Pharmaceutical Processing, May 2015

■ CONTRACT MANUFACTURING, PACKAGING & NEW EQUIPMENT TECHNOLOGY FOR THE BIOPHARM/PHARMACEUTICAL INDUSTRY

OFFICIAL MEDIA SPONSOR OF

W W W. P H A R M P R O . C O M • V O L U M E 3 0 , N U M B E R 4 • M AY 2 0 1 5

JUST SCRATCHING THE SERVICE Dow Development Labs relies on voice of the customer to grow their topical dermatological CMO business.

INSIDE THIS ISSUE: ■ STERILE PROCESSING Nitrogen Sparging and Blanketing Detecting Pyrogens ■ BIOPHARM Downstream purification processes ■ OPERATIONS Legal competitive advantages Implementing lean practices ■ FACILITY Distribution center safety

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MAY 2015 | PHARMACEUTICAL PROCESSING

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■ IN THIS ISSUE

6

On Top Of Their Game

Official Media Sponsor of the INTERPHEX Show

How Dow Development Laboratories is positioning itself as the go-to source for topical product development services.

GENERAL MANAGER, MANUFACTURING GROUP TOM LYNCH, 973-920-7782 tom.lynch@advantagemedia.com EDITORIAL DIRECTOR JEFF REINKE jeff.reinke@advantagemedia.com

14 Keeping Pharmaceutical

EDITORIAL ADVISORY BOARD

Processing Pure

Michael J. Beier, Senior Vice President of Operations TITAN PHARMACEUTICALS, INC.

A closer look at the benefits of near-pure nitrogen to deoxygenate water in timeefficient and cost-effective ways.

Dr. James V. Blackwell, PhD, Consultant BIOPROCESS TECHNOLOGY CONSULTANTS, INC. Ronald C. Branning, Vice President Global Quality GENENTECH INC.

16 Downstream Processing Advantages For BioPharma

Robert F. Dream, Vice President H.D.R. COMPANY LTD. Johanna Carmel Egan, VGP Project Management ELI LILLY

Why continuous purification systems and chromatography alternatives are in high demand.

Girish Malhotra, President EPCOT INTERNATIONAL Allan F. Pfitzenmaier, President VECTECH PHARMA CONSULTANTS INC.

18 Improving Pharma’s

Susan Polizzotto, Manager, R&D QA GMP Compliance US SANOFI PASTEUR

Value Chain

Carlos Villalobos, Sr. Dir. Global Engineering BRISTOL-MYERS SQUIBB

How legal departments can actually create a competitive advantage.

Richard G. Whitfield, Senior Director PFIZER

20 Safer, Cleaner And More Efficient

Patrick Wong, Director of Global Engineering BRISTOL-MYERS SQUIBB (BMS)

page 6

Insight on new technologies that improve the security, cleanliness and energy efficiency of your distribution center.

24 Shared Service Management In Lean Manufacturing

page 10

How shared service management can help improve internal collaboration – enhancing lean manufacturing approaches.

32 Testing To Detect Pyrogens A look at the use of the Monocyte Activation test to help improve pyrogen detection.

■ D E PA RT ME NT S 3 Right Now on PharmPro.com 4 From the Editor 10 What’s Hot 23 New Products ■2

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MAY 2015 | PHARMACEUTICAL PROCESSING

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RIGHT NOW ON PH A R M PRO.CO M

■ NEWS

Cholesterol Drug Stimulates Same Receptors as Marijuana If you want the benefits of medical marijuana without the "unwanted side effects" of cannabis, new research should leave you on a high note. According to a research report appearing in the April 2015 issue of The FASEB Journal, fenofibrate, also known by the brand name Tricor, may benefit a wide range of health issues, such as pain, appetite stimulation, nausea, as well as immune and various psychiatric and neurological conditions. This suggests that fenofibrate may be the starting point for a new class of cannabis-like drugs to treat these types of conditions.

In much the same way, parenteral manufacturers are seeking availability of filling lines to do the equivalent of the routine drive to work, as well as the weekend camping outing on the unpaved road.

Flexibility has become a strong business driver, especially for clinical and small scale operations.

Read more at: http://bit.ly/1b05aWd

How Drug Manufacturers Are Impacting The Death Penalty Debate

by Meagan Parrish

Memory, as well as connections between brain cells, were restored in mice given an experimental cancer drug. The drug, developed by Astra Zeneca, proved disappointing in treating solid tumors but appears to block damage triggered during the formation of amyloidbeta plaques, a hallmark of Alzheimer's disease. The new study, funded by an innovative National Institutes of Health (NIH) program to test failed drugs on different diseases, has led to the launch of human trials to test the efficacy of AZD05030 in Alzheimer's patients.

Polls generally show that the majority of Americans are on board with the death penalty. In October 2014, Gallup reported that 63 percent of Americans were in favor of capital punishment while 33 percent were opposed. But when it comes to carrying out executions in recent years, the vote of one group of individuals — drug manufacturers — has begun to hold more sway. Public pressure on drug manufacturers to stop selling the chemicals, coupled with some companies’ opposition to the practice has cut off supplies, leading to shortages of the drugs used in lethal injections. Now, several states scrambling to figure out if and how they’ll be able to be able to go ahead with scheduled executions.

Read more at: http://bit.ly/1E5Pdv6

Read more at: http://bit.ly/1yy9Yx6

■ ARTICLES

■ REPORT

The Flexible Filling Line: The Crossover Vehicle for Aseptic Manufacturing

U.S. Pharmaceutical Market to Increase by 40% by 2020

Read more at: http://bit.ly/1PSrVfc

In Alzheimer's Mice, Memory Restored With Cancer Drug

by Paul Valerio, IPS People want it all, don’t they? The type of cars many drive is one indicator. Crossover vehicles have become a very popular vehicle segment. They offer: practicality while still maintaining a cool factor; spaciousness with decent fuel efficiency; and car-like handling with the safety of all wheel drive for slippery conditions.

by Andy Szal, Digital Reporter A newly released report expects the U.S. pharmaceutical market to expand dramatically by 2020, due in large part to changes under the Affordable Care Act. The analysis by research firm Global Data projects the market to rise from an overall value of $395 billion in 2014 to nearly $550 billion by 2020.

Read more at: http://bit.ly/1Nf9PQl

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■ FROM THE EDITOR

Capital Investments: Regulations, Technology and ROI ■ Jeff Reinke, Editorial Director

P

Pharmaceutical processors face a number of challenges in determining the direction they should take when considering internal investments – but a lack of options have never been amongst them. As of late those choices seem to have gotten only more taxing.

Within this issue of Pharmaceutical Processing alone, we discuss new options to consider when looking at production and development trends, as well as new validation, manufacturing and packaging approaches. Adding to this complexity are regulatory concerns hitting this summer, and efficiency-laden developments related to the Internet of Things (IoT) movement.

So it seems the (often limited) pool of investment funds is still serving multiple masters. At least the regulatory requirements will overlap with areas of technological investment. More specifically, enhanced trackn-trace, security and labeling technologies could potentially check multiple boxes. Similarly, tying all these technologies together through an Enterprise Resource Planning (ERP) software platform helps build a more connected production strategy – feeding into IoT goals.

Then there are the familiar production and packaging dynamics that accompany single-use equipment technology, sustainable packaging materials and more efficient machinery that can help cut energy, water or material costs.

The growing number of contract service, manufacturing and packaging organizations currently focused almost exclusively on assisting with specific endeavors can represent the ability to meet several goals through outsourcing specific functions.

At the end of the day, internal investment decisions will never be simple. But by garnering a greater understanding of all facets of the organization via enhanced connectivity, analyzing the generated data, and making it available to more people internally, the areas deserving the highest investment priority could become clearer.

Have a comment or question about Pharmaceutical Processing?

My E-mail is: jeff.reinke@advantagemedia.com

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STORY

On Top Of Their Game Dow Development Laboratories, LLC positions itself as the go-to company for topical product development services. n By Mike Auerbach

W

hile much of the attention and development of pharmaceuticals is focused on oral solid dosage forms, the market for topical treatments of dermatological indications is growing. In fact, according to recent reports the dermatology market is expected to grow to more than $13 billion by 2017.

As the market for dermatology products increase, so does the need for expert contract formulation and product development services. With this in mind, Debra Dow is working to assemble a team best suited to assist in the development of high-quality topical medicine, with knowledge and understanding of FDA dermatology division regulations and a track record for success.

Dow is a co-founder of Symbio, LLC, a specialty clinical research organization with extensive expertise

conducting clinical studies in dermatology, and has recently opened Dow Development Laboratories, (DDL) in Petaluma, Calif. The new laboratory facility is set-up to provide full scope topical product development services.

The team has experience and resources to take dermatology product from concept through the product development process, concluding with submission of the regulatory application. In collaboration with Symbio, DDL is a CRO that can bring API through product approval, in manner that offers unique efficiencies in dermatology development.

HISTORY AND BACKGROUND Symbio opened in 2002 and has become a leader in the management of pivotal clinical dermatology studies in the U.S. According to Jared Holley, a project manager at Symbio, this

success can be attributed to strong relationships with U.S. dermatologists and clinical research sites, consistent, high-quality service, and the partnerships they form with their sponsors.

Symbio was working out of a small laboratory in Colorado, but to better serve their clients and expand the services they offer, the company decided to re-locate to a larger facility in Petaluma, about two years ago.

Holley, who was involved in initial planning, says very few organizations bring together CMC with clinical development in the contract dermatology industry. In addition to providing complete topical product development services, DDL ensures compliance with FDA and/or EU regulations.

Construction on the new facility began in December 2013, and it was completed in May 2014, with a grand opening on July 15, 2014.

Recent internal investments have played a key role in DDL's growth.

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Holley adds, “Initial team members were focused on creating quality systems, SOPs, procedures, and the equipment acquisition required to become an FDAapproved facility for manufacture of clinical supplies. The FDA audited DDL in November 2014 and gave the company a clinical manufacturing license. Holley attributes the speed with which DDL was PHARMACEUTICAL PROCESSING | MAY 2015

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able to create and grow the company to the team’s extensive experience working together in a very similar environment and business structure during their time together at Dow Pharmaceutical Sciences.

Dow Development Labs, LLC currently has 16 people on staff with the intention of ramping up to 30 by the end of the year.

STORY

THE SERVICES THAT MATTER For a company to be successful, they have to offer something that either no one else offers, or do that “something” better than anyone else. For DDL, that something is formulation development expertise.

“The service that we pride ourselves on and consider our core competency and expertise is formulation development,” explains Holley. “Clients come to us with a vision for their product and we bring it to life, ensuring strong science supports the product idea for a smooth regulatory pathway. We are the best at creating a formulation that is stable, delivers the drug to the site of target indication, and is aesthetically elegant for ease of use by future patients. That is our core expertise.”

He continues, “Creating a quality formulation is the first step in the product development process, and most important. Our scientists have experience in choosing optimum excipients to attain a quality formulation, understand both the art and the science behind topical formulation development, and are experienced in positioning the program for regulatory approval.

“Various experiments are designed to develop formulations, assess skin penetration profile, select packaging, select preservative systems, conduct stability studies, and manufacturing process scale-up for GLP and GMP batches. DDL is able to manufacture batches to support up to Phase II clinical evaluation, and routinely transfers the technology package to a well-known CMO for manufacture of registration batches.

“After technology transfer, the work is not done for DDL, as we will manage the NDA submission and support the program by negotiating with the FDA through submission of the regulatory application”.

DDL supports their topical formulation services with an analytical team specializing in API and drug 7n

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STORY

it’s a retinoid that requires extensive effort to be stabilized.

Sometimes it’s a peptide with large molecular weight, and we need to devise a way to get the API to the site of action. We are often asked to modify or optimize existing formulations to improve efficacy, penetration, safety or elegance. DDL works hard to ensure the formulation works well and that the client’s expectations are exceeded,” he states.

COMPLETE PROGRAM MANAGEMENT In addition to their expertise in topical development, DDL prides themselves on being efficient, focused on quality and responsive to client needs.

“By managing the complete topical product development program, laboratory teams work together to support non-clinical and clinical teams, which allows us to maintain efficient project timelines and budgets.” Holley adds, “As the company grows, the focus will be to maintain a nimble, responsive and efficient company focused on meeting the goals of our client’s. DDL doesn’t develop its own products, so our teams are focused on making our clients’ projects a success. We are equipped to manage a full topical development program – we can promise certain things that a larger company can’t.”

DDL's understanding of dermatological substances, and the related approval processes, help them realize a number of efficiencies, and pass them along to clients.

product method development and validation, product stability testing, and very soon, in-vitro release evaluation. Formulation and analytical teams work very closely together in development efforts – collaborating on writing the CMC section of IND and NDA documents.

“Our team understands what the FDA Dermatology division is looking for in regulatory submissions, as well

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as the best ways to present the data,” offers Holley. This experience allows DDL to more efficiently move through the regulatory process for client development programs. Additionally, DDL offers clinical labeling, packaging and distribution services with experience in creating custom labels and packaging.

Holley also admits that every project and every client brings a different set of challenges. “Sometimes

DIFFERENTIATORS Debra Dow is very clear that DDL is different from other service providers in its expertise, technologies and staff.

“We have expertise in the whole process – from starting the formulation to scale-up. Sometimes companies have a technology that they’ve built their business on. We are just a very broadbased, very experienced group of people that have done a lot of topical product development,” she states.

Holley adds, “We are bringing clinical and topical development together.

Our team has a better understanding of the big picture in topical product development – attaining clinical efficacy. For example, our team members MAY 2015 | PHARMACEUTICAL PROCESSING

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understand the details required for conducting successful clinical studies, and we bring that into our development process. We provide the complete topical development program.”

“We look at the broad picture,” says Dow. “We want to make a product that patients are going to like and are going to use.” Having built a solid foundation on which to grow and establishing themselves as a premier supplier of topical product development services, DDL is excited about the future.

“In the next five years we want to expand on what we have established already,” says Dow. “In the contract business it’s all about what clients ask you to do. So we are certainly open to making decisions based on clients’ needs.

“Our core competency is topical development and that’s not going to change. The part of our business that will develop and expand depends on

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STORY

DDL's team offers extensive development experience.

whether we get into small scale manufacturing or more clinical labeling, analytical services etc. Those decision will

be driven by client needs. We keep our ear to the ground and try to anticipate what clients will need.” n

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W H AT ' S H O T

Hygienic Sight Flow Indicators The Clark-Reliance Corporation has announced two new lines of hygienic sight flow indictors. The Jacoby-Tarbox Hy-Sight and Hy-Sight Full View flow indicators are designed to shorten cleaning cycles while maximizing the view of flow in sterile or hygienic processes. They feature: • A cleanable design that achieves controlled intrusion by following ASME BPE requirements and surpasses CIP and SIP requirements.

• According to the company, the largest view of any slim, low-profile sight indictor, including a 360-degree view of process conditions.

• Head materials of 316L stainless steel.

■ Clark-Reliance; www.clark-reliance.com

WHAT’S HOT Induction Seals With Lower Peel Force EdgePull™ induction seals from Tri-Seal, a division of Tekni-Plex, Inc., offer: • Lower peel force to remove.

• The seals peel cleanly, which means no adhesive residue/strings to contaminate the contents after opening.

• The pull tab is designed with enhanced strength to resist delamination from the rest of the structure when removed by consumers.

• The liners are typically used with closures ranging from 28 to 63 mm and for a wide range of narrow and wide-mouthed containers that benefit from a tamper-evident device.

■ Tri-Seal, Inc.; www.tri-seal.com, www.tekni-plex.com

Glove Box Controls For Relative Humidity or Oxygen Levels The NEW Nitrogen Purge Series of Glove Boxes from Flow Sciences allow for purging relative humidity or oxygen levels down to about two percent.

These enclosures are capable of protecting the process by nearly eliminating moisture or oxygen with the flow of inert gas. Safety of operator and process is accomplished with HEPA filtration, a one way check valve and the ability to connect to a house exhaust system. The design uses AGS guidelines, with a 28” depth and comfortable 10” oval glove ports which allow for minimized technician arm, wrist and shoulder fatigue while maintaining a controlled environment. The Nitrogen Metering System (FS1500) is designed to conserve nitrogen, with features that include: • Trending graphs that display RH%, O2, and temperature.

• Two adjustable flow rates – one for high flow purge and the other for maintaining low flow.

• The nitrogen-saving auto shut off activates when the set point of RH% or O2 is reached.

• Audio and visual alarms trigger when outside the set point range.

■ Flow Sciences, Inc; www.FlowSciences.com ■ 10

MAY 2015 | PHARMACEUTICAL PROCESSING

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■ W H AT ' S H O T

Optimized For Single-Use Systems Meissner’s SPD (Sanitary Process Design) vent option has been designed for use within single-use systems applications. The vent features a full size 1/8” hose barb, compatible with tubing and affixment methods typically used in single-use systems, to support robust closed system sampling operations. The SPD vent’s large knurled grip allows it to be easily manipulated by gloved hands. Multi-turn flow initiation provides precise metering during operations where venting is taking place to a closed system, (e.g. a biocontainer).

■ Meissner Filtration Products; www.meissner.com

Bulk Bag Conditioning System

Ultra Low Temperature Rack Range Precision manufactured in a certified Class 7 clean room production facility, the new 24-, 48- and 96-tube Ultra-Low Temperature (ULT) rack range from Micronic are based on the automation compatible ANSI / SLAS dimensional footprint. Micronic ULT racks incorporate a Twist-Lock design which prevents tubes from turning during screw (de)capping, lead-in tube and cover placement and closed side walls with minimal notches for rack orientation. Traceability and reproducibility is aided by laser-etched alphanumeric visual location aids on top of the racks, and a unique laser-etched 1D barcode on the side of the racks.

■ Micronic; www.micronic.com

Conditioning and emptying bulk bags with agglomerated material can be dangerous if the proper equipment is not utilized. The latest from Material Transfer addresses concerns related to bag breakage, plant structural damage, forklift damage and injury to plant personnel. Anew, patented system utilizes hydraulically actuated pivoting conditioning arms with extended travel, and features "v-shaped" tubular breaker profiles to efficiently return even the most severely agglomerated materials to a free-flowing state. A larger, color touch screen interface allows for easy access to proprietary bulk bag and material conditioning parameters, full recipe management functions, system status and manual mode controls.

Additional features include a compact footprint, full machine guarding and a powered rotary lift table for positioning the bulk bag on all sides.

■ Material Transfer; www.materialtransfer.com PHARMACEUTICAL PROCESSING | MAY 2015

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W H AT ' S H O T

Faster Screen Changes The SWECO QuickChange PT (QCPT) allows for changing round separator screens faster, as its two self-contained pneumatic cylinders, which are mounted within towers on each side of the unit, rise up to engage a bracket on the cover or frame in lifting the frame stack. Additional features include a motor start-up interlock and an internally adjustable pressure regulator. The QuickChange PT has a smaller footprint than previous systems and is available in both carbon and stainless steel for 48” and 60” units.

■ SWECO; www.sweco.com

WHAT’S HOT WHAT’S HOT

PAT Solution For Pharmaceutical Packaging

Compact, Modular Fermentor/Bioreactor Sartorius Stedim Biotech has launched a new version of its proven stainless steel fermentor/bioreactor – the BIOSTAT D-DCU. The compact, modular, in-situ sterilizable system is suitable for microbial and cell cultures, and is supplied in working volumes of 10 to 200 liters.

Typical application areas include the process development and production of small-batch biopharmaceutics, vaccines, enzymes, antibiotics and other secondary metabolites. The modular design of the BIOSTAT D-DCU enables flexible configuration of the bioreactor system to meet individual customer needs.

■ Sartorius Stedim Biotech; www.sartorious.us ■ 12

DIR Technologies’ Induction Integrity Verification System (I2VS) provides induction sealing integrity analysis for bottles without packaging line slowdown. Inspection is performed through the closed cap, without physical contact in an entirely passive, non–destructive fashion. The infra-red technology could replace conventional inspection techniques that rely on sampling. Additionally, the Sachet Full Monitoring System (SFM) provides in-line inspection of sachets and pouches. Both are either in use or in trials on packaging lines for several leading pharmaceutical packaging companies due to features that include real-time quality control solutions that help increase operational efficiency and reduce batch failure.

■ DIR Technologies; www.dir-technologies.com.

Safe Storage of Noxious And Odorous Chemicals The new Safestore Vented Chemical Storage Cabinets from Air Science are designed to store noxious or odorous chemicals, minimizing health and environmental risks in handling chemical vapors, residues and VOCs. The Air Science Multiplex filtration system protects the safety of personnel during use, maintenance and decontamination with advanced carbon filtration technology that serves as an alternative to ducted cabinets for a broad range of applications. Safestore cabinets isolate and trap biological and chemical vapors to prevent operator exposure, cross contamination, and negative ecological impact.

■ Air Science USA; www.airscience.com MAY 2015 | PHARMACEUTICAL PROCESSING

■ PHARMPRO.COM

■ W H AT ' S H O T

Compact, Modular, Multi-Purpose Autoclave Under the Sterimega Plus trademark, Telstar has developed a new compact steam sterilising autoclave with GMP design that includes: • Hinged, front-facing access panels for work areas with limited space.

• Primarily for steam sterilisation of solid, porous and gravitational liquid.

• Configurable with a pass-through chamber for sterilisation and/or the biodecontamination processes.

• A modular design that enables the technical area to be readily located on either side of the equipment.

• Two heat exchangers to cool the water supplied to the liquid ring vacuum pump and the associated effluents sent to drainage, via a closed-circuit cooling system. According to the company, this provides a savings of more than 60 percent on water consumption.

• State-of-the-art control systems that include a 10.4” touch screen and a completely redesigned user interface.

■ TELSTAR; www.telstar.com

Decorated Tubes For Effervescent Tablets With Brilliance, Sanner GmbH offers an expressive packaging solution for effervescent tablets. Features include: • Photorealistic printing.

• A convenience closure that allows the tubes to remain tightly closed at all times, while the tablets are protected against light and moisture with a long shelf life.

• Available in up to eight colors, with metallic effects available.

• Comprised of a shock-proof and scratch-resistant material.

■ Sanner GmbH; www.sanner-group.com

Experience the Ultimate in Pneumatic Conveying.

Find out how we can solve your pneumatic conveying challenges. Visit us at vac-u-max.com or call 800-VAC-U-MAX.

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PROCESS

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How Nitrogen Sparging and Blanketing Keep Pharmaceutical Processing Pure Ensuring continuous supplies of near-pure nitrogen to deoxygenate water can be a time-efficient and cost-effective way to formulate today’s medicines. n By David J. Connaughton, Product Manager, Parker Hannifin Corporation, Filtration and Separation Division

P

ure water is as necessary to a pharmaceutical manufacturer’s existence as oxygen is to the patients it serves.

The trouble is, water doesn't want to be pure. It wants to dissolve things, and as a universal solvent, it’s very good at that. In pharmaceutical manufacturing the dissolved oxygen and CO2 in water can mean death to the manufacture of products designed to preserve the health of customers.

So to ensure purity in the manufacture of medicines, dissolved oxygen and CO2 must be removed and prevented from contaminating the water supply. This is especially true of water stored in tanks.

Oxygen in water can lead to microbial growth and CO2 can affect water’s pH. One procedure to remove these impurities is called sparging. Typically, nitrogen is used not only to deaerate water, but to prevent oxygen and CO2 reabsorption.

While nitrogen makes up 78 percent of the air we breathe, harnessing its properties for pharmaceutical manufacturing can be problematic and expensive. Nitrogen can be ordered from outside vendors but delivery, storage and handling high pressure cylinders in the working environment can be costly and hazardous. It also represents a finite supply that can be exhausted quickly when there’s an unexpected rise in demand.

The costs to address these issues can be high and difficult to budget for,

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especially as the price of gas continues to increase. The environmental impact of truck-based deliveries is also gaining significance.

An alternative would be to generate the nitrogen needed on demand. In the pharmaceutical world, this investment is easily justified considering the value of the product, and the potential harm that introducing contaminated water can have on consumers.

churn its contents. Sparging increases the rate of agitation in the tank, with sintered stainless steel plates or rods (called sparging elements) purging the water on a continuous basis.

In addition to preserving pH and eliminating microbial growth, deaerated water containing low concentrations of oxygen and carbon dioxide minimizes corrosion, as well as iron and copper oxide scale.

DYNAMIC DUO Nitrogen sparging and blanketing practices can prevent oxidation in the manufacturing process. Sparging and blanketing practices introduce nearpure nitrogen into the water tanks and maintain a protective layer of nitrogen.

In other words, nitrogen sparges the water to remove any dissolved oxygen and CO2. Humid air in the head space is replaced by pure, inert nitrogen.

This may be maintained by a precise valve-control system that automatically adjusts the nitrogen content to maintain the protective blanket as the tank is filled or emptied, or by simply having a continuous purge of low pressure nitrogen.

The nitrogen – when bubbled through water – agitates it and forces out oxygen and CO2 dissolved in it to prevent bacterial and algae growth.

This can supplement the use of pumps that serve this purpose. However, a 500-gallon tank pumping at a gallon a minute can take up to 10 hours to

SUPPLIED OR MAKE YOUR OWN? There are two ways pharmaceutical plants may obtain nitrogen. The nitrogen can be received from a supplier as a gas in high-pressure cylinders or as a liquid in micro-bulk tanks (dewars) and bulk tanks. Relying on an outside supplier, however, is subject to price increases, rental agreements, hazmat fees, surcharges and taxes. Delivery of gas also requires access to the facility by a third party, and creates a security situation for the plant to manage.

An alternative to sourcing is to generate the nitrogen on-site via PSA (Pressure Swing Adsorption) nitrogen generators. Payback on such equipment can be two years or less. Nitrogen can be generated for eight to 12 cents per 100 cu. ft., while gas-utility companies charge 50 cents to a dollar or more per 100 cu. ft. The plant relies on an energy-intensive cryogenic process to cool air to extremely low temperatures MAY 2015 | PHARMACEUTICAL PROCESSING

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Tank Liquid Level

PROCESS

Drainback preventing riser must extend above highest liquid level

Overflow Line

Inlet Outlet

Valve Sparging Elements

to separate the nitrogen from air.

Nitrogen generators are also capable of producing up to 99.999% pure compressed nitrogen at dew points to -58 degrees F (-50 degrees C) from nearly any compressed air supply. The generators are designed to continually transform standard compressed air into nitrogen at safe, regulated pressures without operator attention.

Technical standards on water quality have also been established. The American Society for Testing and Materials (ASTM), the U.S. Clinical and Laboratory Standards Institute and the International Organization for Standardization (ISO 3696) classify purified water into Grade 1–3 or Types I–IV depending upon the level of purity. These organizations have similar, although not identical, parameters for highly purified water. Many laboratory, pharmaceutical, medical, research and dialysis applications require ultrapure water to meet one of these standards.

Nitrogen generators, such as those from Parker, use high-efficiency prefiltration to remove all contaminants down to 0.01 micron from the compressed air stream. The filters are followed by dual pressure vessels filled with carbon molecular sieves (CMS).

PHARMACEUTICAL PROCESSING | MAY 2015

In one vessel at operating pressure, the CMS adsorb oxygen, carbon dioxide, and water vapor. The other vessel, operating at low pressure, releases the captured oxygen, carbon dioxide, and water.

Cycling the pressures in the CMS vessels causes contaminants to be captured and released while letting the nitrogen pass through. A final sterilegrade filter removes microbial contamination. Nitrogen purities can be set with a flow control valve. Reducing the flow increases purity while increasing flow decreases purity.

For example, a system that produces a flow of nitrogen as high as 1,530 std. ft3/h at 99.9% purity can achieve higher flow rates if gas of lower purity is acceptable for that application. A built-in oxygen analyzer measures the oxygen concentration of the nitrogen stream. The system requires a minimum feed pressure of 110 psi and can operate at pressures up to 140 psi. The resulting nitrogen has a dew point as low as -58°F (-50°C).

On-site nitrogen generators are also compact, freeing up floor space.

They’re typically freestanding, housed in a cabinet, or skid-mounted. They come as packages with pre-filters, fi-

N2 Generator nal filters and a buffer tank. The plant needs to connect a standard compressed air line to the inlet of the generator (after ensuring that a sufficient supply of compressed air is available) and attach the outlet to a nitrogen line.

When connecting a generator to a large tank of water, it is important to prevent back-flow of the water into the generator if compressed air is lost. A check valve may be used, but a more reliable method is to run a vertical leg above the level of the water overflow pipe (the highest water level in the tank) and then back down again into the nitrogen generator. With this plumbing configuration, if the compressor goes down, water in the line would only rise as high as the level of the water in the tank. Therefore, water would not back flow into the generator and cause damage. (See diagram) Pharmaceutical manufacturers rely on a continuous supply of purified water for their operations. They must also ensure the purity of water stored for intermittent needs. Therefore, these plants need to have FDAcompliant nitrogen sparging and blanketing practices to ensure high purity demineralized water. On-site nitrogen generation has several advantages. n 15 n

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TRENDS

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BioPharma Industry Seeks Downstream Processing Advances Continuous purification systems and chromatography alternatives are in high demand.

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ownstream processing continues to impact capacity at the majority of biopharmaceutical manufacturing facilities, and industry respondents are clamoring for advances in this area, according to our soon-to-be-released 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production [1].

Indeed, manufacturers we surveyed for this year’s report are considering a range of new technologies to help ease the bottlenecks they’re currently experiencing.

Downstream processing’s inability to keep pace with upstream advances in recent years have been well-documented, and our annual studies have shown for some time that downstream is contributing to significant capacity bottlenecks at respondents’ facilities. With that in mind, it’s not too surprising that many biomanufacturers are insisting that the industry focus on downstream advances this year.

When we asked industry respondents to identify the single most important biomanufacturing trend or operational area that the industry must focus its efforts on this year, downstream processing advances emerged as the second-leading area.

So, for the industry as a whole, downstream processing now ranks as a bigger concern than manufacturing cost reductions and single-use system integration and implementation.

This year’s result marks a significant departure from last year, when downstream processing advances ranked as only the 6th-most important trend to respondents, behind the likes of biosimilars and continuous processing. As such,

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the industry appears to be coming to the conclusion that it’s time for downstream processing advances to emerge.

WHICH DOWNSTREAM INNOVATIONS ARE MOST INDEMAND? Almost all (97.4 percent) of qualified industry respondents this year said that they are considering new downstream purification technologies. Presented with a wide range of technologies, the following emerged as those most broadly in active consideration to address production issues or problems: (place graph 2 here) The results contain some interesting divergences from last year. For example, active interest in continuous purification systems showed a significant rise from 32.4 percent of respondents last year to half in this latest report, while fewer respondents this year expressed interest in membrane technology, one of last year’s leaders (39 percent vs. 49 percent).

Also of note: More than one-third (37 percent) of respondents this year reported actively considering alternatives to chromatography, with this representing a large increase from last year’s 21 percent, and by far the largest share of respondents signaling an interest this decade.

The uptick in consideration of chromatography alternatives aligns with separate results from our survey indicating close attention to chromatography. In fact, when we asked industry respondents to consider the new products and services suppliers develop, and identify the top five (from more than 20) they would like their suppliers to focus developments ef-

fort on, we found that chromatography products tied for the top ranking, cited by 36 percent of respondents.

Tellingly, chromatography products were joined at the top by disposable purification products (also 36 percent), supporting the industry’s need for advances in downstream processing. Last year, these areas ranked 5th and 6th, respectively, in terms of new product development areas of interest.

The industry’s renewed attention to downstream processing advances appears to be backed by budget increases, too, as almost two-thirds (66 percent) of survey respondents said they would increase their funding for new technologies to improve efficiencies/cost for downstream production.

That led all areas, surpassing the 62 percent planning increases in new capital equipment spending and the 59 percent expecting to grow their budgets for process development.

Those latter areas will see more significant budget increases, though, as new capital equipment spending is tabbed for an overall spending increase of 6.1 percent, compared to a 5.3 percent hike for process development and a 5.2 percent estimated increase for new downstream production technologies. Nevertheless, the 5.2 percent growth for downstream technologies ranks as the largest forecast increase in this area since 2012.

HOW ARE MANUFACTURERS IMPROVING DOWNSTREAM? Interest in novel technologies is clearly growing, but it’s also important MAY 2015 | PHARMACEUTICAL PROCESSING

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to see what biomanufacturers have been able to successfully implement to improve their downstream operations. We investigated this topic, finding a large portion of respondents implemented the following during the 12 months prior: • Optimized running conditions (51.2 percent) • Developed downstream processes with fewer process steps (47.6 percent) • Investigated single-use disposable downstream technologies (46.3 percent) For the most part, these were also top-ranking areas last year, with the use of disposable downstream technologies and membrane-based filtration technologies each creeping up slightly in the rankings. By contrast, fewer this year report having used or evaluated ion exchange membrane technologies and alternative ion exchange technologies.

It’s also worth noting that this year, 8.5 percent said they switched to protein A alternatives, up from 6.9 percent.

n BIOPHARMACEUTICAL

CONCLUSION Results from our 12th annual survey of the biomanufacturing industry show that downstream processing is rising in importance in the minds of many, to the point where it is one of the most critical areas facing the industry today. In response to continued bottlenecks – with 46 percent of respondents experiencing “serious” or “some” bottleneck problems owing to downstream processing – the industry is looking to downstream processing advances to provide it with answers.

Not only are chromatography products and downstream purification products atop the list of new technologies in demand, but anticipated spending on new downstream technologies is also up from the past couple of years, with those budgets potentially spent on continuous purification systems and chromatography alternatives, which are being actively considered by a growing share of industry respondents. In other words, this could be an interesting year for downstream processing. n

TRENDS

REFERENCES: 1. 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, BioPlan Associates, Inc. Rockville, MD., April 2015 Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989.

Survey Methodology: The 2015 Twelfth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from over 230 responsible individuals at biopharmaceutical manufacturers and CMOs in 30 countries.

The methodology also included over 150 direct suppliers of materials, services and equipment to this industry. This year's study covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time, and assesses differences in the world's major markets in the U.S. and Europe.

Filling flexibility from benchtop to production For over 25 years Flexicon’s expertise has offered filling and capping solutions to users as they scale-up from research to full scale fill/finish. Our asepticsu single-use technology has brought simplicity and security to high purity liquid filling applications.

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■PHARMPRO.COM

VALUE CHAIN

Moving Up The Value Chain How pharmaceutical legal departments can create a competitive advantage for the enterprise.

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n-house legal departments across the pharmaceutical industry are being asked to manage everincreasing risk and compliance challenges, as well as increasing litigation costs as cases increase. In fact, it has been estimated that 2014 saw a 25 percent rise in patent cases – a critical driver of corporate revenue given that generic manufacturers that win patent cases can take over 65 percent of a pharmaceutical’s revenue base and they win an estimated 70 percent of the time.

At the same time, these legal departments are facing pressures familiar to all legal departments, regardless of industry: lowering overall legal spend and evolving from a company cost center into a strategic business partner. These requirements mean that the department has to do more with less, while increasing visibility, predictability, and responsiveness.

Traditionally, however, in-house legal departments have not invested in building the skills, processes, and tools to support this evolution from a cost center into a true driver of business value for the enterprise. One way to think about this evolution is to view legal departments as falling in different stages on a maturity curve: • Stage 1: Legal as a Cost Center. o A department that primarily reacts in mitigating known risks. o Has undefined and/or inefficient business processes. o Operates as an independent “silo” with infrequent collaboration with other departments. o Has a reputation as simply a cost of doing business.

• Stage 2: Legal as a Tactical Success. o Department that is cost-efficient. o Uses predictable, repeatable pro-

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cesses to respond to internal and external needs. o Is viewed as a valued partner that is often brought in by the business to facilitate solutions.

• Stage 3: Legal as a Competitive Advantage. o Department that actually drives positive bottom line business results by optimizing legal spend and performance. o Operates with foresight to protect the company’s brand and reputation by preventing risks from becoming legal issues. o Leverages data to predict likely outcomes and support informed business decision making.

The best legal departments will be those that create lasting competitive advantages for their companies by embracing this change and moving up the value chain. At Mitratech, we have found that many legal departments beginning to embrace this new model through the implementation of key tactics, including: • Optimizing overall spend – moving beyond simply cutting legal costs to optimizing spend for business outcomes even outside of the department.

• Protecting intangible assets like corporate brand reputation proactively, in concert with strategic positioning.

• Proactively mitigating risk in a way that increases business investment opportunities.

• Facilitating decisions by predicting successful business outcomes – in addition to advising in a way that prevents legal risk.

• Minimizing commercial friction to the point of being an accelerant of revenue.

Let’s examine one example of how these can be applied specifically in the pharmaceutical industry.

EXAMPLE: In a recent Inside Counsel article, the example of one pharmaceutical company that proactively mitigated risk and averted compliance issues through emerging legal technology was highlighted. The article noted that “a major pharmaceutical company used data analytics available through e-discovery technology used in litigation and investigations to detect and avert potential liability relating to off-label marketing, unapproved patient populations, Sunshine Law compliance and unsupported product claims.

“The legal department interviewed subject-matter experts to gather the keywords, concepts and metadata necessary to construct a profile of documents requiring closer scrutiny. After sampling email and other unstructured data, the company used predictive, concept and relationship analytics, as well as email communication visualization to automatically segment the one percent of documents that indicated a potential compliance violation.”

This example demonstrates how proactively mitigating risk through the use of data and analytics enabled this pharmaceutical company to drive value to the business and lowered the risk of litigation costs.

What’s the lesson here? GCs must embrace their role as a driver of real competitive advantage and enterprise value. Legal departments cannot simply view themselves as a cost center. If one competitor is able to effectively apply these legal tactics in a way that their peer companies are not applying, they will win market share and drive shareholder value through an enhanced brand reputation, increased overall revenue and increased corporate profitability. n MAY 2015 | PHARMACEUTICAL PROCESSING

■ PHARMPRO.COM

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The One Solution For Contained Product Transfer Volkmann high quality, vacuum conveying systems not only contain your product during transfer, they meet cGMP cleanliness standards and are explosion-proof, all while giving you dense phase vacuum conveying free of segregation, damage or abrasion.

Volumetric And Gravimetric Feeders Hapman’s PosiPortion volumetric or gravimetric feeder feeds a wide range of free-flowing or sluggish bulk solids, granules and powders. Customized programmable controls provide accurate doses or continuous delivery by weight or volume. The exclusive flexible hopper is engineered with steep side walls, large inside corner radii and a long throat to maximize natural in-flow while facilitating external agitation to maintain the integrity of your material without degradation, segregation or agglomeration.

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HCP Wrap Around Case Packer The HCP wrap-around case packer handles cases or trays with the following features: • Inner or outer fifth flaps.

• Custom in-feed and product-handling systems.

• Speeds up to 30 cases/min.

• An all-servo design features Allen-Bradley multi-axis Kinetix servos, allowing for maximum uptime, quick changeovers and easy operation.

• A Nordson Pro Blue system with electric dispensing glue guns ensure fast, strong case seals.

• Category 3 Safety compliant.

• Optional stainless steel wash-down construction is available.

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FACILITY MAINTENANCE

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Dock Management: Sealing The Perimeter n By Mary Blaser, director of marketing and business development, Rite-Hite Environmental Enclosures Corporation

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harmaceutical warehouses are busy places. And while a steady flow of shipments in and out generally puts a smile on managers' faces, the repeated opening of loading dock doors also generates concern.

Open doors create opportunities for heated or cooled air to escape the building and rain, wind, snow and contaminants to get inside, creating safety, security and cleanliness risks. Open doors also invite potential airborne intruders – like bugs, leaves, dust or dirt – to enter. If not sealed properly, even closed dock doors may leave facilities vulnerable to these threats.

Fortunately, warehouse managers can significantly address these problems with the right system of dock seals and shelters – improving facility safety and security while saving thousands of dollars per year in wasted heating/cooling cost expenditures. Here are some considerations for getting started.

LOSING ENERGY (AND MONEY) AT THE LOADING DOCK While it’s a vital link between a facility and the pharmaceuticals shipped in and out every day, the loading dock presents the greatest opportunity for energy losses and damage to precious materials and products. Any opening can allow conditioned air to leave and foreign contaminants like dust, water and even rodents to enter. Larger openings only exacerbate these issues.

Even when trailers are at the loading dock, gaps often exist between the trailer and the edges of the dock opening.

Swing-open trailer doors usually lead to 1” to 2” gaps. While that might seem insignificant at first glance, it equates to a 2.5-square-foot hole at just one dock opening. Depending on the climate of the facility, this represents anywhere from $600 to $1,200 quite literally flying out the door every year. Now extrapolate those figures over multiple dock doors and the financial loss is significantly more profound.

But the sides of the dock opening aren’t the only gaps in the building’s perimeter. Many facility managers forget about the “fourth side” of the dock – the bottom end, where the leveler, trailer, and dock seal or shelter meet. Depending on the size of the opening, that gap could result in another $200 to $900 lost annually.

CONTAMINATION CONCERNS Sealing all gaps at loading dock doors can protect the facility from potential contamination concerns as well. Gaps between

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the loading dock wall and the trailer can let in dust, debris, rain and sunlight – which is potentially damaging for some lightsensitive products. Exposure to these elements can damage products and equipment, leading to even more profit-erosion.

And while the pharmaceutical industry is held to the highest of sanitation and hygiene standards for manufacturing, processing and storage applications, the loading dock is often overlooked. Preventing potential contaminants from entering is a good start to maintaining a clean environment and secure supply chain.

LOOKING FOR LIGHT Every loading dock and dock opening configuration and structure will be different. Understanding the size and types of trucks that come to the facility also plays a major role. For example, trucks with hydraulic lift gates will have different impact points against dock walls than trailers whose doors swing open. In almost all cases, however, the first rule of thumb is to look for light leaks along the dock door perimeter – where there’s light coming through, there’s energy leaving the facility and an opportunity for contaminants to enter.

These light leaks are no different than the ones that often appear on the sides and sometimes tops of trailers.

Remember, even the smallest, most seemingly harmless gaps can add up to hundreds of dollars in lost energy annually.

If you can see daylight at your loading dock doors, that means there’s a gap to be filled and you’ll need to source the right product to fit each type of gap. Understanding these things can help lead to more informed decisions on properly sealing these gaps to save energy and help you pass your next quality inspection.

SEALING SOLUTIONS Not all seals and shelters work for every situation at the loading dock. Determining the best products that work in concert with one another to properly seal the dock opening is essential in maximizing energy and cost savings.

While foam compression style dock seals generally offer a great deal of energy efficiency, even highly durable fabric can suffer from significant wear-and-tear due to constant friction.

Seals can also present potential access issues. Dock shelters, in contrast, tend to offer greater access to loads, but unless the right model is selected, energy efficiency tends to be lower than that of a seal (80-85 percent compared to 90-95 percent).

MAY 2015 | PHARMACEUTICAL PROCESSING

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FACILITY MAINTENANCE

Vertical storing dock levelers enable the dock door to form a tight seal along the floor and protect forklifts from damage.

SEALING THE PERIMETER Getting a consistent, gap-free seal along trailer sides, tops and corners, as well as at the bottom of dock door openings, will create an environmentally secure and energy efficient dock. An effective system of sealing products starts with a dock shelter that is specifically designed to overcome the most difficult sealing challenges.

Dock shelter head curtains help seal gaps and create a seal at the top of the trailer. However, sealing and blocking out daylight completely can be a challenge, made worse at facilities that are serviced by trailers of varying sizes, where head curtains aren’t frequently adjusted correctly to reach lower trailers. Therefore, a head curtain that utilizes weight and gravity can create a solid connection with the trailer top. The weight is necessary to maintain a tight, consistent seal across the full width of the trailer as it bounces during loading and unloading.

Also, the head seal must adjust to a wide range of trailer heights without requiring pull ropes or other forms of manual adjustment. This type of shelter header essentially “does PHARMACEUTICAL PROCESSING | MAY 2015

it all” and eliminates the need for an additional overhead rain diversion device. Additionally, facility managers should make sure their dock shelters provide a solid seal at trailer top corners, where side curtains and head curtains come together. This area is notoriously difficult to seal and requires specially-designed equipment to ensure an effective seal in this area.

On the sides of the trailer, keep the 2.5 cumulative square feet of opening created by exposed hinge gaps covered completely by hooks on the shelter side curtains. In applications where trailer doors are opened inside the building for security purposes, make sure that the shelter side curtains are designed to provide an effective seal along trailer sides.

COMPLETING THE SEAL: THE CHALLENGE OF DOCK LEVELERS While it is critical to effectively seals gaps along the sides and top of the dock opening, don’t forget the aforementioned “fourth side” – the bottom. In most cases, this involves the dock leveler. Gaps typically exist below and around the leveler 21 n

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FACILITY MAINTENANCE

and dock bumpers which present another challenge to industrial hygiene and sanitation.

Installing a seal under the leveler can offer a barrier against the elements on the facility’s exterior. Inside, lip corner seals, filler pads and other components keep the inside of the dock protected. In essence, anywhere there is daylight visible at a dock door opening when a trailer is in place, a gap exists which must be filled to prevent infiltration of contaminants and loss of heating and cooling energy, and a product is available to fill it.

Sealing under and around the leveler will help keep dirt, debris and refuse out of leveler pit and close gaps that allow dirt, dust and insects into the building. Sealing these gaps will also help reduce heat transfer through the steel leveler deck and – as on the other three sides of the dock opening – will help prevent heated or cooled air from escaping the building.

Experts estimate that pharmaceutical warehouses and other industrial facilities can save up to $1,000 per year per dock position in total energy savings, depending on climate, by using under-leveler seals.

Vertical storing dock levelers provide another option for control of the fourth side. Considered the gold standard environmental protection of dock openings, vertical levelers differ from pit-style levelers in that they allow the loading dock door to close directly onto the pit floor, rather than onto the leveler.

This minimizes outside air infiltration, helps reduce contami-

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nants from entering a building and also helps protect the dock door from damage.

Additionally, vertical dock levelers improve security by minimizing points of entry at the dock. Additionally, their vertical design makes it easy to clean or wash down the pit floor when the leveler is in the upright and stored position, which is critical in the pharmaceutical industry.

PROPERLY SEALING THE DOCK A dock seal or shelter creates a unified, seamless connection between the back end of the semitrailer and the inside of the loading dock in forming a crucial environmental barrier to keep wind, rain, dust, bugs, and other contaminants outside the building – and valuable conditioned air inside.

Today’s leading seal and shelter products can also guarantee: • Protection against burning from the heat of trailer marker lights.

• Provide state-of-the art materials for the longest wear.

• Offer custom designs to match the specific, unique needs of individual customers.

However, regardless of site specifics, facility managers should mandate an effective dock sealing system that takes all four sides of the opening into account, thus protecting and securing the integrity of the product as it moves into and out of a facility during manufacturing, processing and shipping. n

Thousands of dollars in HVAC energy can escape the building and contaminants can enter it through the dock doorway. Dock seals close up the gaps between the truck and the door frame.

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MAY 2015 | PHARMACEUTICAL PROCESSING

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Vacuum Conveyors with cGMP Design

Meissner’s FlexGro single-use biocontainer assemblies offer use with rocker-style bioreactors. The biocontainer assemblies are available in design options up to 50 L and are delivered pre-sterilized for immediate use. Additional features include: • TepoFlex polyethylene (PE) multi-layer film - an exceedingly clean film platform devoid of slip agents.

• Assemblies can be easily customized to specific enduser requirements via various sampling and process connection options.

• Multiple standard assembly designs are available.

■ Meissner; www.meissner.com.

Volkmann offers their line of PPCVS vacuum conveyors for transferring a wide variety of bulk materials without separation or segregation to ensure a dust and emissions-free workspace. Additional features include: • A one-piece, gap-free design with a polished stainless steel surface.

• All pneumatic operation with a simple air hook-up.

• A patented QX filter system with a unique connection to the filter plate – replacing the commonly used felt seal or O ring to ensure isolation of the process down to the 0.3 micron size.

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M A N U FA C T U R I N G

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How Shared Service Management Can Help Make Your Organization Lean n By Nancy Van Elsacker

PUT THE CUSTOMER VALUE FIRST The first principle of Lean says that the customer should always come first: “What does he want to pay for?” Lean says: Only do that which is of value to your customer.

This sounds logical, but how often do we do things to please our boss instead of our customer?

Think of reports, authorization or checks. The customer also comes first when introducing shared service management. This is most evident when the supporting departments become a single shared service desk. This offers the customer a considerable benefit, because he Nancy Van Elsacker, president of no longer has to think about whether he TOPdesk, a global provider of serhas to send a request to HR, facilities or IT vice management solutions. departments. The customer, which in this case also happens to be an employee, can go to a single portal instead. After all, it makes no differSHARED SERVICE MANAGEMENT AND LEAN ence to the customer who processes his request so long There is a long way to go in becoming a Lean organias the services can be requested more easily and are zation, and it can be difficult to know where to begin. readily available.

The Lean management philosophy has its origins in manufacturing. It has been growing in popularity since OPTIMIZE THE VALUE STREAM the turn of the century because it contributes to imThe value stream refers to the chain of activities from reproved quality, efficiency and an organization’s learning quest to delivery. Which steps add value for the customer? capabilities.

The steps without value must be eliminated or minimized.

There are five basic Lean principles: In shared service management, the value stream is • Value. improved when the supra-departmental processes are • Value stream. coordinated to form a single shared process. Think, for • Flow. instance, of a common process, such as an employee • Pull. changing positions within the organization. If the HR, IT • Perfection. and facilities departments still work independently of one Combined, they lead to improved company results, another, the manager has to issue three different authowith more being produced against the same costs. A rizations before this process can commence. When you similar result is achieved when shared service manageapply shared service management processes, you bring ment is introduced. This is achieved by strengthening the different processes together. This enables you to fully the collaboration between different supporting departmap the value stream of this process. ments. With shared service management, organizations The value stream can then easily be optimized by rework toward making the service management more moving duplicate steps. The manager only has to issue a Lean.

S

ervice Management is a customer-focused approach to delivering information technology. Service Management provides a framework to structure IT-related activities and the interactions of IT technical personnel with customers and clients. Shared service management (some call it enterprise service management) is an important development in the collaboration between an organization’s supporting services. The Lean management philosophy is also becoming more popular. Both offer many advantages for the organization and its users, but shared service management also can make an organization more Lean.

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single authorization for the position change, after which all departments know they can get to work. This eliminates two superfluous authorization steps without losing any value.

ADD FLOW TO YOUR ACTIVITIES Once the value stream is mapped, it is time to simplify and standardize the process as much as possible. This prevents obstructions in the process, such as waiting times. When all activities are picked up and processed at the right time, flow is created.

In shared service management, the flow principle becomes apparent when an organization has gained experience in communally processing a supra-departmental process. In the previously mentioned process of an employee changing positions within an organization, HR, facilities and IT must swing into action. These departments’ activities are mutually dependent to a certain extent.

The first step is often that HR applies a change in the staff administration because the other departments need this information to perform their tasks. The IT department has to know which authorizations they must assign, and the facilities department wants to know whether they must supply a mobile phone, and which company car.

When these departments work in the same tool, everyone can see the progress. In addition, the tool makes sure that the task is not visible until it can be picked up. This prevents unnecessary obstructions.

PULL: SUPPLY ON TIME The pull principle concerns services only being supplied when the customer asks for them, and that they are then supplied on time. This is a tricky principle, and can only be adhered to when the value stream is mapped and there is flow in the process. Only then can the process be controlled and predicted.

In shared service management, the pull principle is apparent when a shared process is under control. Let’s take the commencement process as an example. When someone is hired but won’t start work for another three months, it’s a waste to immediately order supplies for them. In this time, the price of the products may drop or a newer product may become the new standard. When the commencement process is fully under control across all departments, you can determine when these items must be ordered so that the new employee has everything they need to get to work on their first day.

STRIVE FOR PERFECTION The fifth Lean principle states that you should always continue striving for perfection. Lean says that you can never reach perfection, but striving for it is important.

Continue improving by taking small steps.

PHARMACEUTICAL PROCESSING | MAY 2015

n

LEAN MANUFACTURING

With shared service management, you strive for completely integrated services and supporting departments.

In the future, you may not speak about separate IT, facilities and HR function, and there will be a single services department. To achieve this, the departments must join forces with regard to tools, processes and the service desk, with each department maintaining its own areas of expertise. This complete departmental integration cannot be achieved in the short term, but the important thing is the steps you take in that direction.

The shared service management implementation comprises various phases. Most organizations start where there is nothing shared. In this phase, each of the organization’s departments has its own processes and procedures. They hardly work together and there is a strict division of tasks.

The first step organizations take toward shared service management is making it a shared tool. Organizations that use a shared tool already work in a single package, but still have different ways for the customer to approach them, as well as their own processes and procedures.

This step does provide significant savings, because it reduces the number of applications used. However, customer satisfaction really starts improving in the next step: shared service desk.

In this phase, a shared service desk is set up featuring all of an organization’s supporting departments.

This creates a single point of contact for customers to request all services. Once all departments start using the same processes and procedures, the organization is in phase three: shared process. It is in this phase that the maximum customer satisfaction and cost effciency is achieved.

Regardless of the time and phase an organization starts in, no two organizations take the same path to shared service management. However, there is one way in which practically all organizations are identical: The wish to reach maximum customer satisfaction at the lowest possible cost.

It’s impossible to predict the obstacles that will be faced on the way to shared service management. It is important to set realistic goals for your departments and colleagues. Nothing is more demotivating than not achieving a goal, while few things are as motivating as celebrating success.

Taking many small steps results in a big improvement in an organization’s customer services. By following these aforementioned steps, organizational leaders can keep taking steps toward better collaboration, and, therefore, toward improved services. n Nancy Van Elsacker is president of TOPdesk, a global provider of service management solutions for organizations of all sizes.

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2015

Legacy Drives New Innovation While INTERPHEX and Rockwell Automation might not have a long history, the company is looking to leverage a strong background in the pharmaceutical marketplace to help its customers drive software and automation-focused efficiencies. n Interview by Jeff Reinke

I

NTERPHEX 2015 offered attendees multiple opportunities for conversations focused on new products and approaches. One source of such discussions was the Rockwell Automation Center for the Connected Enterprise.

Pharmaceutical Processing sat down with Rockwell Automation's Paula Puess, Global Market Development Manager and Khris Kammer, Manager of Information Solutions Consulting to get their take on the show, recent market developments and what the future may hold for the pharmaceutical marketplace.

Jeff Reinke: Seeing Rockwell Automation with such a large presence at INTERPHEX is interesting. What drove that decision?

Paula Puess: Although PharmaSuite MES software doesn't have as large a presence in the U.S. pharmaceutical marketplace, we’ve been in this business for a long time. In Europe our software systems are in place with the 20 or so largest manufacturers. So due to some key acquisitions and the continued growth of our core product offerings, Big Pharma knows us quite well on a global level.

JR: I found the Klyo Collaborative announcement, where Rockwell is joining a group of six other design, engineering and consulting firms to aid biopharmaceutical companies with a host of solutions focused on small and large-scale product developments, interesting as well. What do you feel will be the greatest benefit of such a partnership?

Khris Kammer: Anytime you can increase collaboration amongst different providers, the customer will benefit from an ability to get things done more quickly. I think that’s the biggest benefit with the partnership – the ability to integrate the necessary product development in a modular and scalable fashion. This is huge for overcoming the difficult transition from formulation to factory.

JR: In working with either CMOs or Big Pharma clients, what typically comes first – the hardware or the software?

PP: We’ve found that CMOs are typically more production focused, so the equipment or hardware is very well integrated.

They turn to this data and other manufacturing intelligence assets in looking at performance and driving efficiency, but Big Pharma, in general, seems more focused on software implementation as a way to drive greater connectivity throughout the

n 26

enterprise and possibly across multiple locations. This is about insuring product and brand integrity.

KK: On the Internet of Things front, we work closely to get things specified accordingly at the beginning of the project, regardless of the customer type. This is where our past history in the marketplace, applying things we’ve learned from other industries and our confidence in our own products helps in ensuring the processor doesn’t lose time during the integration process.

What’s interesting is that we find a great deal of machine-tomachine communication taking place within the pharmaceutical production facility. Our job is getting all these assets talking to each other so the data is easier to access and utilize. Getting back to your initial question, in general we tend to start with the software and the hardware sort of backs in as we get more focused on production solutions.

JR: Pharma is unique in that, as an industry, it’s at the forefront of many production-focused technologies. In contrast, enterprise-wide data integration has not always been a point of strength. How do you work with processors this respect?

KK: Regardless of industry or the type of customer, we’ve found that the biggest driver or obstacle to innovation and investments in software or automation is cultural, rather than an issue of technology. So while we’re still working with the pharmaceutical marketplace to capture all the potential of our offerings, these are innovative companies that understand the value proposition garnered via the deeper implementation of software and related automation technologies.

So now it’s showing the processor how data-focused approaches will improve performance in multiple areas. What’s unique with Pharma is that there is less need to help them understand why it’s important to access the data being generated.

Rather, we need to pay greater attention to the manner in which they access this information and then act on what they’re seeing.

PP: This is key because this technology leads to so many other areas of pharmaceutical production. Some of the biggest issues relate to regulatory mandates impacting serialization and track and trace. Integrating software applications that help address these regulations also allow for processors to better manage other areas of the enterprise, including supply chain and product development. n MAY 2015 | PHARMACEUTICAL PROCESSING

■ PHARMPRO.COM

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INTERPHEX 2015

3D Printing Pavilion Builds Excitement Ways to implement the manufacturing and prototyping technology within the pharmaceutical marketplace were highlighted at INTERPHEX 2015. n By Jeff Reinke

W

hile many of the conversations in the INTERPHEX exhibition hall surrounded more mature, but increasing significant production technologies like single-use equipment and serialization management, there was one newcomer that definitely stood out. Amongst the educational sessions and product unveilings was a new pavilion dedicated to 3D printing. Within this section Fraser Advanced Information Systems, Nextline and BioBots all offered attendees a closer look at how this technology could help streamline some of their operational challenges.

Nextline (www.nextlinemfg. com) is a service bureau that got its start from traditional molding and manufacturing processes, and later expanding to additive manufacturing. The company works with pharmaceutical processors by providing one-off replacement parts, scalable models and prototypes in materials including a nylon polymer, aluminum, stainless steel and a UV-cured plastic that closely resembles rubber. The company specializes in selective laser sintering and direct metal laser sintering – both of which use a plastic or metal resin to build-up and bind materials together in creating a finished product.

“Our customers typically upload the design data through our site, select a material and provide some additional information about the part or project,” states Greg Paulsen in describing how Nextline works with customers. “If you’re looking to replace a part that can take a long time to get, requires special tooling to re-produce, or is quite expensive, 3D printing can be a very timely and cost-effective option.”

Prototyping is still the primary application for 3D printing, with attendees investigating the technology’s potential to dePHARMACEUTICAL PROCESSING | MAY 2015

sign better packaging and injectable delivery mechanisms to help answer market demands for more customized medicine.

While some of the materials are only suitable for prototyping, many can be used in production environments. Due to the fully sterilizable composition of the nylon, for example, these parts can be used as replacements on functional equipment. The lack of welds also makes them desirable from an anti-contamination perspective. Paulsen points to examples such as sorting wheels that the company has produced specifically for pharmaceutical companies.

Additionally, many bottles and other containers can be customized and utilized via 3D printing’s expanded capabilities. However, this technology is best suited for lower quantity production due to the cost of the materials and time required to produce an individual piece.

The theme coming from the pavilion seemed to be in challenging processors to examine their current approaches to low-quantity sourcing and see if 3D technology would allow for doing it faster, while preserving the value. Options include using a service provider like Nextline or working with the pavilion’s primary sponsor - Fraser Advanced Information Systems, a reseller of 3D Systems’ line of machines.

One of the most interesting points raised during my time in the pavilion helped underscore the potential significance of 3D printing moving forward. The pharmaceutical industry knows how to produce medicinal powder; the food industry has created edible binders; once the right ratios have been developed, could customized solid dosages be printed at home or in the pharmacy? While the significant number of regulatory hurdles involved would obviously need to be addressed, these types of questions have processors looking at 3D technology in a very unique light. n 27 n

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■PHARMPRO.COM

2015

INTERPHEX In Photos INTERPHEX recently opened and closed its doors for 2015. The show offered a number of new product announcements, educational events and networking opportunities for attendees and exhibitors. Some of the highlights are offered below and on-line at www.pharmpro.com.

M

onitors throughout the show floor streamed educational panel discussions that took place on the INTERPHEX Live stage. Moderated

by Somma Tech president and Founder Russ Somma, the sessions offered thought leadership from experts throughout the industry covering topics such as serialization, single-use technology, contract manufacturing and regulatory developments.

Fette was recognized with the Editor’s Choice award for their FE series of tablet presses. This award was presented

by Pharmaceutical Processing as part of INTERPHEX’s Exhibitor Awards program. The panel selecting the award was comprised of: • Angelo DePalma, Consultant • Kristie Grammatikos, Merck • David Hall, Parenteral Drug Association • Jo Anne Jacobs, Cook Pharmica • Patrick Poisson, United Therapeutics Corp.

• Gil Roth, Pharma & Biopharma Outsourcing Association (PBOA) • Jeff Reinke, Pharmaceutical Processing n

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MAY 2015 | PHARMACEUTICAL PROCESSING

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Hydraulic Motors For Washdown Environments

NEW PRODUCTS

Tamperproof Laboratory Autoclaves The combination of secure key-lock and one-touch push button controls make the Priorclave QCS H150 frontloading autoclave one of the safest and most efficient autoclaves available. Additional features include: • The 150-liter laboratory autoclave has a stainless steel, 500 mm diameter sterilizing chamber.

• Push-buttons controls on the Tactrol 2 microprocessor control panel.

• The ability to keep a log of the sterilizing cycle data such as temperature, pressure and time.

• A secure key-lock switch on the front of the control panel which governs access to parameter settings.

• Incorporates epoxy-coated panels and frame members treated with an antimicrobial agent that is effective against bacteria and fungi including MRSA, E.coli, Listeria, Legionella, Campylobacter, Salmonella, and Pseudomonas.

■ Priorclave North America; www.priorclavena.com

Dayton Lamina hydraulic motors feature a unique design that allows four times the torque to be produced at one-quarter the speed, without gear reducers. They are ideal for use in wetted environments and those subject to frequent washdown. Described as low-speed/hightorque motors, they also feature: • A torque range from 0 to 656 in-lbs. and speeds from 0 to 2,255 RPM. • Four flange options.

• A bronze-plated bearing surface, positive metal-tometal sealing, a positive splined drive and a matched gerotor.

• The ability to perform with flow rates from 1 to 8 GPM to deliver from 100 to 1,500 PSI. ■ Dayton Lamina; www.daytonlamina.com.

SIMULATING SYSTEMS

Nanoparticle Homogenizer

FLOW − THERMAL − STRESS − EMAG ELECTROCHEMISTRY − CASTING − OPTIMIZATION REACTING CHEMISTRY − VIBRO-ACOUSTICS MULTIDISCIPLINARY CO-SIMULATION

GEA Niro Soavi has developed the Ariete NS5180 homogenizer, with features that include: • Compliance with EU safety rules (CE standards) and built according to EN ISO 9001:2008 Quality Systems.

• Constructed of high-quality stainless steel and corrosionresistant materials.

• Throughputs from 100 l/h to 50,000 l/h at continuous working pressures from 100 bar up to 1,500 bar.

■ GEA Niro Soavi; www.niro-soavi.com PHARMACEUTICAL PROCESSING | MAY 2015

29 ■

info@cd-adapco.com www.cd-adapco.com

CORPORATE PROFILES 2014

Veltek Associates, Inc.

Finesse Solutions, Inc.

VAC-U-MAX

Company Overview/Mission: VAI is an EPA/FDA registered manufacturing facility specializing in identification and control of, contamination in classified areas. VAI produces a comprehensive set of sterile pharmaceutical grade disinfectants, sanitizers, sporicides, cleaners, lubricants and detergents. Additionally, we offer, viable monitoring equipment, including our new SMA OneTouch ICS, cleaning equipment, and laboratory services.

Company Overview/Mission Finesse Solutions, Inc. based in Silicon Valley California provides intelligent bioprocess management solutions. Our mission is to empower clients with innovative single-use sensors, bioreactors, controllers and software for upstream and downstream bioprocessing. In addition to our own products, we are the only supplier offering integration expertise, allowing our clients freedom to choose preferred key units of operation. From a single-use bioreactor for research and development to a fully integrated SmartFactory, we have a bioprocess solution for our customers.

Company Overview/Mission: Since 1954, VAC-U-MAX has defined leadership in bulk material handling, specializing in the design and manufacture of pneumatic conveying systems and support equipment for the conveying, weighing, and batching of dry bulk materials. As a pioneer in vacuum conveying, VAC-U-MAX has had many firsts, including the first air-powdered venturi power units, direct-loading of vacuum tolerant process equipment and vertical-wall “Tube Hopper” bulk material receivers. As a UL-listed manufacturer of control panels, VAC-U-MAX furnishes integrated control systems with tie in capabilities to existing control systems.

VAI is proud to introduce a new line of Cleanroom Documentation. We have addressed and solved the questions surrounding particulate and fiber shedding throughout the cleanroom from documentation systems by developing, Core2Print, Core2Write, and CleanPrint 10. Core2Print, is a 316L Stainless Steel, HEPA filtered printing system, Core2Write, is the custom documentation system featuring logbooks, ID tags, forms and labels, and CleanPrint 10, the synthetic, low particulate and non-shedding, writing substrate.

Not only this, but VAI has completely redesigned their garment line to feature more flexibility and space inside while maintaining a sleek design that works for all body types. Our garments provide 100% sterility assurance and a zero chance of cross contamination all while being chemical and splash resistant.

Overall, VAI is proud of its history of innovation. VAI has been an industry leader since 1981 and is committed to continual innovation and improvement in our products to satisfy current and future regulatory requirements.

Products/Services SmartParts™ intelligent components provide modular, scalable and highly configurable measurement and control. They are the building blocks for Finesse G3 bioprocess controllers.

TruBio ® software is user-friendly, configurable, can harmonize old and new equipment, and integrate in-line and offline data.

TruFluor ® single-use sensors, designed for maximum stability with minimal drift, have an embedded SmartChip™ which holds sensor manufacturing lot and factory calibration information.

G3 Universal™ controllers easily scale from lab to cGMP-compliant production, enabling sophisticated cell culture recipes to run on any size or brand of vessel.

SmartFactory™ provides an operations management solution for single-use facilities which optimizes plant-wide resource utilization and integrates manufacturing information.

Finesse provides products and services for biopharmaceutical manufacturing and research, including hardware systems and automation solutions for applications ranging from development through production.

Products VAC-U-MAX is a global manufacturer of pneumatic conveying components and complete material transfer systems for the handling of powders, pellets, granules and other bulk materials for applications including loss-in-weight feeder refill, tablet press loading, or blender loading.

Product range includes dilute and dense phase vacuum conveying systems, multi-ingredient handling systems, batch weighing systems, sanitary powder receivers, bulk bag loading and unloading systems, bag dump stations, and control.

VAC-U-MAX offers full test lab capabilities and ability to create any process configuration.

Veltek Associates, Inc.

Finesse Solutions, Inc.

VAC-U-MAX

15 Lee Blvd.

Malvern, PA 19355 Tel: +1 (610) 644-8335 Fax: +1 (610) 644-8336 Website: www.sterile.com

3501 Leonard Court Santa Clara, CA 95054 +1 408 570 9000 sales@finesse.com www.Finesse.Com

69 William Street Belleville, NJ 07109 Phone: (973) 759-4600 Fax: (973) 759-6449 Email: info@vac-u-max.net www.vac-u-max.com

CORPORATE PROFILES 2014

Watson-Marlow Fluid Technology Group Company Overview Watson-Marlow Fluid Technology Group is the world leader in niche peristaltic pumps and associated fluid path technologies. Founded on nearly 60 years of supplying engineering and process expertise and with over one million pumps installed worldwide our pumps are tried, tested and proven to deliver. Watson-Marlow Fluid Technology Group comprises of seven established brands, each with their own area of expertise, but together offering our customers an unrivalled breadth of solutions for their pumping applications.

Check-All Valve Mfg., Co. Company Overview/Mission: Check-All Valve ® Mfg. Co. manufactures a complete line of in-line spring-loaded piston type check valves. With worldwide service, Check-All Valve ® serves a wide range of industries including the chemical, petrochemical, pharmaceutical, food and beverage, water treatment, OEM, MRO and many others. Every Check-All ® valve is designed and built to perform to exact needs and specifications. The Company is ISO 9001 certified and manufactures product lines compliant with CE/PED requirements, Canadian Registration Number guidelines, 3A Sanitary Standards and others.

■ MARKETPLACE

Wesco® manufactures and distributes stainless steel material handling equipment.

Industrial Products, Inc.

www.wescomfg.com

FLEXIBLE MANUFACTURING FACILITY EXCELLENCE AWARD info@customprocessingservices.com phone: 610-779-7001 customprocessingservices.com

Products Offering a contamination-free single use fluid path and a range of products from benchtop to production, Watson-Marlow is the first choice for fluid transfer, metering, dispensing and filling. BioPure has built its reputation as specialists in the design, manufacture and supply of single-use bioprocessing components.

BioPure fluid path components allow the industry to connect with confidence. Our single-use components are manufactured and packed in an ISO Class 7 clean room validated in operational state and has lot numbers molded in for full traceability.

Our Flexicon peristaltic filling and capping solutions bring significant advantages to users as they scale-up from research to production fill/finish. Using our single-use asepticsu technology, our range of fillers/ cappers, clinical scale semi-automatic filling systems and fully automatic production scale systems define simplicity and security in high purity liquid filling applications.

Check-All ® valves are engineered for silent operation. They close quickly and smoothly to eliminate hammer noise. With proper spring selection, our check valves are designed to function equally well in either a vertical or horizontal position. Our insert style check valves easily fit into existing line components, which reduce initial cost and installation time. The seating surfaces are parallel to each other; thereby, eliminating the excessive wear occurring in plug, cone and ball seats.

Check-All ® valves can also be used as low pressure relief valves and vacuum breakers by using the desired spring setting.

Check-All Valve ® provides check valves for practically every service application. We offer metal-to-metal or soft seats in sizes ranging from 1/8 inch NPT to 20 inch flange connections. Pressure ratings are available from full vacuum to 10,000 PSI. Standard or exotic materials are also available and you can choose from a wide variety of spring settings and seat materials for any valve. Most options are available with fast delivery.

Watson-Marlow Fluid Technology

Check-All Valve Mfg., Co.

Group 37 Upton Technology Park, Wilmington, MA 01887 Phone: 800-282-8823 E-mail: info@wmftg.com URL: www.wmftg.com

1800 Fuller Road West Des Moines, IA 50265 sales@checkall.com www.checkall.com Phone: 515-224-2301 Fax: 515-224-2326

For information or to reserve space contact TOM LYNCH E-mail: tom.lynch@advantagemedia.com Phone: 973-920-7782

CENTRIFUGES & DRYERS Nutsche Filter-Dryers Conical Vacuum Dryers Horizontal Peeler Centrifuges Basket & Inverting Filter Centrifuges

856-467-3399 www.heinkelusa.com

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C O N TA M I N AT I O N P R E V E N T I O N

â– PHARMPRO.COM

Improved Detection Of Pyrogens Using The Monocyte Activation Test n n n n

Audrey Borel, PharmD Global Product Manager - Rapid Release Testing Pharma, EMD Millipore Bodo Holtkamp, Biotest AG, GBU Mikrobiologie Gabriele Schmitz, Biotest AG, GBU Mikrobiologie Thomas Hartung, Johns Hopkins University, Center for Alternatives to Animal Testing

P

yrogens are a heterogeneous group of contaminants comprised of microbial and non-microbial substances. The most widely known pyrogen is the endotoxin lipopolysaccharide (LPS), which is produced by gram-negative bacteria. Other microbial substances include those derived from gram-positive bacteria such as lipoteichoic acid (LTA) and particles from yeasts and viruses.

When present in pharmaceutical products, pyrogenic substances can prove harmful to humans by causing life threatening fevers. Therefore, testing of pharmaceutical products for pyrogens is critical to ensure patient safety.

The human response to pyrogenic substances is complex. It is regulated by monocytes, which contain receptors for the various pyrogenic substances and respond with a high sensitivity, especially to endotoxins. The activation starts with LPS binding to toll-like receptor 4 (TLR4) and involves a cascade of intracellular reactions resulting in a release of pro-inflammatory cytokines. The participation of the different receptors in the reaction path is illustrated in Figure 1. There are additional receptors (e.g. TLR2, TLR7, TLR8, TLR9) which, upon binding of their specific ligands, trigger or influence pyrogenic reactions [1].

The traditional methods for pyrogen detection either require animal sacrifice for the Rabbit Pyrogen Test (RPT), or are limited to the detection of endotoxin LPS from the cell walls of gramnegative bacteria (for example in the Limulus Amoebocyte Lysat [LAL] test).

When performing pyrogen testing in pharmaceutical products, the complexity of the human response must be considered. This article will describe a pyrogen detection method based on the Monocyte Activation Test (MAT), which incorporates an assay based on human monocytes conducted in vitro, instead of using animals. Detection of various pyrogenic substances using the MAT and standard methods will be presented.

MATERIALS AND METHODS For analysis of the pyrogenic reactions, the PyroDetect System (EMD Millipore, Darmstadt, Germany), which is based on MAT, was used to assess pyrogens known to interact with different receptors on and in monocytes.

The PyroDetect System uses cryobFigure 1: Signal transfer in the induction of pro-inflammatory cytokines. Binding of specific ligands to TLR2 and TLR4 at the cell surface or to TLR7 and TLR8 in endosomes, and association of the adaptor protein lood, which is pooled and frozen huMyD88 induces a cascade of intracellular reactions.

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man whole blood, as a source of monocytes. The monocytes activated by pyrogens produce cytokines which are detected in an enzyme-linked immunosorbent assay (ELISA).

The MAT employing fresh or cryo-preserved human blood was described and validated as an in vitro pyrogen test [2,3]. It has been included in the European Pharmacopoeia (EP) since April 2010 [4].

For cryoblood incubation, sample or endotoxin are mixed with cryoblood in a cell culture plate and kept in an incubator at 37°C for 8-24 hours for interleukin-1ß (IL-1ß) production.

For the IL-1ß detection, the cryoblood incubation mixture is transferred into an ELISA plate coated with a monoclonal antibody specific to IL-1ß. Interleukin molecules present in the culture supernatant are bound by the immobilized antibody. After removal of unbound components by several washing steps, an enzyme-linked polyclonal antibody specific for IL-1ß is added. With the addition of the substrate, a color reaction is started, which allows the detection of the bound IL-1ß in an ELISA reader.

The pyrogen concentration in the sample is then determined from the IL-1ß concentration via an endotoxin standard curve, and analyzed with the PyroDetect data analysis tool.

RESULTS The broad pyrogen spectrum detected by the PyroDetect system was evaluated against a set of substances.

Lipopolysaccharide is detected by the system down to a concentration of 25 pg/ml, corresponding to 0.25 endotoxin units (EU). This reaction is enhanced by soluble peptidoglycan (PGN) up to a concentration of 10 µg/ml, resulting in a reduction of the limit of detection for LPS by a factor of 10. In addition, a general increase in IL-1ß production was observed for all LPS concentrations.

Although this enhancing effect could increase sensitivity, it may create a problem for pyrogen analyses according to the European Pharmacopoeia. If the values for recovery of a defined amount of control endotoxin (spike) exceed the limits of 50 to 200 percent, the test is not regarded as valid [4]. The interference may be overcome by dilution, but is restricted by the contaminant limit concentration (CLC; for intravenous infusions 5 EU/kg body weight/hour) and the limit of detection (LOD) of the test system.

The MAT therefore may not be applicable for substances administered in large volumes. Alternatively, the interfering effect offers the chance for a better differentiation of the inflammatory reactions. In the example of peptidoglycan, the pure substance alone does not induce any IL-1ß response at concentrations between 10 pg/ml and 100 µg/ml (data not shown).

The pyrogenic activity of lipoteichoic acid could be detected down to a concentration of less than 1 µg/ml. The PHARMACEUTICAL PROCESSING | MAY 2015

addition of peptidoglycan resulted in similar effects as observed in the reaction to LPS, i.e. a marked reduction of the LOD. Pyrogenic activation by RNA reported for human TLR8 [5] was confirmed for E. coli RNA as well as synthetic GU-rich 20-mer RNA molecules. As expected, no activation was induced by its counterpart with all uridin residues replaced by adenosin. For E. coli RNA, an LOD of 12.5 µg/ml was calculated; the respective value for the synthetic oligonucleotide was about a factor of 10 lower.

The MAT also detects the pyrogenic effect of poly (dT) and its enhancement by the imidazoquinoline compound R848, reflecting the cooperation between the receptors TLR7 and TLR8 [6].

CONCLUSION Results demonstrate that MAT is suitable for the detection of various pyrogenic substances which have a direct or indirect influence on fever response in humans. In comparison to the RPT, the sensitivity of the MAT is equal or better [7] but the MAT allows improved standardization without requiring animal sacrifice.

The advantage of the MAT is even more pronounced in comparison to the LAL test which only identifies endotoxins and is subject to false positive reactions to glucans [8].

Detection of the broad spectrum of pyrogens in pharmaceutical products using the MAT allows improved patient safety and offers the chance to abandon animal tests for pyrogen control.

The data presented in this article was originally published in BIOspektrum (2010; 16, 779-781).

Download the application note with full results and data at: www.merckmillipore.com/INTL/en/20140918_142235 n REFERENCES 1. Takeda K and Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17: 1-14 2. Hoffmann S, Peterbauer A, Schindler S et al. (2005) International validation of novel pyrogen tests based on human monocytoid cells. J Immunol Meth 298: 161-173 3. Schindler S, Spreitzer I, Löschner B. et al. (2006) International validation of pyrogen tests based on cryopreserved human primary blood cells. J Immunol Meth316: 42-51 4. European Pharmacopoeia 6th Edition (6.7) (2010) Chapter 2.6.30 Monocyte Activation Test 5. Heil F, Hemmi H, Hochrein H. et al. (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.

Science 303:1526-9 6. Jurk M, Kritzler A, Schulte B et al. (2006) Modulating responsiveness of human TLR7and 8 to small molecule ligands with T-rich phosphorothiateoligodeoxynucleotides. Eur J Immunol 36:1815-26 7. Poole S and Mussett MV (1989) The International Standard for Endotoxin: evaluation in an international collaborative study. J Biol Stand 17:161-171 8. Cooper JF, Weary ME, Jordan FT (1997) The impact of nonendotoxin LAL reactive materials on Limulus amebocyte lysate analyses. PDA J Pharm SciTechnol 51:2-6

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SP ECIA L A DV E RT I SI N G SE C T I ON

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NEW PRODUCTS

P ro d u c t S h ow c a s e Double Planetary Mixer

Discover the Future of Single-Use Manufacturing Finesse CellWorld Conference and Expo September 21–22, 2015 San Francisco, California Finesse.com/CellWorld

Pharmaceutical Vacuum Receivers for Fine Powders VAC-U-MAX pharmaceutical receivers are designed to convey free to nonfree flowing powders for use in many applications including loading tablet press machines, blenders, mix tanks, and loss-in-weight feeder refill. Units are USDA accepted and constructed of stainless steel, with convey rates from 500 to 5000 pounds per hour and beyond. Variety of discharge valve types and finishes are available, including bead blast, satin or mirror polish.

VAC-U-MAX www.vac-u-max.com info@vac-u-max.com

(973) 759-4600

For information or to reserve space contact

The Ross Double Planetary Mixer lined with Teflon features: • The ability to process viscous pastes and dough-like materials.

• The ability to provide gentle but thorough agitation.

• Removable Teflon scrapers for the sidewall and vessel bottom.

• Identical blades that rotate on their own axes while orbiting a common axis.

• A 1.5 HP inverter-duty motor.

• Explosion-proof limit switches.

■ Charles Ross & Son Company; www.mixers.com

TOM LYNCH tom.lynch@advantagemedia.com Phone: 973-920-7782 Fax: 973-607-5492 ■ ADVERTISERS INDEX The Advertisers Index is provided as a reader service. Although every attempt has been made to make this index as complete as possible, the accuracy of all listings cannot be guaranteed.

Brookfield Engineering Lab . . . . . . . . . . . . . . . . . . . . 11

Reed Exhibition Companies . . . . . . . . . . . . . . . . . . . 35

Capsugel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Vac-U-Max . . . . . . . . . . . . . . . . . . . . . . . . 13, 30, 34

CD-adapco . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Veltek Associates Inc . . . . . . . . . . . . . . . . . . . . . 3, 30

Check All Valve . . . . . . . . . . . . . . . . . . . . . . . . 23, 31

Volkmann, Inc. . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Custom Processing Services . . . . . . . . . . . . . . . . . . . 31

Watson-Marlow Fluid Technology Group . . . . . . . . . . . 17, 31

Finesse Solutions LLC . . . . . . . . . . . . . . . . . . . 30, 34, 36

Wesco Industrial Products . . . . . . . . . . . . . . . . . . . . 31

Heinkel Filtering Systems . . . . . . . . . . . . . . . . . . . . . 31

n 34n 34

MAY 2015 | PHARMACEUTICAL PROCESSING

SAVE THE DATE INTERPHEX LIFE SCIENCES INNOVATION WEEK 2015

OCTOBER 15-16

PUERTO RICO CONVENTION CENTER SAN JUAN, PUERTO RICO

www.INTERPHEXPUERTORICO.com

Benefits

Finesse cGMP SmartFactory

• Open System

Meet a biotech operations management solution for single-use facilities

• Scalable Automation / MES

that optimizes plant-wide resource utilization, integrates manufacturing (batch) information, and facilitates training and record management.

• Easy Integration • Rapid Execution

SmartFactory will increase productivity and optimize asset utilization while retaining an open architecture. This enables the process flow to

• Efficient Capital Utilization

be designed and scaled using the best available equipment — such as Finesse SmartSystems — without compromising quality or compliance.