Pharmaceutical Processing - 08 Aug 2009

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AUGUST 2009

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2009 FACILITY OF THE YEAR AWARD

DELIVERING EXCELLENCE Orchid’s API Facility Wins Regional Excellence Award

CUT TO THE CHASE Mini Jacketed Lab Reactors Cut Development Time at GSK

PUZZLE PIECES ERP Software for Stress-Free Regulatory Compliance

12 KEY STEPS TO ADDRESS USP CHANGES Strategies to stay current with the recent changes to chapters <61> and <62> SUBSCRIBE NOW!

Keep up-to-date on your industry by subscribing to Pharmaceutical Processing’s Weekly e-newsletter at w w w. p h a r m p r o . c o m

6 STEPS TO ENSURE CONTENT COMPLIANCE Effective strategies for enforcing content compliance and reducing costs in regulated environments

Working with your process to develop a specialized solution. Advanced Scientifics is a leader in the design and manufacture of single use/flexible bags/containers for the Pharmaceutical and Biotechnology industries. We offer a wide variety of single use containers to help speed your product to market - quickly and effectively. As a part of Advanced Scientifics’ single use systems, we offer a multitude of solutions for flexible containers. Our design engineers will produce the designs and quotes to your specific requirements within 48 hours of receipt. Finally, Advanced Scientifics’ aggressive lead times and pricing will provide sterilized and packaged product in as little as 3 weeks. Added to this is the security of supply Advanced Scientifics brings to your process. With redundant international manufacturing and a complete documentation and testing package, your process will be secure and your supply reliable. Contact us at 800-724-4158 with your specific application today!

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Tiny valves that can stand up to anything. Think about ITT.

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■PHARMPRO.COM

■ IN THIS ISSUE ■ C OV ER STORY

Official Media Sponsor of the INTERPHEX Show Volume 24, Number 08

FA C IL ITY OF THE YE A R A W A RD R EG ION AL EXCEL L E NCE

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Delivering Excellence

On the Cover: Orchid's Aurangabad facility manufactures nonpenicillin - noncephalosporin APIs, penicillin APIs, and carbapenem APIs.

Orchid Chemicals & Pharmaceuticals Limited’s Aurangabad, India API facility combines state-of–the-art building/technical concepts with innovative equipment applications.

PUBLISHER, MIKE KELLY 973-920-7751 [email protected] EDITOR-IN-CHIEF, MICHAEL AUERBACH 973-920-7055 [email protected] PRODUCTION MANAGER, SUSAN FRANK 973-920-7158 [email protected] ART DIRECTOR, BEVERLY BLAKE 973-920-7116 [email protected] ADMINISTRATIVE ASSISTANT ANA DACOSTA 973-920-7126 [email protected] WEB EDITOR, BRENT TOMASINO 973-920-7479 [email protected] AUDIENCE DEVELOPMENT GAIL KIRBERGER 973-920-7482 [email protected]

12 GSK Cuts Development Time With Jacketed Lab Reactors

CORPORATE OFFICE: 100 Enterprise Drive Suite 600, Box 912 Rockaway, NJ 07866-0912 973-920-7000 CHIEF EXECUTIVE OFFICER, RICH REIFF PRESIDENT, GEORGE FOX CHIEF FINANCIAL OFFICER, TERRY FREEBURG VICE PRESIDENT, HUMAN RESOURCES, SUSANNE FOULDS

Mini versions of production equipment provide a wealth of scale-up information.

18 Compliance Documents: Solving The Puzzle Pharmaceutical ERP software for stress-free regulatory compliance.

page 12

22 12 Key Steps To Address USP Changes Strategies to stay current with the recent changes to chapters <61> and <62>.

26 6 Steps To Ensure Content

page 18

Compliance Effective strategies for enforcing content compliance and reducing costs in regulated environments.

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From The Editor

16

What’s Hot

INNOVATIONS 20 Cleaning and Sanitizing 24 Washing Systems

page 20

EDITORIAL ADVISORY BOARD Michael J. Beier, Senior Vice President of Operations TITAN PHARMACEUTICALS, INC. Dr. James V. Blackwell, PhD, Consultant BIOPROCESS TECHNOLOGY CONSULTANTS, INC. Ronald C. Branning, Vice President Global Quality GENENTECH INC. Robert F. Dream, Vice President H.D.R. COMPANY LTD. Johanna Carmel Egan, VGP Project Management ELI LILLY Girish Malhotra, President EPCOT INTERNATIONAL Allan F. Pfitzenmaier, President VECTECH PHARMA CONSULTANTS INC. Susan Polizzotto, Manager, R&D QA GMP Compliance US SANOFI PASTEUR Carlos Villalobos, Sr. Dir. Global Engineering BRISTOL-MYERS SQUIBB Richard G. Whitfield, Senior Director PFIZER Patrick Wong, Director of Global Engineering BRISTOL-MYERS SQUIBB (BMS)

page 24

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AUGUST 2009 | PHARMACEUTICAL PROCESSING

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■ FROM THE EDITOR

It's Time... ■ Michael Auerbach, Editor in Chief

Y

You know you have crossed some irreversible line in the parent/ child relationship when your 68 year old mother asks you if you know anyone who can get her marijuana. This request didn’t come from some Woodstock-era hippie looking for a trip (no pun intended) down memory lane. No, this came from my very square mother who was looking desperately for a remedy for my father’s unrelenting nausea. Her request came several months ago, during a particularly bad patch of time during my father’s treatment for pancreatic cancer. The combination of the cancer and the chemotherapy was causing

After I picked myself and the phone receiver off the floor and steadied my spinning head I said, no, I’m sorry I don’t know anyone who sells the stuff… almost non-stop nausea and none of the prescribed medications, OTC products or anecdotal remedies was helping. In fact, it was their very own doctor who suggested they try marijuana. Of course, he couldn’t get it for them, but if they knew someone… After, I picked myself and the phone receiver off the floor and steadied my spinning head I said, no, I’m sorry I don’t know anyone who sells the stuff. It wasn’t long afterwards that she told me a friend of a friend had some and even came over and showed them how to roll a “joint” and smoke it. My reason for relating this story to you is that I believe it’s time for this country to pass a national law legalizing marijuana for medical use. According to the National Organization for the Reform of Marijuana laws website (www.norml.org) only 14 states - Alaska, California, Colorado, Hawaii, Maine, Maryland, Michigan, Montana, Nevada, New Mexico, Oregon, Rhode Island, Vermont and Washington have some sort of medical marijuana law on the books, allowing its use in some shape or form for medicinal purposes. I think it’s time for this country to stop making the moms, dads and grandparents of this country into "criminals". What's your opinion? Have a comment or question about Pharmaceutical Processing? My E-mail is: [email protected]

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SALES OFFICES Phone: 973-920-7751; Fax: 973-607-5678 Advertising Representatives PUBLISHER MICHAEL KELLY AR, CA, CO, ID, 5340 Park Avenue KS, LA, MN, MO, Downers Grove, IL 60515 MT, ND, NE, NM, Tel: 973-920-7751 OK, OR, SD, TX, UT, Fax: 973-607-5678 WA WY, Alberta, Cell: 773-230-7483 British Columbia, Canada [email protected] KEITH JORDAN AL, CT, DC, FL, GA, 25 Northwest Point IA, IL, IN, MA, MD, Elk Grove Village, IL 60007 ME, MS, NC, NH, RI, Tel: 973-920-7755 SC, TN, VA, VT, WV, WI, Fax: 973-607-5675 Ontario, Canada [email protected] DE, KY, MI, JENNIFER NATALE NJ, NY, OH, PA 898 North Graham Street Allentown, PA 18109 Tel: 484-3503137 Fax: 973-607-5677 [email protected] Media Sales ANDREA HEFFNER Representative 199 East Badger Road, Suite 201 Madison, WI 53713 Tel: 973-920-7774 Fax: 973-607-5460 [email protected] Reprints NICHOLAS J. IADEMARCO Director of Sales,Wright's Reprints Toll Free: 877-652-5295 [email protected] www.wrightsreprints.com Postal/Email List Rentals Statlistics 203-778-8700 PHARMACEUTICAL PROCESSING® (ISSN #1049-9156, USPS #001-314), (GST Reg. #844559765) is a registered trademark of and is published monthly 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 additional 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 $69 for U.S.A., $91 for Canada, $105 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 manufacturers' claims or statements in items reported. Copyright ©2009 Advantage Business Media. All rights reserved.

AUGUST 2009 | PHARMACEUTICAL PROCESSING

■PHARMPRO.COM

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Tumble Mixer Achieves Real Time IBC Blend Uniformity Company offers a “plug and play” Near-Infrared PAT System for blend uniformity analysis for IBC tumble blending. The LANCIR II System’s design consists of a self-contained, battery operated wireless NIR diode array spectrometer mounted on an IBC. The wireless signal can be received up to 1,000 feet away from a wireless PC running the system’s proprietary software. Custom Powder Systems, Springfield, MO 65803. www.custom-powder.com or call 417868-8002

Pressure Gauge Takes Measurements In Harsh Media Applications The Type 5503 differential pressure gauge provides reliable low differential pressure measurement in high static, wet-wet pressure applications. Equipped with wetted materials of 316SS, Monel or Hastelloy C, the rugged Type 5503 D/P pressure gauge is specifically designed to monitor a wide variety of caustic liquids and gases. Ashcroft Inc., Stratford, CT 06614. www. ashcroft.com or call 800-328-8258

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PHARMACEUTICAL PROCESSING | AUGUST 2009

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COVER STORY

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Delivering Excellence Innovative equipment applications and a forward-looking design help build an advanced API facility ■ By Mike Auerbach, Editor-In-Chief

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rchid Chemicals & Pharmaceuticals Limited’s desire to build a cost effective, well-integrated, intermediate and sterile API facility, with stateof–the-art building/technical concepts and equipment has resulted in their Aurangabad carbapenem facility winning the 2009 Facility of the year award for Regional Excellence. ABOUT THE COMPANY Orchid Chemicals & Pharmaceuticals Limited is an integrated pharmaceutical company based in Chennai (Madras), India. Located approximately 400 kms away from Mumbai; the Aurangabad facility is intended for the manufacturing of non-penicillin - non-cephalosporin APIs, penicillin APIs, and carbapenem APIs. The carbapenem based product manufacturing section of the factory has four (Intermediate/API/Sterile/ Hydrogenation) production blocks supported by a dedicated solvent recovery plant, water systems, various utilities, an effluent treatment plant and warehouse. These facilities were newly constructed in fiscal year 2006-2007 and are well integrated in terms of layout planning, cGMP building design, state-of-the art systems, and innovative equipment. Special emphasis has been given to the design of the production facilities so contamination and cross contamination can be avoided.

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AUTOMATION A KEY FACILITY DRIVER At Orchid, automation was implemented for various reasons and was a major part of the facility design. All equipment is automated by using tools like Distributed Control System (DCS) or Programmable Logical Controllers (PLCs). DCS or PLCs are technological tools commonly available in the market but their application in API manufacturing is unique. Commenting on the reason why automation was used so extensively in the plant, Mr. V .S. Padalkar – Vice President of Projects & Engineering at Orchid said, “(The) primary aim in designing the facility (with a high level of automation) was human and product safety, consistency in all operations, and technological excellence to motivate and attract talented employees.” ADVANCED FACILITY DESIGN – AVOIDING CONTAMINATION As the Aurangabad location is designed for multiple products, it was a great challenge to incorporate various types of product manufacturing blocks with a special emphasis on avoiding cross contamination, environment awareness and advanced safety features. The new facility comprises eight distinct blocks: 1.) Intermediate block (Plant-17) 2.) API block (Plant-31) 3.) Hydrogenation block (Plant-41)

AUGUST 2009 | PHARMACEUTICAL PROCESSING

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COVER STORY

Left: Partial view of the Auraganbad facility from the main entrance. Above: Corridor around the cleanroom with the adjacent technical area. Right: The advanced powder handling system featuring split valves.

4.) Sterile block (Plant-32) 5.) Solvent recovery plant including tank farm (Plant-33) 6.) Effluent treatment block (Plant- 46) 7.) Fire hydrant water tank and pumping station (Plant-43) 8.) Infrastructure facilities like utilities, transformer etc. (Plant- 44) All facilities have sufficient systems/equipment to produce four types of Carbapenem products with easy change over procedures. Commenting on the facility layout Mr. Padalkar said, “We are using various types of toxic chemicals in carbapenem manufacturing. Suitable systems are provided at each stage for containment of it. The facility layout was planned to take care of separate service and production areas with all support systems in a well designed manner.” MATERIAL AND PERSONNEL FLOW CRUCIAL TO SUCCESS In the Aurangabad carbapenem facility sufficient room and space is provided for all relevant functions. Designated routes for personnel, material and product flow prevents product mix up, cross contamination, contamination from environment, and operator exposure to product. Waste and unusable residue disposal systems are in place. The utmost care was taken during facility design to assure the cleanability of each area and its attendant systems and equipment. Indoor storage areas are controlled to maintain required temperature, humidity, and illumination which protects against degradation or chemical alteration of raw material and products. Dispensing and sampling areas are provided with a greater level of protection in respect to manufacturing blocks. Support functions such as like utilities, in-process quality control lab, cafeteria, training room, in plant maintenance, day storages, laundry, wash rooms etc. are provided within each production block to control personnel movement within the campus. PHARMACEUTICAL PROCESSING | AUGUST 2009

As Mr. Padalkar explains, a facility mock-up study was done to ensure proper flow of material/ people to prevent contamination “Yes, it was part of the pre-design stage and since all relevant technical functions were involved in the initial phase of the study, further design basis and actual implementation faced far less challenges. It is fine example of good team work.” ADVANCED PROCESSES REQUIRE ADVANCED PROCESSING EQUIPMENT In order to manufacture their products with the speed and efficiency they needed, Orchid relied heavily on the ingenuity and cooperation of many equipment suppliers. Some of the innovations implemented at the Aurangabad facility are highlighted below: Agitated Nutsche filter and dryer (ANFD) with gas knife: Traditionally, filter/dryers and pan dryers have suffered from the inability to recover the product “heel” left after normal discharge operations which results in less yield, slower filtration rates, and concerns about batch to batch product integrity (degradation of left material). To overcome these problems engineering solutions such as tilting, providing pushers, fluidizing beds, and additional ports have been designed, but for Orchid's needs the solutions had limitations for high level cGMP practices in commercial production. To overcome this problem, Orchid worked with Rosenmund – Switzerland who supplied an ANFD with a gas knife system; this innovative technique was first successfully implemented and commissioned in India at Orchid. Self contained powder handling system for sterile products: Certain processes, such as powder handling operations like milling, sifting, blending, and dispensing pose potential for product exposure to environment as well as risk to operator. 9■

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COVER STORY

Automated cleanroom operation was designed to avoid operator exposure.

Protection of operators, security of the products and continuous unrestricted flow of the material were the main criteria to design this system. To fulfill these basic requirements Orchid decided to work with Novindustra AGSwitzerland, and they provided a cost effective, compact, user friendly, state-of-art, self contained powder handling system. This high tech system has ‘split valves’ with active and passive valve sections. This system has components which are easy to dismantle for cleaning, sanitization, sterilization. All system parts are well designed and engineered to make a maintenance free system. Solid charging by closed systems: Orchid's facility features closed solid charging systems for

NOW

all type of reactors and drying equipment. Conventionally pneumatically operated systems are available but the company worked with a supplier to develop a PLC operated, fully automatic system which would be user friendly in terms of operations, maintenance, cleaning, disassembling and assembling. The advantages of this proprietary system in comparison to conventional pneumatic conveying systems are: highly compact, efficient, suitability for a range of powdery non-hygroscopic/hygroscopic materials, easy to clean, explosion proof, non destructive, and totally enclosed dust free operation. This system not only meets the general requirements of conveying material for different applications but also is ideally suited for charging material to reactors under inert gas protection. The system has been designed to comply with cGMP norms. Nitrogen blanketing system for centrifuges (filtration equipment): In centrifuges, various types of product filtrations having solvents are processed. Solvents and products are subjected to very high rotating speed during the separation process. Also due to high speed, bearing housings may develop sparks. Therefore, to avoid any kind of explosion, it is essential to purge the centrifuge before start up with nitrogen. Similarly, when the centrifuge is in operation it is recommended to provide continuous nitrogen blanketing. As per normal practice followed in the industry as well as previously used by Orchid, nitrogen is used for inertization of the centrifuge. Earlier nitrogen purging was operator based and

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COVER STORY

Exterior view of the sterile and API facility.

its vent was open to atmosphere so there was no assurance the inertization of the centrifuge was effective and there was a huge consumption of nitrogen as well. To eliminate this unsafe procedure, Orchid developed an innovative blanketing system with their supplier. Nitrogen purging and blanketing of the centrifuges consists of a series of pressure reducing valves to get to the required pressure and has back pressure regulated valves at the vent to hold the specified nitrogen inside the centrifuge basket for inertization purpose. Pressure switches are provided to monitor the nitrogen pressures which are interlinked to the control system. This blanketing system provided following advantages: • Ensure proper inert atmosphere in the centrifuge for safety. • Avoid loss of nitrogen thereby reducing nitrogen consumption. Orchid has realized a 90% reduction in the use of nitrogen; saving a lot of energy. • Since the system is closed solvent lost to the atmosphere is eliminated and pollution significantly reduced. • Ensures consistent product quality, less human exposure and operator interference. When asked about the relationship between the company and its suppliers, and the requirement for the development of many new, proprietary processes/equipment, Mr. Padalkar explains, "Orchid strives to bring excellence in any work we do, whether it is processes, hardware, facility, environmental protection, safety, cGMP and so on. This is not just to meet any statutory or regulatory requirements for the time being, but to surpass such requirements and be at the forefront of technical superiority in our industry. Some of the concepts, even though they were new to vendors, were so well co-ordinated with the vendors that the provided stateof-art solutions benefitted both our company and the vendors. Most of them were quite receptive of any changes and trying out new ideas for the first time. It was really a great learning and trailbreaking experience for both sides." SUMMING IT ALL UP Finally, when asked why he thought the Facility of the Year judges selected his facility for the award, Mr. Padalkar offer this explanation, "We are very proud and overwhelmed by this prestigious recognition. The following comment by the respected judges reflects our uniqueness and special efforts taken in this project to meet timelines and budget with utmost safety and cGMP at every step of project. PHARMACEUTICAL PROCESSING | AUGUST 2009

'“Their timeline and safety record were very good, especially considering the location. This project was well-executed and the first to use certain technologies in India. They brought in a lot of technology in a place where it’s difficult to do so. The challenges and how they overcame them are appreciated. They were able to increase their productivity all with local expertise”' We have built a facility for the present and future with advanced technologies with in-house expertise only. This project is a unique blueprint in many ways for our kind of industry - a multi-product flexible facility, with reduced product cost, increased productivity, fully in-house expertise, an excellent safety record, strict compliance to cGMP, and superb team efforts with extraordinary leadership."

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SCALE-UP

GlaxoSmithKline Cuts Drug Development Time by Using Jacketed Lab Reactors Mini versions of production equipment provide a wealth of scale-up information

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Above: A scientist drains product from the manual bottom valve of a 2-L jacketed lab reactor. Right: A 2-L reactor with associated vapor trap (right) and distillate receiver (the glass ball). An insitu IR probe is inserted into the vessel on the left via a glass adapter (blue cap).

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he traditional way to develop a process for producing a new drug is to do the initial development in round-bottomed laboratory flasks and make the transition to small-scale productiontype reactors when the process is ready for piloting. Many pharmaceutical companies still do it this way, but more and more companies are switching from flasks to laboratory-scale jacketed reactors that are miniature versions of production equipment. The chief advantage to using a jacketed lab reactor is that researchers can obtain information early in the process-development stage on how a process will work in actual production, including data on the safety of a process, says Roy Flanagan, team manager of process safety and design with GlaxoSmithKline’s Chemical Development Dept. in Research Triangle Park, NC. This enables a company to get a drug to market faster and more than justifies the cost of the equipment, he says. GlaxoSmithKline plc (GSK), for example, has invested hundreds of thousands of dollars on jacketed lab reactors for its Worldwide Research & Development operations, says Flanagan, but has likely saved millions of dollars by getting critical information early in the development of a process. “A blockbuster drug can generate revenues of $1 billion/yr, or $3 million/ day,” he points out, “so getting products to the market faster can have a large positive effect on the bottom line.” In contrast, he says, the

AUGUST 2009 | PHARMACEUTICAL PROCESSING

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SCALE-UP

Left: Another view of the 2-L jacketed lab reactor. In the foreground is a programmable directdisplacement pump for metered, mass dosing. Above: A 2-L jacketed lab reactor with a dosing bottle on a scale at left.

fact that a process has worked well through scale-up from small to large flasks is no indication that it will work well in production. “In the past, when we used flasks, we had some unpleasant surprises the first time we tested a process in a pilot reactor, and many times we had to go back and redevelop a process. We have had far less of these problems since we adopted the jacketed lab reactors. We typically identify problems early and solve them before we get to the pilot stage.” Another basic advantage of using a jacketed lab reactor is safety. Flanagan points out that product is removed from a lab reactor through a valve at the bottom of the vessel, whereas a flask is usually emptied by picking it up. “It can be dangerous having people picking up a 22-L flask,” he says. “Also, if you heat up a flask using a traditional mantle and the reaction starts to run out of control, there’s no way to cool it.” While GSK has used jacketed lab reactors at some sites for several years, during 2005 and 2006 Flanagan led a multi-site group to formalize the implementation of the technology in all of the company’s five major research centers. GSK continues to improve the use of the technology through a laboratory reactor “site champions group” that has a representative from each of the five centers. The Research Triangle Park (RTP) operation is one of two U.S. headquarters sites for GSK, the other being in Philadelphia, where the company has one of its pilot plants. RTP has about 7,000 employees, of whom some 3,000 work in Research and Development. Chemical Development at

PHARMACEUTICAL PROCESSING | AUGUST 2009

RTP is a relatively small department, with about 150 employees, but it has developed processes for some high-profile drugs, such as the AZT AIDS drug, Valtrex for herpes, Zyban for smoking cessation, and the Avodart prostate treatment. At any one time the department may be working on 15–20 projects, says Flanagan. SCALED-DOWN PILOT PLANTS Chemical Development has 29 jacketed lab reactors, all supplied by De Dietrich Process Systems, Inc. (De Dietrich calls them Miniplant reactors). GSK also uses De Dietrich pilot-scale reactors in its pilot plant operations in Philadelphia. Using equipment from the same manufacturer at both the development and pilot stages makes for a smooth transition in the scale-up of a process, says Flanagan. “Our lab reactors are scaled-down versions of our pilot plant vessels,” he says, “just as our pilot plants are scaled-down versions of production equipment.” The 29 jacketed lab reactors at RTP consist of five 1-L kits, six 2-L kits, two 6-L kits, six paired 20-L kits (12 vessels), and two paired 50-L kits (four vessels). All of the smaller kits are made of durable borosilicate glass and most are elliptical in shape, rather than round-bottomed, so their mixing characteristics are similar to those of a typical production-size reactor. A couple of conical-shaped vessels have also been installed for specialized studies. The 50-L kits are made of glass-lined steel and Hastelloy, identical to those found in pilot plants. The head of each lab reactor has a large central port for 13 ■

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the agitator motor, which has either a single or double mechanical seal to ensure that the vessel contents are not compromised during operation. Several other ports are available for other purposes, including: the addition of reactants and other materials (two ports), a glass riser for distillation overhead, a thermowell for temperature measurements, and other process analytical technology (PAT) functions, such as turbidity, near-infrared and pH measurements. “The head has as many available ports as we can get away with,” says Flanagan. In the glassware above the reactor is a manual valve that allows either reflux or removal of distillate. Each of the small reactors has a graduated receiver for distillate, but each pair of 20-L and 50-L vessels shares a single condenser and valves which allow distillate to flow from one vessel to the other. “This gives us the flexibility to reflux or distill from either vessel throughout the entire process,” says Flanagan. “There is also a phase separator between them, so we can perform an azeotropic removal of water and direct either phase to either vessel.” Product is removed through a valve at the bottom of the vessel — a manual valve on the smaller reactors and a pneumatically operated valve on the 20- and 50-L units. The design of the valve practically eliminates dead space and makes for a free flow of product through the valve, says Flanagan, so that essentially all of the product can be evacuated. In contrast, a round-bottomed flask is normally picked up to be emptied and this can be a rather hazardous procedure for larger vessels, as noted earlier. Alternatively, product may be vacuumed from a flask — a problematic operation. Work on new drugs starts in RTP’s Drug Discovery Department, where potential drug candidates are made in quantities of up to a few grams in standard glassware. Those that show promise are moved on to Chemical Development, where processes to make active ingredients are initially scaled to produce quantities of up to 100 grams in 1- or 2-L jacketed lab reactors. It is at this scale that most of the process development is done and basic problems are solved, says Flanagan. “In these smaller reactors we devote almost 100% of the work to process development and very little to making material to support studies,” he says. “When we scale

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SCALE-UP

up to the 6-L and 20-L reactors we are probably down to 30% development, and when we get to the 50-L scale 90% of the work is for production of material for testing and we are just tweaking the process.” He explains that preparation of material at the smaller scale is mostly for development studies, including toxicity tests, but at the 50-L scale an active ingredient is made in quantities of up to 5 kilos and supplied to RTP’s Pharmaceutical Development Department, which determines the best way to formulate a product for use by patients (e.g., as a tablet, capsule, or by inhalation). Some of the product may also be used in earlyphase clinical trials. The use of jacketed lab reactors has also enabled GSK to develop GMP (Good Manufacturing Practice) clean-in-place and cleaning verification procedures as a process is scaled up. In addition, the company has performed equipment qualification exercises on all the lab reactors that are used for clinical material preparations. IDENTIFYING PROBLEMS EARLY Flanagan cites a number of examples where the jacketed lab reactors have revealed problems in the early stages of process development. “There have been cases where we have identified balling issues in our small reactors that we may not have seen in round-bottomed flasks.” The reason, he says, is that mixing is done in a flask by a stir bar or paddle, whose mixing action is different from that of an agitator in a reactor. “The effect of agitation with a miniature agitator is similar to that of a full-scale plant agitator in terms of power per unit and shear effects,” he says. “You can also model your process to use real heating and cooling times to get a more realistic demon-

Close-up of a 20-L jacketed lab reactor with a glasslined, retreat-curve (similar to production vessels) and a pneumatically operated bottom valve.

stration of the process on a small scale.” Other cases have involved heterogeneous reactions that use heavy, solid catalysts such as zinc-based or base metal catalysts that tend to settle to the bottom of the vessel. These processes “may work beautifully in a roundbottomed flask” because the stir bar or paddle is in contact with the bottom of the flask and grinds up the metal, says Flanagan. In contrast, the agitator in a reactor is not in contact with the bottom of the reactor, so the mixing is not as efficient. “Now, when we identify that kind of problem in a lab reactor, we work with our engineers to ensure that the appropriate geometry is selected for the scale-up of the agitator or of the reactor,” he says. In vacuum distillation processes, scaling on the reactor wall is a problem that may present itself when a process is upgraded from a flask to a pilot plant reactor. As the batch is concentrated, scaling occurs on the vessel wall above the level of the process liquid. This happens because the heated AUGUST 2009 | PHARMACEUTICAL PROCESSING

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jacket typically covers the entire vessel and dries residual material entrained in the solvent evaporated from the process. The residue attaches to the wall. "Scaling usually doesn’t happen this way in a flask,” says Flanagan, “because the heating mantle normally covers only the bottom part of the flask, below the liquid level. The upper part of the flask stays relatively cool.” In contrast, he notes that a lab reactor will reveal a potential scaling problem because the entire vessel wall is heated, just like that of a pilot reactor. Phase separations can also create problems when a process is stepped up from a flask to a pilot reactor. Flanagan notes that the way to check a phase separation in the laboratory is to dump the contents of a flask into a separatory funnel, shake the funnel, and wait for the phases to separate. However, this procedure gives no indication of how long the separation may take in a reactor, or whether agitation may produce emulsions, which is important information necessary for scale-up. The best way to obtain this information, he says, is to do the phase separation in a lab reactor that mimics the pilot and production equipment. The use of jacketed lab reactors has also enabled GSK to save considerable time by cutting back on the use of reaction caloPHARMACEUTICAL PROCESSING | AUGUST 2009

rimetry to support intermediate (10–50-L) scale-up. This is a time-consuming procedure in which a process is run in a reaction calorimeter — a small, highly automated jacketed reactor — to obtain detailed information on the safety of the process, such as heat of reaction and gas output. In the past, when RTP worked with flasks, each process was tested in a reaction calorimeter prior to scale-up beyond the 6-L size, says Flanagan. “Today, 90% of the time we don’t use reaction calorimetry for initial scale-up. Instead, we use data collected from jacketed lab reactors.” GSK obtains heat-output data by monitoring process temperatures in the lab reactors, each of which has been characterized to determine its heat-transfer coefficient. Gas-flow monitors are installed on all the smaller vessels to measure offgases. “With reaction calorimetry it usually takes my group a couple of days to run the tests and evaluate the data,” he says, “but with already available data from the lab reactors we can do an evaluation in a couple of hours. We probably do 100 risk assessments per year, so we save about 200 days a year by not doing reaction calorimetry at this point in the development cycle.” For the future, Flanagan feels the reactors will prove valuable in helping GSK meet

SLUG

Left: A pair of 50-L, glass-lined steel jacketed lab reactor’s with shared overhead glassware. Above: A pair of 20-L jacketed lab reactor’s with shared overhead glassware.

the challenges of the U.S. Food and Drug Administration’s Quality By Design (QBD) initiative. One goal of the initiative is to reduce the regulatory burden on industry (and the FDA’s work load) by streamlining the agency’s approval of changes in the manufacturing process for drugs already in production. As in any other industry, pharmaceutical companies are periodically motivated to modify a process to make it more efficient. However, the time and effort required to support such changes, and to get FDA approval, makes it difficult to justify, says Flanagan. QBD would make it easier by allowing a drug company to show that its knowledge of a process is broad enough to permit modifications safely. Through the use of the lab reactors, combined with process analytical technology (PAT), GSK already collects a broad range of data on its processes, says Flanagan, and this will be useful for QBD. The data provide a good understanding of the “design space” for each process, such as temperature limitations and other parameters, he says, “so we would have plenty of information to support a process modification.” ■ 15 ■

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W H AT ' S H O T

Static Mixer Performs With Minimal Pressure Loss  The Furon® Static Mixer offers the means to mix two or more chemicals with minimal pressure loss. Its compact, inline design allows for easy installation into existing fluid handling systems. The mixer contains no moving parts, assuring low operating costs and long life. Mixing components are removable, allowing for easy maintenance and cleaning. Outlet end connection types and sizes can be easily changed to accommodate a variety of piping configurations. All components are constructed from 100% virgin PTFE and high-purity PFA, making the Furon® Static Mixer ideal for use with ultra-pure and highly corrosive chemistries. ■ Saint-Gobain Performance Plastics, Akron, OH 44301. www.tygon.com or call 800-798-1554

WHAT’SHOT Gravimetric Additive Feeder Provides Accurate Metering And Precise Control 


RFID

Tag Withstands A Minimum Of 500 kGy Cumulative Exposure to Gamma Radiation The GammaTag 500, is ideal for high volume items requiring repeated gamma sterilization and is well suited for the pharmaceutical industry. The tag was developed for single use process components and other critical parts for pharmaceutical applications. It is a read/write tag used to identify, record, and access the current status of process components on the spot. Information such as manufacture date, part number, lot number, gamma sterilization date, and other important data may be written to and retrieved from the tag’s memory. It handles typical doses of 25 kGy and a cumulative amount of at least 500 kGy with no loss of data. ■ AdvantaPure, Southampton, PA 18966. www.advantapure.com or call 888-755-4370 ■ 16

The CF-1000 Series gravimetric additive feeder, features a compact feeder that provides accurate metering of additives as well as material usage tracking, which can be utilized in all molding and extrusion applications for pelletized materials. The CF-1000 adds colorant or other free-flowing material to your process, based on a self-calibrating gravimetric controller. This eliminates the over-feeding that typically accompanies volumetric feeders. There is automatic calibration if there is a deviation from the set additive weight; and flow rate is calculated in both percentage or kilograms per hour for extruders. Standard features include: a user-friendly graphic display, integrated TCP/IP card that enables communication for injection molding models, a 0-10 VDC extruder follower circuit available on extrusion models, and an advanced feed-rate algorithm. An integrated automatic venturi loader, along with other sideloading configurations, is optional. ■ Colortronic North America, Inc., Flint, MI 48507. www. colortronicna.com or call 810-720-7300


Checkweigher

Features A User-Friendly Touch Screen Interface The Starweigh™ checkweigher features weighing precision and a user-friendly touch screen interface, as well as a compact footprint which installs over existing conveyors to reduce installation time. Starweigh™ delivers laboratory accuracies in production environments allowing users to maintain tight tolerances throughout the packaging process. The system can be used for a wide variety of container sizes ranging from 30 cc to 2000 cc; even difficult to handle oval and rectangular containers in plastic, glass, or metal can be inspected. Sustained accuracies from +/- 2 mg are delivered at rates up to 400 cpm, ensuring high quality products which meet demanding production targets. The system also offers configurable user security, on-screen “help” functionality, and multilingual operation for maximum workforce flexibility. Advanced communications interfaces enable transfer of valuable data to information networks and real time machine status to SCADA and other factory floor automation systems for fast, error free process integration. ■ Mettler-Toledo Hi-Speed, Ithaca, NY 14850. www.mt.com or call 800-836-0836

AUGUST 2009 | PHARMACEUTICAL PROCESSING

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Freeze Dryer Ideal For MultiUser Labs 䉴 The compact Benchtop™ K Series Freeze Dryer is ideal for busy multi-user university labs. Available with a choice of condenser temperatures from -55ºC to -105ºC, this unit provides an optimized tool for freeze drying all aqueous and most organic based samples. With condenser sizes ranging from 3 to 9 liters, enables users to process just a few samples or undertake multiple user applications. A wide selection of manifold accessories allows any shape or size sample container to be processed. Benchtop K Series Freeze Dryers are easy to operate. The Sentry 2.0 microprocessor controller provides a user-friendly interface with full function control. ■ Virtis, Gardiner, NY 12525. www.virtis.com or call 800-431-8232

■ W H AT ' S H O T

Plasma Coating And Face Seal Valve Technologies Help pMDI Systems Improve Product Performance 䉴 Company's plasma coating technology and face seal valve both help pMDI systems improve product performance. Plasma coating technology helps ensure technical success with inhalation components for challenging hydrofluoroalkane (HFA) formulations by creating a layer that protects against degradation, deposition and corrosion. The ultra thin coating is suitable for both plastics and metals. The face seal valve eliminates the need to prime an inhaler by collecting the dose as the inhaler is fired. Traditional pMDI valves operate on a “dose retention” principle, collecting the dose when the valve stem is released after firing. This can lead to loss of prime or loss of dose, which is why patients are advised to prime these inhalers by firing an uninhaled shot before use. The face seal valve eliminates this extra step. The technology helps ensure patients receive a full dose of medication with every use, including single shot products. Both plasma coating technology and the face seal valve are available as parts of a complete system program, or as stand alone components. ■ 3M Drug Delivery Systems, St. Paul, MN 55144. www.3M.com or call 888-364-3577

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COMPLIANCE

Compliance Documents: Solving the Puzzle Pharmaceutical ERP software for stress-free regulatory compliance ■ By Jay Deaking, President, Deacom, Inc.

P

harmaceutical manufacturers operate in one of the most highly regulated industries – facing an array of restrictions and requirements from the FDA, EPA, OSHA, various state and foreign governments, and their individual customers. Integral to meeting these groups’ standards are the various compliance documents they require, such as product labels, Material Safety Data Sheets (MSDSs), SARA reports, Certificates of Analysis (COAs), and shipping papers. For many drug makers, producing these documents in an accurate and timely manner is a significant challenge, if not an outright headache, because of the use of multiple software systems to run their businesses. When using disconnected systems, spreadsheets, and/or word processing programs to manage data, manufacturers can spend hours or days gathering information, making calculations, and entering the results into word processing documents. But with today’s technology, this labor-intensive and potentially error-ridden process is unnecessary. As this article will discuss, pharmaceutical manufacturers using a single, fully-integrated pharmaceutical ERP software system can integrate regulatory reporting with all other business processes to solve the compliance document puzzle and make regulatory reporting a stress-free operation. Well-designed ERP software should integrate all the data of a pharmaceutical manufacturer, including formulation, regulatory reporting, purchasing, production, inventory, sales, and accounting in one system.

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PUZZLE PIECES The typical process of business growth is how most pharmaceutical manufacturers end up with the patchwork of software systems that complicates reporting. A company may start out managing many processes, such as formulation and quality control (QC), with notebooks and spreadsheets, and others, such as accounting, with standalone software systems. At this stage, any data that must be reported to the FDA, EPA, or other organizations can be readily found among the relatively small amount of data. However, as business volume grows, more formulas are developed and tested, products are pushed into production, and new customers begin knocking at the door. At that time, manufacturers struggle to fit the data puzzle pieces together to create the reports they need. Perhaps a formula management software system, or a system to handle inventory management was added. Now, with more data being created and stored in more places, generating the required regulatory reports can become time consuming and tricky. Often, companies using multiple, disparate systems ask one person to handle all reporting. This person, perhaps a technical or compliance director, keeps track of which forms are due at what times, to what organizations, and what information they require. He searches each system for the appropriate

LABORATORY

REGULATORY REPORTING

ORDER ENTRY

PURCHASING

ACCOUNTING

STORES/POS

PRODUCTION

INVENTORY

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data, makes any calculations, enters the information into the right form, and prints the documents. He does this for COAs, product labels, MSDSs, annual SARA reports, and more. Unfortunately, no matter how diligent this person is, whenever reporting is not integrated with business data, the process is open to inefficiencies and errors. For one, manufacturers create a bottleneck by funneling all reporting to one person. Deadline-sensitive documents may stack up when, for example, this person goes about researching and completing Form Rs – the lengthy SARA reports required for each toxic chemical manufactured, processed, or used beyond certain EPA thresholds. Time spent waiting for documents in the queue is time wasted, perhaps time that shipments can’t go out the door, and this unnecessarily adds to the cost of doing business. Errors are likely, as well. The director may choose the wrong form, or simply make data entry errors or accidental omissions. When mistakes are passed along to customers, companies may face the costs and customer backlash associated with returned shipments – such as extra freight charges, refunds, and potentially a loss of business. Mistakes reported to the FDA, EPA, or OSHA could results in fines and regulatory scrutiny. Overall, a multiple-system environment can complicate reporting and put a pharmaceutical manufacturer at a competitive disadvantage. PUTTING IT ALL TOGETHER Pharmaceutical manufacturers can create a more efficient and accurate reporting process by integrating all their business processes – formulation, QC/QA, production, inventory control and lot tracking, sales, purchasing, accounting, and regulatory reporting – in one software system designed for the pharmaceutical industry. When all data is stored in a single, pharmaceutical ERP system, report generation is no longer like trying to assemble a complex puzzle. Because all the pieces required for each document – raw material usage and properties, QC test results, sales order information, formula data, and the like – are all managed in real time within the ERP system, report generation can become an automatic process. In a well-designed system, companies would set up configurable document templates for each report they are required to produce. A configurable form is one a manufacturer can adapt within the ERP system to fit its business needs, without needing to alter the software’s programming code. A familiar program such as Microsoft Word will let users configure the documents by arranging data fields, logos, and other characters to create the design, and include the data of their choice. Once configured, the ERP system can automatically populate these forms with the proper data. Each data field on a form will map to a particular data point in the database. Because data from all processes is stored in that single da-

PHARMACEUTICAL PROCESSING | AUGUST 2009

COMPLIANCE

tabase, there is no need to link to other programs or search disconnected or paper-systems for document generation. When a document is regulated in the system, it’s filled in with the most up-to-date data automatically. For example, because the system stores all formulation, production history, purchasing, and sales data, it can automatically calculate the hazardous material amounts required for SARA reports and show the figures in the appropriate template fields. LOW-STRESS REPORTING With document generation integrated within a comprehensive pharmaceutical ERP software system, drug makers avoid the problems associated with using a patchwork of systems. The puzzle-piece approach to reporting is replaced by a streamlined and compliant reporting process that can provide greater productivity and a competitive edge. Efficiency is one advantage gained by managing regulatory reports this way. Rather than having your compliance director search each system for data to calculate and plug in to each word processing-based report, the system pulls and populates the data automatically. This saves countless hours over the course of a year, allowing companies to direct their compliance efforts to other processes. In fact, any system user with the proper security clearances can generate a COA or other document once the template has been configured. Errors are reduced with this type of system, as well, because manual data entry is eliminated. Process controls in a fully-integrated system can also help manufacturers guard against errors that, if unnoticed, could end up on a regulatory document. For example, the QC process in a well-designed ERP system should allow manufacturers to set pre-defined test ranges for each product. Then, if a user enters a value that falls outside that range, the system would provide a screen prompt highlighting the error. Not only does this guard against typos that could end up on important documentation, it also helps you more easily identify products that do, in fact, fall outside QC ranges and need to be altered or discarded. CONCLUSION With all the regulations facing manufacturers in the competitive pharmaceutical industry, companies shouldn’t spend hours preparing their compliance documentation. Utilizing a single, integrated ERP software system designed for pharmaceutical manufacturing can streamline the regulatory reporting process through configurable document templates for a faster, error-free process. With the regulatory compliance document puzzle solved, drug makers can focus on what really matters – their business. About the author: Jay Deakins is the President of Deacom, Inc., the producer of an integrated accounting and ERP software system for midto-large-sized pharmaceutical and chemical manufacturers with hard-to-handle requirements. Contact Jay at [email protected] or visit www.deacom.net. 19 ■

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■ I N N O VAT I O N S

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Nozzle Features A Retractable And Remain-In-Place Design Liquid activated, retractable CIP spray nozzles remain in place during production, eliminating the need to install and uninstall spray devices for the CIP cycle. Constructed of 316L stainless steel with a minimal number of maintenance free parts, the nozzle features a retractable spray head that fully extends under liquid pressure during CIP. The force of rotating spray jets provides a scrubbing action that ensures complete cleaning of components. ■ Evaporator Dryer Technologies, Inc., Hammond, WI 54015. www. evapdryertech.com or call 715-796-2313

CLEANING &

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Cleaner

Features A Biodegradable Blend Of Citric Acid

The biodegradable Micro® A07 Citric Acid Cleaner is ideal for the removal of oxide, scale, mineral deposits, milkstone, and inorganic soils. This biodegradable blend of chelating citric acid and anionic surfactants offers enhanced cleaning performance compared to simple citric acids and other citric-based products. With a typical pH of 2.5, Micro A07 is milder than most acids, yet powerful enough to replace more aggressive acid cleaners. Micro A07 is used in CIP, ultrasonic baths, immersion, mild agitation, and filter membrane cleaning applications. This cleaner is zeroVOC, phosphate free, non-corrosive, carries no hazardous shipping regulations, and is NSFRegistered for USDA A1 use. ■ International Products Corporation, Burlington, NJ 08016. www.ipcol.com or call 609-386-8770 ■ 20


Disinfection

System Includes Waste Containment Bucket

The #30-3 TruCLEAN deluxe disinfection system comes complete with a 36-liter bucket with casters and stainless steel sieve, waste containment bucket and stainless steel sieve, mop frame, and adjustable handle. Buckets are available in red, white and blue. This DELUXE #30-3 will allow the use of the bucket-in-bucket concept with a sieve for the waste containment bucket or use a sieve alone on the 36 liter bucket. Both options are designed for small area cleaning and disinfecting. Dip mop in bucket, press mop on sieve to release excess disinfectant and apply to surface. Compatible with gamma, ETO and autoclave sterilization – up to 250˚ F (121˚C) for 30 minutes. ■ Perfex Corporation, Poland, NY 13431. www.perfexonline.com or call 800-848-8483


Pressure

Washers And Steam Cleaners Feature All-Electric Operation

The E-Series is an all-electric line of pressure washers and steam cleaners. The 100% all-electric E-Series has a compact, portable design, perfect for all types of cleaning processes such as washing down conveyors, cleaning mixing and storage tanks, and disinfecting and sterilizing. The E-Series provides instant and continuous heat without the hassle of preheating storage tanks or heat transfer fluid. Standard features include a NEMA 4 electrical enclosure, stainless steel float tank, long-life heating elements, and adjustable digital temperature control. The E-Series is UL and CSA approved by ETL. A wide range of options and configurations are available in any voltage in 50 and 60 Hertz. ■ Sioux Corporation, Beresford, SD 57004. www.sioux.com or call 888-763-8833

Spray Nozzle Offers 360º Coverage  The HydroWhirl™ S slotted rotating spray nozzle offers quick, efficient tank cleaning. The HydroWhirl™ uses less water and lower pressure than static tank washers, offers complete 360˚ degree coverage, and features a low maintenance dual-bearing design for long service life and lower operating costs. ■ BETE Fog Nozzle, Inc., Greenfield, MA 01301. www.bete.com or call 413-772-0846 AUGUST 2009 | PHARMACEUTICAL PROCESSING

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NEW PRODUCTS

Vial Isolators Protect, Preserve And Contain FreezeDried Products LYOGUARD® vial isolators are single-use devices made with a unique expanded ePTFE membrane, to reduce product “fly-out” and product cross-contamination, while improving sterility in small-scale aseptic processing applications. This biocompatible membrane allows vapor to pass through the isolator, but its microstructure prevents contaminants from entering the vial. W. L. Gore & Associates, Inc, Newark, DE 19702. www.gore.com or call 800-368-4673

Dehumidification System Simplifies Integration With Other AC Components The Integrated Custom Air Handler (ICA) dehumidification system has simplified the complex task of integrating 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 standard components engineered for maximized performance. ICA incorporates many advanced features including a double wall construction with superior no-through metal design in either 2.5 or 4 inch wall thickness. Munters Corporation, Amesbury, MA 01913. www.munters.us or call 800-843-5360

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Manifold Valves Offer Method Of Blocking, Bleeding And Calibrating Pressure Instruments 2-, 3- and 5-Way manifold valves combine the function of a tee, calibration valve, isolation valve and all tubings and fittings into a single valve configuration. These valves are designed to connect a system impulse line and transmitter. R-Type manifolds provide differential pressure of flow recorder to impulse tubing. D-Type, T-Type and H-Type manifolds bolt directly to differential pressure instruments to eliminate the need for piping, valves and fittings. Innovative Pressure Technologies, Erie, PA 16509. www.inpressure.com or call 814-8335200 PHARMACEUTICAL PROCESSING | AUGUST 2009

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TESTING

12

Key Steps to Address USP Changes

Strategies to stay current with the recent changes to Chapters <61> and <62>

R

ecently, the United States Pharmacopeia (USP) General Microbiology chapters have harmonized with corresponding microbiology chapters in the European and Japanese Pharmacopeias (EP and JP). The goal of pharmacopeial harmonization is to promote consistency of microbiology methods used by companies globally. This harmonization includes revisions to the existing USP <61> Microbial Limits Test that creates two new chapters: USP <61> Microbial Enumeration and USP <62> Absence of Specified Organisms. Celsis International plc – a provider of life science products and laboratory services to the pharmaceutical, biopharmaceutical, and consumer products industries – out-

changes. Also, media for enrichment, subculture and selection have changed for most microorganisms.

3

Find out how the changes apply to inventory that was validated with current (prior to May 2009) standards. Based on changes in these harmonized chapters, products may need to be revalidated. Reasons include, but are not limited to, media requirements, testing conditions and the amount of sample to be used. For example, if you are using the USP method and want to continue to use it but the media has changed, you will need to revalidate using the new media. Companies should also consider the possibility of a sample

Understand how the new chapters impact the requirements for growth and recovery of specified microorganisms and specified microorganisms tests. lines the key steps the pharmaceutical industry should take to ensure they are ready to address these harmonization changes.

that previously used a specified dilution not being acceptable at that same dilution with the newly specified media.

KEY STEPS TO PREPARE FOR HARMONIZATION CHANGES Following are the top steps companies in the pharmaceutical industry should take to ensure they are prepared for changes to the General Microbiology chapters USP <61>: Microbial Limits Testing and the addition of USP <62>: Absence of Specified Organisms.

Know how changes to USP <61> will alter sample amounts for bulk vs. small batches. Depending on the test or combination of tests, the required sample amounts may vary. As per harmonized USP <61> in the section covering testing of products, the amount used for the test should be 10g or 10mL. For fluids or solids in aerosol form, it is necessary to test 10 containers. For transdermal patches, 10 patches are to be tested. Additional information to justify using less product is provided in the harmonized chapters; examples include small dosage units, small batch sizes or limited number of articles in a batch.

1

Understand that changes to the USP will not affect alternate microbial test methods, such as Rapid Methods. Rapid Microbial Methods (RMMs), such as those provided by Celsis, are accepted microbiology tests that can be used in lieu of the tests as defined in the USP Microbiology Chapters. Those who have implemented such alternate methods are unaffected by the changes to the USP.

2

Understand how the new chapters impact the requirements for growth and recovery of specified microorganisms and specified microorganisms tests. In USP <61> (formerly called the Microbial Limits Test, now renamed the Microbial Enumeration Test), the most obvious change is the separation of the Absence of Specified Microorganisms test into a new chapter, USP <62>. USP <62> is a new chapter that describes the requirements for growth and recovery of specified microorganisms such as Salmonella or S. aureus. Note that all of the specified microorganism tests have undergone

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Determine when and how often to test (i.e. at which stages within the production process – from raw materials to finished goods). Given the number of changes to USP <61> and the addition of USP <62>, it’s important to plan ahead not only for the type of analysis to be performed, but for the time and cost required to do so effectively. Should the analysis not meet the initial requirements, additional testing may be necessary which could require extra time. Be sure to build enough flexibility into your schedule to accommodate these scenarios, and consider using rapid microbial screening methods. Absence of contamination can be determined in 18-24 hours (vs. an average of five days), significantly reducing production cycle times.

AUGUST 2009 | PHARMACEUTICAL PROCESSING

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If you outsource to an analytical lab, evaluate how this contract facility is meeting the new requirements of USP <61> and the addition of USP <62>. Since significant changes are a result of harmonization with EP methods, contract labs with global customers typically have already screened products to the new USP and EP chapters, giving them a head start. Many contract testing labs such as Celsis Analytical Services offer validation services in addition to routine analysis to ensure that testing is in compliance with the new harmonized requirements. Make sure that your lab partner stays abreast of changes in the USP so you can be confident that their services are performed according to current pharmacopeial requirements.

7

If you currently have internal testing methods to screen for contamination and to enumerate specific organisms, consider how you will need to reconcile your current methods with the USP guidelines. Given the significant changes to USP <61>, if you have your own methods for testing microbial limits, you need to ensure that they are fully validated and adhere to updated methods. Remember that the new USP methods are now more inclusive for more organisms, which can have an impact on microbiological media used in testing for specific pathogens, incubation temperatures and duration times.

8

Recognize how changes to USP <61> and <62> prohibit retesting and determine how this will impact your operations. Under the new USP guidelines, retesting of an original sample is not allowed. However, it is acceptable to perform additional analysis on a sample that screens positive for contamination using a rapid method. For this reason, non-destructive rapid testing methods are preferred.

TESTING

Suitability Test, and they must now specify which microorganisms are required to be absent. The Suitability Test ensures that any antimicrobial activity inherent in the test sample will not adversely affect the reliability of the test.

12

Understand that the specified organisms in USP < 61> and USP <62> may not be all inclusive. The organisms listed in USP <61> and USP <62> are example organisms. Each user should also consider testing for organisms that are specific to their facility or to their products. FOR MORE INFORMATION Download the Celsis White Paper Concerning Changes to USP <61> and the addition of USP <62> online at www.celsis.com/usp.

LESER SAFETY VALVES SINGLE-TRIM DESIGN!

9

Familiarize yourself with the additional organisms that have been specified in the new USP <62>. It’s important to note that more organisms have been specified in the new USP <62> chapter than in previous USP editions. Organisms such as Candida albicans, Clostridia species, and bile-tolerant Gram-negative bacteria may be necessary to test for, depending on specific product formulation and utilization.

High Performance, API Series, Compact Performance, Clean Service, Critical Service, Modulate Action

10

Recognize how changes to USP <61> and USP <62> alter incubation times. USP <61> describes microbial enumeration tests, which are the plate count procedures for bacteria, yeast and mould. Although the plate count procedure itself will not change, the incubation temperatures and times for bacteria do change slightly. In USP <62>, tests for specified microorganisms are included. Not only do new modifications change many microbiological media utilized in testing for specific pathogens, but updates also affect incubation temperatures and duration.

11

Understand how updated methodology of the Method Suitability Test in USP <61> and USP <62> impact the types of organisms and different growth media that are included. The Method Suitability Test replaces the Preparatory Test for product inhibition. Both the growth-promotion organisms and the methodology have been significantly updated to include more types of organisms and different growth media. Companies are strongly encouraged to revalidate products to conform to the new USP <61> and <62>

PHARMACEUTICAL PROCESSING | AUGUST 2009

LESER Safety Valves for every industrial application The-Safety-Valve.com LESER LLC 10615 Texland Blvd., Suite 100 Charlotte, NC 28273 USA

Phone: 704-587-3670 E-mail: [email protected] www.leser.com

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■PHARMPRO.COM

■ I N N O VAT I O N S

 Rotary

Vial Washer Operates At Speeds Up To 100 VPM

The RW500 rotary vial washer is a compact and fully automatic vial washer with a footprint of only 37” x 40”. The machine can handle 1 cc – 100 cc glass or plastic vials at a rate of 100 vials per minute (vial size dependent). The washer features a servo controlled main drive, Allen Bradley CompactLogix PLC, and color touch screen HMI. The RW500 has a low WFI consumption and truly simplistic design. The machine can be integrated with company's automatic trayloaders or sterilization tunnel. It is an ideal replacement of or alternative to labor intensive and inefficient batch style machines. ■ PennTech Machinery Corporation, Ivyland, PA 18974. www.penntech-corp.com or call 215-396-2200

WASHING

SYSTEMS

 Mobile

CIP System Can Be Used To Clean Virtually Any Size Vessel

The Mobile CIP System (MCIP) eliminates the necessity and expense of piping a permanent CIP installation in each tank. It includes everything needed for effective, repeatable, user- controlled in-place cleaning. The computer-controlled unit is fully programmable. It provides continuous monitoring and control of all cleaning parameters. An optional onboard dosing pump automatically dispenses additives and provides precise control of additive delivery, ensuring repeatable dosing. The system provides high pressure, 360 degree cleaning at very low flow rates and ensures 100% cleaning effectiveness that matches or exceeds the performance of installed systems. MCIP can be used to clean virtually any size tank or vessel. With the MCIP, capital costs for permanent CIP installations can be eliminated, and the convenience of a mobile cleaning system added to any operation. ■ Gamajet Cleaning Systems Exton, PA 19341. www.gamajet.com or call 800-289-5387

 Washers

Custom Engineered To User Requirements Tray and bin washers are custom engineered to each user's needs and requirements and built with long lasting materials and components. Equipment reduces the time required of personnel who are responsible for the cleansing of lab equipment allowing for higher productivity. ■ Alvey Washing Equipment, Mason, OH 45040. www.alveywashing.com or call 513-923-5665

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IBC

Chamber Washing System Eliminates Need For Split Valve Docking

Chamber washing systems and mobile washing systems for IBCs, washing tanks and other process equipment are provided with controls to meet the client’s needs and can be 21 CFR Part 11 compliant. Company also offers a proprietary high containment washing system for IBCs (bins) and drums that does not require a complicated chamber washer and the associated split valve docking in the washer. ■ SERVOLIFT, Wharton, NJ 07885. www.servolift.com or call 973-442-7878


Glass

Washer Features An Efficient Water Management System

Hotpack® large-capacity glassware washers incorporate a high-efficiency water management system that sets a new benchmark for conserving energy and reducing operating costs. The large-capacity glassware washers offer high volume throughput of virtually all sizes and types of lab glassware and plasticware. All washers offer a spray arch water delivery system that ensures a thorough washing and rinsing. This feature projects a vertical “wall of water” equally across the entire chamber. Separate plumbing systems for wash and rinse cycles minimizes detergent carry-over to provide a clear final rinse. An intuitive touch-screen control interface, which is located at eye level, enables easy selection from a range of preset or user-defined programmed operating options. ■ SP Industries, Inc., Stone Ridge, NY 12484. www.spindustries.com or call 845-687-5315 AUGUST 2009 | PHARMACEUTICAL PROCESSING

■PHARMPRO.COM

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NEW PRODUCTS

Multi-Parameter System Takes Simultaneous Measurements The LiQC multi-parameter system is designed for simultaneous determination of density, refractive index, pH/conductivity and color. The LiQC increases productivity by combining single measurements into one automated process. A sample is filled into a sample vial, placed onto an automatic sample changer, and assigned a barcode label. LiQC chooses the appropriate method, pumps the sample into the various flow-through cells, and performs all measurements. Mettler-Toledo Inc., Columbus, OH 43240. www.mt.com or call 614-438-4505

Dispensing Pump Ideal For Fully Automated Aseptic Fill/Finish The 520Di dispensing pump accurately meters, doses, and transfers fluids in sanitary environments. The 520Di accepts eight different tubing materials and sizes up to 9.6mm for flow rates ranging from 4 microliters/min up to 3.5 liters/min and pressures up to 100 psi. The 520Di is also suited for benchtop media or reagent preparation in laboratory suites. The 520Di has full dispensing capability, enabling accurate batch dispensing and automatic or single-shot operation. Watson-Marlow Pumps Group, Wilmington, MA www.watson-marlow.com or call 800282-8823

DOES IT TAKE TO SELL A GALLON OF GOOP? Whether the goop you make is in liquid, injectable, or capsule form - with DEACOM, you only need one software system to manage your entire business. The DEACOM Integrated Accounting and ERP Software System seamlessly integrates all areas of your business - from formulation and QC testing, to lot tracking and invoicing - giving you a comprehensive view of your entire operation from a single system.

Dust Collector Maximizes Space The Cyclone maximizes collection efficiency and cuts overall costs, while meeting clean air needs. The HE (High-Efficiency) series Cyclones serve as primary receivers in dilute phase pneumatic conveying systems. They can handle high temperatures, high-moisture content, and high airflow. Units lie horizontally and can be custom built to meet needs where space is limited. AIRLANCO, Falls City, NE 68355. www.airlanco.com or call 800-500-9777

PHARMACEUTICAL PROCESSING | AUGUST 2009

Visit Deacom, Inc. at www.deacom.net to schedule a web-based demonstration, and learn how DEACOM can maximize your productivity and profitability today.

610-971-2278 ext. 15 [email protected] www.deacom.net

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COMPLIANCE

Content Compliance Within The Life Sciences Industry Effective strategies for enforcing content compliance and reducing costs in regulated environments ■ By Stephen Bergson, Executive Vice-President Commercial Operations, Virtify, Inc.

W

ith global health and regulatory authorities continuing to push for tighter regulations surrounding disclosure, transparency and e-standards, pharmaceutical and other life sciences companies are increasingly challenged by fragmented, quasi electronic, paper-based processes and often out-of-date technology systems. Many organizations simply lack the process and technology to effectively operate and comply in a rapidly changing regulatory environment. The impact is significant, often translating into costly product delays, regulatory fines and lost business opportunities. Life sciences companies must re-evaluate their existing processes and systems and consider new ways to encourage collaboration, streamline workflow, and keep costs in check to improve content compliance. Although there are content management “like” systems, most are “document-centric” and lack the underlying standards-based business intelligence required by life sciences companies. In this article, I recommend strategies and best practices to help life sciences companies manage and automate these processes to streamline content compliance and reduce development costs while bringing higher quality products to market faster and more efficiently. THE COST OF CONTENT COMPLIANCE The cost of bringing new drugs to market today ranges from $800 million to $1.2 billion and research firm IDC estimates that roughly 26% of that cost goes toward the content requirements associated with regulatory compliance. As the industry and regulators work together to improve the new drug submission and approval process, there are a number of different global standards and regulatory mandates such as Clinical Trial Disclosure, Electronic Common Technical Document (eCTD) and Structured Product Labeling (SPL), which life sciences companies must comply with throughout the product lifecycle. The impact of non-compliance to these standards is significant and includes costly product delays, regulatory fines, and lost market opportunities. A current example of regulatory fines is occurring in the State of Maine, where there is a $10,000 fine per day for noncompliance with clinical trial posting rules. Other state, national and international regulatory bodies are enacting their own mandates and oversight activities as well.

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To satisfy these existing and upcoming compliance mandates, avoid costly delays in approval and/or penalties and the potential negative impacts to their brand image, life sciences companies must take stock of their existing business processes pertaining to content management and reuse. These new processes should be enabled through the usage of state-of-the-art system solutions and technologies providing an integrated, collaborative solution across the product life cycle – from discovery through commercialization. Best practices and information technology can play a huge role here. The right technologies can promote compliance and operational efficiency by automating the transactional tasks within quality compliance, regulatory affairs and clinical support operations. By automating and streamlining the complex content exchange and submissions requirements throughout the product lifecycle, companies can enforce regulatory compliance and automate the many tasks required for clinical trial disclosure, e-submissions, global labeling, and other standards. SIX STEPS TO ENSURE CONTENT COMPLIANCE WITHIN THE LIFE SCIENCES INDUSTRY 1. Automate process and workflow. If your current processes are manual or “document centric,” you are vulnerable to errors and discrepancies. You may also lack the ability to easily track history and gain visibility into whether or not a submission is compliant. A two-phase process can help you achieve an automated workflow: Phase 1. Look for an easy-to-use content management environment that has regulatory guidelines built in. It should include an XML-based technology backbone to comply with the new technology mandates for communicating with the regulators during submissions, labeling, disclosure activities and other forms of interactions. Make sure that the content compliance system is designed to manage the entire lifecycle of the regulated content – from internal authoring, review, approval and external communication, to compare, reconcile and maintain regulatory documents going forward. It should also be configurable to automatically track milestones and notify stakeholders and content contributors when a form has moved (e.g. parent/child relationship tracking) to the next stage in the workflow and/or requires an action from them. Phase 2. During this phase, the content compliance system AUGUST 2009 | PHARMACEUTICAL PROCESSING

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is integrated with your existing information systems automating workflow, minimizing data duplication and entry during the present day highly automated regulatory submissions process. 2. Optimize submissions through collaborative content authoring and review. Traditionally, regulated submission procedures have not been conducive to multiple authors and reviewers. In most cases, a significant amount of effort and time is ineffectively spent throughout the process as contributors wait to be emailed their section to add content or review. Then, once that process is completed, the content and feedback needs to be compiled, verified and published which leads to significant resource efforts and time delays. Ideally, your content system features collaborative authoring with role-based access control. This enables authorized authors and reviewers to work on a document simultaneously, greatly reducing cycle time. Reviewers can simultaneously add comments for authors allowing all to view their respective comments by tracking their text edits to show their suggested changes – hence streamlining the overall process. The technology should automatically facilitate version control, tracking all changes, so there’s no risk of overwriting another’s work accidentally. In addition, the system should be based in the XML technology while retaining every detail of revision history in the event of a future change or audit.

COMPLIANCE

3. Reuse and repurpose content to satisfy global requirements. With the advent of common/similar global regulatory requirements, content management solutions should be viewed in the context of compliance within both the U.S. and international regulatory guidelines. To accomplish this goal, the content management solution requires a level of integrated and configuration capabilities to enable the compliance objective to be met for the client. Submitting information for the same product in multiple countries should not require you to reinvent the wheel each time to ensure compliance with varied submission standards and requirements. Look for a solution that is “standards-ready” and pre-configured to comply with different global standards and regulatory mandates such as Clinical Trial Disclosure, eCTD, SPL/PLR, and other electronic submissions standards so that your users can focus on content, and not compliance. 4. Enable easy adaptation to evolving standards. As regulations continually evolve, in such areas as electronic submissions, disclosure standards, labeling the regulatory communication process and submissions requirements are likely to change too. Look for a solution that incorporates FDA and other global requirements and is designed to absorb and validate changes as quickly as possible. The technology should allow you to rapidly add new form fields or modify existing ones. In addition, look for a solution that

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PHARMACEUTICAL PROCESSING | AUGUST 2009

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COMPLIANCE

meets 21 CFR Part 11 requirements and provides validation with a built-in audit trail, security and authentication. 5. Evaluate both Software-as-a-Service and perpetual licensing. Look for solutions with flexible delivery options, and choose the option that best fits your needs: 1) A perpetual software license allows for the outright purchase, installation and in-house operation of the software with an annual maintenance fee for upgrades and support; 2) A Software-as-a-Service (SaaS) model allows the provider to license the application to the customer for use as a service or “on demand” for a monthly fee, eliminating the often large, upfront costs associated with software purchase and implementation. 6. Focus on ease-of-use. Your content compliance solution must appeal to the people that need to use it – business users, managers, regulatory professionals, clinical staff, etc. As such, your solution should be able to work within your existing organizational framework and include

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the ability to extend and adapt over time. It should also leverage a familiar intuitive interface that doesn’t require a change in behavior on the part of your users. Many Web 2.0 applications provide familiar, desktop conventions and “Microsoft Office®-like” authoring environments. SUMMARY Faced with the daunting challenge of upgrading quasi electronic, fragmented, often paper-based-processes make timely postings, filings and ongoing regulatory communications nearly impossible. Life science companies must look to improved business processes and technologies to comply with the changing regulatory environment. The steps recommended above are very practical and achievable strategies to ensure compliance and manage costs in this environment. Each of these strategies can be used individually or in conjunction with others to take greater control of the regulated content lifecycle. The benefits are multi-dimensional. Streamlining the lifecycle content management process reduces the risk of delays and potentials for fines, while continuously increasing your overall compliance and regulatory communications throughout the world. ■ About the author: Stephen Bergson is the executive vice president of commercial operations for Virtify, Inc. (http://www.virtify.com), a provider of Enterprise Content Compliance software solutions for life sciences companies. He can be reached at [email protected].

Laminar Flowand Exhaust Fume Hoods

• Cycle Development Services • Process Engineering • FDA Title 21 CFR Parts 11 & 212 Compliance Touch screen control over shield, FFU and light

• GAMP5, BS EN-285, ASME & ASME BPE-2007 • System Rebuild & Controls Retrofit • SCADA Systems ETC Sterilization phone 215.355.9100 x1224 • fax 215.357.4000 125 James Way, Southampton PA. 18966 USA *See Website For Details. Offer valid for new equipment purchases only.

www.etcSterilization.com ■ 28

Horizontal and vertical airflow designs. Dozens of standard tables and chemical benches.

Application-specific materials and configurations — • HEPA/ULPA filtration • Exhaust fume purification • Stainless steel • Chemical-safe polypropylene • Static-dissipative plastics • Thermal-resistant polycarbonate Free-standing and bench-top designs Ionization, UV/germicidal lighting, airflow monitoring

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AUGUST 2009 | PHARMACEUTICAL PROCESSING

S P ESCPE I AL C I AL ADVE ADVE RTIRTI S I NG S I NG S E CSTI EC ON TI ON

PPrroodduucctt SShhoowwccaas see Twist & Dry™ Spray Dry Nozzle

The Digital Met30+ Universal Pharmaceutical Metal Detector

Petro-Canada’s PURETOL White Mineral Oil

The Met30+ Universal Pharmaceutical metal detector remains stable to the worst imaginable external interference like shocks and vibration, while at the same time delivering unrivalled sensitivity to metal contamination – even in the presence of extremely high product signal. It is able to detect metal particles as small as 0.25 mm ferrous, 0.3 mm non ferrous, and 0.4 mm stainless steel. Lock Inspection Systems www.lockinspection.com; 800-227-5539

Produced from one of the purest base oils in the world, PURETOL meets the highest standards of purity and quality. • PURETOL USP and PURETOL NF grades meet FDA 21 CFR 172.878 and 21 CFR 178.3620(a) regulations for direct food contact • PURETOL white mineral oils are Kosher, Pareve and Halal certified Petro-Canada is the world’s largest producer of pharmaceutical grade white oil. Petro-Canada lubricants.petro-canada.ca; 866-335-3369

Natoli Continues To Deliver Fette Die Segments

SmartHood™ Ductless Fume Hood

CSI offers state of the art custom fabrication for high purity stainless steel process systems and components. Specific examples include skid systems, utility stations and flow transfer panels for the biotechnology and pharmaceutical industries. Process skids can include tanks, heat exchangers, valves, pumps, wiring and piping. We adhere to ASME BPE standards for design, materials, construction, inspections, and testing. CSI www.csidesigns.com; 800-654-5635

For over two years now, Natoli has been in partnership with Fette to manufacture die table segments. Natoli serves as the only company officially authorized from Fette to manufacture die table segments. Natoli produces standard die segments and carbide segments that support special shape tablets. Natoli’s advanced system of micro-precision engineering, delivers superior die segments that are delivered with a quick turn around time at competitive prices. Natoli Engineering Company, Inc. www.natoli.com; 636-926-8900

Terra Universal’s SmartHood™ features onboard filtration that removes organic fumes and submicron particles to allow safe indoor exhaust release. Its rear baffle system, removable for easy cleaning, optimizes nonturbulent airflow into bonded activated charcoal filters for chemical vapor removal and/or HEPA particle filters. A Smart Controller monitors operating conditions and issues alarms to indicate carbon filter breakthrough, excessive HEPA backpressure, or a drop in air speed past the operator. Options include GFI outlets and probes to monitor RH, pH or temperature. Terra Universal, Inc. www.terrauniversal.com; 714-526-0100

Advanced Scientifics Sales Support Expansion

Humidity and Temperature Transmitter

Sony’s XCI 100 Series - It’s a Whole New Kind of Smart

Here at Advanced Scientifics, as our customer list grows so too does our Sales and Marketing staff. The company has acquired two new hires, Rob Noss as a Southeast Sales and Heather Weaver as a Marketing Representative. Rob comes to Advanced Scientifics from Glaxo Smith Kline where he worked as a Pharmaceutical Sales Representative for two years. Rob graduated from York College of Pennsylvania with a Bachelor’s of Science in Marketing. Heather is a recent graduate of Pennsylvania State University where she received a Bachelor’s of Arts degree in Advertising/Public Relations from the College of Communications. Advanced Scientifics, Inc. www.advancedscientifics.com; 717-692-2104

The ROTRONIC HygroFlex 5 is the newest product from ROTRONIC using the groundbreaking HygroClip2 with AirChip 3000 technology. The HygroFlex 5-series is ideal for all applications where exact measurement of humidity and temperature is of decisive importance for the pharmaceutical industry. The HygroFlex 5 innovations include: accuracy of ±0.8% RH and ±0.1°C; Auto-diagnostics and automatic correction; relative humidity, temperature, dew point; interchangeable probes for easy maintenance; wide choice of probes for every application. Rotronic Instrument Corporation www.rotronic-usa.com; 631-427-3898

BETE has expanded the range of the Twist & Dry™ series with the new TD-K. A new high-pressure backup ring on the TD body raises capacity from 3,500 psi to 10,000 psi for operating conditions up to 450° F. The modified design provides greater yield capacity and safe, leak-proof operation at 10,000 psi.BETE developed this addition to the TD series in response to dryer operators who wanted to increase yield by operating at higher pressures. The new high-pressure TD nozzle provides customers the opportunity to increase productivity while maintaining the convenient locking mechanism and superior performance of our TD Twist & Dry™ nozzles. BETE Fog Nozzle, Inc. www.bete.com; 413-772-6729

High Purity Stainless Steel Process Systems and Components

In the world of smart cameras, Sony’s 100 series is genius for label and packaging inspection, and bar code reading. With its 1 GHz VIA Pentium-class processor, Sony smart cameras are open to a variety of software packages, including Cognex® VisionPro™ software. Sony Electronics, Inc. www.sony.com/smart; 201-930-7000.

■PHARMPRO.COM

■ MARKETPLACE Clean Air Solutions, Inc. Ph 208-634-4219 • Fax 208-634-5569 Cleanroom Fogger

• Consistant & Repeatable Fog Output • Visualize/Video Cleanroom Airflow Patterns • Trace Migration Paths www.cleanroomfogger.com

Decanting Centrifuges

Super Centrifuges

Inverting Filter Centrifuges

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Microorganism

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• Dry Powders from 0.5 to 40 microns • Jet & Mechanical Milling • Inert & Low Temperature Milling • High Purity & Contamination Free • ISO 9001:2000 Registered • cGMP FDA Inspected • Established 1946

Sanitization & Disinfection of HVAC & Dust Collector Systems, cGMP Clean Rooms, Building Structure, Ceiling/Floor Plenums & High Surfaces. InnerSite, Inc., provides contracting for BioProcessing & Pharmaceutical Mfg.

The Jet Pulverizer Co., Inc. 1255 N. Church St., Moorestown, NJ 08057 Ph. (856) 235-5554 Fx. (856) 778-7712

Contact Mark Mateson - [email protected]

For information or to reserve space contact MIKE KELLY E-mail: michael.kelly@ advantagemedia.com Phone: 630-971-9739 Fax: 630-309-2499

■ ADVERTISERS INDEX

■ 30

800-230-0010 ®

www.tollprocessing.com

A world leader in vacuum pump technology Lower operating costs with Busch COBRA vacuum pumps! Houston, Texas 281-214-8400 Los Angeles, California 562-926-8422 Bayamon, Puerto Rico 787-798-5045

Virginia Beach, Virginia 757-463-7800 S. Plainfield, New Jersey 908-561-3233 Chicago, IIlinois 630-545-1310

1-800-USA-PUMP www.buschusa.com

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.

Advanced Scientifics . . . . . . . . . . . . . . . . . . . .2

Petro-Canada Lubricants . . . . . . . . . . . . . . . . . 21

Deacom Inc. . . . . . . . . . . . . . . . . . . . . . . . 25

Reed Exhibition Companies . . . . . . . . . . . . . . . 10

Environmental Tectonics Corporation . . . . . . . . . . . . . . .28

Scarab Genomics . . . . . . . . . . . . . . . . . . . . . 31

IMA North America Inc . . . . . . . . . . . . . . . . . . .7

Terra Universal . . . . . . . . . . . . . . . . . 11,17,27,28

ITT Engineered Valves . . . . . . . . . . . . . . . . . . .3

Veltek Associates Inc . . . . . . . . . . . . . . . . . . . .5

Leser LLC . . . . . . . . . . . . . . . . . . . . . . . . . 23

Walker Barrier Systems . . . . . . . . . . . . . . . . . 17

Natoli Engineering . . . . . . . . . . . . . . . . . . . . 32

Western States Machine Co . . . . . . . . . . . . . . . 27 AUGUST 2009 | PHARMACEUTICAL PROCESSING

Fette Die Segments Manufactured by Natoli …the only licensed manufacturer.

Natoli is proud to be the only licensed manufacturer of Fette die table segments. Natoli’s advanced system of micro-precision engineering, manufactures Fette die segments of exceptional quality that are delivered quickly, worldwide at competitive prices. Natoli manufactures standard round, special shape, multi-tip and carbide lined die segments.