company’s table top machine line. The modular design allows for reproducible filling and closing of syringes, vials, cartridges, eye drop and nasal spray bottles. Possible filling systems include rotary piston pumps, disposables, time-pressure, peristaltic pumps, mass-flow. A separate module accounts for in-process-control. ■ groninger USA L.L.C., Char-lotte, NC 28273. www.groningerusa.com or call 704-295-9000 INTERPHEX 2011 Booth No. 3671

Save Valuable Time We work with you to design your assembly, provide assembly labor, package, and sterilize per your requirements

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3295




Containment Enclosure For Processing Hazardous APIs In cooperation with ILC-Dover, company is able to provide custom-designed contain-ment options for the GRANUMILL® Jr. size reduction system. The new flexible enclosure set-up allows for use in both containment and non-containment operations, eliminating the need to purchase a second machine solely for containment use. The new enclosure is capable of meeting an Occupational Exposure Banding 5 classification for the containment of high-potency compounds. ■ Fluid Air Inc., Aurora, IL 60502. www.fluidairinc.com or call 630-665-5001 INTERPHEX 2011 Booth No. 3953

Maintaining compliant conditions within transfer carts are prevalent problems within many pharmaceutical manufacturers. (Not with our carts.)

A successful design requires unique engineering skills and an understanding of the facility and process. (These are our strengths.)

Each product we design-build at CPS/ ICS will: Increase your yield. Increase your productivity. And increase your profi ts. We guarantee it!

To learn more about how we can create increases in your pharmaceutical processes, call 417-868-8002 or visit integratedcontainmentsystems.com or custom-powder.com

And please plan to visit us at INTERPHEX!

Come see our Cart and visit with one—or more—of our Process Improvement Experts at INTERPHEX, Booth #2479!

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H I G H L I G H T S

INTERPHEX2011™

Cell Culture System/Accessories Available Ready-To-Use Company’s ReadyToProcess platform is a complete suite of ready-to-use systems and accessories for cell culture and fermenta-tion, filtration and purification, fluid manage-ment, and connectivity. The ReadyToProcess platform is designed to simplify and acceler-ate bioprocessing, reducing time-consuming routines, and ultimately increasing manufac-turing agility. ■ GE Healthcare, Piscataway, NJ 08854. www.gelifesciences.com/readyto-process or call 800-526-3593 INTERPHEX 2011 Booth No. 3123

Humidity And Temperature Transmitter For Use In Clean Rooms The HUMICAP® HMT120 is designed specifically for use in cleanrooms and other critical environments. Its smooth enclosure is easy to clean and easy to install. Interchangeable probes can be swapped without special training, easing cleanroom burden, and a variety of other calibration options are also available. ■ Vaisala Inc., Woburn, MA 01801. www.vaisala.com or call 781-933-4500 INTERPHEX 2011 Booth No. 2045


� Controller Allows Up to Four Sensor Inputs in a Compact ¼ DIN Package The Signet 8900 Multi-Parameter Controller features up to four channels in a compact, cost-effective ¼ DIN package for measuring flow, pH, ORP, conductivity, pressure, level and temperature. The controller can be configured with many I/O options by the user in the field. Flexibility is achieved via plug-in modules for either two or four input channels, universal AC line voltage or 12 to 24VDC opera-tion, up to four analog outputs, and up to eight relays.Input

versatility allows mixing and matching of up to four of the following sensor types: flow, pH, ORP, conductivity/resistivity, pressure, temperature, level

as well 3rd party sensors with a 4-20mA output (8058 Converter Module sold separately). Digital S3L connectivity between sensor and instrument allows improved noise immunity in longer cable runs for enhanced system integrity, particularly in industrial environments. ■ GF Piping Systems, Tustin, CA 92780. www.georgfischer.com or call 800-854-4090

■ INNOVAT IONS

MONITORS



INDICATORS|CONTROLLERS

� Stainless Steel Flow Meter Features Bluetooth Compatibility The IZMAG™ stainless steel electromagnetic flow meter is designed to meet the needs of the pharmaceutical and biotech industries. Units feature a visual display, 360° position-ing, and Bluetooth compatibility for simple data gathering. The IZMAG™ has no mov-ing parts, offers bi-directional metering for all conductive liquids and is suitable for use at high temperatures or under vacuum conditions. Bluetooth compatibility allows operators to download data easily even if the flow meter has been located in an inacces-sible position. A flexible design enables the customization of the flow meter to provide additional functionality such as: filling con-trol, flow control, data capture or printing of on-the-spot reports. ■ GEA Diessel GmbH, Steven 1, D-31135 Hildesheim, Germany. www.diessel.com or call 49 5121 7420

� Relative Humidity, Temperature, Dew Point Measuring Instrument

The HygroPalm23-series is a handheld measuring instru-ments for relative humidity, temperature and dew point. Based on AirChip3000 technol-ogy it is an ideal instrument for climatic measurements. In combination with advances in sensor technology and integra-tion, the HygroPalm2-series provides superb precision and state-of-the-art functionality, taking humidity and temperature measurement to a whole new level

of performance and reliability (< 0.8 %rh / 0.1 K). ■ Rotronic Instrument Corp., Hauppauge, NY 11788. www.rotronic-usa.com or call 631-427-3902

Wireless Sensors For Temperature And Humidity � Wireless sensors are designed to monitor, document, and alarm; refrigerators, freezers, storage rooms, warehouses, and clean rooms. The sensors have a line-of-sight range of 100 feet, and will communicate with the display unit where the temperature and hu-midity values are stored and displayed as a chart. The sensors are effective inside refrigerators and freezers, with a reduced range. The display unit features an internal alarm to trigger an auto dialer, an exter-nal relay and the ability to download the stored data to a computer for archiving and printing. ■ Two Dimensional Instruments, Crestwood, KY 40014. www.e2di.com or call 877-241-0042

� Portable Room Pressure Differential Monitor With Data Logger Option The ACCUSTAT™ P2 portable and P2DL portable data log-ger are capable of real time readings of .001” WG resolution (or Pascals) on a large LED display. The P2DL unit allows for storage of over 34,000 pressure readings time stamped in permanent non-volatile memory; multiple sampling

rates between 1 second to 5 minutes; and standard USB connection to custom software and Auto Graph-Scaling for PC

viewing for export to Excel®. Both models use a Ni-MH battery that operates over 48 hrs on a single charge. ■ Biological Controls, Inc., Eatontown, NJ 07724. www.biologicalcontrols.com or call 800-224-9768

v

pp1103_innovations_monitors.indd46 46pp1103_innovations_monitors.indd46 46 2/28/2011 1:55:52 PM2/28/2011 1:55:52 PM



■ INNOVAT IONS

Data graphing software provides real-time view and data capture

Specializing in Pharmaceutical Applications for 25 Years

HQ, Inc. 210 9th Street Drive West, Palmetto, Florida 34221Email: [email protected] • www.thermodot.com • Phone: (941) 723-4197

Wireless sensors can be placed in any application whether rotating, spinning, moving…

Accurate temperature measurement of materials being subjected to a specifi c manufacturing process is critical to the outcome of a consistent high quality product

b iData can be viewed locally in real-time, via Ethernet or Internet connection

Data c

Temperature Solutions For Your Process

Conductivity Sensor Ideal For High Pressure, High Temperature Applications � The Model CSX2 is a two-electrode sensor that measures electrolytic conductivity at a range of 1.0-50,000 µS. It is de-signed for high temperature service up to 200°C at pressures of 250 psig. At temperatures below 100°C, the CSX2 is rated for pressures up to 400 psig. The unit features rugged construction with a 316 stainless steel outer body and center electrode, separated by a PEEK® (poly ether ether ketone) internal insulator. All possible leak paths are double-sealed with EPR O-rings for maximum on-stream reliability. The CSX2 provides highly accurate and reliable conductivity measurement in a wide range of demanding industrial process plant applications. The unit features a weather-resistant aluminum junction box that allows easy access to the terminal strip or the signal conditioner. The junction box is both explosion-and weatherproof and features a 0.75-inch FNPT connection. It includes a low temperature (80°C) 0.5-inch polyamide cable gland with reducer bushing. The signal conditioner amplifies the conduc-tivity signal, allowing noise-free transmission for hundreds of feet. ■ Electro-Chemical Devices, Irvine, CA 92614. www.ecdi.com or call 800-729-1333

� Valve Controller With Intermediate Control Improves Plant Operation

The AXIOM series features integral valve monitoring with non-

contact position sensing and discrete control capabilities for automated on/off valves. The AXIOM® Expeditor (AMI80) allows standard discrete (open/closed) automated valves to be readily upgraded to offer ex-panded capabilities with intermediate control.

Fill control, flow dampening, and thermal shock reduction are a few application examples where the Expeditor may improve process per-formance and prevent damage to equipment. No special pneumatic bleed pilots or air filtration systems are required with the AXIOM’s standard pneumatic solenoid technology. Full open and closed cycling, as well as intermediate control, is achieved using the Expe-ditor’s simple operation and control system integration. A standard discrete 24 VDC output is used for the On/Off solenoid operation and a 4-20mA analog input is used for intermediate control. Valve position monitoring is performed via a standard 4-20mA input circuit so exact valve position may be observed at all times. ■ StoneL, Fergus Falls, MN 56537. www.stonel.com or call 218-739-5774


pp1103_innovations_monitors.indd47 47pp1103_innovations_monitors.indd47 47 2/28/2011 1:58:09 PM2/28/2011 1:58:09 PM

Table 1: The minimium standard operating procedures needed for software validation.

Software validation is a process. It is often mandated by regulatory requirements to ensure that mission-critical software applications perform according to their intended

use. In highly regulated systems environments, it is well understood that soft-ware errors can have cata-strophic results on regula-tory controlled processes if the applications are not properly designed, tested and implemented. While much focus is given to vali-dation testing, governance of the validation process is often overlooked.

All regulatory processes are governed by standard op-erating procedures (SOPs) to ensure quality and compli-ance. In a recent warning letter, a medical device company

was cited for 21 CFR Part 11 violations and for the lack of an adequate quality system. These violations resulted in a 21-item 483 warning letter from the FDA. In response to the warning letter, the company stated: “We are in the process of evaluating software validation SOPs with protocols and procedures for validation”. Failure to docu-ment and follow validation SOPs could result in warning

letters or risk compromising the entire validation effort. The first step prior to conducting a validation exercise is to

have adequate quality procedures in place documented by your company’s SOPs. I am often asked the question, “…which SOPs do I need for software validation and verification…?” Table 1 highlights the minimum SOPs you need for software validation.

The main SOP you will need is the Non-Product Computer Systems Validation SOP. This is the SOP that provides gov-ernance for the entire validation process. This SOP should include key definitions used throughout the validation process within your company, responsible personnel within your pro-cess and detailed procedures for each validation lifecycle stage. Figure 1 (above) illustrates a typical validation process.

During the validation planning phase, it is important to as-sess the state of your SOPs to ensure that your process is documented across all validation lifecycle stages. GAMP 5 rec-ommends a risk-based approach to software validation, thus it is important to have a risk assessment SOP in place for gov-ernance during software validation. Your risk assessment SOP should highlight your risk methodology, documentation require-ments and processes. Remember, “… if it is not documented, it did not happen…” therefore a written risk assessment is a key element of your overall quality program. It is recommended that an SOP be in place covering this vital part of validation.

One SOP that is often overlooked is the data migration SOP.

A Risk-Based Approach To Validation And Verification While much focus is given to validation testing, validation governance is often overlooked■ By Valarie King-Bailey, M.B.A., CEO, OnShore Technology Group, Inc.



■ V A L I D AT I O N

W

t

W

v

v

■

SOFTWARE VALIDATION SOPs

Non-Product Computer Systems Validation SOP (main)

Training SOP

21 CFR Part 11 SOP Disaster Recovery SOP

Backup and Recovery SOP Validated Systems Administration SOP

Incident (Deviation) Reporting SOP Retrospective Validation SOP

Validation Protocol Development SOP Validated Systems Change Control SOP

Custom Software Development SOP Validation Risk Assessment SOP

Supplier Audit (Vendor Assessment) For Validated Systems SOP

Validation Testing SOP

System Security For Validated Systems SOP CAPA/NC Management For Validated Systems SOP

Validation Reporting SOP Data Migration For Validated Systems

Validation Document Control SOP

Figure 1: A typical validation process.

pp1103_feature_validation.indd 48pp1103_feature_validation.indd 48 2/28/2011 3:10:03 PM2/28/2011 3:10:03 PM

-


Working with many enterprise systems such as Enterprise Resource Planning (ERP), Enterprise Content Management (ECM), and many others data migration is an essential factor during installation and deployment. If a system is validated and requires migration of data (mandated by predicate rules) to be transferred from one system to another, your migration SOP should define the overall process required for validation. When deploying new systems, many IT professionals simply move/transition data from one system to another without confirming the accuracy and validity of this process during validation. If the migrated data is subject to predicate rule re-quirements, you may want to document in your SOP that this information must be migrated in a specific controlled manner. Best practices for migration during validation require the de-velopment of a migration plan, migration test protocols, and

acceptance testing to a specific confidence interval. It is im-portant to have a migration SOP in place to ensure accuracy and quality when transitioning from one system to another.

Another important SOP to remember is the Custom Software Development SOP. Many times, when deploying en-terprise software applications, customization (programming) is required to meet your specific company requirements. Your Custom Software Development SOP must define the full software development lifecycle stages and required docu-mentation and controls for managing custom code. This is a significant area of vulnerability during the validation process and must be clearly defined to ensure the quality and integrity of your enterprise deployments. Things to remember if you are customizing code for validated systems are:

• Ensure that programmers are properly trained


1BRING YOUR NEW GENERATION DRUGS INTO THE MARKET PLACE FASTER

Tel: +1 208 376 7008 Email: [email protected] Web: www.powdersystems.com

Visit us at Interphex booth #1827 and we’ll show you how we do it!

We are Powder Systems Ltd (PSL) your premium international manufacturer of filtration, drying and complete containment solutions for 22 years.We support pharmaceutical, biopharmaceutical, sterile, chemical and laboratory industries worldwide.

Filter DryersTray DryersContinuous LinersContainmentDispensing and SamplingChargingMills and MicronizersDrum FillingSievingTablets and Capsules


■ V A L I D AT I O N


pp1103_feature_validation.indd 49pp1103_feature_validation.indd 49 2/28/2011 3:10:39 PM2/28/2011 3:10:39 PM

■ P H A R M P R O . C O M■ V A L I D AT I O N


• Start with a clearly defined set of user re-quirements

• Separate the development and testing functions

• Code must be under strict change control• Clearly define your software development

lifecycle methodology• Conduct vendor audit if software develop-

ment is outsourced• DOCUMENT EVERYTHING (your SOP

should define all documentation require-ments for customized systems)Finally, you should always have a disaster

recovery SOP. This SOP provides governance for processes in case of any type of disaster which may impact your validated system.

Many people confuse disaster recovery with backup and recovery. The two are very differ-ent. Disaster recovery procedures kick in when you have any type of natural or man-made di-saster such as a flood, fire or other such event that results in the loss of the entire system. The disaster recovery policy should provide procedures that clearly state and categorize the type of disaster, key personnel and their detailed contact information, and more impor-tantly specific detailed procedures to recover the system in case of a disaster event. Many times, a disaster recovery policy is developed at the corporate level for validated systems. You should check to see if your company has such a policy and reference it with your vali-dation package. If you do not have one, it is highly recommended that you develop one for software validation. This is good best practice.

In contrast, back up and recovery proce-dures provide governance over routine sys-tem administration tasks related to daily, in-cremental, and full backups for the validated system during the production phase. Backup and recovery happens routinely – not as a result of a disaster event. Things you should make your IT team aware of for backup and recovery of validated systems are:• Restoration of the system must be fully

documented• All Backup and Recovery activities and sys-

tem logs must be documented and kept as part of the validated systems package

• If you have a Test system that mirrors the production environment, all patches must be tested in this environment before they are applied to the production environment.

• DOCUMENT EVERYTHING!The other SOPs referenced above are

typical in most companies that conduct software validation. These SOPs provide critical governance to ensure that you have a fully documented validation process that can withstand the scrutiny of an audit. Beyond compliance objectives, having good governance in place makes good business sense. These SOPs help you avoid common errors as well as save you time and money. Good governance for software validation is documented through your SOPs. How good is your validation governance? ■

About the author: Valarie King-Bailey can be reached at 312-321-6400 or [email protected]. www.onshoretech.com

3296

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■ INNOVAT IONS

AUTOMATION SYSTEMS

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We have vacuum

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Meter Monitors Dissolution Bath Vibration � The portable Model 205 Digital Vibration Meter kit features a 100 mV/g accelerometer to quantify very small levels of vibration in pharmaceutical test processes and comparative studies. The Model 205 is sensitive down to 10 micro inches from 30 to 300,000 RPMs to accommodate slow and fast process cycles. The Model 205 can also be used to measure vibration levels on equip-ment such as aerators, dissolution and shaker baths, blowers, centrifuges, compressors, mix-ers and pumps. The multi-parameter Model 205 measures in velocity, displacement and accel-eration. ■ Balmac Inc., Plain City, OH 43064. www.balmacinc.com or call 614-873-8222

pp1103_innovations_control.indd 51pp1103_innovations_control.indd 51 2/28/2011 1:58:49 PM2/28/2011 1:58:49 PM

Dr. Karl Schick, SciLog Inc.'s vice president of R&D, and Dean Pighin, BioProcess Automation Engineering Manager at SciLog, stand with the company's SciFlex TFF single-use system. The white tubing makes up part of the disposable flow manifold.

T he pharmaceutical industry has embraced the concept of single-use systems. Offering higher lev-els of sterility, lower capital costs and virtually no cleaning requirements, the disposable alternatives

to traditional stainless steel are now used across numerous applications in both upstream and downstream processing. A driver for this recent growth is the availability of reliable and comparatively inexpensive disposable sensors.

BACK IN THE DAY … Automation in tangential flow filtration (TFF) units is vital

to ensure product consistency, according to Karl Schick, vice president of R&D at SciLog Inc. Schick remembers a time when TFF units relied on a lot of human interaction and less than ideal instrumentation.

“In a manual TFF system, you usually have three dia-phragm valves to work with. Using an analog readout, the

needle would jump back and forth because of the peristaltic pump, and the operator would have an estimate - but not an accurate output - of what the pressure was. A judgement call was necessary to adjust the back pressure to get the driving force for the filtration.

“Now, with pressure, conductivity and temperature sen-sors, and a digitally controlled peristaltic pump, we can op-timize the process,” explains Schick.

PRE-CALIBRATION IS KEYIn order to transfer the benefits of automation to a single-

use TFF system, Schick set out to develop a single-use flow manifold that incorporates disposable pressure, conductiv-ity and temperature sensors. The sensors had to withstand the gamma-irradiation used to sterilize the manifold, be relatively inexpensive and remain stable during extended storage periods.

“The idea is to avoid the in-field calibration, as it com-promises the whole single-use approach. To do that, the sensors need to be calibrated before they are inserted into a manifold and sterilized. So it is very important that the sensors are pre-calibrated, and that the calibration data sur-vives the gamma radiation and storage period,” says Schick.

A memory device inside the sensor stores the sensor’s identification number and associated calibration factor, and is designed to withstand gamma-irradiation, steam steriliza-tion, under pressure and high concentrations of NaOH. The stored value can then be used to reliably calculate the pres-sure, conductivity or temperature in relevant units.

UNDER PRESSURE TO YIELD & CHANGE Schick’s single-use fluid manifold and disposable sensors

were incorporated into SciLog’s SciFlex TFF and normal flow filtration (NFF) units, with the later using system software used to monitor, control and maximize the product yield. As the NFF unit’s filter becomes covered by filter cake and the application-defined pressure limit is reached, the liquid handling system switches from constant output rate mode to constant pressure mode.

This automated process safely continues the NFF process until a predetermined filtrate cut off rate is reached. The filtrate collected after the pressure limit is reached contrib-utes to 30–35 percent of the total filtrate yield.

Compared to the days or even weeks it takes to clean

Taking the Guesswork Out of Single-Use Systems The advent of disposable sensors helps to optimize processing■ By Luke Simpson, Associate Editor


■ P H A R M P R O . C O M■ S I N G L E - U S E

pp1103_feature_singleuse.indd 52pp1103_feature_singleuse.indd 52 2/28/2011 3:12:26 PM2/28/2011 3:12:26 PM


■ S I N G L E U S E

and validate a stainless steel filtration system, Schick esti-mates that “to change over a tubeset and filter would take about half an hour to 45 minutes, depending upon the time it would take to sanitize. To switch from one product to an-other could probably be done in less than an hour.”

LIVING THE DREAM — UPSTREAM Single-use technologies are arguably more prevalent in

upstream processing, where disposable bioreactors are armed with dissolved oxygen and pH sensors, amongst oth-ers. Like SciLog’s flow manifold, disposable bioreactors and their associated sensors are usually combined and gamma irradiated prior to use.

Finesse Solutions is one of the companies producing single-use sensors for upstream processes. Finesse CTO Dr. Mark Selker believes that his company’s sensors are set apart by the fact that they don’t use fiber optics.

“By not using fiber optics, you mostly avoid sensitivity to physical movement and you basically eliminate photodegre-dation as an issue,” explains Selker.

That said, how do they compare to traditional sensors in terms of reliability?

“I will stack our dissolved oxygen sensor against any electrochemical sensor, in terms of repeatability, precision, accuracy, drift, sensitivity to bubbles and the ability to maintain sterility. People who say that a single-use dissolved

oxygen sensor isn’t as reliable as traditional sensors haven’t used one before,” states Selker.

He adds, “I will concede that the pH range is limited,” due to the nature of measuring ion concentration in a liquid.

MIX AND MATCH? While some companies promote the combination of

single-use and stainless steel components, also known as hybrid systems, Finesse CEO Dr. Barbara Paldus prefers to keep her company’s focus on “pure” single-use systems.

“We do hear that hybrid systems have a lot of problems, and we think people are better off sticking with either pure stainless or pure single-use. There are now complete up-stream single-use systems where you can go from a three-liter plastic vessel to a 50-liter wave rocker for seed innocu-lant to a 50-liter bag bioreactor — so you can do your entire mixing, buffer preparation, media preparation and growth in single-uses systems today.

“Downstream is where things become more complicated, and that’s where people tend to use hybrid systems because there are certain parts of the downstream process where the invention has not caught up with the process — there just aren’t always single-use solutions” says Paldus. ■

More information on single-use sensors and systems can be found at www.SciLog.com/process and www.finesse.com.

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pp1103_feature_singleuse.indd 53pp1103_feature_singleuse.indd 53 2/28/2011 3:12:13 PM2/28/2011 3:12:13 PM

T hose familiar with Alton Brown’s Good Eats - a cooking show that emphasizes scientific precision in the kitchen - know that almost all cooking instru-

ments used by the chef are multi-taskers, capable of performing duties above and beyond those specified by the manufacturer. Brown’s approach is designed to save space and money by avoiding unnecessary equipment purchases, and encour-ages innovative uses for everyday tools.

Pharmaceutical processors work in a much more complicated kitchen, but the appeal of a

small set of tools that perform a wide variety of functions still exists. Like single-purpose instruments, multifunctional calibrators and meters are evolving as the processing demands of manufacturers change, resulting in higher ac-curacies, more support for wireless and data logging, and cost savings.

GOT PERFORMANCE? Unlike single-purpose instruments, the

performance of a multifunctional instrument is difficult to assess at-a-glance. In fact,

equipment specifications for multifunctional calibrators produced by Beamex Inc. follow a slightly different set of principles, according to Ned Espy, Consulting Director at Beamex.

“Our specifications are ‘compound’ statements that in-clude a percentage of both full scale and reading, indicat-ing good performance over the entire measurement range. Most single-purpose instruments are a fixed accuracy based on full scale or simple engineering units, psi or degrees Farenheit, for example.”

Similarly, cost comparisons become more complex as functionality is bundled into one device. Espy offers a few points to consider:

“When comparing calibration instrument pricing, accuracy impacts the price more than any other factor. A multi-function calibrator is almost always price advantageous compared to the combined cost of single-purpose instruments, especially if you

factor in the annual recertification costs.“Reliability risks - putting all of your eggs in one basket

- should be considered, as well as the investment required to have multiple field technicians supplied with multifunctional

instruments versus single-purpose equivalents,” adds Espy.

INSTRUMENTATION TECHNOLOGY DRIVERS One of the big drivers for instrumentation innovation is the

need to improve efficiency, according to Espy.“There is more and more pressure to do more work with less

resources, and there are definite efficiency gains in moving to higher levels of automation and streamlining investments when it come to calibration management,” explains Espy.

“In regards to calibration, I am seeing a constant push for better accuracy. In the biopharmaceutical market, process temperature requirements are as tight as ± 0.25 °C and very low pressure measurements of ± 0.01 in H2O are required. This pushes the technology we offer.”

FDA initiatives also play a role in instrumentation develop-ments by Beamex.

“The FDA is currently evaluating how to lower the cost of validation, which could be helpful in the area of docu-mented calibration, software upgrades and for calibration procedures,” adds Espy.

John Bickers, Division Product Manager for Portable Instrumentation at Testo Inc., also sees demand for new valida-tion-friendly instrumentation technologies.

“The market was the primary driver for us to develop multi-function meters with logging capabilities. Additionally, demands by contractor’s customers to have more data and reporting have been a driver for the contractor’s feature requests.”

That said, “GMP and regulatory drivers remain the leading requirements to be met,” adds Bickers.

Wireless communication is another way that Testo facilitates data management in its instrumentation.

“We have wireless probes that communicate up to 100 feet, wireless logging probes that communicate up to 600 feet to a multi-channel monitor or alarm base and Bluetooth data communications between meters, printers and PCs,” explains Bickers. ■

Instrumentation Goes Multi-functional, Seeks Validation Validation costs, calibration management requirements and the need for higheraccuracies are driving the development of instrumentation technologies.■ By Luke Simpson, Associate Editor


■ P H A R M P R O . C O M■ INSTRUMENTATION

The Beamex MC5 Multifunction Calibrator

Testo's 435 Mutifunction Reference Meter

pp1103_feature_insidersperspecti54 54pp1103_feature_insidersperspecti54 54 2/28/2011 1:59:55 PM2/28/2011 1:59:55 PM

� Digital Pressure Gauge Features Easy-to-Read Graduations The Ashcroft® type D1005PS digital pres-sure gauge features a ½” tall, 4 ½ digit LCD that makes it easy to read and to resolve the ±0.5%FS accuracy. At the touch of a button, the display can be changed to readout in any of the 9 pre-programmed units of measure. The D1005PS also provides peak load indica-tion, an optional backlit LCD and a stainless steel sensor and inlet for use with a variety of wet or dry pressure media. ■ Ashcroft, Stratford, CT 06614. www.ashcroft.com or call 800-328-8258

Test Gauge with ±0.25% Accuracy � The Type 312.20 test gauge is suitable for gaseous or liquid media that will not obstruct the pressure system or corrode copper alloy wetted parts. With pressure ranges up to 10,000 psi the 312.20 is applicable for calibration and testing laboratories. ■ WIKA Instrument Corporation, Lawrenceville, GA 30043. www.wika.us or call 770-513-8200


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CFS 1200 and the NEW CFS 1500 C Liquid Filling & Sealing Machines These fully-automatic cGMP compliant machines fi ll and seal liquids/semi-solids into two-piece hard capsules at speeds of 1,200 and 1,500 capsules per hour. This helps scientists exploit the potential of lipid-based formulations for poorly soluble compounds.

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Actuator Can Be Coupled to Various Body Assemblies or Valve Bodies � The C27 actuator of-fers higher bench ranges that allow for an increase in pressure drop capacities and an increase in flow capacities. Because the stem and yoke are shorter in the new actuator design, the valve assembly is also more compact, which means the unit will require less space when installed in a gas, oil, water, steam or corrosive liquid transfer system. ■ Cashco Inc., Ellsworth, KS 67439. www.cashco.com or call 785-472-4461

REGULATORS |GAUGES

pp1103_innovations_actuators.ind55 55pp1103_innovations_actuators.ind55 55 2/28/2011 2:00:43 PM2/28/2011 2:00:43 PM

Manufactur-ing clini-cal trial material

(CTM), and the costs for the associated fill/finish and release work, most likely are not the costliest portions of the pharma-ceutical process chain. But delays in starting the clini-cal trial can make the most dogged project managers wince in pain. As they approve a change order for the delay, they know a gap has been created in the project’s timeline and budget. With the intense focus today on timely CTM manufacture (to keep clinical pro-tocols on time and on budget), many companies are looking for cGMP contract manufacturing organizations (CMOs) that can perform all of the required processes needed to release their material for clinical trial use. These processes include excipient and API release for GMP manufacture, formulation, in-process testing, environmental monitoring, filter integrity testing, and final release testing. CMOs with the most capabil-ity and flexibility can produce CTM much quicker than those that must subcontract the work to an approved GMP testing house. Their expertise and expansive services portfolio allow the product to be released faster to the clinic, minimizing any impact on the timeline and cost of the specified clinical protocols.

Selecting a CMO that does not have comprehensive capa-bilities in-house and readily available will add unnecessary time in the CTM process. The customer must perform a GMP audit of the CMO, plus all of the other companies (formula-tors, laboratories, labelers, etc.) the CMO uses in the supply chain. This will add significantly to the overall cost and time for the technical transfer of the product.

A CMO that has all of the required capabilities in-house will enable more rapid response time and greater project control. For example, obtaining in-process testing results may require 24 hours if performed by an outside lab. But these tests can be completed in the same day if processed by the

CMO’s lab. In addition, if there are time or tempera-ture constraints on the formulation process, then faster turnaround for the in-process testing becomes a necessity, since the mate-rial cannot go through a waiting period.

Some limited-capability CMOs are adding testing and other functions to create a more streamlined process. But this involves more than just installing the equipment and setting up testing methodologies. They may lack the exper-tise necessary to perform

the tests quickly and correctly. In addition, limited-capa-bility CMOs frequently struggle with keeping a laboratory staff occupied due to the lack of work in a certain process. Pharmaceutical testing requires a high degree of knowledge. A full-service CMO with an in-house specialized laboratory performs this work on a routine basis and has accumulated significant experience that will pay off in time and cost.

THE QUICKEST PATH TO SUCCESSFULLY RELEASED CTM

CTM is difficult to schedule since it revolves around the clinical program’s start time and is tied to its success. A CMO that meets the production schedule can minimize po-tential restart activities.

Working with a full-service, experienced CMO is the quick-est route to successfully released CTM. To help illustrate this principle, let’s review the CTM process from the first steps through the completion of an early-stage clinical final drug product (FDP). (see chart above) I. RAW MATERIALS - All raw materials used in GMP manufacturing for clinical material will need QC inspection and QA release. Starting with the container closure system, the glass, stoppers, and crimp caps need to be inspected for defects and for dimensional state. These activities are performed by a trained QC analyst that should be found at CMOs with qualified in-house QC laboratories. Excipients

Clinical Trial Material Production And Testing What your CMO is not telling you ■ By Alexander Mello, Director, Project Management, Microtest Laboratories, Inc.


■ P H A R M P R O . C O M■ CLINICAL TRIALS

pp1103_feature_clinicaltrials.in56 56pp1103_feature_clinicaltrials.in56 56 2/28/2011 1:47:23 PM2/28/2011 1:47:23 PM


■ S L U G

reported rapidly so as to not hold up formulation and fill/finish activities. The samples are kept on-site, are available for immediate testing, and there are no issues with integrity. Additionally, if there is an assay problem (out of specifica-tion or assay failure), it can be addressed immediately and steps can be taken to determine root causes in real time. Typically, while in-process testing is underway, the formu-lation is being mixed and awaiting test results in order to move forward with the filling process. This represents a critical “go/no-go” step in the process. In fact, there may be several of these steps, depending on the formulation. III. FINAL DRUG PRODUCT - The FDP testing = release

Stability chambers used to test clinical trial materials.


■ CLINICAL TRIALS

used in the manufacture of clinical material will need to be minimally assessed for identity. Typically, FTIR is utilized unless there is a USP/EP test for identity in the monograph. A CMO’s fully operational analytical department has the flexibility to test for all different types of assays including wet chemistry. With a standing GMP laboratory on site, there is a major gain in time since the samples do not need to be sent to a third-party lab for analysis. When samples are shipped off site, many things can occur that slow down the release process. Samples can get compromised during shipment (lost shipments, sample exposure/contamination, etc.) or at the external testing facility, and lab turnaround times may not fit the production schedule. The bottom line: when samples must leave the CMO, there is a loss of control that frequently results in delays and inefficiencies. II. IN-PROCESS TESTING (DURING THE FORMULATION STEP) - For in-process testing of any for-mulation, it is critical to have assay capability at the CMO. In-process testing can range from simple procedures, such as pH or osmolality, to complex, such as HPLC or GC. In-pro-cess testing at the clinical stage does not require a full vali-dation program, but the assay must be qualified. Obviously, one does not want to fill/finish a formulated FDP when the formulation is not correct. This will result in too much time, effort, and cost being spent.

Having the testing capabilities in-house provides attrac-tive benefits. The assays can be tested quickly and results

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Assmann Corporation • Garrett, IN 46738Fax: 888-TANK FAX (826-5329) E-mail: [email protected]

Manufacturing facilities in Garrett, IN and Marshall, TX

Toll-free: 888-357-3181www.assmann-usa.com

• Double wall containment in one integral, space-saving unit

• Secondary tank has a capacity 120% of inner tank, exceeding EPA standards

• Capacities from 20 to 6,550 gallons

• Molded in pump shelf and liquid sump area

• Large or small access openings

• Custom fitting packages available

WHY ASSMANN?See our website: www.assmann-usa.com

• Double Wall • Vertical • Horizontal • Conical• Secondary Containment • Feed Stations • Fork Liftable Containers • Open Top • Miscellaneous Tanks • Accessories/Fittings

■ P H A R M P R O . C O M■ CLINICAL TRIALS


of the FDP = distribution to the clinic. Therefore, the testing needs to be performed in an expeditious and fully compliant man-ner. A fully capable CMO has the ability to test and release the FDP under GMP condi-tions. By having the laboratory on-site, these tests can be run immediately after fill/finish is completed. The test data can be reviewed and the CoA can be issued within a very short time. This capability allows for quicker release of the FDP and faster shipments to the clinical sites in order to meet the needs of the client. Additionally, it allows for the client to perform only one audit for both manufacturing and testing, which is a benefit

from both a cost and time savings perspec-tive. FDP tests for clinical trial materials must be qualified or validated to provide the confidence the assays are robust.

CONCLUSION There are major value-added components

of having a fully capable laboratory directly tied to your clinical trial manufacturing orga-nization. This allows for a more streamlined process and directly impacts the overall timing of a product release on a tight clinical program schedule. Today’s pharmaceutical firms operate in a highly competitive market. For companies and their investors, being

first to clinic represents a valuable first step moving products forward in the pipeline and onward to final revenue generation.

About the Author Alex Mello is Director of Project Management, Manufacturing, for Microtest Laboratories. Mr. Mello’s 15 years of experience span Aseptic Fill/Finish, Microbiology, Method Transfer, Stability of Drug Product, Medical Devices/Combo Devices, and Sterilization Sciences. He holds a graduate degree in Biological Sciences and is a Specialist Microbiologist (NRM). To contact Alex directly, contact 800-631-1680 ext. 121 or [email protected].

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We don’t stand still. Raw materials are com-bined. They are pressed into tablets or pumped into bottles, then cloaked in tam-per-evident layers. Products are packaged;

boxes are cartoned; pallets are wrapped. Our production lines don’t stop…until they have to.

For companies using traditional methods to test for mi-crobiological contamination, shutting down the line due to a potential contamination event is like opening a fire hydrant and watching money gush out. By the time you’ve detected a problem, the company’s already invested quite a bit of time and effort, and has significant capital tied up in inventory.

RAPID METHODS FOR ENHANCED RISK MANAGEMENT

You can cap the hydrant, or at least get the flow down to a mere trickle, by taking advantage of the risk management benefits of rapid microbial methods (RMMs). Earlier detec-tion through rapid methods reduces the potential impact of events by reducing the volume of product that may be impacted – specifically, product that needs to be scrapped or reworked.

By identifying a problem faster, corrective action can be initiated sooner and undoubtedly more effectively. It is easier to isolate and identify events that may have led to a

contamination event yesterday than to try to trouble shoot those same events 4, 5 or even more days later. You may easily remember the events of yesterday, but recalling pre-cise details of what was different five days earlier is a lot trickier.

T he benefits of using a rapid detection method are made clear in Figure 1, a simplified contamination event timeline.

Assume it takes this company 1-2 days to formulate and package a product and then, using traditional microbiologi-cal methods, an additional 4 to 7 days to test for micro-biological quality. In this example, micro results indicating contamination are available after 5 days of micro-hold and the 7th day of overall production. An investigation and corrective action is initiated. Several days later, replace-ment product needs to be produced to replace the original contaminated batch. That product is also subject to micro-biological testing. We are now at the 17-day point in our production timeline before the product is available to be released to distribution - a full 10 days beyond the planned 7-day production schedule.

On the second timeline, we see that using Celsis’ AKuScreen™ assay reduces the microbiological testing time to 18-24 hours. This means that detection of the problem and initiation of corrective action happens within 24 hours of production. The benefits of rapid detection also extend to the screening of replacement product. In the example above, the release of replacement product is at the 9-day point. This is a full 8 days faster than in the traditional methods scenario; under the traditional testing scenario, the manufacturer is still in crisis-mode at day 9.

Key takeaway: The benefits of a rapid method actually double in a crisis, when the issues of time and responsive-ness are most critical.

COMPARING TRADITIONAL AND RAPID METHODS Using traditional methods, a product sample is added

to a growth medium and incubated for multiple days to encourage the growth of any microorganisms that might be present. Pharmaceutical companies typically wait 4 to 7 days for microbial limits results; 14 days or more for sterile products.

Incubated samples are individually inspected for visual - and often very subjective - indicators of microbial growth. For most pharmaceutical companies, 99% of the time sam-

Reduce the Impact of Contamination Events The quicker you detect a problem the faster you can fix it ■ By Judy Madden, Vice President, Celsis International Ltd.



■ CONTAMINATION

ss

tst

O

s

t

T

w

T

A

wFigure 1: The benefits of the rapid detection method are made clear in this simplified contami-nation event timeline.

■

pp1103_feature_contamination.ind60 60pp1103_feature_contamination.ind60 60 2/28/2011 1:53:19 PM2/28/2011 1:53:19 PM

Figure 2: The Impact Report provides a graph that identifies the economic impact by six-month periods along with cumulative discounted cash flow.


ples will be free of microbial contamination. Yet it is not until the end of the incubation period, after a significant amount of time and materials have been invested, that the absence of contamination can be confirmed.

By contrast, rapid methods deliver definitive results much faster. The Celsis system is an objective, instru-ment-based diagnostic assay that is simple yet state-of-the art. Incubated samples are placed in the instrument and software controls the precise dispensing of reagents. The system monitors the level of enzyme-mediated reactions to indicate the presence of microorganisms, rather than grow-ing them to visually detectable levels. Because of the sensi-tivity of the test, the sensitivity of the instrument and the standardization provided by automation, the absence of con-tamination from bacteria, yeast or mold can be confirmed in 24 hours against a microbial limits specification.

ONE COMPANY’S EXPERIENCE Rapid may be the best-kept secret outside the microbio-

logical laboratory. Some of the largest and most successful companies in the pharmaceutical and consumer product industries benefit from the efficiencies offered by RMM systems. However, the use of RMMs has not been widely publicized by companies and is considered a competitive advantage by some. For example, the company discussed below implemented the Celsis system in 1996 and now uses the technology worldwide.

The company, a manufacturer of pharmaceutical prod-ucts, was experiencing issues with inventory and periodic in-house contamination events. They were using traditional microbiological methods for screening raw materials and finished goods with a 5-day hold at each step. The value of their daily finished goods production at the time was roughly $75,000.

Celsis completed its Financial Impact Assessment to dem-onstrate to the company the value of implementing a rapid microbial system.

Easily available information including the value of daily finished goods, the reduction in micro-hold days, the fre-quency of contamination events, instrumentation and re-agent investments, was keyed into the Impact Assessment. The model calculated a five-year net present value (NPV) of over $677,000, payback of less than 9 months and savings relating to more rapid containment of contamination annual-ized at $64,000 per year.

Projecting these savings over the company’s five facilities with an 18-month roll-out program, increased the 5 year NPV to almost $2.5 million with a payback of just 15 months. The later rollouts were financed through the working capital efficiencies generated from the earlier placements. Annualized contamination savings alone rose to almost half a million dollars.

The Impact Report (see Figure 2) provides a graph that identifies the economic impact by six-month periods along with cumulative discounted cash flow.

The cost of the rapid system is shown in red. The initial outflow represents the initial investment in the instrument, followed by the implementation period and the ongoing cost of reagents.

Above the line, in blue, is the positive impact of the reduction in working capital requirements driven by the reduction in inventory held in quarantine and safety stock. This includes the initial release of inventory during the implementation period and the ongoing value of redeploying that money into productive investments.

At the top of each bar, in green, are the savings from the reduced impact of contamination events. In many cases, these savings pay for the program on their own - the green bars are larger than the red bars in each period.

In addition, the company was able to introduce some in-process testing at a critical point in production to detect con-tamination even earlier and to further reduce the potential impact of a contamination event. Their total micro-hold was reduced from ten days to only three days, and was redistrib-uted to better manage risk as it occurs in their operation.

Celsis also provides an Environmental Impact Report documenting the sustainability improvements resulting from implementation; from reducing water and energy consump-tion to minimizing the amounts of liquid, solid and hazard-ous waste requiring disposal.

No one stands still. Products are packaged; boxes are cartoned; pallets are wrapped. What has changed is the potential financial impact of contamination events. From a mighty hydrant to a minor trickle, earlier and faster detec-tion with a rapid microbial method has improved the risk profile and generated company-wide savings. ■



■ CONTAMINATION

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pharm pro mar 2011

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