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Pharmaceutical Processing WWW.PHARMPRO.COM • VOLUME 28, NUMBER 8 • OCTOBER 2013Official Media Sponsor of INTERPHEX 2014™CONTRACT MANUFACTURING, PACKAGING & NEW EQUIPMENT TECHNOLOGY FOR THE BIOPHARM/PHARMACEUTICAL INDUSTRYENABLINGPROGRESSCatalent’s clinical biologicsmanufacturing facility helpsbring new products to marketINSIDE THIS ISSUE:■ CONTRACT SERVICESQuality Control andMicroscopy ServicesBrazil’s Emerging Market■ SOLID DOSAGECoaters Go High-Tech■ PACKAGINGOptimizing PharmaceuticalPackagingConquering GlassDelamination■ BIOPHARM
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W W W. P H A R M P R O . C O M • V O L U M E 2 8 , N U M B E R 8 • O C T O B E R 2 0 1 3INTERPHEX 2014™Official Media Sponsor of
■ CONTRACT MANUFACTURING, PACKAGING & NEW EQUIPMENT TECHNOLOGY FOR THE BIOPHARM/PHARMACEUTICAL INDUSTRY
ENABLING PROGRESSCatalent’s clinical biologics manufacturing facility helps bring new products to market
INSIDE THIS ISSUE:
■ CONTRACT SERVICESQuality Control and Microscopy Services
Brazil’s Emerging Market
■ SOLID DOSAGECoaters Go High-Tech
■ PACKAGINGOptimizing Pharmaceutical Packaging
Conquering Glass Delamination
■ BIOPHARMSingle-Use Pumps for Biopharm Manufacturing
Genomic Analysis Improves Mammalian Cell Culture
Potent/Aseptic Parenteral Manufacturing
pp1310_cove_online.indd 1pp1310_cove_online.indd 1 10/8/2013 1:20:05 PM10/8/2013 1:20:05 PM
You Direct. Mobius® FlexReady Solutions Perform. Picture this: A premiere performance with an unmatched combination of TFF and Chromatography operational flexibility and scalability from a single system.
Mobius® FlexReady solutions for TFF and Chromatography were designed to optimize your product’s manufacturability and accelerate time to clinic. This modular and scalable fully-automated system features Smart Flexware® assemblies as well as the ability to quickly change from chromatography to TFF for rapid, reliable separation and purification.
Need a complete process train? With the Mobius® FlexReady platform and services, we can help create an integrated upstream and downstream solution that further reduces the time and resources needed to get your drug to clinic.
Picture a great performance, every time. Picture Mobius® FlexReady Solutions
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EMD Millipore is a division of Merck KGaA, Darmstadt, Germany
EMD Millipore and the M logo are trademarks of Merck KGaA, Darmstadt, Germany. Mobius and Flexware are registered trademarks of Merck KGaA, Darmstadt, Germany.
© 2013 EMD Millipore Corporation, Billerica, MA USA. All rights reserved. PS-13-09106.
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■ IN THIS ISSUE
■ P H A R M P R O . C O M
■ 4
12 Potent/Aseptic Parenteral Manufacturing
Latest equipment, trends, and observations.
16 Single-Use Pumps Take Center Stage
Single-use pumps meet the challenges of biopharmaceutical manufacturing.
20 Pharmaceutical Access in Emerging Markets
How the latest developments in Brazil will change your business strategy.
24 Using Genomic Analysis Trends to improve mammalian cell culture for
biopharmaceutical production.
28 Scanning Electron Microscopy Services
SEM offers the quality control needed for ever smaller API particles
32 Coaters Go High-Tech Achieving high-quality oral solid dosage
manufacturing through continuous tablet coating improvement.
36 Optimizing Packaging Active and protective solutions help ensure
product efficacy.
38 Conquering Glass Delamination
The material selection process may alleviate ongoing concerns.
■ COVER STORY
8 Enabling Progress Catalent's clinical-stage biologics facility is a critical
part of the company's global capabilities.
page 12
page 16
page 25
page 28
■ DEPARTMENTS
6 From The Editor
22 What’s Hot
INNOVATIONS35 Clean Room Equipment
On the Cover: Catalent's new state-of-the-art facility offers expanded mam-malian cell line and biomanufac-turing capabilities.
CORPORATE OFFICE: 100 Enterprise DriveSuite 600, Box 912
Rockaway, NJ 07866-0912973-920-7000
CHIEF OPERATING OFFICER/CHIEF FINANCIAL OFFICER, TERRY FREEBURG
VICE PRESIDENT, TOM LYNCHCHIEF MARKETING OFFICER/CHIEF DIGITAL OFFICER,
PRESCOTT SHIBLESVICE PRESIDENT/HUMAN RESOURCES,
SUSANNE FOULDS
Official Media Sponsor of the INTERPHEX ShowASSOCIATE PUBLISHER
BILL KOENEN, [email protected]
EDITORIAL DIRECTORJEFF REINKE, 973-920-7784
EDITOR-IN-CHIEFMICHAEL AUERBACH, 973-920-7055
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AUDIENCE DEVELOPMENT ASS0CIATE DIRECTOR GAIL KIRBERGER, 973-920-7482
PHARMACEUTICAL PROCESSING® (ISSN #1049-9156, USPS #001-314), (GST Reg. #844559765) is a registered trademark of and is published 9 times a year (monthly, except bi-monthly in January/February, July/August and November/December) by Advantage Business Media, 100 Enterprise Drive, Suite 600, Box 912, Rockaway, NJ 07866-0912. All rights reserved under the U.S.A., International, and Pan-American Copyright Conventions. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, photocopying, electronic recording or otherwise, without the prior written permission of the publisher. Opinions expressed in articles are those of the authors and do not necessarily reflect those of Advantage Business Media or the Editorial Board.Periodicals Mail postage paid at Rockaway, NJ 07866 and at addi-tional mailing offices. POSTMASTER: Send return address changes to PHARMACEUTICAL PROCESSING, P.O. Box 3574, Northbrook, IL 60065-3574. Publication Mail Agreement No. 41336030. Return undeliverable Canadian addresses to: Imex/Pitney Bowes, P.O. Box 1632, Windsor Ontario N9A 7C9.Subscription Inquiries/Change of Address: contact: Omeda Customer Service, P.O. Box 3574, Northbrook, IL 60065-3574, 847-559-7560, Fax: 847-291-4816, email: [email protected]. Change of address notices should include old as well as new address. If possible attach address label from recent issue. Allow 8 to 10 weeks for address change to become effective. Subscriptions are free to qualified individuals. Subscription rates per year are $57 for U.S.A., $75 for Canada, $87 for Mexico & foreign air delivery, single copy $10 for U.S.A., $20 for other locations, prepaid in U.S.A. funds drawn on a U.S.A. branch bank.Notice to Subscribers: We permit reputable companies to send announcements of their products or services to our subscribers. Requests for this privilege are examined with great care to be sure they will be of interest to our readers. If you prefer not to receive such mailings, and want your name in our files only for receiving the magazine, please write us, enclosing your current address mailing label. Please address your request to Customer Service, P.O. Box 3574, Northbrook, IL 60065-3574.Printed in USA: Advantage Business Media does not assume and hereby disclaims any liability to any person for any loss or damage caused by errors or omissions in the material contained herein, regardless of whether such errors result from negligence, accident or any other cause whatsoever. The editors make every reasonable effort to verify the information published, but Advantage Business Media assumes no responsibility for the validity of any manufactur-ers' claims or statements in items reported. Copyright ©2013 Advantage Business Media. All rights reserved.
page 16
page 25
page 35
m Equiipmpment
page 22
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WWhatever your opinion of the FDA is you really can’t fault the agency for trying to get new therapies to patients as quickly as possible.
Here’s a brief rundown of some of the programs available:Fast Track is a process designed to facilitate the development,
and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
Breakthrough Therapy designation is designed to expedite the develop-ment and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demon-
strate substantial improvement over available therapies.
Accelerated Approval regulations allow drugs for serious con-ditions that filled an unmet medical need to be approved based on a surrogate endpoint that enables faster approval.
Priority Review designation means FDA’s goal is to take action on an application within 6 months - compared to the usual 10 months.
When a drug gets one of these designations, it’s fairly common for the developing company to announce this to the press. After all, achieving one of these designations makes the company look good both to the public in general and its stockholders – a win all around.
But there is one FDA designation which has been getting some notice recently due to its lack of use. Expanded Access, sometimes called "Compassionate Use," is the use of an investigational drug out-side of a clinical trial to treat a patient with a life-threatening disease who has no comparable or satisfactory alternative treatment options.
Recently, there have been at least two cases where patients have appealed to companies to allow access to drugs under the Compassionate Use designation and have been turned down.
Personally, I think this is wrong. If the denials were based on le-gal or safety concerns, I’m sure these issues could be worked out.
If companies are quick to announce when developing products re-ceive one of the other designations – I’m sure the public relations ben-efits of a compassionate use tag would far outweigh any negatives.
What do you think?
■ FROM THE EDITOR
■ P H A R M P R O . C O M
Compassionate Use
Have a comment or question about Pharmaceutical Processing? My E-mail is: [email protected]
Whatever your opinion of the FDA is you real-
ly can’t fault the agency for trying to get new
therapies to patients as quickly as possible…
■ Michael Auerbach, Editor in Chief
SALES OFFICES
Phone: 973-920-7793; Fax: 973-607-5682
ASSOCIATE PUBLISHER BILL KOENEN AL, CT, DC, FL, GA, IA, IL, IN 199 EAST BADGER ROAD, SUITE 201 KY, MA, MI, MO, NH, NJ, NV Madison, WI 52713 NY, OH, PA, SC, TN, VT, WI Tel: 973-920-7793 NEW BRUNSWICK, ONTARIO, Fax: 973-607-5682 QUEBEC, CANADA [email protected] ASIA, EUROPE
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SUBSCRIPTION CHANGES Omeda Customer Service [email protected] 847-559-7560
LIST RENTALS Infogroup Targeting Solutions Senior Account Manager Bart Piccirillo; 402-836-6283; [email protected] Senior Account Manager Michael Costantino; 402-863-6266 [email protected]
■ 6 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
EDITORIAL ADVISORY BOARD
Michael J. Beier, Senior Vice President of Operations
TITAN PHARMACEUTICALS, INC.
Dr. James V. Blackwell, PhD, ConsultantBIOPROCESS TECHNOLOGY CONSULTANTS, INC.
Ronald C. Branning, Vice President Global Quality
GENENTECH INC.
Robert F. Dream, Vice PresidentH.D.R. COMPANY LTD.
Johanna Carmel Egan, VGP Project Management
ELI LILLY
Girish Malhotra, PresidentEPCOT INTERNATIONAL
Allan F. Pfitzenmaier, PresidentVECTECH PHARMA CONSULTANTS INC.
Susan Polizzotto, Manager, R&D QA GMP Compliance
US SANOFI PASTEUR
Carlos Villalobos, Sr. Dir. Global EngineeringBRISTOL-MYERS SQUIBB
Richard G. Whitfield, Senior DirectorPFIZER
Patrick Wong, Director of Global EngineeringBRISTOL-MYERS SQUIBB (BMS)
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Product is pumped from one room to another in a completely enclosed sin-gle-use system.A ccording to the
definition found at businessdictionary.com an “enabling
technology” is ”equipment and/or methodology that, alone or in combination with associated tech-nologies, provides the means to generate giant leaps in performance and capabilities of the user.”
While the pharmaceutical in-dustry’s past has not been chock full of advancements that could be classified as “enabling”, recent developments have pointed the way toward a more technologi-cally advanced future for pharma-ceutical manufacturing.
Indeed, as many companies have begun to embrace advanced technologies they are finding little use for older technologies, as new equipment and processes are showing them the way to more efficient, less costly and higher quality manufacturing.
For companies in the biopharmaceutical contract manufac-turing segment of the industry this confluence of technology could not have come at a better time. As the biopharm market continues to grow, biopharmaceutical product sponsors and service providers are looking for the best tools and techniques to bring products to market faster and with the best quality.
One such company is Catalent. The company has combined the latest single-use equipment with their own technologies to design and commission a world-class contract manufacturing facility in Madison, Wisconsin for the devel-opment of clinical trial materials that are used worldwide.
BACKGROUND & HISTORYCatalent is a global leader in
development solutions, and ad-vanced delivery technologies for drugs, biologics and consumer health products. The company offers numerous technologies at dozens of facilities around the globe (see chart).
The biologics site in Madison started as a spin-off from the University of Wisconsin-Madison with funding from angel investors and was housed in an old army facility out-side Madison. The company’s main focus was developing a process to make pharmaceutical proteins from the milk of transgenic cows as this was viewed, at the time, as a cheap way to manufacture pharmaceutical proteins. It was during this time that the company moved to a larger facility in Middleton, WI.
In 2003, Cardinal Health bought part of the company and then bought the rest of it. Catalent as it operates now was created in April 2007 when The Blackstone Group, a global investment and advisory firm, acquired the Pharmaceutical Technologies and Services segment of Cardinal Health.
GLOBAL TECHNOLOGIES & GLOBAL REACHAs it takes a long time to get a cow to the stage where it
can be milked, the company was also concurrently develop-ing its proprietary GPEx® system to make higher expressing mammalian cell lines. As Gregory Bleck, PhD the company’s Director, R&D Platforms explains, this turned out to be
Enabling ProgressCatalent's clinical-stage biologics facility is a critical part of the company's global capabilities■ By Mike Auerbach, Editor in Chief
■ 8 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R M P R O . C O M ■
■ C O V E R S T O R Y■
MADISON BIOLOGICS MANUFACTURING SERVICES:
• Process development focus with extensive non-GMP and GMP experience,
laboratories and support functions
• Solutions for difficult to express proteins
• Flexible cGMP production scale from 10 L to 1000 L
• Tailored process development for mammalian cell lines
• Extensive use of single use technologies to eliminate cross contamination
• Unidirectional flows throughout facility
• Growing to 100,000+ square feet and 100+ employees
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the capacity for making production material has quadrupled.For more specifics, the Madison site now boasts bioreac-
tors up to 1,000 liters in size, compare to the 200 liter biore-actors in the old facility. In addition, through a comprehen-sive Operational Excellence (OpEx) program, Catalent has increased the number of runs per suite by 20% which lets them run multiple products per suite while keeping them completely separated.
As part of the global Catalent network of facilities, the team in Madison was able to leverage the experience of oth-ers within the Catalent organization. “One of the great things about being part of Catalent,” says Jenkins, “is that at the end of the day you might think we have a nice manufacturing facility here in Madison with about 100 people, but it’s really backed up by the 8,000 people who have a lot of experience in manufacturing, not necessarily biologics, but they know how to get stuff to market – which is a great thing to have. Catalent pays a lot of attention to this business.”
He continues, “Two years ago we were the largest invest-ment Catalent made in its business. That’s a level of commit-ment they have to biologics. Think of all of the things going on in Catalent – all of the other divisions - and they have a strong commitment to biologics and also integrating this facility in to the rest of Catalent. It’s a great solution for our customers.”
“A lot of our customers are small companies – less than hundred people or even university researchers trying to get a product to market – and the ability to deal with one company that is reliable and to be able to go from DNA con-struct to an injectable in a clinic is very powerful.”
THE TRANSITION TO SINGLE-USE TECHNOLOGIESFor Catalent, the decision to move to single-use technolo-
gies in their Madison facility was a defining moment because they decided to abandon all of their stainless steel equipment and jump totally into single-use. “A lot of companies that make the transition to single-use keep their stainless steel equipment on the side – we abandoned all of our stainless steel equipment and you won’t see any stainless steel biore-actors in Madison,” says Jenkins, “we sold all the stainless steel equipment to a competitor. We view this as a positive.”
good timing. “At this time, Mad Cow disease was identified, so even though there was very limited risk, all investors wanted to stay away from cows, they didn’t want to deal with any possible connections. We had GPEx® to fall back on.”
In addition to the GPEx® cell line platform the company has also licensed SMARTag™ Technology from Redwood Biosciences which is designed to develop optimized Antibody Drug Conjugates.
Under the global Catalent umbrella, the Madison facil-ity, which is currently set-up to manufacture Phase 1 and Phase II batches for clinical trials, can help a client take a gene and deliver a product to a clinical trials site anywhere in the world. Relying on the global network of Catalent fa-cilities, once the bulk product is released from the Madison facility it is sent to the company’s clinical fill/finish facility in North Carolina and then to one of several clinical pack-aging facilities in the US or Europe, and then on to the com-pany’s extensive clinical trial distribution network.
Speaking to the capabilities and technologies Catalent has to offer, Bleck offers his views. “We have unique tech-nologies all through Catalent – we do more than manu-facturing - we want to offer solutions to our customers to make better products. We are continuously developing our own IP internally and exploring arrangements with other technology companies to access unique offerings that will add value to our customers and enable them to provide better products.”
THE MADISON, WI BIOLOGICS FACILITYAs Catalent’s facility in Middleton, WI began to fill up it
was decided to expand and look for a larger building to house their growing operations.
The facility they selected was a former electronics man-ufacturing building and was essentially a big, wide-open warehouse. This proved to be good choice as this layout resulted in minimal obstacles in facility design – except for the required support pillars which were integrated into the facility. Michael Jenkins, PhD., the facility’s General Manager explains how the empty facility worked in their favor. “We wanted an open area with good ceiling height. Which is absolutely critical to what we do because biore-actors take up a lot space. We put in the appropriate infra-structure from the start so things would work - and made sure the infrastructure was properly sized for our needs.”
Compared to the site in Middleton the new Madison facil-ity has more than doubled in size. In addition the manufac-turing area available to the company has tripled in size, and
■ P H A R M P R O . C O M
PHARMACEUTICAL PROCESSING | OCTOBER 2013 9 ■
■ P H A R M P R O . C O M
■ C O V E R S T O R Y
BIOLOGICS TECHNOLOGIES
SMARTag™ Technology is a precision protein-chemical engineering technology for the development of advanced antibody drug conjugates (ADCs). The novel, site specific protein modification and linker technologies, enable the generation of homogenous bioconjugates engineered to enhance potency, safety and stability.
GPEx® Technology is a proprietary, pseudo-typed, high-titer vector that generates stable mammalian cell lines - in record time. Virtually any cDNA (mAb and multigenic applications) can be packaged into the GPEx® retrovector and used to transduce a mammalian cell line. To date, over 400 different mAb and mAb fusions and over 60 different recombinant proteins have been produced using the GPEx® system.
Disposable bioreactors eliminate any cross contamination concerns.
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■ P H A R M P R O . C O M■ C O V E R S T O R Y
■ 10 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
air handling system. Air in that room is completely separate from the air using in other areas. In fact, over 25% of the build out cost was from HVAC. Jenkins explains. “If you want to get the maximum number of runs from your process you want to keep these areas separate – it becomes very ex-pensive in terms of air-handling. We have great capacity in our suites and you get there by investing heavily in separation of product – and HVAC is a huge part.”
The flow of people and product through the facility was also carefully thought through. The lab areas are separate from the office areas. Personnel enter the GMP production areas through an entrance corridor and exit through an exit corridor. This is a key compliance item and one of the keys to being Phase III compliant, which Catalent is looking at for the facility in the future. Commenting on the facility design and work area segregation, Jenkins points Catalent’s GPEx® technology as a major reason. “Almost every cell line we work with is from our GPEx® technology, but we also work with non GPEx® cell lines and we have a special lab to work with these cell lines
until they have been tested enough to be released into the facility. We have great separation between the GMP areas and the development areas.”
FINAL THOUGHTSThere is little doubt that
the implementation of sin-gle-use technologies and Catalent’s own intellectual property has created a world-class Phase I and Phase II bi-ologics manufacturing facility in Madison, WI. By leaving stainless steel in its past the team at Catalent has reduced costs, increased produc-tion and improved quality. Looking toward the future the team is exploring expanding the facility to include manu-facturing of commercial scale products and there is defi-nitely a sense of anticipation in the air. “It’s a real exciting place to be,” says Jenkins. ■
route to the next suite.By separating the process into multi-
ple rooms more efficient production is achieved. Product spends about 18 days in the terminal bioreactor room and then is transferred through the wall from the TFF skid to depth filtration, then to the steril-izing filter and then to a mixing vessel in a plastic bag. Once product is pumped out of the first room cleaning can begin, and what was once a 3 day process with stainless steel equipment, now takes one day.
“It’s a simple process actually,” says Jenkins, “but everything that touches the product will be thrown away at the end – no cross contamination and it’s a completely enclosed system.”
ADDITIONAL FEATURESWhile single-use technologies get a lot of
the attention in the Madison facility, other features of the building and its design con-tribute greatly to the facilities success.
For example, in the bulk fill room where material is taken out of the disposable bag and put in a transport container and shipped to the client features a very robust
One of the key benefits to moving to sin-gle-use was that team did not have to include any of the infrastructure necessary to sup-port stainless steel equipment such as steam lines, CIP carts, etc. all of that infrastructure is unnecessary. In addition, the construction timeline was significantly compressed.
“The typical timeline for a GMP stainless steel facility is to finish construction in a year and six months for validation” says Jenkins. “We went from the start of con-struction to ready for GMP production in about a year.Single-use equipment enables that.”
Being a reliable supplier of quality prod-ucts is of critical importance to Catalent and single-use technologies help them ac-complish that goal. Single-use equipment allows them to keep their manufacturing processes in a closed system. The company employs an ‘alcove strategy’ - suites are divided into separate rooms and material is pumped through single-use tubing through a port in the wall from one suite to another. This allows products to be separated from one another and also eliminated product from being wheeled through hallways en
Catalent’s Worldwide Facilities & Capabilities
pp1310_coverstory.indd 10pp1310_coverstory.indd 10 9/20/2013 3:05:36 PM9/20/2013 3:05:36 PM
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With the ever-increasing complexity of paren-teral products such as cytotoxics and con-jugations, it has been necessary for pharma-ceutical/biotech equipment manufacturers
to develop equipment, that not only protects the products, but also the operators and the environment. This article traces the development of the use of isolators to accomplish these tasks, as well as the latest isolator equipment being offered in the aseptic/potent area.
THE WORLD’S FIRSTThe world’ first filling line with freeze drying for aseptic/
toxic products was licensed by the FDA in 1993 (formulation and compounding was also accomplished in isolators). The anti-cancer proprietary drug (Navelbine) was the first drug to be filled in this facility located in southwestern France. Thereafter, a number of toxic products were filled on this line on a CMO basis. Filling equipment, at that time, was not designed for use with isolators, since isolators were a relatively new concept, except for use in sterility testing ap-plications and mostly soft wall configurations. The footprint of the equipment for filling and freeze dryer loading and unloading was so large, it was necessary to use half-suits in order to access the necessary areas for interventions. In
addition, the major issue of “tightness through the tabletop” had to be addressed. Penetration tightness was not only necessary to contain the toxic material, but also to prevent vaporized H2O2 being used for de-contamination, from es-caping into the environment. (See picture of facility below left.)
LATER DEVELOPMENTThis facility included all of the normal items of equipment
found in a typical aseptic/toxic liquid filling suite today as well: vial washer, de-pyrogenation tunnel, filler, freeze dryer, separate capper and external vial washer. As other facili-ties began to come on line: Switzerland 1995, England 1996, Germany and Japan 2002, the filling and freeze dryer load-ing and unloading systems were adapting to isolator technol-ogy. The width and tightness of the fillers and the automatic loading and unloading conveyor systems for freeze dryers were being implemented. It was not until the end of 2004 that two US facilities installed a filling line for aseptic/toxic applications, without freeze drying capacity, even though additional facilities were added in Europe. It was not until 2005, when an aseptic/toxic facility with freeze drying ca-pacity was built, primarily for clinical purposes. This com-pany was very concerned with potential exposure of the op-erators to toxic substances being filled. One of the products
had an OEL of 35 nanograms. In the beginning, they required the operators to use PAPRS to op-erate the facility. Using extensive monitoring, it was determined this level of containment could be reached using the isolators. Eventually, the operators could reduce their gowning require-ments to normal Class C gowning. Reduced gowning represents additional significant sav-ings over normal Class A or B gowning.
THE BALLROOM CONCEPT By 2005, the “ballroom” concept of a filling
suite had been initiated. This concept of includ-ing all of the equipment for aseptic filling and freeze drying were to be contained in one filling suit, including vial washer, tunnel, accumula-tor, filler, freeze dryer loading and unloading system, capper and external vial washer and tray-off. Utilizing this system within a Class C
POTENT/ASEPTIC Parenteral ManufacturingLatest equipment, trends and observations■ By Jim Spolyar, SKAN
■ 12 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R M P R O . C O M■ PARENTERALS
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equipment. This uni-direc-tional airflow from above to below, restricts the particles produced by the filling op-erations from contaminating the terminal HEPA filters above the chamber. This ISO 5 environment in the isola-tors replaced the previous method of operation in a traditional cleanroom of ISO 5 classification. The stainless steel and glass barrier and a leak tight chamber, added additional protection for the product, operators and the environment. In addition, the isolators could operate in positive or negative pres-sure. Normally, during the liquid fill portion of a cycle for aseptic/toxic products, the isolators, including the freeze dryer loading and unloading units operate in positive pressure. Depending on the toxicity of the product, many companies choose to operate the isolator over the freeze dryer unloading operation in negative pressure, since there
New filters can be changed from the outside and fea-tures many safety features.
room, since normally all process rooms are the same level, eliminates the need for airlocks between these rooms. In a “greenfield site”, this could represent a savings of up to 35% of the floor space.
DECONTAMINATION OF ISOLATORS USING H202In the beginning of the use of isolators for these applica-
tions and continuing today, decontamination using vapor-ized hydrogen peroxide is the material of choice. Materials of construction of the isolators were tested for the best compatibility with H2O2. Glass and stainless steel are very good for the de-contamination cycle, while aluminum and some plastics lengthen the cycle. Gloves made of Chlori-Sulfate-Polyethylene (CSM), formerly Hypalon, have been determined to best suited for H2O2 decontamination.(1) Decontamination of the isolators in the early stages of de-velopment was accomplished using remote generators deliv-ering vaporized hydrogen peroxide. These generators were being offered by companies independent from the isolator manufacturers. In 1997, the first fully integrated system was offered, combining the delivery system with the isolator us-ing the same control systems.
AIR HANDLINGIsolators for sterile filling applications have uni-directional
airflow in the working chambers from the ceiling to the floor. It is necessary to maintain a Class A (ISO 5) over the
■ P H A R M P R O . C O M
■ PARENTERALS
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■ P H A R M P R O . C O M■ PARENTERALS
■ 14 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
These small batches of normally high value products, which need to be aseptically and perhaps freeze dryed, has required the filling line manufacturers to develop new machines which are small and flexible for batches between 500 to 10,000 units. Isolators needed to be adapted to this new reality. Thus, the development of the mod-ular system with rapid H2O2 airlock for entry of components for production and other items. The filler is also modular and mounted on an L flange which can be ex-changed with another filler with the same L flange-ie one with a syringe filler and one with a vial filler. The modular isolator can be equipped with FIPA filters as well to protect the product and operators and elim-inate cross contamination issues.
REFERENCES (1) Sigwarth V. and Starek A. “Effect of
Carrier Materials on the Resistance of Spores of Bacillas Stearothermophilus to Gaseous Hydrogen Peroxide”: PDA Journal of Pharmaceutical Science and Technology, Jan. 2003 Vol. 57 No.1
(2) NA press release: 05.28.2009 New form of targeted cancer therapie brings new hope for patients with advanced HER2 positive breast cancer ■
aseptic isolator. The transfer time should be as short as possible, between 15 to 20 minutes for a complete cycle with a spore reduction of 106 of Geobasillus stearother-mophilus. By utilizing this device, numer-ous entries and exit of items can be made into an aseptic isolator chamber, without compromising the aseptic nature of the main chamber. This has become a frequent addition to aseptic isolators for production, as well as sterility testing. The airlock is loaded from the Class C or D cleanroom. After the de-con cycle, the sliding door to the isolator is opened and the items trans-ferred. If there is anything to be removed, such as trash, it can be placed in the air-lock, door closed and then removed into the cleanroom for disposal. Monitoring plates can also be removed in the same manner.
SMALL SCALE ASEPTIC FILLINGBiotechnologically developed and pro-
duced medicines are increasing. For ex-ample, a well know Swiss pharmaceutical concern introduced an antibody conjugation which showed positive effects for advanced HER2 breast cancer(2). This and future similar substances are becoming patient and illness specific. These developments require relatively small batches of product.
is potentially powder within the enclosure. The method of handling airflow is critical in an aseptic/toxic system, to eliminate the issue of cross-contamination and for safety reasons as well. The previous system chan-neled the air flow through ducts into the BIBO (bag-in/bag-out) filters located in the technical area. This required the washing and drying of the ducts from the filling equipment to the BIBO’s.
With the development of a patented safe change filter system (FIBO), the contamina-tion is retained at the level of the isolator and the need for BIBO’s is eliminated.
This system has been made possible by the development of the special filter. It can be changed from the outside and has all of the safety features, including a Kevlar liner to prevent glass shards from damaging the filter. These filters are built into the return air channels of the isolator. These filters can be changed without the use of protective cloth-ing or breathing apparatus. THE RAPID H2O2 AIRLOCK
For the entry and exit of packaging equipment, tools, pre-sterilized vials and syringes, and material for microbiological monitoring, the rapid H2O2 airlock was an excellent addition for attachment to an
Modular isolator with filler and freeze dryer interface.New air handling system with FIPA filters directly on isolator.
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Quattroflow 1200 Quaternary Diaphragm Pumps show-ing the plastic single-use pump-head option.In the multi-billion-dollar global
biopharmaceutical industry, a fur-ther emphasis is being placed on the development and manufacture
of advanced biologically derived drugs (termed here as biologics). These biologics offer exciting potential for the development of block-buster drugs that can provide as-yet-unknown treatments for a wide array of diseases. While pharmaceutical drugs are derived from more traditional chemical pro-cesses and reactions, biologic-based drugs are the result, as the name implies, of biologically induced processes, such as intracell growth processes (mammalian cells, bacteria, viruses and such), and the subsequent harvesting and purifying of target sub-stances, such as proteins, molecules and enzymes. These substances are then used to create drugs, vaccines or antitoxins. In essence, cells are used as miniature process
vessels to create new sub-stances.
The development of new biologically derived drugs, however, is just one opportunity for manufac-turers. Another equally important goal is to com-mercialize these products as early as possible in the typical 20-year patent window. Patent submission needs to occur during the drug-development process. Following a pat-ent filing, much occurs, including further product development, toxicity checks and clinical trials. Hopefully, Food & Drug Administration (FDA)
Biologics-manufacturing operations take place in extremely sterile and time-sensitive conditions. Pump technology like that found in single-use quaternary diaphragm models are able to satisfy the product containment and speed-to-market requirements that are paramount in these types of operations.
approval also occurs during this period. Following FDA approval, the developers need to take all the necessary steps to properly produce the product in commer-cial scale and execute the market–introduc-
tion plan. If the drug’s development takes ad-ditional time after patent approval, the patent
may run through a good portion of its window of protection before the drug has a chance to
be commercialized. In some cases, there are only about seven years left on the patent for the product
when it goes to market. Every year a drug is covered by its patent can be worth billions of dollars in sales, so
every day that the development process can be accelerated means that much more to the bottom line.
From a process-equipment standpoint, permanent and sin-gle-use quaternary diaphragm pumps, such as Quattroflow™ pumps, represent a growing technology that both helps en-able the efficient development of new biologic drugs and then facilitates the speed to market of the end-product. Single-use pumps, such as those using disposable pump chambers, fea-ture replaceable wetted parts, meaning that no cleaning and validation process is needed during a product-development process that can require multiple trials. This is a great ad-vantage for drug manufacturers who are looking to maximize their production operations through the implementation of cutting-edge pumping technology.
“The biopharm industry is adopting disposables faster than the general population is trying to recycle,” said Mark Sitcoske, who heads High Purity New England, Smithfield, RI, USA, a company that specializes in single-use pump technology.
Essentially, the driving force in the process to create these target products is to promote growth of biologic material in a highly controlled, sterile environment with adherence to strict operational parameters, such as the correct pH (acid-ity) level, temperature, oxygen level and nutrient feed. An imbalance in any of these parameters can cause unwanted biologic processes to occur, such as the formation or growth of competing and undesirable organisms, or it could cause the target biologic process to not occur at all. Once the raw
■ By Wallace Wittkoff
SINGLE-USE PUMPS Taking Center StageSingle-use pumps meet the challenges of biopharmaceutical manufacturing
■ 16 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R M P R O . C O M ■
■ B I O P H A R M
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Automated concentration and diafiltration process using only five components.
■ P H A R M P R O . C O M
biologic product is produced, the desired target components (proteins, molecules, etc.) can be purified by using a num-ber of techniques. These techniques include filtration (such as tangential/cross flow and chromatography), separation (through a centrifuge) or certain chemical reactions.
The critical issue in these target-component extraction techniques is that biologics are extremely sensitive to change or damage from outside influences, such as shear, temperature changes and light. That means the extraction process that these target components are subjected to re-quire a type of pump that can reliably deliver the following desired operational characteristics:• High purity and sterility• Very low volume and surface area exposure; 15 ml/73.5
cm2 in the smallest pump• Low levels of leachables and extractable• No mechanical spalling/shedding of contact materials• Controlled/constant flow, as needed• Low shear, slip and collateral effects• Low pulsation• Self-priming and negative suction lift• Controlled pressure• No heat addition• High volumetric efficiency
THE CHALLENGEThe harvesting and purification of biologic target materi-
als is accomplished using separation and filtering processes. There are generally three purification processes (that can also be used in combination) as follows:• Tangential Flow Filtration (TFF)—Also known as cross-flow
filtration. For this process the biologic feed stream flows horizontally with positive pressure across the filter mem-brane. As it passes across the membrane, the portion of the feed stream that is smaller than the membrane’s pore size passes through the membrane. This is different from what is known as normal-flow (NFF), or “dead-end,” fil-tration, in which the feed flows entirely through the filter membrane with the size of the pores determining which portion of the feed is allowed to pass through and which will remain trapped in the filter membrane. TFF is different from NFF in biologics applications because the tangen-tial motion of the fluid across the membrane causes any trapped particles to be “rubbed” off, similar to passing your hand across a piece of sandpaper. This mode of oper-ation means that a TFF process can operate continuously with relatively high solids loads without fouling of the fil-ter, which is also known as filter blinding.
• Chromatography Columns—A typical chromatography col-umn is a glass, steel or plastic tube that is filled with res-ins that are compressed in a certain format through which a feed stream product flows to either capture or purify this feed stream. These chromatography columns contain filter media that need careful handling. A resin, for exam-ple, can cost as much as $10,000 an ounce, making proper
feeding of the resin extremely important• Centrifuges—A centrifuge, really a separator and not a
filter, consists of an elaborate vessel that can be fed with a biologic substance and spun around a central axis in order to separate the materials according to their different specific gravities/weights, or to separate particles that are suspended in the liquid. The biologic’s target product can be the high, intermediate or low specific-gravity substance that is spun out of the centrifuge. As centrifuges spin at high speeds, a proper, constant feed rate is essential in order to minimize potentially severe vibration that could cause equipment damage.In all three processes that are used for target feed stream
purification, the requirements of the pump are precise: constant, low-slip, and low-shear, low-pulsing flow. Any de-viation from these requirements can result in deleterious effects for the substance being handled, as well as damage to the media that are used in the filter (membranes for TFF and resins for chromatography columns), which are costly. Improper flow and transfer rates can also produce the un-balanced operation that results in a damaged centrifuge.
SINGLE-USE PUMPS NEEDEDOne key manufacturing trend that can reduce develop-
ment cost and increase speed-to-market is the adoption of single-use technologies. In certain cases, permanent stainless-steel process lines are very costly to set up, lack the production flexibility in biologic development, and have complex and time-consuming cleaning and validation requirements. Therefore, much expense and time can be saved by simply starting each trial process with a fresh, sterile set of single-use process-equipment components. These components can consist of bags instead of stain-less-steel vessels, special agitators instead of stainless-steel shaft agitators, single-use tubing, coupling and valves in-stead of their stainless-steel equivalents, and filter systems, many of which are single-use by their very nature.
“Many of the leading filtration and purification system designers worldwide prefer Quattroflow pumps; there’s a rea-son for that,” said Jeff Blease, President of Triangle Process Equipment, Wilson, NC, USA, a pioneering company behind the
PHARMACEUTICAL PROCESSING | OCTOBER 2013 17 ■
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■ 18 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
buying public as quickly as possible, an additional $500 or more for a replaceable pump head essentially be-comes an attractive cost of doing business. The total cost of using a single-use pump is less because the cost to replace the head may pale in comparison to the cost of validating the clean-ing (which can run in the tens of thousands/millions of dollars), plus the entire cost to install a permanent stainless-steel process line. A common notion in this in-dustry is that the cost of the paper backing up the equip-ment used is higher than the
equipment itself. The Quattroflow, by using a standardized and documented single-use variation, reduces that paper and cost.
For cases where the total cost of a per-manent stainless-steel process line is more attractive, the Quattroflow pump head can be converted to a stainless-steel head with the same controlled flow, low-shear, low-slip and high-purity operation, with the addition of desirable high-cleanability attributes.
CONCLUSIONAdvances in the ability to produce and
use biologically derived drugs has created an exciting opportunity for manufacturers in the biopharmaceutical market. However, while this continuing trend is packed with possibilities, they can only be realized if the development and manufacturing pro-cesses for these products are optimized, both in regards to speed-to-market consid-erations and contaminant-free production requirements. Single-use positive displace-ment quaternary diaphragm pumps— can dependably meets these challenges and allows biopharmaceutical manufacturers to confidently meet many of their most crucial biologic-handling and manufacturing needs.
ABOUT THE AUTHOR: Wallace Wittkoff is the Director, Global Segment Marketing – Hygienic for Pump Solutions Group (PSG®), Oakbrook Terrace, IL, USA. He can be reached at +1 (502) 905-9169 or [email protected]. ■
As biologics go from development to clinical trials and then to commercializa-tion, proper scale up is essential. The same pump technology in a lab needs to handle flowrates as low as 1 L/hr (o.0047 gpm), as well as commercial production flow rates of 20,000 L/hr (88 gpm) or more. This scale-up capability assures that the pump’s opera-tion does not adversely affect repeatability and production rates.
Quattroflow pumps also possess the ver-satility to be fitted with explosion-proof mo-tors, DCA motors or air motors; essentially you can drive Quattroflow pumps in any way you can drive other pumps. Because of the controlled low-slip aspect of this pump tech-nology and high turn-down capability, this pump also benefits from new generations of vector drives for precision applications.
The essential element that Quattroflow pumps help to contribute to speed to market is the commonality of single-use configurations. Basically, a single-use pump enables biophar-maceutical manufacturers to optimize the cost of cleaning and validating their pumps. The result is not only a quicker production pro-cess, but one that delivers preferred levels of product purity and sterility with no chance for cross-batch or cross-product contamination.
Single-use pumps that are made from FDA/USP class VI conforming/approved ma-terials also have a lower cost compared to their stainless-steel counterparts. Further, for example, with a 500-liter batch of bi-ologics, which has a market value of $5 million-plus and the need to offer it to the
use of quaternary diaphragm pump technology in the Americas. “The Quattroflow pump gives you the low shear of a peristaltic pump along with the low pulsation and high-pressure capabili-ties of rotary lobes without the inherent dangers and drawbacks of either technol-ogy, such as burst tubing, excessive temperature rise, or rubber and metal shav-ings contaminating the pro-cess from upset conditions.”
THE SOLUTIONFor a growing number,
the solution to the strict single-use pumping require-ments that are demanded in the biologics-fil-tering process can be found in the positive displacement quaternary diaphragm technol-ogy that has been developed by the German company, Quattroflow, which also introduced to the market the single-use configuration for use in critical product-handling applications in the pharmaceutical and biotech industries
Quaternary diaphragms are driven one after another by a connector plate, which moves back and forth out of its central po-sition in a stroke that is generated by an ec-centric shaft, with the length of the stroke determined by the angle of the eccentricity. This technology has been modeled on the operation of the human heart—which is eminently capable of pumping whole human blood, one of the most shear-sensitive prod-ucts around—with its four pumping cham-bers and check valves keeping product flow constantly moving forward.
The Quattroflow’s pump chambers con-tain no rotating parts that can be subject to friction, meaning that there is no oper-ational heat buildup that can compromise the product. This mode of operation also means that the pumps can run dry, are self-priming, and produce little or no shear because of low slip. In addition, they offer low-pulsation, leak-free operation while hav-ing great dry/wet suction-lift capabilities. These pumps can provide constant flows from 1 L/hr (0.0047 gpm) to 20,000 L/hr (88 gpm) with some of the highest turn up/down capabilities in the industry.
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What happens when you stir the benefits of single-use technology and GE Healthcare Life Sciences‘ expertise into the field of microbial fermentation? You get the only system available on the market offering purpose-built performance and flexibility suited for microbial fermentation. It’s optimal design maintains high-mass transfer, provides exceptional temperature control, and increases gas dispersion — all with the added benefits of single-use technology.
To download the application note, or to inquire about our complimentary process modeling service, visit: www.gelifesciences.com/xdr-50mo
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largest pharmaceutical market by 2020, after the US and China. Despite its strong economic growth, Brazil is facing increasing
pressure to control healthcare expenditure and, at the same time, to promote innovation and improve access to healthcare.
In pursuit of this difficult task, decision-makers are dis-cussing several initiatives, some of them already converted into law, which will reshape the pharmaceutical market in the next few years. In the context of increasing competition and stricter regulatory hurdles, Brazil will become a much more challenging business environment.
DECREASING TAXATIONS ON PHARMACEUTICALSEven though international companies operating in the
Brazilian healthcare market represent approximately 20 per-cent of the total healthcare manufacturers based in Brazil, they represent 75 percent of market share.
Decreasing taxation on medicines for human use is seen as an effective way to promote and incentivize the 550+ lab-oratories in the internal pharmaceutical sector. Two different measures adopted in the last year confirm this strategy: 1) On November 28, 2012, the Brazilian Committee on
Constitution, Justice and Citizenship approved a replace-ment bill proposing a constitutional amendment that would prohibit the collection of taxes on medicines for human use. The import tax, however, will remain in place as it “serves as an instrument of government economic policy, which should continue providing the flexibility to manoeu-
■ By Davide Zaganelli, Global Emerging Markets Manager, Alliance Life Sciences
EEmerging markets are considered the new frontier for pharma-ceutical companies, and represent hope for an industry seek-ing new strategies and partnerships to balance the stagnation in more mature markets. With expectations of reaching 30 percent of the nearly $1.2 trillion US global spend -- and 50-70 percent of the $70 billion annual US growth forecasted in the pharmaceutical sector by 2016 -- it is clear why emerging mar-kets present an enticing opportunity for pharma.
But emerging markets defy the effectiveness of a uniform approach and call for local business planning based on a com-prehensive and global perspective. For this reason, interna-tional pharmaceutical companies must be willing to implement market-specific strategies and local thinking within their global business strategy. Furthermore, evolving political stances, in-creasing international competition, and rising local manufactur-ers are toughening market access environments and creating new, and sometimes unexpected, risks for drug makers.
Brazil provides one of several examples in which business conditions for drug makers are quickly changing, emphasizing the importance of identifying, evaluating, and foreseeing such changes as early as possible in order to improve and consoli-date market positioning.
LATEST REFORMS AND NEW CHALLENGES With over $220 billion of healthcare expenditure, strong eco-
nomic growth, and drug prices adjusted annually (2.7-6.31 percent increase estimated in 2013), Brazil is destined to become the third
■ EMERGING MARKETS
■ P H A R M P R O . C O M
Pharmaceutical Access in Emerging MarketsHow the latest developments in Brazil will change your business strategy
■ 20 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
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vre its rates and the need to protect the domestic market from indiscriminate entry of foreign products.”
2) On March 13, 2013, a tax deferral measure was officially pub-lished to suspend goods circulation taxes in the state of São Paulo for domestic products and imported pharmaceutical ingredients or intermediate drug products purchased by the Foundation of Popular Medicines (Fundação para o Remédio Popular). The Foundation is linked to the Department of
Health of the state of São Paulo and is responsible for devel-oping, producing and distributing pharmaceutical products in Brazil. This rule is valid for imported generic or biosimi-lars not yet available in the country.
SEEKING NEW PARTNERSHIPS Brazil recognizes that the development of technology in
healthcare is necessary to strengthen national industrial man-ufacturing, reduce dependency on product importations and achieve better control over expenditure.
To date, 34 technology transfer partnerships between pub-lic and private laboratories have been agreed upon for the production of 28 drugs (including Pramipexole, Tenofovir, Clozapine, Quetiapine, Olanzapine, Tacrolimus, Rivastigmine, and Donepezil), and three vaccines. According to the Ministry of Health, at least 20 new partnerships are expected over the next four years, including biological products and medical devices.
For instance, in October 2012, Boehringer-Ingelheim and the Institute of Drug Technology (Farmanguinhos) agreed on a partnership for the local production of Pramipexole for Parkinson’s disease treatment. Boehringer-Ingelheim will sup-ply the active ingredient that Farmanguinhos will convert into tablets. The expectation is to produce internally 50 percent of the country’s demand by 2016 and 100 percent by 20181.
In the medium- and long-term, stakeholders are not only seeking internal development, but they are also hoping to increase competitiveness of Brazilian pharma companies abroad. A further step in this direction was made earlier this year when Brazil’s President Dilma Rousseff announced that the recently created Brazilian Enterprise for Research and Industrial Innovation (Embrapii) will be responsible for promoting partnerships between public innovative research institutions and private companies to create new products and processes.
INCREASING GENERICS MARKET SHAREGenerics were introduced in Brazil 30 years ago, and met
with general consumer and prescriber distrust. Today, gener-ics market share in Brazil is still lower than in other markets, e.g. 26 percent in 2012 compared to 66 percent in Germany, and 60 percent in the UK and US, but it is expected to in-crease to 45 percent by 2020. According to the Pro-Generics association, by the end of 2013 the market share of generic drugs should increase to 30 percent.
The Brazilian government is aggressively promoting the
use of generics and seeking to further increase confidence in patients and prescribers by ensuring rigid quality controls and lower prices. With a price at least 35 percent cheaper than brand-name drugs, and with several Brazilian companies operating in the sector, generic manufacturing was identified as an ideal way to increase budget control and boost local manufacturing.
WHAT DOES THIS MEAN FOR YOUR COMPANY?In the coming years, the favorable healthcare environment
will allow local companies and generic drug makers to rapidly increase their market share and negatively impact on inter-national manufacturers of branded products. Moreover, key decision-makers are expected to adopt stricter regulatory, pricing and reimbursement regulations to further develop in-ternal pharmaceutical manufacturing.
As a direct consequence, market access in Brazil will be-come increasingly challenging for international pharmaceuti-cal companies, making it necessary for global businesses to evaluate and adapt their business strategy to local realities.
Strategic offerings, including technology transfer agree-ments, will be a key factor to secure continued market sales growth in the next few years. International pharmaceutical companies should also consider financial/outcome-based pricing agreements and other alternative approaches to meet the increasing demand for access to healthcare without im-pacting excessively on budget.
Keeping track of legislative, pricing and reimbursement changes, foreseeing how competitors’ launches will impact your portfolio, and linking Brazil to global decisions and in-ternational referencing pricing are essential for identifying and bending gaps and trends that shape the pharmaceutical market in your favor.
REFERENCES1 http://www.brazilpharmanews.com; Accessed 19th April
20132 ANVISA and brazilpharmanews; Accessed 19th April 2013 ■
■ P H A R M P R O . C O M
PHARMACEUTICAL PROCESSING | OCTOBER 2013 21 ■
Despite its strong economic growth, Brazil is facing increasing pressure to
control healthcare expenditure and, at the same time, to promote innovation
and improve access to healthcare.
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Field Portable NIR Spectrometer � The SM-3500 field por-table NIR spectrometer can help combat coun-terfeiting by allowing identification and authentication using spectral matching and principal component analysis. Steps involved in these measurements include taking sample spectra of authentic drugs to form a known reference and checking target drugs against those spectra for authentica-tion. The SM-3500’s portability makes it well-suited for counterfeit screening applications, as it can be used at manufacturing facilities, warehouses, hospitals, pharmacies and field locations for govern-ment agencies. The UIV/VIS/NIR/SWIR range of the SM-3500 across a 350-2500nm spectral range, allows it to deliver a number of benefits including minimal or no sample prep, rapid analysis — as quickly as a sample per second, non-destructive – analysis can be performed with the drug still in its packaging, information on structural and chemi-cal characteristics can be measured, and criminal and sub-standard counterfeits can be identified. It also has third party chemometrics analysis programs can be used to provide more quantitative analy-sis of active ingredient concentrations and excipients, useable with physical/chemical identifiers/markers in genuine drugs and it is e asy-to-use, potentially operated by non-scientific personnel. ■ Spec-tral Evolution , Lawrence, MA 01840. www.spectralevolution.com or call 978-687-1833
Vision Module � The LabelSync™ 450 Vision Module is de-signed to capture and sync a bottle’s unique serialized label with its individual line code. The ma-chine can handle bottles 30-1500 milliliters in volume at speeds up to 300 per minute. Seamlessly compatible with a wide range of serialization software and vision components, the LabelSync 450 verifies each code’s readability, confirms that each bottle belongs on the line (line security), establishes a one-to-one relationship between the two codes, and enables high-integrity iden-tification processes downstream. The LabelSync 450’s vision system is comprised of four cameras whose combined viewpoints offer 360-degree label inspection, as well as a fifth camera to read secondary line code. The stainless steel module’s transfer belts are servo-controlled, and its height adjustment is quick and repeatable. The LabelSync 450 can be equipped with its own print capability, so that it can print, inspect, and synchronize codes all in one efficient footprint. LabelSync 450 can print on the bottom of bottles, as well as on caps and topserts; this versatility helps enable secure end-of-line aggregation. In the process, the module codes the bottles, verifies these codes’ readability and commissions the codes for tracking. Should a top or bottom code not be required at the unit level, Labelsync 450 also can be used to track loose bottles heading into a case packing station. ■ Omega Design Corporation, Exton, PA 19341. www.omegadesign.com or call 800-346-0191
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� Single-Use Laboratory Bioreactor The UniVessel® SU is a second generation of single-use bioreactor. This single-use stirred tank bioreactor can be operated in a choice of working volumes ranging from 0.6L to 2L, and it is
suitable for the cultivation of mammalian cells, including stem cells, insect and plant cells. Typical areas of application for the UniVessel® SU are process development and optimiza-tion, as well as production of seed cultures and cell banks. It combines the proven design of conventional glass vessels with the efficiency and flexibility of single-use systems. Supplied as a completely preassembled and presterilized unit, this laboratory bioreactor is instantly ready to use right out of the box. It eliminates the need for labor-intensive steps, such as autoclaving or installation of probes, minimizing the time needed for preparation. The new UniVessel® SU can be used interchangeably with glass vessels to help laborato-ries better manage peak workloads despite challenging timelines. Each UniVessel® SU is equipped with integrated single-use sensors for pH and dissolved oxygen measurement. ■
Sartorius Stedim Biotech , Bohemia, NY 11716. www.sartorius.us or call 631-254-4249
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Braid-Reinforced Silicone Hose � Silicone hose is reinforced for enhanced pressure capabilities. Called APSH, its applications include those in the pharmaceutical process industry. APSH is braid reinforced and ad-dresses applications involving greater flow volume needs - those where the fluid path must handle a higher pressure rating than unreinforced tubing is able to. The braiding also gives the user a much higher safety factor if there’s concern that the pressure-handling ability of unreinforced tubing may be marginal for the intended application. APSH hose is suitable for air transfer as well as fluid and works within a wide range of temperatures: 100°F (73°C) to 400°F (204°C). ■ AdvantaPure, a Division of NewAge Industries , Southampton, PA 18966. www.advantapure.com or call 888-755-4370
Fabricated Vessels � High-quality tanks and ves-sels are used for a wide range of processes and industries. Fabrication projects of virtually any size or complexity can be completed with greater effi-ciency and faster deliveries. Fabrication capabilities include vessel capacities up to 100,000 gallons, vacuum and/or high internal pressure design, and variable speed agitators. There are many choices for materi-al of construction available including carbon steel, stain-less steel, aluminum, titanium, Monel, Hastelloy and Inconel. They include custom ports, manways and nozzles. The tanks and vessels have heating/cooling jacket or coils, heat tracing, and sheathing and insulation. They have a sanitary design as well as special coatings and tank liners. The units meet code requirements such as ASME, USFDA, BISSC, ABS, API650, API620 and U142. ■ Ross Engineering Inc. , Savannah, GA 31405. www.mixers.com or call 800-524-7677
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Ampule Filling and SealingMachine � The RSF3L has a capacity of up to nine thousand ampules an hour, and it offers features to satisfy the demands for liquid products in a sterile envi-ronment. It has perfect re-peatability of the ampule filling and sealing, simple and quick size change-overs, and the possibility to easily connect it to a sterilization tunnel installed upstream from the machine itself. The structure of the machine facilitates efficient cleaning, which is import-ant for this particularly delicate product. Glass fragments do not enter the ampule feeding lines because, if there are any, they drop into the basin in the bottom of the machine. The filling unit installed on the ma-chine’s work surface is easy to dismantle and sterilize. The ampules are automatically loaded directly from boxes or open-sided baskets onto the conveyor where they are held firmly in position by a support. From here, they are subsequently transferred by a continuous-motion scroll to a variable speed star wheel and then to the rake conveyor. Ampule presence on the rake conveyor is controlled electronically on the neck. Sterilization-In-Place (SIP) of the entire dispensing system. ■ Marchesini Group, Pianoro (Bo), Italy. www.marchesini.com or call +39 051.651.87.11
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Biopharmaceuticals continue to be a growing, important class of pharmaceutical products on the market, and many of these products are pro-duced using mammalian cell culture. Monoclonal
antibodies, currently the dominant class of biopharmaceu-ticals, generally require mammalian cell culture production to enable addition of critical post-translational modifications such as glycosylation. Since these products are often given to patients at high doses, total bulk drug requirements for a single product can be as high as 7,000 kg per year. When monoclonal antibodies first entered the market, there was significant concern over the ability of the industry to pro-duce enough product to treat eligible patients worldwide. To be able to meet this high demand, the industry has developed cell line development and cell culture technolo-gies that improve the overall performance and viability of production cell lines in the bioreactor. This article reviews emerging approaches to improving biopharmaceutical pro-duction cell lines and cell culture performance through the application of genomics and related technologies. Together these technologies are positioned to cause significant changes that will enable each and every mammalian cell cul-ture run to provide high yields of biopharmaceutical prod-ucts with desired quality attributes.
INTRODUCTIONDemand for biopharmaceutical products, especially mono-
clonal antibody-related products, continued to grow at a very healthy pace in 2012 with total biopharmaceutical sales reaching nearly $130 billion, or approximately 13% of the total pharmaceutical market1 2. In 2012, there were 34 biopharma-ceutical “blockbuster” products with annual sales over $1 billion, of which over 60% were produced in mammalian cell culture. Five of the top ten selling pharmaceutical products are now biopharmaceuticals, four of which are monoclonal antibodies3. These products, Humira, Enbrel, Remicade and Rituxan, combined with Avastin, Herceptin and the long list of monoclonal antibody products in development make monoclonal antibodies the fastest growing class of biophar-maceutical products. In addition, as the patents governing the exclusive rights to many of these blockbuster biophar-maceutical products begin to expire, the pharmaceutical in-dustry worldwide has shown a growing interest in developing follow-on biologics or biosimilars to provide lower cost alter-natives to the current innovator products on the market.
Despite the growing market demand for innovator and biosimilar biopharmaceutical products and the associated requirement for increasing amounts of mammalian cell culture capacity to meet this demand, ongoing advances in cell culture process yields coupled with signifi cant expansion of manufac-turing capacity in the last decade, have enabled the industry to meet the market demand for these products to date. However, as these advanced medicinal products reach expanded mar-kets worldwide and as newer, higher dose innovator products progress through clinical trials and onto the market, additional advances in cell line development and cell culture technology will be required to continue to produce enough product using the available mammalian cell culture capacity.
Cell line development and cell culture advances in the past 2-5 years include many orthogonal approaches to improve expression levels and productivity in the bioreactor. These include improvements in the parental cell lines, advances in genetic methods to improve gene expression through a vari-ety of means, improved media and feed composition, alterna-tive supplements or analysis to enable enhanced productivity in the bioreactor, and single use bioreactors that enable di-versifi ed manufacturing strategies and local production. Each of these advances utilized alone or in conjunction will con-tribute to improvements in supply of bulk biopharmaceutical products over the next decade and will enable these life-sav-ing medicines to reach greater patient populations worldwide.
Using Genomic AnalysisTrends to improve mammalian cell culture for biopharmaceutical production■ By Susan Dana Jones, Ph.D., Vice President and Senior Consultant, and Dawn M. Ecker, Consultant, BioProcess Technology Consultants
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Figure 1. Total sales in the US and Europe of traditional pharmaceuticals (blue) and biopharmaceuti-cals (green) are shown by year for the past decade. Sales information was obtained from company annual reports and other publically available sources.
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protein expression. Of the 392 proteins that were identified in the proteomic analysis, 32 were differentially expressed. In the high-producing cell cul-ture, several proteins related to protein metabolism were up-regu-lated, including eukaryotic translation initiation factor 3 and ribosome 40S. In addition, several intermediate filament proteins such as vimentin and annexin, as well as histone H1.2 and H2A, were down-regulated in the high producer. These studies provide additional insight into methods to engineer host CHO cell lines for better growth, viability, and transgene expression.
Nicolas Mermod’s group at the University of Lausanne have focused their efforts on understanding the mechanism of transgene recombination into the genome during the initial phases of cell line development and the secretory pathway functions that are essential for cell health and productivity of the secreted product encoded by the transgene. 8 This work could lead to advances at the cell line development stage that could create production cell lines with greater genetic stabil-ity, cell health, and ability to produce the desired protein.
Many mechanisms for integration of transfected plas-mids into mammalian cell genomes such as CHO cells have been suggested in publications, but none of the proposed mechanisms explains the results that are obtained when analyzing the genomes and transgene structures of CHO pro-duction cell lines. In collaboration with the Swiss Institute of Bioinformatics and Selexis SA, a cell line development and engineering company co-founded by Dr. Mermod, his group has evaluated the data from CHO cell production cell lines and proposed a novel molecular integration model that may explain transgene integration. Dr. Mermod’s laboratory is cur-rently evaluating this model and has shown that when they block competing recombination pathways and use plasmids containing matrix-attachment regions, transgene expression levels are significantly increased compared to control cul-tures. Therefore, the integration model they have developed has some scientific merits, and it also may have a practical value to allow improved methods for cell line construction.9
Overall, the studies of the CHO genome and differential ex-pression have successfully identified target pathways for molec-ular engineering of the parental cell lines and for identification of high producers using biomarkers. Exploitation of these ad-vances in cell line engineering has only recently been initiated within the industry but the productivity impact on newer CHO production cell lines can already be seen. For example, Selexis has recently launched a series of engineered versions of their host CHO-M cell line designed to address many of the secre-tory bottlenecks associated with difficult to express proteins.10
Leveraging their knowledge of the CHO-M cell line genome and transcriptome, Selexis identified potential issues with the CHO-M secretory pathways such as stalled translocation, im-
IMPACT ON CHO CELL LINE ENGINEERINGIn the past decade, numerous companies and academic
groups have focused significant efforts on using genomic, proteomic, and transcriptomic studies to generate a complete understanding of CHO cell biology under different conditions. The hope and promise of these studies was that they would provide actionable results that could facilitate CHO host cell and production cell line engineering for greater viability and productivity, and could contribute to better control of overall performance in the bioreactor. Goals of these studies included identification of unique biomarkers that indicate better performance or identification of targets for knock-in or knock-out cell line engineering. Since a rapid rate of cell growth to achieve maximum biomass quickly and sustained viability throughout the culture should lead to greater pro-duction of the desired protein from a bioreactor, many of the studies focused on achieving one or both of these goals. The publication of the CHO genome in 20104 provided the exten-sive information that is necessary to implement such studies and reach actionable conclusions.
Colin Clark and his colleagues at the National Institute for Cellular Biotechnology in Dublin, Ireland, have published nu-merous studies on differential expression analysis in a vast number of production CHO cell lines. These studies have in-cluded proteomics, transcriptomics, and microRNA (miRNA) analysis to filter out false positive and false negative results and obtain a clear understanding of those genes that are actively involved in enabling high viability and productivity of CHO production cells in culture. In one such study, Doolan et al.5 performed microarray and proteomics analysis of CHO cells to identify specific genes that contributed to faster cell growth. The analysis of mRNA levels and protein levels was performed on two CHO production cell lines that expressed the same transgene but grew at different rates. They report that they identified 118 transcripts and 58 proteins that were expressed at different levels in the two cell lines, and of those 21 gene can-didates showed up in both sets. By using silencing RNA (siRNA) to inhibit expression of selected gene candidates, the group found that a protein known as valosin-containing protein (VCP) is a major contributor to CHO cell growth and viability. VCP is therefore one example of a protein that could be manipulated by engineering parental or production CHO cell lines to im-prove growth and viability. In another publication by the same group, Sanchez et al.6 showed that the tumor suppressor MiR-7 also appears to inhibit proliferation of CHO cells in culture. Therefore, inhibition of MiR-7 is another approach to improving cell growth and viability in the bioreactor.
Carlage et al.7 studied the impact of a known inhibitor of apoptosis, Bcl-X(L), on expression patterns of host cell genes in a CHO cell line that was expressing a transgene. Production CHO cells transfected with the gene encoding this apoptosis inhibitor had higher levels of transgene expression than a parallel non-transfected culture. Using proteomic analysis, the two cell lines were compared at various times during cell culture to identify any differential
gu-slation 40S.
e filament annexin, as well down-regulated in the
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Corporate/Press%20Room/Top-Line%20Market%20Data%20&%20Trends/Top_20_Global_Products_2012_2.pdf
4 Xu X et al. “The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line,” Nat Biotechnol. 2011;29(8):735–741
5 Doolan P. et al. “Microarray and Proteomics Expression Profiling Identifieds Several Candidates, Including the Valosin-Containing Protein (VCP), Involved in Regulating High Cellular Growth Rate in Production CHO Cell Lines,” Biotechnol Bioeng. 2010 May 1;106(1):42-56
6 Sanchez, N. et al. “MiR-7 triggers cell cycle arrest at the G1/S transition by targeting multiple genes including Skp2 and Psme3,” PLoS One. 2013 Jun 6;8(6):e65671. doi: 10.1371/journal.pone.0065671. Print 2013
7 Carlage T. et al. “Proteomic profiling of a high-producing Chinese hamster ovary cell culture,” Anal Chem. 2009 Sep 1;81(17):7357-62
8 Mermod, N. “CHO genome sequencing and engineering to improve clone selection and expression” Presented at IBCUSA Cell Line Development and Engineering Conference, 20-22 May, 2013, La Jolla, CA
9 Dr. Nicolas Mermod, Personal communication10 Dr. Pierre-Alain Girod, Personal communi-
cation ■
tion cell line allowing for better understanding of culture conditions and paving the way for maximum productivity of the cell line. With these industry-wide advances in understand-ing CHO cell biology and their application to the production of biopharmaceuticals, the industry continues to evolve to more efficient, more productive, and more robust cell culture approaches that should be able to meet the growing demand for these products.
REFERENCES1 Data derived from the BioProcess
Technology Consultants Biopharmaceutical Database.
2 IMS Health Inc. Total Unaudited and Audited Global Pharmaceutical Market, 2003 – 2012 [Internet]. Danbury (CT): IMS Health Inc; 2013 Aug [cited 2013 Aug 13]. 1 p. Available from: http://www.imshealth.com/deployed-files/imshealth/Global/Content/Corporate/Press%20Room/Total_World_Pharma_Market_Topline_metrics_2012.pdf
3 IMS Health Inc. Top 20 Global Products 2012 [Internet]. Danbury (CT): IMS Health Inc; 2013 Apr [cited 2013 Aug 9]. 1 p. Available from: http://www.imshealth.com/deployedfiles/ims/Global/Content/
proper folding, incomplete post-translational modifications or insufficient cellular respi-ration to handle the increased protein load. They then used transposon-based vectors to express over 100 different auxiliary proteins which could overcome secretion bottlenecks associated with the CHO-M cell line and built combinatorial CHO libraries containing differ-ent combinations of these proteins. Using the resulting SURE CHO-M Library, Selexis was able to boost productivity of a non-natural mini-body by over 10 fold without any changes in gene copy number or transcription levels. Such improvements are emerging throughout industry as it exploits the wealth of data that has recently become available through genom-ics and associated technologies.
CONCLUSIONAs more products enter the market and as
biopharm sales expand into new geographic areas, mammalian cell culture must become a more efficient production method to meet this continually increasing market demand. Many have recognized this need for improvement in cell culture and have made significant efforts in understanding and engineering the produc-
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Nano Particle Size and Zeta Potential Analyzer The NanoPlus utilizes photon correlation spectroscopy and electrophoretic light scattering techniques to determine particle size and zeta potential. Compact and easy to use with an extended analysis range, intuitive software, and multiple sample cells to fit the user’s application, the instrument can measure particle size in the range of 0.1 nm to 12.30 µm with sample suspension concentrations from 0.00001% to 40% and zeta potential of sample suspensions in the -500 mV to +500 mV range with concentrations from 0.001% to 40%. The instrument is available in three model configurations: a nano particle sizing instrument; a zeta potential instrument; and a combination nano particle sizing and zeta potential instrument. The NanoPlus has an array of compatible sample cells for both zeta potential and nano particle size measurements. The optional NanoPlus AT automatically controls the pH of sample suspensions and conducts titrations in a pH range from 1 to 13. ■ Micromeritics Instrument Corp. , Norcross, GA 30093. www.micromeritics.com or call 770-662-3688
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PHARMACEUTICAL PROCESSING | OCTOBER 2013 27 ■
■ I N N OVAT I O N S
Energy Management System The company has been working with its clients to solve humidity and moisture control chal-lenges specializing in pharmaceutical process applications including gel cap production, pill production, moisture regain prevention, packaging, and storage applications. The dehumidifi-ers precisely control the environmental conditions by independently controlling temperature and humidity levels eliminating moisture problems while increasing product consistency and decreasing downtime. The latest patented product is the BrySmart™ Energy Management Sys-tem and with unmatched expertise in applying dehumidification systems, the EcoDry™ Series Product can save over 40% annual operating cost over traditional desiccant dehumidification systems. ■ Bry-Air, Inc. , Sunbury, OH 43074. www.bry-air.com or call 877-379-2479
Abrasive Cloths ABRATEC™ abrasive cloths are made with vari-ous levels of abrasive grits backed with unique Quiltec® fabric. The two sided cloth remediates corroded equipment with the abrasive side and wipes away residue with the Quiltec. Quiltec fabric is durable and abrasion resistant. This abrasion resistance and sealed border technol-ogy allow the Quiltec side to remove sanding debris without contributing additional particles to the remediation process. ABRATEC abrasive cloths are designed to work with solvents, in-cluding IPA/water blends, improving the ability to remove biofilm buildup. Cloths are also avail-able irradiated with a dose of 25-50 kGy, which helps maintain the integrity of sterile environ-ments. ■ Contec, Inc., Spartanburg, SC 29303. www.contecinc.com or call 864-503-8333
EQUIPMENTCLEAN ROOM
Integrated Custom Air Handler Dehumidification System The Integrated Custom Air Handler (ICA) dehumidification system simplifies the integra-tion of a desiccant dehumidifier with other air conditioning components. ICA is customizable to multiple configurations, offers ten rotor sizes, seven desiccant options, and a range of stan-dard components engineered for maximized performance. ICA incorporates many advanced features including an innovative double wall construction with superior no-through metal design in either 2.5 or 4 inch wall thickness. Sur-face options of galvalume, textured aluminum, stainless steel or any combination allow an ef-fective choice for all operational environments. ■ Munters, San Antonio, TX 78201. www.munters.us or call 800-843-5360
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Today, all pharmaceutical and biopharmaceutical companies follow testing requirements which set standards for inspection of visible particulates, and also for examining the size and quantity of
sub-visible particulates in final products. These quality con-trol mechanisms are typically employed at the end of the production cycle, and are typically done via optical inspec-tion. However, pharmaceutical developers and manufactur-ers are finding that they need the high resolution provided by a scanning electron microscope (SEM) to characterize, control, and elementally quantify the size and shape of these particles.
In particular, the con-tinuing trend toward smaller particles for active pharmaceutical ingredients (API), and better quality of the final
product, has pushed particle dimensions into the sub-mi-crometer regime, which is beyond the capability of optical measurement tools. 1
This article will review some different types of unwanted particulate matter found in pharmaceutical products and the advantages of using scanning electron microscopy with energy dispersive spectrometry (SEM-EDS) as a means to fully characterize particle matter during the manufacturing process. In addition, periodic sampling of the final product for the active matrix and coating thickness will be pre-sented.
PARTICLE CONTAMINATION Particulate matter can range in size from sub-microns
up to several hundreds of microns. In most cases, parti-cle size distribution and total count are required. Foreign particles or particulate matter in drug powder products is an area of extreme concern. Unwanted particles should
be controlled and their sources identi-fied. Contamination due to an excessive amount of particulate matter in pharma-ceutical products might lead to quality and safety problems. Particle contamina-tion in manufacturing sites might even re-sult in the suspension of production.
Scanning electron microscopy provides visual information about the organic and inorganic submicron particles (size, shape, and morphology), and also chemical iden-tification based on the X-ray energy lines.
TYPICAL SOURCES OF PARTICLE CONTAMINATION
Depending on the nature of the sample (organic, inorganic, or metallic), and the type of information desired, the imaging and chemical characterization capabilities of SEM-EDS lead many pharmaceutical laboratories to use this technology to evaluate morphology, size, shape, and elemental composition of metallic and or-ganic sub-visible particles.
Sources of particulate matter vary
Scanning Electron Microscopy ServicesSEM offers the quality control needed for ever smaller API particles■ By Gary Brake, Marketing Manager, SEMTech Solutions
■ 28 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
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Above: Figure 1. SEM Images and EDS spectra of common pharmaceutical contaminants.Right: Figure 2. Backscattered electron image and EDS map of a multi-vitamin cross-section.
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Above: Figure 3. Oxygen (O) EDS map of the multi-vitamin in Fig. 2.Right: Figure 4. Coating thickness of an ibupro-fen tablet.
■ P H A R M P R O . C O M
depending on the development process, equipment used, location, and overall facility cleanliness. But, even the clean-est rooms can produce particulate matter shed by gowns, gloves, skin, sample preparation equipment, and glassware. Containers and closures, specifically rubber closures, con-tribute particulate matter due to leaching, chemical reac-tions, friction, and changes in physical properties.
Some of the most common materials identified in pharma-ceutical environments are stainless steel, silica, aluminum, salts, minerals, organic fluorinated compounds, and carbo-naceous materials in varying sizes and shapes.2 SEM Images and EDS spectra of some of these particles are shown in Figure 1.
ACTIVE INGREDIENTS IN PHARMACEUTICAL TABLETS
Pharmaceutical tablets are composed of a number of different materials, each of which is designed to improve performance. The Active Pharmaceutical Ingredient (API) is intended to act on the particular disease or the symptoms of the disease. The other components, referred to as ex-cipients, act as fillers, bulking agents, tablet disintegrants, and tablet coatings (to protect the core and to mask taste). Consistent performance of the tablets depends directly upon the amount of each excipient in the tablet.
During development, it is useful to have a means to in-vestigate the distribution of excipients and API within the tablet itself. The use of EDS maps and BSE (Back Scattered Electron) images of tablet cross-sections are two related means of directly examining excipient and API distribution within a tablet. The example shown in Figure 2 highlights the quantitative methods using a multi-vitamin tablet as a test case using a backscatter image of the tablet cross-sec-tion along with the accompanying EDS map.3
In addition to visually seeing all of the elements, the EDS system can provide quantification by percent of the total elements as shown in Table 1. Of note in the table is the in-corporation of oxygen that was purposely excluded from the EDS map of Figure 2.
Since oxygen bonds tightly with other elements to form ox-ides, it was left out of the comprehensive EDS map. Shown in Figure 3 is the oxygen element EDS map in green. It is inter-esting to note the various elements that the oxygen binds to by overlaying Figure 3 on top of Figure 2. As a note, the green that is shown in Figure 2, is the combination of the mutliple colors from the Iron (Fe), Zinc (Zn), and Calcium (Ca).
QUALITY CONTROL Besides monitoring for particulates in a production line,
and quantifying the API within the tablet, another quality control check can be obtained by measuring thickness of the tablet’s coating. Figure 4 shows the thickness value of a tab-let coating from an Ibuprofen sample using a Back Scattered Electron (BSE) Image.
Tablet coatings have numerous functions including
strengthening, controlled release, ease of handling and packaging, pro-tection of the tablet from moisture, improved taste, facili-tate swallowing, and to provide tablet identity.
The adhesion of a coating to the tablet is influenced by the strength of the interfa-cial bonds between film and tablet. Poor adhe-sion results in peeling, which reduces film func-tionality. The mechani-cal protection provided by the coating can also be compromised by loss of adhesion, leading to the accumu-lation of moisture at the film-tablet interface. This could affect the stability of moisture sensitive drugs.
SUMMARY Implementing a SEM-EDS particle-characterization program
is a key step towards optimizing the design and therapeutic effect of new pharmaceutical products, and controlling unde-sirable contamination. SEM imaging provides the resolution required to evaluate both the size and shape of nanometer scale particles. The large depth of focus of the SEM reveals fine surface detail, even over large, irregularly-shaped par-ticles. SEM and EDS image-based particle analysis provides qualitative and quantitative capabilities for nanoscale parti-cles far beyond the capability of optical microscopy.
REFERENCES 1. Lich, B., Wilfen, U., 2009, When Size & Shape Matter, Drug
Discovery & Development. Vol. 12 Issue 2, p. 26 2. Vicens, M.C., 2012, A New Picture of Particles, Drug
Discovery & Development. 3. Carlton, R.A., 2010, Image Analysis of EDS and Backscatter
SEM Images of Pharmaceutical Tablets, Microscopy and Microanalysis, v. 16 (Suppl2), p. 662-663. ■
PHARMACEUTICAL PROCESSING | OCTOBER 2013 29 ■
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Table 1. Quantitative Analysis of the Multi-vitamin Tablet
Elt. Intensity (c/s) Atomic % Conc Units
C 84.95 37.169 25.796 wt.%
O 93.39 49.951 46.179 wt.%
Mg 46.42 3.310 4.648 wt.%
Si 6.49 0.295 0.479 wt.%
Ca 233.44 8.133 18.834 wt.%
Fe 7.89 0.456 1.472 wt.%
Zn 6.54 0.686 2.593 wt.%
100.000 100.000 wt.%
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A powerful alternative for pharmaceutical dosage formsPolymer choices in pharmaceutical dosage forms have always been a balancing act between performance and development time, and historically has been shaped by the interactions of gelatin. The fi rst generation of HPMC capsules, which relied on a secondary gelling agent, were recognized by formulators as having issues with dissolution performance and product stability. Fortunately, new scientifi c discoveries in polymers and capsule manufacturing have resulted in the creation of the next generation of capsules – one that offers better performance and reduced development time compared to gelatin and fi rst-generation capsules.
Capsugel, the market leader in research and development in this area, is now offering these second-generation HPMC capsules under the trade name, Vcaps® Plus capsules.
In a number of studies, Vcaps Plus capsules have been shown to deliver optimized compound stability and predictable in vitro dissolution while also helping to eliminate the complexity in formulation development. Known globally for their reliable and predictable performance, Vcaps Plus capsules are well suited for over-the-counter (OTC) or off-patent products as well as for new chemical entities (NCEs).
True pH and ionic media independent performanceTraditionally, HPMC capsules were created using secondary gelling agents and ionic gel promoters, which have been found to interact with dissolution media and delay compound release from the capsule. The activity of the gelling agent kappa-carrageenan, for example, is enhanced by potassium and calcium cations contained in many foods. The extent of the resulting delay in dissolution time was shown in an in vitro test in which caffeine-fi lled traditional HPMC capsules were dissolved in a number of dissolution media. In the simulated normal acidic environment of the stomach (pH 1.2 USP), 90% of the caffeine was dissolved within approximately 15 minutes (Figure 1). Adding 2 g/L of potassium chloride (KCl) to this medium resulted in no dissolution after 15 minutes and a caffeine dissolution between 70% and 80% after more than one hour. Increasing the KCl content to 9 g/L delayed caffeine release even further, with a dissolution rate of just over 10% in 45 minutes. Results with simulated milk fl uid were equally disappointing. Similar delays in dissolution times were observed and attributed to carrageenan in an independent study (Ku et al., 2011). Of course, such long delays in capsule dissolution are unacceptable particularly for rapid-relief products.
Capsugel addressed this situation by developing a proprietary new thermal gelation manufacturing process for Vcaps
Plus capsules that eliminates the need for gelling systems all together and provides true pH and ionic media independence in disintegration. In vitro tests showed that these second-generation HPMC capsules had similar rates of dissolution at pH levels of 1.2 and 6.8 and with simulated milk fl uid, achieving a nearly complete dissolution of the caffeine contents within approximately 30 minutes (Figure 2). Even adding 2 g/L or 9 g/L of KCl to the dissolution medium did not affect the performance of Vcaps Plus capsules, with dissolution of over 90% within 30 minutes, even under the most disadvantageous condition.
These fi ndings were supported by an independent study that compared the dissolution performance of traditional and second-generation HPMC capsules (Ku et al., 2011), and underscores the superior performance of Vcaps Plus capsules.
Ideally suited for moisture sensitive compoundsWhile gelatin capsules have been effectively used for over a hundred years, due to their excellent fl exibility and highly desirable dissolution properties, they are not typically the polymer choice for moisture sensitive compounds. Vcaps Plus capsules on the other hand have a three-fold lower moisture content than gelatin capsules and are less hygroscopic. That equates to fewer broken capsules due to brittleness and less of a chance of drug degradation compared to gelatin capsules.
Next generation HPMC capsules greatly expand pharmaceutical uses by Dominique Cadé, PhD
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■ 30 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
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Improved stability at high and low temperaturesCapsugel in-house studies and an independent study conducted at Wyeth (Ku et al., 2010) have demonstrated the superior stability of Vcaps Plus capsules. An exposure of up to one week to temperatures ranging from 4°C to minus 18°C did not change the appearance or performance of unfi lled Vcaps Plus capsules in closed high-density polyethylene (HDPE) bottles. The same stability was found with empty Vcaps Plus capsules in fully-fi lled glass bottles that were heated for 24 hours to temperatures ranging from 40°C to 60°C.
In long-term storage condition studies, including a 6-month storage at 40°C and 75% relative humidity and 2 years at either 25°C and 65% relative humidity or 30°C and 70% relative humidity, Vcaps Plus capsules disintegration and dissolution characteristics remained unchanged. The wider temperature capabilities of Vcaps Plus capsules make them the perfect choice for longer term storage and when used in progressively unpredictable home environments.
Superior machinabilityTraditional and second-generation HPMC capsule attributes have been compared on many common high-speed capsule fi lling machines (Ku et al., 2010). With respect to fi lling and rejection rates, Vcaps Plus capsules performed much like gelatin capsules and were superior to traditional HPMC products. In addition, Vcaps Plus capsules can be adapted for use with liquid compounds.
Wide regulatory and industry acceptanceVcaps Plus capsules are manufactured in certifi ed ISO 9001 facilities and in accordance with IPEC’s (International Pharmaceutical Excipient Council) Good Manufacturing Practice (GMP) Guide for Bulk Pharmaceutical Excipients. They are acceptable for use in pharmaceutical and dietary supplement oral dosage applications in major markets of the US, Canada, EU, Japan, and Australia. In addition, Vcaps Plus capsules are certifi ed Kosher Ko and Halal by IFANCA, and are approved for vegetarians by the Vegetarian Society.
References
Ku, S.M., Li W., Dulin, W., Donahue, F., Cadé, D., Benameur, H., Hutchison, K., Performance qualifi cation of a new hypromellose capsule: Part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps® Plus, Quali-V and gelatin capsules. Int. J. Pharm. Vol. 15; 386(1-2):30-41, 2010.
Ku, M.S., Lu, Q., Li, W., Chen, Y., Performance qualifi cation of a new hypromellose capsule: Part II. Disintegration and dissolution comparison between two types of hypromellose capsules. Int. J. Pharm. Vol. 15; 416(1):16-24, 2011.
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100
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Time in minutes
0 3 6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75
Influence of gelling systems on HPMC capsules in dissolution testing
pH 1.2 USPpH 6.8 USPpH 6.8 JP2Simulated milk fluidpH 1.2 – 2 g KCI/LpH 1.2 – 9 g KCI/L
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Time in minutes
0 3 6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75
In vitro dissolution of caffeine in Vcaps® Plus capsules
pH 1.2 USPpH 6.8 USPpH 6.8 JP2Simulated milk fluidpH 1.2 – 2 g KCI/LpH 1.2 – 9 g KCI/L
For more information about Vcaps® Plus capsules visit VcapsPlus.com.
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Figure 1 Figure 2
PHARMACEUTICAL PROCESSING | OCTOBER 2013 31 ■
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The bottom line, it’s a hot topic for life sciences companies fighting to stay competitive in today’s pharmaceutical marketplace. More than ever, oral solid dosage manufacturers are paying closer
attention to the overall operational costs of processing equip-ment and not just the upfront capital cost of acquisition.
To stay on top of their game, pharmaceutical companies are demanding manufacturing facilities that yield high-ef-ficiency processing while lowering the overall cost of drug development. This has resulted in continuous improvements in the design of processing technologies, which has led to operational cost savings and higher efficiencies.
Specifically, tablet coaters are undergoing technology ad-vances that are increasing cost efficiencies and changing the ways companies bring their solid dosage drugs to market.
NEW TABLET PAN GEOMETRYThe tablet pan may seem like a basic part of a coater, but
it’s playing an increasingly important role in the efficiency of pharmaceutical campaigns. Different pan sizes and shapes can affect the overall number of defects in a batch.
Traditional tablet pans are short in length and large in di-
ameter. This creates a thick tablet bed when solids are put in the coater. A thicker tablet bed has a zone in the middle that is slow moving, and tablets in this area do not get exposed to the surface of the bed as often. That means it takes longer and uses more coating solution to get the tablets fully covered.
Manufacturers of high-efficiency coaters have changed the geometry of coating pans, making them longer in length and smaller in diameter. With these pans, the tablet bed spreads wider, so there is no slow-moving zone. Because the tablets stay in constant motion, they enter the spray zone more often for higher efficiency and better uniformity. The shallow tablet depth also produces less static force on the cores. This re-sults in gentler handling and less damage to the tablets.
A smaller diameter coating pan also prevents twinning, or tablets sticking together in the tablet bed. Twinned tablets must be sorted out and are often counted as rejects, which impacts overall batch consistency. If the tablet bed is thin-ner in the narrow pan, the tablets will stay in motion and thus prevent twinning. This benefit is particularly valuable to pharmaceutical companies manufacturing elongated or flat tablets. These tablets are more likely to stick together than their round counterparts.
Coaters Go High-TechAchieving high-quality oral solid dosage manufacturing through continuous tablet coating improvement■ By Martin Hack, Vice President and General Manager, L.B. Bohle, LLC
■ 32 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
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Advances in tablet coating technology is leading to increased efficiencies for pharmaceutical manufacturers.
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BETTER MIXING CAPABILITIESMixing is a prerequisite for homogenous and uniform
tablet coating. Tablet consistency is a large factor in quality control and time-to-market for tablet drugs. To achieve high uniformity tablets must be mixed adequately. For cosmetic coatings drug manufacturers can typically get uniform tab-lets with traditional coaters but the process is inefficient. More time and coating solution are required, increasing the operational costs of the manufacturing process.
For example, with conventional coaters, tablet weight must increase 4 to 5 percent to achieve a uniform coat. But through advances, the newest coaters achieve the same coverage with only 1.5 to 2 percent weight gain. These ma-chines also can achieve a 4 percent coefficient of variation, which is better than any traditional coater.
High uniformity is also realized with the latest mixing systems. The most advanced systems use spiral baffles to constantly move tablets through the coating pan. One of the baffles moves tablets to the back of the pan, while the other brings them forward. The upper and lower baffles expose all tablets to the spray equally. This enables higher spray rat-ers, which shortens the time required to coat tablets in each batch. Additionally, pharmaceutical manufacturers can attain tablet homogeneity in each batch, with tablet coating unifor-mity at less than 4 percent relative standard deviation (RSD).
AIR FLOW BED TECHNOLOGYConventional tablet coaters send air flowing from the top
or side of the coater. The air travels across the spray zone, through the tablet bed and out of the coater. However, this brings hot air into direct contact with the coating spray as it is airborne and it can dry part of the solution before it con-tacts the surface of the tablets.
With the airflow entering from the top or side traditional coaters are also prone to producing a spray cloud effect where the coating spray meets turbulent air. This spreads the solution out causing it to cover the pan and spray arms in addition to – and often times instead of – the tablets. All that coating material is wasted. When dried the spray solu-tion gets trapped in the machine’s filter system. The spray cloud can also cost manufacturers tablets by causing them to stick to the pan. Those tablets must then be rejected.
Advances in air flow bed technology are increasing manufac-turing efficiency by eliminating this spray drying. New designs allow the airflow to enter the coater from beneath the tablet bed. It is distributed much more evenly and it covers the entire length of the pan. That means all the air flowing through the tablet bed is in the direction of flow, so no hot air is left in the spray zone. Spray drying is almost eliminated entirely.
When spray drying is drastically reduced, manufacturers will also decrease the volume of wasted coating solution. When airflow partially dries an airborne droplet of coating material it tends to bead, bouncing off the core and landing on the tablet pan instead of dispersing on the tablet surface. That tiny dried bead is wasted material. That, ultimately, means that the cam-
paign will use more coating solution in total, at an increased cost to the manufacturer. Modern air flow bed technology reduces airborne drying, ensuring that droplets are wet when they hit the tablet surface. That results in less coating solution used to achieve uniformity and less total material consumed.
REDUCED CLEAN-UPPharmaceutical manufacturers want to campaign batches
until they absolutely need to stop. Design improvements have helped manufacturers reduce the amount of wasted coating solution left on the tablet pan and spray arms. This means manufacturers can campaign longer without stopping to clean the coater.
A reduction in cleaning time helps to boost a company’s overall efficiencies in terms of waste management. A typi-cal coater’s wash cycle uses 400 gallons of water. Because newer machines require fewer cleanings, manufacturers
PHARMACEUTICAL PROCESSING | OCTOBER 2013 33 ■
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Top: The latest coaters feature new technologies that can uniformly coat a tablet with signifi-cantly less weight gain. Bottom: Maintaining proper gun-to-bed distance is critical for functional coatings. A laser measurement sensor mounted in the spray arm of the coater monitors this criti-cal parameter.
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■ 34 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
gained more importance in the last few years. Equipped with additional function-ality, such as gastro resistance for drug delivery in the intestine or insolubility for a sustained drug release, these coatings sig-nificantly improve drug delivery.
Active coating also allows the combina-tion of several drugs into a single dosage form. This eases up the development of new fixed-dose combinations, which are growing in the market. Sophisticated coaters are required to produce the high coating uniformity and low spray losses that these functional coatings demand.
Some of the latest functional coating technology has the ability to measure the gun-to-bed distance online by way of a laser measurement sensor. This sensor is mounted in the spray arm of the coater.
Maintaining proper gun-to-bed distance is critical for functional coatings. Typically, these coats are a high weight gain application, with the coating adding 10 percent to 15 percent more weight to the tablets. This large weight gain will cause the tablet bed to grow, and the gun-to-bed distance is narrowed over time.
Now coaters can automatically retract or extend the nozzles via a recipe parameter. Manufacturers can make this gun-to-bed distance a control variable. With a PID loop, the sensor will measure the gap and the system will automatically adjust to maintain the proper distance between the gun and the bed.
With the latest improvements in tablet coating technology, pharmaceutical manu-facturers can be assured they are providing customers with the best solid dosage drugs, all the while reducing their operational costs.
ABOUT THE AUTHORAs vice president and general manager of L.B. Bohle, Martin Hack oversees all compa-ny operations in North America and Puerto Rico. In his 13 years with the company, he also served as a supervisor for project man-agement, service and parts. Prior to joining L.B. Bohle, Mr. Hack was a control engineer for Niro Inc. (Columbia, Md.), where he was responsible for equipment projects in the pharmaceutical industry. He holds a Bachelor of Science in electrical engineering from Virginia Polytechnic Institute and State University. ■
make it onto the tablets. With an inefficient machine, expensive filters will require fre-quent replacing, increasing overall manufac-turing operating costs.
FUNCTIONAL COATINGBesides instant release, or so-called cos-
metic coatings, functional coatings have
potentially can save thousands of gallons of water and reduce wastewater processing costs each month.
Furthermore, advanced coaters do not waste as much coating solution so manufac-turers don’t need to change filters as often. All coaters have dust collectors or filter sys-tems to catch solidified solution that doesn’t
www.tri-mer.com
Tri-Flow filter technology provides:
For Pharmaceutical Manufacturers
Dust Collector for Tableting Operations
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Temperature Data Loggers � Two new temperature data loggers are now avail-able. The TR-701 comes in two versions: the TR-701NW with integrated Ethernet and the TR-701AW with Wireless integrated 802.11b/g Wi-Fi. The new units will automatically “push” current readings and recorded data via FTP to a server of the user’s choos-ing, or via email at a set interval or fixed time of day. The 700W Series has an internal web server for directly viewing current readings. These devices are fully compatible with the company's free cloud based WebStorage Service and utilize the RTR-500 Series data file format for seamless integration with TandD’s wireless networks. The devices incorporate an email client for directly sending warning emails, without the need for a PC. In addition, the 700W Series has a contact closure for triggering an external device in the event of an alarm condition. Both of these units have a temperature range of -40° to +110° C and can be expanded with an optional sensor with a range from -60° to +155° C. ■ TandD Corporation, Santa Fe, NM 87501. www.tandd.com or call 518-669-9227
Isolator Cleaning Tool � The EasyClean® 360 Isolator Cleaning Tool’s unique design makes it the perfect solution for effective and efficient aseptic environment cleaning. The tool’s 360-degree, contoured swivel gets into those hard-to-reach spaces while its overall slim, lightweight ergonomic design withstands the rigors of everyday use and sterilization. The EasyClean® 360 System’s cleanroom laundered polyester cover fits over a conformed pad, enabling quick changes for meeting effective wiping protocol over varied surfaces. ■ Berkshire , Great Barrington, MA 01230. www.berkshire.com or call 413-446-6605
Mobile Ductless Fume Hood � The Mobile EDU is ideal for classroom demonstrations and industrial training. It is totally self-contained and provides all around visibility. The EDU is easily moved from laboratory to laboratory. The ductless design allows easy installation and the base is mounted on large heavy duty wheels for ease of transport. The height is 77.5" which allows it to easily pass through a standard door. The multi-layered EDU filter has been independently tested to have 99.9% filtration efficiency for chemicals normally found in a typical chemistry curric-ulum. These units exceed OSHA, ANSI, BSI and AFNOR Safety Standards. ■ Air Science USA, Fort Myers, FL 33906. www.airscience.com or call 800-306-0656
■ P H A R M P R O .C O M
EQUIPMENT
PHARMACEUTICAL PROCESSING | OCTOBER 2013 35 ■
■ I N N OVAT I O N S
CLEAN ROOM
■ P H A R M P R O .C O M
� Foldable Stainless Steel Floor Crane Floor cranes are portable and retract into a compact size when not in use, to save space in storage. Floor cranes provide an ergonomic solution to many material handling challeng-es. They are smaller, less expensive and safer alternatives to motorized lift trucks. Narrow enough to pass through standard door open-ings, narrow aisles and elevators, floor cranes can be maneuvered in areas off-limits to other lifting equipment. The new foldable floor cranes feature 100% stainless steel construction and have no painted surfaces. Ruger® floor stainless foldable cranes are available with lifting capac-ities of 1,000 lbs. Construction is exceptionally robust, with structural tubing 1/4" to 1/2" thick, large casters and totally welded fabrication. ■
David Round Co., Streetsboro, OH 44241. www.rugerindustries.com or call 800-535-2725
The ewing current
� Reusable Goggle The Acuity™ Goggle is a reusable goggle that is validated sterile and does not yellow, or produce an offensive odor, when irradiated. The Acuity Goggle™ retains its visual trans-mittance through its lifespan and is comfort-able for extended wear. This goggle includes the patented low-particulating strap. It's delivered with Certification of Processing and Validation Compliance Letter. ■ ARAMARK Cleanroom Services , Downers Grove, IL 60515. www.aramark-cleanroom.com or call 630-455-9024
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Top right: Desiccant packets on a continuous strip can be automatically cut and dropped during the packaging process. Right: Integrating desiccants and barriers into plastic containers is a viable alternative.P rotecting the efficacy of pharmaceutical products
through packaging solutions typically requires a combination of active agents and passive bar-riers. Packaging experts have turned to various
types of protective packaging to safeguard drug products against degradation, which can lead to loss of stability, shortened shelf life or an ineffective drug delivery. These agents, primarily moisture, oxygen and odor adsorbents, complement and enhance passive barriers.
Although sorbents are essential to the quality, stability and appearance of packaged pharmaceuticals, such products can increase the complexity of the manufacturing process. The added steps can slow cycle times and provide opportunities for errors and rejects. They also involve multiple materials and components that must be sourced and managed, impacting the supply chain. Some technologies may even require proprietary equipment that ties the manufacturer to a single provider.
Thus, it is key that pharmaceutical packagers utilize active packaging solutions that minimize complexity and enhance efficiency, and pharmaceutical packaging innovators such as Clariant have developed technologies to do just that.
UNIVERSALIZED PLATFORMS OFFER FLEXIBILITYIn all types of containers, desiccants play an active role in
controlling the impact of humidity on drugs, which can af-fect degradation, dissolution or the therapeutic properties of APIs. Because the plastic containers used for most drug prod-ucts are semi-permeable, they allow some moisture to enter
through the container walls. Placing “drop-in” style desiccant
packets and canisters in plastic con-tainers is an affordable and effective way to take advantage of plastic’s cost advantages and resilience, while maintaining the necessary conditions in-side the product package.
To accelerate the speed and improve the efficiency of adding drop-in desiccants, high-speed insertion technology, such as desiccant packets on a continuous strip, have been developed. These packets are automatically cut and dropped during the packaging process. As a further enhancement to reliability and efficiency, strip packets with holes in each seal facilitate optical detection of the cut point. Clariant’s Continu-Strip® Hole Punch packets feature a hole in between every seal to avoid mis-cuts during automatic insertion.
The pharmaceutical industry’s demand for even faster inser-tion is driving increased use of desiccant canisters, which offer a rigid, uniform shape to enable high-speed processing. Because canisters are already separate parts, they allow the use of a fast, efficient hopper system for continuous, seamless insertion, and eliminate the step of cutting desiccants from a reel.
Because of process optimization advantages - potentially doubling insertion speeds compared to packets - desiccant canisters have become the gold standard for protection.
Further, the industry has developed canister-style oxygen scavengers, such as PharmaKeep® humidity-neutral oxygen scavengers, to provide active absorption of oxygen within the drug package. Like desiccants, these canisters can be inserted using high-speed equipment.
Care should be taken with manufacturers who have taken a proprietary approach to their canister/equipment solutions, re-quiring packagers to use only their desiccants on their specific insertion machinery. A more prudent strategy is to choose a universalized platform combining standard equipment and des-iccants that can be used on any insertion machine.
INTEGRATING PROTECTION INTO THE POLYMERAnother strategy for process optimization is integrating pro-
■ By Mark Florez, Marketing & Communications Manager, Clariant Healthcare Packaging
■ 36 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R M P R O . C O M ■
■ P A C K A G I N G
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Optimizing Pharmaceutical PackagingActive and protective solutions help ensure product efficacy
Desiccant canisters' rigid shape enables high-speed processing.
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tection such as desiccants and bar-riers directly into the plastic struc-tures of containers. This approach can be seen in the use of multi-layer blow-molded bottles that incorporate passive barriers to oxygen, ultraviolet
light and other threats. By custom-izing the layers, materials and design,
packagers can create bottles that will work on any line, using standard equipment.
Active polymers can be molded into various shapes and sizes to provide protection directly into container walls or devices. Applications include vials, dosers, dispensers, inhalers and bottles. Plastic housings and delivery device components can be molded from these poly-mers to maintain low humidity levels and pro-tect sensitive reagents from moisture.
The main advantage of integration is avoiding the cost and complexity of sourc-ing, purchasing, inserting and verifying the presence of a separate desiccant. Designing packaging using polymers with integrated sorbents can lower material and processing costs and reduce the number of suppliers involved. Fewer packaging components also lighten the burden posed by change manage-ment - including regulatory review.
Integrated actives eliminate the possibility that drop-in desiccants will be removed from the packaging by a pharmacist or consumer, leaving the contents without protection. They also conserve space, allowing smaller packages to be used or enabling more prod-uct to be put in an existing container.
COMBINING PROTECTIONOther advancements in pharmaceutical
packaging take integration a step further, build-ing active protection directly into the package closure for part consolidation and other pro-duction benefits. Integration of a desiccant into a cap or other closure device, for example, can reduce a three- or four-component package down to just two pieces: the container and the closure. This approach reduces part handling and the burden of managing changes in mate-rials, components and suppliers. Multi-function closures with integrated active agents can de-liver production advantages to pharmaceutical companies and packagers, beginning with the elimination of desiccant insertion. An example is Clariant’s IDC® Integrated Desiccant Closure, a screw-on or snap-on pharmaceutical cap that combines tamper-evident, child-resistant and
twist-off functionalities with a built-in desic-cant, while eliminating the induction seal.
As with polymer integration, including the desiccant in the closure avoids the equip-ment and processing time needed to insert a drop-in desiccant separately. Both methods can reduce cycle time because there is no longer a need for quality checks to verify that a desiccant was placed in each bottle.
PHARMACEUTICAL PROCESSING | OCTOBER 2013 37 ■
■ P A C K A G I N G
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CONCLUSIONPharmaceutical manufacturers rely on
active and passive protection to maintain the efficacy of their products. Innovative packaging options such as high-speed desic-cant insertion and integration of protective elements into the packaging itself are making a significant contribution to streamlined pro-cessing and overall cost reduction. ■
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■ 38 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R M P R O . C O M■ B I O P H A R M
Since 2008, glass delamination has been the sub-ject of recalls for a variety of drug products. Manufacturers of pharmaceuticals and glass containers have joined together to identify risks
for delamination and have developed strategies that could reduce occurrences. The compatibility of a glass container for a given drug formulation is associated with methods of glass manufacture, formulation and surface composition. Action can be taken to mitigate the risk of delamination and include tighter controls over glass manufacturing and han-dling of glass containers, predicting delamination potential, coating glass surfaces or using alternative plastic materials.
As the pharmaceutical industry continues to advance bio-therapeutics, complex drug formulations are inevitable, which could be a challenge to any container material. In certain cases it is possible the pharmaceutical formulation may need to be modified to be suitable with today’s common container mate-rials. Selection of appropriate container materials early in drug development stages will provide added assurance of successful development and commercialization of quality medicine
There are various aspects to be considered when selecting the appropriate container closure system. Glass delamination is a serious issue, but overall compatibility through-out shelf life encompasses several factors of risk. The container must be compatible with the drug or biologic formulation as well as the pharmaceutical manufacturing process, and protect the final product during storage and shipping. Hazards can include inter-actions between the container materials and the pharmaceutical product resulting in leachables; shift in pH; reduced activity or potency of active, pharmaceutical ingredients; and/or formation of particles in addition to glass lamella. Another critical consid-
eration for sterile drug products is for all com-ponents in a system to be compatible, ensuring proper fit. Dimensional in-consistencies, fine cracks or chips can compromise the container closure integrity, putting the final product and patient at risk. Choosing the proper container material early in the development pro-cess can help to prevent compatibility issues while maintaining the safety and
efficacy of the drug product. There are a variety of benefits and potential risks to the use of both glass and polymeric materials. Knowledge of the compatibility of container closure materials with the drug product, as well as the intended use, can help pharmaceutical manufacturers make the right choice when se-lecting materials for their pharmaceutical products.
UNDERSTANDING COMPATIBILITY OF CONTAINER CLOSURE MATERIALS
The process for selecting container closure materials compatible with pharmaceutical products and the intended use is an important aspect of delivering safe medicines to patients. In today’s regulatory environment assessing and managing risk is key to successful drug development and commercialization. The physical and chemical nature of ma-terials used in a container closure system can exhibit behav-ior that has the potential to compromise the drug or biologic product, resulting in harm to a patient.
Even though glass has a long history of use with a variety of pharmaceutical products, it has been the subject of several recalls often associated with delamination. Review of Medwatch FDA safety alerts, associated with glass, included as many as 15 recalls in 2010. This number decreased to 12 in 2011 and 10 in 2012; through second quarter of 2013 only five were noted. It is s not clear if the recent reduction in recalls is due to increased control measures, improved quality of glass, or if the events are fairly random and unpredictable. Considering the multiple vari-ables associated with numerous drug or biologic products , it is difficult to ascertain the ultimate cause of delamination. While there is a concerted effort to improve glass quality and tighten manufacturing controls, the fact remains that the material se-lection is significant when ensuring container closure suitability throughout the pharmaceutical lifecycle.
The manufacturing and use of pharmaceutical products in-cluding its container components entail some degree of risk and therefore, an informed decision relies on understanding potential hazards. Whether the container material is a polymer or glass there are multiple formulations and manufacturing and processes that can influence the chemical and physical nature. Challenges include understanding current weakness in a given application in addition to unexpected hazards that could be experienced such as those associated with formulations enhanced for solubility with novel excipients. Recent estimates show that approximately 90% of pipeline drugs fall into low solubility categories of the Biopharmaceutical Classification System BCS.1 The approaches to overcome poor drug solubility employ use of co-solvents, emulsified systems, molecular complexes, amorphous drug
Conquering Glass DelaminationThe material selection process may alleviate ongoing concerns■ By Diane Paskiet, Director, Scientific Affairs, West Pharmaceutical Services, Inc.
Figure 1: Material Suitability Risk Chart
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PHARMACEUTICAL PROCESSING | OCTOBER 2013 39 ■
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■ B I O P H A R M
n forms and modification of the aqueous microenvironment. It is not always readily understood if these novel medicines will pres-ent unforeseen challenges to container materials.
It is important to realize that no one material can perform optimally under all conditions. Material compatibility and per-formance data will guide benefit to risk analysis. Major consid-erations for selecting materials suitable for the drug product’s intended use include permeation, leaching, sorption, chemical interaction, dimensional consistency , alteration in the physi-cal properties and ensuring functional characteristics during rigors of processing, storage and distribution.
CONSIDERATIONS OF GLASS AND POLYMER CONTAINER MATERIALS
Glass is an non-permeable transparent material that is typed or rated for use based on chemical resistance but this test alone will only indicate the solubility of glass in waterafter autoclave. All glass is not equal, dif-ferent elemental compositions, manufacturing and form-ing processes will influence suitability for use. The risk of using glass stems beyond this challenge since this test will not indicate the potential for delamination, surface adsorption or extractable elements that could leach and interact with the pharmaceutical product. The variability in dimensions is another critical concern since a poor fit can result in leak-age and loss of sterility. Glass does have high compression strength, yet can be broken easily, and applied strain can cause a crack to propagate, leading to fractures during filing or distribution. Data should be acquired at the appropriate time to scrutinize overall suitability of glass for intended use.
Polyethylenes (PE), polypropylenes(PP) and cyclic olefin poly-mers (COP), such as Daikyo Crystal Zenith® (CZ), or copolymers (COC) are commonly used materials for injectable containers. The type of polymer selected, as well as the drug product for-mulations and manufacturing processes will influence suitability for use. Just as with glass, not all polymer types or formulations behave in the same manner. The same container attributes and risks should be scrutinized for all materials being considered. Table 1 shows a broad based comparison of vital properties of glass and two different polymer types derived from materials data sheets. In general terms, all materials will have weaknesses and need to be examined relative to function with other compo-nents in the system, final drug or biologic form, filling/manufac-turing, processing, storage and distribution.
The comparison of two types of plastic with glass indicate glass and cyclic olefin polymers have the highest performance ratings; however, there will be allowable tolerance for each pharmaceutical product/container closure combination depend-ing on final formulation and intended use. Data on the candi-date materials should be gathered at the appropriate stages to show shelf-life compatibility by understanding the impact of potential leaching, degradation, formation of particles, transmis-sion or permeation of gases or vapors, dimensional consistency or material instability in various environments. The propensity of a drug or biologic formulation to interact with a specific
material’s surface and other sensitivities related to the active ingredient or excipients is case by case and may not be readily observed. A high level Material Suitability Risk Chart (Figure 1) derived from literature and material data sheets illustrates the likelihood of quality impact with concern of relative occurrence. The drive to improve quality is for industry to move toward proactive approaches providing innovative solutions rather than to react to failures or even worse, recalls. Identifying suit-ability pitfalls of current and innovative container closure ma-terials will result in a greater upfront investment by the phar-maceutical company, but scrutiny of components and systems early in the development cycle can reduce risk of failure due to material incompatibility.
RATIONALIZATION FOR EARLY QUALIFICATION OF CONTAINER CLOSURE MATERIALS
Only one out of approximately 8,000 new chemical entities makes it to the market, and the related overall research and development process takes on average approximately 13.5 years.3 Failures or interaction of container closure materials
Table 1: Comparison of Vital Properties of Glass and Polymers
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■ P H A R M P R O . C O M■ B I O P H A R M
with pharmaceutical products can occur over short (days) or long (years) periods of time and may only occur after being subjected to certain processing, storage conditions and possibly near the end of the drug product’s shelf life. The container closure qualification process is dynamic and progresses throughout the pharmaceutical development cycle with an initial step of assessing risk for intended use. It is difficult to determine failures when a final dosage form or the processing con-ditions have not been confirmed, but early understanding of the probability of a hazard occurring for a specific use can help narrow down material options and alert to mitigating these risks. Recent cost estimates for full de-velopment of novel medicine vary and range to $1.8bn for the full development (capital-ized).4 Will the cost for a science based- data driven material selection process for container closure suitability tip the economic scale at this level of investment? The benefit of a com-prehensive container closure risk assessments will certainly outweigh a product recall and/or adverse event. While it is uncertain if the mysteries of glass delamination have been un-locked, it is clear that due diligence in the ma-
terial selection process will play a central role in supplying quality medicines to patients.
REFERENCES:1. Ralph Lipp, Ph.D. , “The Innovator
Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities,” American Pharmaceutical Review, April 30, 2013.
2. Stephen Perrett and Gopi Venkatesh at Eurand, “Enhancing the Bioavailability,” Innovations in Pharmaceutical Technology, Issue 19, Samedan Ltd. 2006.
3. S.M. Paul, D.S. Mytelka, C.T. Dunwiddie, C.C. Persinger, B.H. Munos, S.R. Lindborg, A.L. Schacht, “How to improve R&D pro-ductivity: the pharmaceutical industry’s grand challenge,” Nature Reviews Drug Discovery, vol. 9, 203-214, 2010.
4. S.Morgan, P.Grootendorst, J.Lexchin, C.Cunningham, D.Greyson, “The cost of drug development: a systematic review,” Health Policy, vol. 100, issue 1, pg. 4-17, April 2011.
ABOUT THE AUTHORDiane Paskiet has more than 20 years of expe-
rience in polymer analysis relating to product failures, deformulation and migration studies. She has served as a project advisor in sup-port of qualification studies associated with container closure systems for IND and NDA filings. Her current responsibilities as Director of Scientific Affairs include coordination of studies for technical support and innovations as well as providing a forum for education of those technologies. Previous to this role, she was in charge of site operations for West-Monarch Analytical Laboratories.
Diane is currently serving a five-year term on the United States Pharmacopeia (USP) Packaging, Storage and Distribution Expert Committee and Chair of the PQRI Parenteral and Ophthalmic Drug Product (PODP) Leachables and Extractables Working Group. She holds a degree in chemistry from the University of Toledo and a QA/RA Graduate Certificate from Temple University School of Pharmacy. Diane has authored national and international papers on the subject of leachables and extractables and is a faculty member of the PDA Training Institute as well as a frequent speaker and organizer of conferences. ■
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■ 41 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
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■ MARKETPLACE
■ P H A R M P R O . C O M
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.■ ADVERTISERS INDEX
■ 42 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
Brookfi eld Engineering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Capsugel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13, 30-31
Cook Pharmica LLC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Elizabeth Companies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7, 41
EMD Millipore Corporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Hamilton Company. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 41
Hospira Worldwide Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41, 44
Ligand Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Precision Fabrics Group Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40, 41
Quattrofl ow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Ross, Charles & Son Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41, 42
Tri-Mer Corporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34, 41
Vac-U-Max . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37, 41
Veltek Associates Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5, 41
Xcellerex Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19, 41
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Average No. Copies Each Issue During
Preceding 12 Months
No. Copies of Single Issue Published
Nearest to Filing Date20,627 18,489
14,175 13,0450 0
48 40
0 014,223 13,085
5,840 4,8950 0
332 3506,172 5,245
20,395 18,330232 159
20,627 18,48969.7% 71.4%
required and will be printed in the October 2012 issue of this publication.17. Signature and Title of Editor, Publisher, Business Manager, or Owner Gail Kirberger, Associate Director, Audience Development
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