The Drug Development PLUS: and Analytical Toolbox
January 2012 Volume 36 Number 1
FDA’s Perspective on Starting Materials
The Authority on Drug Development & Manufacturing
Antibody–Drug Conjugates Looking ahead to an emerging class of biotherapeutic
PEER-REVIEWED Assessing Tablet-Sticking Propensity
Jim Miller’s Outsourcing Outlook: Contract Services in 2012
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R. Gary Hollenbeck, PhD Chief Scientific Officer, UPM Pharmaceuticals
Larry L. Augsburger, PhD Professor, Department of Pharmaceutics, University of Maryland
Ruey-ching (Richard) Hwang, PhD Senior Director, Pharmaceutical Sciences, Pfizer Global R&D
David H. Bergstrom, PhD COO, NovaDel Pharma Inc.
Mansoor A. Khan, PhD Director, FDA/CDER/DPQR
Rory Budihandojo Director, Quality Systems Audit, Boehringer-Ingelheim Shanghai Pharmaceuticals Co. (China)
Russell E. Madsen President, The Williamsburg Group, LLC
Todd L. Cecil Vice-President Compendial Science United States Pharmacopeia
Jim Miller President, PharmSource Information Services Bio/Pharmaceutical Outsourcing Report
Zak T. Chowhan, PhD Consultant, Pharmaceutical Development
R. Christian Moreton, PhD Vice-President, Pharmaceutical Sciences, Finnbrit Consulting
Suggy S. Chrai, PhD President and CEO, Chrai Associates, Inc.
Fernando J. Muzzio, PhD Director, NSF Engineering Research Center on Structured Organic Particulate Systems, Dept. of Chemical and Biochemical Engineering, Rutgers University
Sanjay Garg, PhD Professor, Pharmaceutical Sciences, University of South Australia
P h a r mTe c h . c o m
Heidi M. Mansour, PhD Assistant Professor, College of Pharmacy, University of Kentucky
Metin Çelik, PhD President, Pharmaceutical Technologies International (PTI)
Tim Freeman Director of Operations, FreemanTechnology
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Pharmaceutical Technology publishes contributed technical articles that undergo a rigorous, double-blind peer-review process involving members of our distinguished Editorial Advisory Board. Manuscripts should be sent directly to the managing editor at 485 Route One South, Building F, First Floor, Iselin, NJ 08830, USA.
James Polli, PhD Professor, School of Pharmacy, University of Maryland Gurvinder Singh Rekhi, PhD Director, Research and Development, Elan Drug Delivery Inc. Susan J. Schniepp Pharmaceutical Consultant, Schniepp & Associates, LLC David R. Schoneker Director of Global Regulatory Affairs, Colorcon Eric B. Sheinin, PhD President, Sheinin and Associates Charles A. Signorino, PhD CEO, Emerson Resources, Inc. Heinz Sucker, PhD Professor Emeritus, Pharmaceutical Institute, University of Bern Scott Sutton, PhD Microbiology Network Lynn D. Torbeck Statistician, PharmStat Consulting Read board members’ biographies online at PharmTech.com/eab.
Moheb M. Nasr, PhD Vice-President, CMC Regulatory Strategy, Global Regulatory Affairs, GlaxoSmithKline Garnet E. Peck, PhD Professor Emeritus of Industrial Pharmacy, Purdue University
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Parenteral Drug Association Training and Research Institute (PDA TRI) Upcoming Laboratory and Classroom Training for Pharmaceutical and Biopharmaceutical Professionals March 2012 Lyophilization Week April 12-15, 2012 | Bethesda, Maryland | www.pda.org/lyoweek • Fundamentals of Lyophilization | March 12-13 • Validation of Lyophilization | March 14-15
April 2012 An Introduction to Visual Inspection – Session 2 April 3-4, 2012 | Bethesda, Maryland | www.pda.org/visualsession2
The 2012 PDA Annual Meeting Course Series April 19-20, 2012 | Phoenix, Arizona | www.pdaannualmeeting.org/courses • Reprocessing of Biopharmaceutical Products – New Course | April 19 • Recommended Practices for Manual Aseptic Processes – New Course | April 19 • Biotechnology: Overview of Principles, Tools, Processes and Products | April 19-20 • Sterile Pharmaceutical Dosage Forms | April 19-20 • Implementation of Quality Risk Management for Commercial Pharmaceutical and Biotech Manufacturing Operations – New Course | April 19-20 • Process Validation and Veriﬁcation: A Lifecycle Approach – New Course | April 19-20 • Process Simulation Testing for Aseptically Filled Products – New Course | April 20 • Investigating Microbial Data Deviations – New Course | April 20
May 2012 Environmental Mycology Identiﬁcation Workshop May 2-4, 2012 | Bethesda, Maryland | www.pda.org/mycology2012
2012 Aseptic Processing Training Program Bethesda, Maryland | www.pda.org/2012aseptic • Session 1: January 9-13 and February 6-10, 2012 – SOLD OUT • Session 2: March 5-9 and March 26-30, 2012 – SOLD OUT • Session 3: May 14-18 and June 4-8, 2012 • Session 4: August 20-24 and September 10-14, 2012 • Session 5: October 15-19 and November 5-9, 2012 Laboratory Courses The PDA Training and Research Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.
For more information on these and other upcoming PDA TRI courses please visit www.pda.org/courses
January 2012 Volume 36 Number 1
➲ On PharmTech.com
On the cover
Pharmaceutical Technology is the authoritative source of peer-reviewed research and expert analyses for scientists, engineers, and managers engaged in process development, manufacturing, formulation and drug delivery, API synthesis, analytical technology and testing, packaging, IT, outsourcing, and regulatory compliance in the pharmaceutical and biotechnology industries.
Cover Story: Antibody–Drug Conjugates
42 Looking Ahead to
an Emerging Class of Biotherapeutic by Amy Ritter A successful antibody–drug conjugate requires careful selection of the drug, antibody, and linker. Compositing by Dan Ward. Images: Nick Koudis/Ingram Publishing/Getty Images
Features Technical Forum
63 Designation of
Regulatory Starting Materials in the Manufacturing of Drug Substances: Impact on ANDA Review Time
Moderated by Rich Whitworth and Stephanie Sutton Industry experts discuss formulation and technical challenges in multilayer tablet manufacture.
52 Broadening the Drug Development and Analytical Toolbox Patricia Van Arnum A look at recent advances in accelerating reaction discovery, inducing chirality and stereochemical analysis, and nanotech applications for protein elucidation. Plus: Formulation Development Forum.
➲ Find additional interviews from this month’s technical forum on multilayer tablet technology on PharmTech.com/multilayer.
Reader comment “Scientific facts should play a leading role, but not an exclusive role, in determining what drugs are available to whom,” in response to a blog post on “Is HHS Using Scientific Standards?” Read more conversations on our blog at blog.PharmTech.com
Free eNewsletters Visit PharmTech.com/enews for: • ePT : Weekly eNewsletter keeps you current with industry news and business notes. • Sourcing and Management: A monthly eNewsletter to help you maintain a healthy supply chain. The January issue provides an API market outlook. • Equipment & Processing Report: Monthly reports on cutting-edge techniques and technologies. The January edition focuses on isolated robots.
Most popular articles • FDA–EMA Joint Manufacturing Inspections to Begin in 2012 • FDA Warns Novartis of Violations at Three Plants
Barbara Scott, FDA The author describes how providing appropriate information about the API in the Common Technical Document can aid FDA’s review of an abbreviated new drug application.
• Views from Pharma Leaders: A Year in Review and a Look Forward
Departments/Products Peer-reviewed research FormulaTion develoPmenT
57 Assessing TabletSticking Propensity Matthew P. Mullarney, Bruce C. MacDonald, and Allan Hutchins The authors designed an upper punch with a removable punch tip to determine a tablet formulation’s propensity to stick by weighing the mass of powder adhered to the punch tip.
18 In the Field 26 In the Spotlight 81 Pharma Capsules 71 Company Product and Service Profiles 82 Industry Pipeline 86 Showcase/Markeplace 90 Ad Index
Continued on page 10 pharmtech.com
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Columns inside usP
From The ediTor
12 Here’s to a
28 Budget Crunch, Politics
67 global Harmonization
year of Compromise
Shape Policy Agenda
opportunities and Challenges
Anthony DeStefano and Kevin Moore
The benefits of harmonization may be on the industry’s wish list, but buying into change is another story.
Pressure to approve new user fees opens the door to action on drug shortages, prices, and regulation.
To keep moving forward, the Pharmacopoeial Discussion Group needs industry participation.
14 Cutting Prices
68 Contract Services for 2012
to Save Sales
Tracey T. Lefteroff
Copay coupons may help patients and drugmakers, but who ends up holding the bag?
Challenges remain, particularly for early-stage biopharm companies.
Recent private-equity buyouts of CROs show the up- and down-side for investors.
38 Innovations for 2012
16 All Systems Slow
Control, a Senior Compliance officer Technology may expedite operations, but the absence of the human element could cost dearly.
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88 Innovator Liability Still Not Viable after Pliva v. Mensing
Zach Hughes Recent legal decisions have further divided generic and brand manufacturer cases. Pharmaceutical Technology is selectively abstracted or indexed in: - Biological Sciences Database (Cambridge Scientific Abstracts) - Biotechnology and Bioengineering Database (Cambridge Scientific Abstracts) - Business and Management Practices (RDSI) -Chemical Abstracts (CAS) -Current Packaging Abstracts -DECHEMA - Derwent Biotechnology Abstracts (Derwent Information, Ltd.) -Excerpta Medica (Elsevier) -International Pharmaceutical Abstracts (ASHP) -Science Citation Index (Thomson) Pharmaceutical Technology is proud to be a member of DCAT, IPEC, and PDA. PHARMACEuTICAL TECHNoLogy (ISSN 1543-2521) is
published monthly, except two issues in June, by Advanstar Communications, Inc., 131 W. First St., Duluth MN 55802-2065. Subscription rates: US and possessions — 1 year (13 issues), $70; 2 years (26 issues), $125. Canada and Mexico — 1 year, $95; 2 years, $145. All other countries 1 year, $135; 2 years, $250. International price includes air-expedited service. Single-copies (prepaid only) — US, $8; outside the US, $10. Back issues (if available): US and possessions — $21; all other countries — $25. Include an additional $6.50 per order plus $2 per additional copy for US postage and handling. If shipping outside the US, include an additional $10 per order plus $3 per additional copy. Periodicals postage paid at Duluth, MN 55806 and additional mailing offices. POSTMASTER: Please send address changes to Pharmaceutical Technology, PO Box 6188, Duluth, MN 558066188. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: Pitney Bowes, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian G.S.T. number: R-124213133RT001. Printed in the U.S.A. pharmtech.com
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Here’s to a Year of Compromise Angie Drakulich
The benefits of harmonization may be on industry’s wish list, but buying into change is another story.
t is in the New Year that we often set goals to improve ourselves, whether it’s trying to get fit, move up the career ladder, spend more time helping others in need, or any other number of personal quests. But individuals aren’t the only ones who make long-term goals—so do governments, organizations, and for our purposes, this industry. Harmonization of drug development and manufacturing approaches comes to mind. I’m a big supporter and follower of harmonization initiatives, but I get the feeling that not everyone in industry is as gungho about the idea. At several industry meetings during the past year, I’ve asked people what they think of harmonization and whether they believe certain aspects of pharma manufacturing will ever be harmonized (e.g., elemental impurity limits). I’ve asked conference participants, for example, about why it’s necessary for each nation or region to have its own pharmacopeial guide and for an international pharmacopeial guide to exist. And, for drugapplicants working to bring a product to the global market, is there a way to avoid filling out the same information on 20 different forms? Inspections are another area lacking harmonization. We all know how many audit or inspection teams companies must accommodate in a given year. Most of the answers I’ve gotten are along the lines of, “ I don’t know,” or “They would never agree to compromise on that,” or, “There’s too much national pride for one
Angie Drakulich is editorial director of Pharmaceutical Technology. Send your thoughts and story ideas to [email protected]
country to change its standards to match another’s.” I get that compromise is difficult. In fact, before coming to Pharmaceutical Technology, I spent several years working for a nonprofit focused on the work of the United Nations. So I understand how much effort is required to engage productive dialogue and garner compromise among a diverse and global audience. I also get that the bio/ pharmaceutical industry is highly protective of its information and practices—it is a competitive, patent-based, trillion-dollar industry after all. But I also think that some of the key elements of harmonization are getting lost in translation. Industry seems to want globally standardized approaches to their processes and quality systems as well as minimal routes for filing marketing applications and other required documents. Reaching these goals would make life easier for all parties involved. Having an agreed-upon, worldwide approach to quality and supplymanagement, for example, could literally solve many of the drug-product contamination and adulteration issues that have plagued the industry in recent years. And yet, many companies and national regulatory or standard-setting bodies seem unwilling to give up their current practices or accept that another company, organization, or nation for that matter, may have a better way of doing things. Perhaps my vision of global harmonization is too lofty or naïve. But there is reason to hope. The International Conference on Harmonization was established in 1990 with the aim of increasing “international harmonization of technical requirements to ensure that safe, effective, and high quality medicines are developed and registered in the most efficient and cost-effective manner.” In its 20-plus years, ICH has
P h a r mTe c h . c o m
managed to gain consensus across North America, the European Union, and Japan, on 16 Efficacy guidelines, 10 Quality guidelines, nine Safety guidelines, and has several multidisciplinary guidelines in the pipeline. The members of ICH’s Global Cooperation Group extend the reach of these guidelines to eight additional countries, including the leading markets in Asia. Other global standard-setting bodies, such as the International Pharmaceutical Excipients Council and the International Society for Pharmaceutical Engineering, are working to shape global industry practice. And new industry groups working to share best practices throughout the world seem to be popping up every month (e.g., the Rx–360 and IQ consortiums). I hope you will take time to learn more about global harmonization efforts and talk with your colleagues about how your organization might become involved, whether that means providing feedback, working to implement harmonized guidelines, or sharing them with your global partners. In the meantime, Pharmaceutical Technology will do its best to keep you apprised of happenings tied to harmonization and what it means for your day-to-day operations—and that’s just one of many resolutions we intend to keep this year. PT Michelle Hoffman, our editorial director from 2007 to 2011, has moved on to pursue new scientific opportunities. We have the highest regard for her and the contributions she made to Pharmaceutical Technology over the past few years, and we wish her all the best. As the new Editorial Director, I have many hopes and goals for Pharmaceutical Technology in the year ahead. Our team will be working to improve the types of articles and resources we bring to you in print and online. I am also happy to announce that 2012 is Pharmaceutical Technology ‘s 35th anniversary. We will be celebrating the occasion with retrospective and forward-looking articles in the coming months. We welcome your ideas and feedback.
JORG GREUEL/PHOTODISC/GETTY IMAGES
FROM THE EDITOR
cutting Prices to Save Sales Erik Greb PharmTech.com/forum
Copay coupons may help patients and drugmakers, but who ends up holding the bag?
s patent protection expires for top-selling drugs, some firms are scrambling to stay one step ahead of generic-drug competitors. Pfizer and others are wooing insured consumers by offering copay coupons, which reduce the cost of a branded drug. These coupons are intended to discourage a patient from switching to a generic therapy. To redeem the coupons, consumers often must submit personal information that allows the firms to promote products to individual patients. The coupons may help consumers, but they oblige plan sponsors, such as employers or state governments, to pay
high prices for branded drugs when generic alternatives are available. Drug companies can prevent plan sponsors from knowing when enrollees have redeemed the coupons by processing them through a “shadow claims system,” according to a Nov. 3, 2011 statement from the Pharmaceutical Care Management Association. Copay coupons will increase costs for these sponsors by $32 billion over the next decade, according to research from Visante. At a time when state governments and private companies are pinching pennies, it’s hard to believe that they will allow drug companies to use these tactics for
long. Arrangements such as Pfizer’s agreement to manufacture generic Lipitor for Watson, in exchange for a share of net sales, seem comparatively more benign. They don’t appear to constrain patients’ choice or force payors to spend more than necessary. In fact, these arrangements might be the “least bad” option for drugmakers without new blockbusters on the horizon. PT
Erik Greb is an associate editor of Pharmaceutical Technology.
Read Erik’s blogs at blog.PharmTech.com.
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All Systems Slow Cautionary Tales from the Files of “Control,” a Senior Compliance Officer
Technology may expedite operations, but the absence of the human element could cost dearly. Drained “We have a complicated computercontrolled manufacturing system for our product,” explained our GMP Agent-In-Place. “It includes several vessels, computer-controlled valves, and computer-controlled clean-in-place (CIP) systems. With low production levels at startup, everything ran fine—there was only one batch in process at a time. But when product demand increased, we began to process two batches at once. We didn’t think it would be a problem because they would be in separate vessels. However, when the first batch was done, we needed to clean the last vessel prior to processing the second batch. Apparently, during validation we never checked the upstream valve status during the last vessel’s CIP procedure, because the computer opened the bottom valve to drain on the penultimate vessel. The entire second batch was drained before we realized there was a problem—a $200,000 problem.”
Double-duty filter “Sometimes processing aides do more than we think,” began our GMP AgentIn-Place. “For instance, we used a depth filter in our production to help separate the proteins. We changed to a different manufacturer and the first lots produced all met the release criteria. The test results looked normal. It was only when the stability data showed faster degradation that we saw a problem. The degradation was clearly associated with the change of filter, and caused a recall of several batches. The customer was not pleased. 16
“After an enormous amount of investigation and testing, it turned out that the original filter had also removed protease from the resultant filtrate that becomes our product. The protease would proteolyse our protein product over time, showing up as degradation in our stability studies,” sighed our Agent.
The entire second batch was drained before we realized there was a problem. Hazy days “A lot can happen with filtration,” our GMP Agent-In-Place said. “We use a filter-aid during the production process of our sterile-liquid product. Filter-aid is also known as diatomaceous earth and is mined from the ground—its chemical composition can vary. “During a stability study, when the samples were initially retrieved, we’d sometimes see a slight haze wafting from the bottom of the vial. We would only see it upon first movement; the haze would dissipate into the air. Exploratory testing was conducted to identify the haze. The haze could not be collected, so we tested the liquid for a variety of compounds. We identified some cadmium in our products. It turned out that cadmium was in the filter-aid we had used. Because filteraid is mined, it is variable, and at least
P h a r mTe c h . c o m
one location had some cadmium contamination. “The identification of cadmium in our product resulted in a long medical assessment, including testing every batch that’s still in-date. We found detectable levels in hundreds of batches. The release of filter-aid now includes a test for heavy metals. The search for the source of the haze is still ongoing.”
Unseen “Sometimes it’s the simple stuff that gets you,” grumped our GMP AgentIn-Place. “Someone forgot to place the temperature probe in a vessel. The computer-controlled heating step continued to pump heat into the vessel’s jacket and thereby into the product waiting for the probe to report the proper temperature. Because the probe wasn’t in the vessel, it never sensed the correct temperature. When this was discovered hours later, the product was overcooked and had to be rejected.” PT Pharmaceutical Technology’s monthly “Agent-in-Place” column distills true industry tales from the files of Control, a senior compliance officer. If you have a story to share, please email it to Control at [email protected]
We won’t use any names, but if we do use your experience in the column, you’ll receive a Pharmaceutical Technology T-shirt.
Operational Excellence in Bioprocessing Services?
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In the Field
18 .....Market Report from Europe 22 .....Brazil’s Pharma Market Expectations 20 .....Corporate Social Responsibility 24 .....FDA–EMA Inspections
Continuous processing in pharmaceutical production has been making only small inroads into Europe’s drug sector, which continues to be dominated by batch-manufacturing systems. However, the introduction of continuous technologies is gaining momentum in the region primarily due to R&D schemes backed by public-sector funds. Attention is shifting from relatively small-scale continuous processes, particularly in areas such as tableting and coatings, to concepts in which the production of intermediates or even of the whole drug is transferred from batch to continuous manufacturing. contin. on page 20
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PHOTO: IMAGE SOURCE / GETTY
The European Union market takes steps toward continuous processing and modular facilities.
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