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
PharmTech.com
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
Choose Choice. Sustained-Release
Immediate-Release
Taste Masking
Lyophilization Aseptic Filling
Multi-Therapy
Solubilization
No other partner gives you more formulation options – royalty free. Get access to the industry’s widest range of complex formulation technologies for small molecules and biologics, and benefit from expertise forged over thousands of projects. At Patheon, we’re not tied to any technology. That means science alone drives the development of an optimal formulation, and you’ll never pay us a royalty. Our commitment is to your success.
Choose choice – choose Patheon. Call +1 866-PATHEON (+1 866-728-4366) or email
[email protected] US Headquarters
European Headquarters
Patheon Inc. 4721 Emperor Blvd, Suite 200 Durham, NC 27703-8580 USA P: +1 919 226 3200 F: +1 919 474 2269 www.patheon.com
Patheon UK Ltd. Kingfisher Drive Covingham, Swindon Wiltshire SN3 5BZ UK P: +44 1793 524411 F: +44 1793 487053 www.patheon.com
Published 9/11
PATH0214R0
Editorial Director Angie Drakulich
[email protected] Executive Editor Patricia Van Arnum
[email protected] Managing Editor Susan Haigney
[email protected] Editor (Europe) Rich Whitworth
[email protected]; Scientific Editor Amy Ritter
[email protected]; Associate Editors Erik Greb
[email protected], Stephanie Sutton
[email protected], and Christopher Allen
[email protected] Art Director Dan Ward Washington Editor Jill Wechsler
[email protected] Contributing Editors Jim Miller
[email protected]; Hallie Forcinio
[email protected]; Susan J. Schniepp
[email protected]; Lynn D. Torbeck
[email protected]; and Eric Langer
[email protected] Correspondents Hellen Berger (Latin/South America,
[email protected]), Sean Milmo (Europe,
[email protected]), and Jane Wan (Asia,
[email protected])
LAB BLENDERS MAXIBLEND® LAB BLENDER 0.5, 1, 2, 4, 8 and 16 qt. 316L SS interchangeable V-Shells, DoubleCones & Bins. Large & Small Bottle Blending attachments. High speed JOUFOTJëFSCBST'JYFEPSWBSJBCMF speed. PLC controls with timers. Can be supplied with NIR probes
EDITORIAL OFFICE
1"5 UIFOFX4*'5/#-&/%™ attachment for integrated sifting & blending. ALSO AVAILABLE: MINIBLEND™
485 Route One South, Building F, First Floor, Iselin, NJ 08830, USA Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com
EDITORIAL ADVISORY BOARD
/&8 4*'5/#-&/% (Patent Pending)
PILOT SCALE BLENDERS
"7"*-"#-&'03"-BLENDERS
45"/%"3%'&"563&4
MAXIBLEND® 5-10
1, 2, 3, 5 and 10 cu. ft. 316L SS, interchangeable V-Shells or Bins. All stainless steel construction. Pharmaceutical finish. On-caster design. PLC controls. Low maintenance.
015*0/"-'&"563&4 Variable speed. Intensifier bars for both V-Shells & Bins. Built-in lift system to raise or lower the shell. Stainless steel cart. Portable safety guard. cGMP butterfly valve. NIR probes (PAT).
ALSO AVAILABLE:
MAXIBLEND® 1-2-3, MAXIBLEND® 1-2.
SIMPLEBLEND™
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
JANUARY 2012
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
GlobePharma, Inc., P.O. Box 7307, North Brunswick, NJ 08902-7307 5FMt'BY &NBJMTBOOJ!HMPCFQIBSNBDPNt8FCXXXHMPCFQIBSNBDPN 'BDF#PPLUPP
Pharmaceutical Technology
James P. Agalloco President, Agalloco & Associates
Roger Dabbah, PhD Principal Consultant, Tri-Intersect Solutions
1, 2, 3, 5 & 10 cu. ft. capacity shells. Stand alone, tumble blender with V-Shell, Bin or a Double-Cone Shell. Available with or without intensifier bar. Portable.
4
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
Pharmaceutical Technology’s eNewsletter Team: • ePT, Editor Christopher Allen,
[email protected] • Sourcing and Management, Editor Patricia Van Arnum,
[email protected] • Equipment & Processing Report, send content and ideas to
[email protected] • Send product releases to
[email protected]
For more than 30 years, VAI has pioneered the design and manufacture of hundreds of clean room solutions.
• Cleanest wipe in the industry
• Saturated wipes are made with WFI
• Asepti-Fill® closed filling system
• Lot Specific Documention for all wipers
• Laundered in Class 1
• Laser cut sealed edges
Quadruple Bagged using the ABCD Introduction System®
No other company offers this broad a range of wipers…
Dry cleaning wipe
70% USP IPA in Water for Injection saturated wipe
STERI-PEROX® WIPE
HYPO-CHLOR® Wipe
DECON-Clean® Wipe
ALCOH-Wipe®
STEEL-BRIGHT® Wipe
DAS-Wipe®
Saturated Hydrogen Peroxide Wipe
Saturated Sodium Hypochlorite Wipe
Removes residue from disinfecting agents
Saturated with DECON-AHOL® WFI 70% USP Isopropyl Alcohol
Stainless Steel Cleaning wipe
Stainless Steel cleaning and lubricant wipe
www.sterile.com 1-888-4-STERILE
PureWeld®XL tubing The performance weldable fluid path that lowers your risk Engineered by the world leader in biopharm peristaltic pumps, this weldable tubing eliminates connectors, pumps longer than other TPE tubing without shedding and has the ADCF purity to deliver total process security.
SALES OFFICE Publisher Michael Tracey
[email protected] Director of Sales Paul Milazzo
[email protected] Eastern Sales Manager Suzanne Fillweber
[email protected] Mid-West Sales Manager Irene Onesto
[email protected] Display, Web, Classified, and Recruitment Representative Tod McCloskey
[email protected], Executive Assistant Barbara Sefchick
[email protected] 485 Route One South, Building F, First Floor, Iselin, NJ 08830, USA Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com
Sr. Production Manager Karen Lenzen, International Licensing Maureen Cannon
[email protected], tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440-891-2650, Circulation Manager Anne Brugman
Contact us for a free sample
BioPharmaceutical Division PureWeld Pumpsil Bioprene
wmtubing.com 800-282-8823
President, CEO Joseph Loggia, Executive Vice-President, Finance & CFO Ted Alpert, Executive Vice-President of Corporate Development Eric I. Lisman, Chief Administrative Officer Tom Ehardt, Executive Vice-President, Pharma/Science Group Ron Wall, Vice-President/General Manager, Pharma/Science Group David C. Esola, Vice-President, Information Technology J. Vaughn, Vice-President of Media Operations Francis Heid, Vice-President of Human Resources Nancy Nugent, Vice-President, General Counsel Ward D. Hewins, Director of Content Peter Houston
©2012 Advanstar Communications Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/ educational or personal use, or the internal/educational or personal use of specific clients is granted by Advanstar Communications Inc. for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978.750.8400 fax 978.646.8700 or visit http://www.copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept. fax 440.756.5255 or email:
[email protected]. Advanstar Communications Inc. provides certain customer contact data (such as customers name, addresses, phone numbers, and e-mail addresses) to third parties who wish to promote relevant products, services, and other opportunities that may be of interest to you. If you do not want Advanstar Communications Inc. to make your contact information available to third parties for marketing purposes, simply call toll-free 866.529.2922 between the hours of 7:30 a.m. and 5 p.m. CST and a customer service representative will assist you in removing your name from Advanstar’s lists. Outside the US, please phone 218.740.6477. Pharmaceutical Technology does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take responsibility for any losses or other damages incurred by readers in reliance of such content. Pharmaceutical Technology welcomes unsolicited articles, manuscripts, photographs, illustrations, and other materials but cannot be held responsible for their safekeeping or return. Single issues, back issues: Call toll-free 800.598.6008. Outside the US call 218.740.6480. Reprints of all articles in this issue and past issues of this publication are available. Email
[email protected] or call 800.290.5460 ext. 100 (international 717.505.9701 ext.100). Direct mail lists: Contact Tamara Phillips, Marketing Services, tel. 440.891.2773,
[email protected]. Display, Web, Classified, and Recruitment Advertising: Contact Tod McCloskey, tel. 440.891.2739,
[email protected]. Permissions: Contact Maureen Cannon, tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255,
[email protected]. To subscribe: Call toll-free 877.527.7008. Outside the U.S. call 218.740.6477.
6
Pharmaceutical Technology
JANUARY 2012
P h a r mTe c h . c o m
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
Issue extras
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
Fda PersPecTives
48 Multilayer-
63 Designation of
Tablet Technology
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.
Pharma ingredienTs
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
jublHS.com 800.655.5329
Bologna in his hair is hilarious to Beck. Nearly as funny as when his dad chases him around the house or his sister tickles his tummy. Beck can laugh at bologna in his hair and silly times with his family because his pediatrician gave him an injection that cleared up that nasty virus. Beck doesn’t think about that medicine or how it helped him get back to being happy and healthy, but we do. Beck is the son of a JHS employee
Scan the barcode or visit jublHS.com to review a video about our organization
Helping people is what you do best. Let Jubilant HollisterStier take care of the details getting there. Spokane, WA, USA • Montreal, Quebec, Canada • Roorkee, Uttarakhand, India • Salisbury, Maryland, USA
Solid Dosage • Non-Sterile Topicals & Liquids • Sterile Ophthalmics & Otics • Sterile Injectable Fill/Finish
Full Service Contract Manufacturing …Multiple Dosage Forms …Clinical to Commercial …Regulatory Excellence
Continued from page 8
Columns inside usP
From The ediTor
washingTon rePorT
12 Here’s to a
28 Budget Crunch, Politics
67 global Harmonization
year of Compromise
Shape Policy Agenda
opportunities and Challenges
Angie Drakulich
Jill Wechsler
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.
PharmTech Talk
bio Forum
ouTsourcing ouTlook
14 Cutting Prices
36 Venture-Capital
68 Contract Services for 2012
to Save Sales
Funding Falls
Jim Miller
Erik greb
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.
Packaging Forum
38 Innovations for 2012
agenT-in-Place
16 All Systems Slow
Hallie Forcinio
Control, a Senior Compliance officer Technology may expedite operations, but the absence of the human element could cost dearly.
Packaging innovations boost productivity, meet regulatory requirements, and protect products.
Others fill the page with words.
deliver API’s. Grams to tons. On time. No excuses.
We just
C-MLabs.com l 262.251.5044
Visit Us At Informex Booth #1617
viewPoinT
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
“Now we can mix high viscosity emulsions 600% faster.” The Ross PreMax is the first batch rotor/stator mixer that delivers both ultra-high shear mixing quality and high-speed production. In side by side tests, the PreMax produces gels, creams and lotions much faster than a traditional high shear mixer.
John Paterson PreMax Inventor Employee Owner
With a patented, high-flow rotor/stator design, the PreMax also handles viscosities far beyond the capacity of ordinary batch high shear mixers. In many applications, this can eliminate the need for supplemental agitation.
Contact Ross today to arrange a no-charge test in our laboratory. Call 1-800-243-ROSS Or visit mixers.com
The PreMax with a Delta generator operates with a tip speed of 5,000 fpm and handles viscosity up to 50,000 cP.
*Patent No. 6,000,840
Scan to learn more.
Free Tag Reader: http://gettag.mobi
Here’s to a Year of Compromise Angie Drakulich
PharmTech.com/forum
The benefits of harmonization may be on industry’s wish list, but buying into change is another story.
I
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].
12
Pharmaceutical Technology
JANUARY 2012
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?
a
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.
Trust. Safety. Efficiency. Enterprise quality management solutions that enable high value organizations to safely and efficiently deliver products and services to market.
Contact us to learn why 43 of the top 50 pharmaceutical companies rely on TrackWise. (888) 261-5948 | www.spartasystems.com/pt1 |
[email protected] 14
Pharmaceutical Technology
January 2012
P h a r mTe c h . c o m
AUGUST STEIN/PHOTODISC/GETTY IMAGES
PharmTech Talk
You’ll Likely
Find Some Of His
Best Work In
Your Medicine Cabinet. WHEN DEVELOPING TOMORROW ’ S MIRACLE DRUGS , it helps to have a
healthy dose of the past. Veteran Metrics scientists, like Mike Ruff, have dedicated their careers to formulating some of the world’s most prescribed and life-changing drug products. With four patents and one patent pending for innovative drug technologies, Mike Ruff personifies our philosophy of “Thoughtful Science.” Why not put him to work on your next project?
PHARMACEUTICAL FORMULATION DEVELOPMENT, CLINICAL TRIAL MATERIALS, ANALYTICAL METHOD DEVELOPMENT & VALIDATION, STABILITY SERVICES, RAW MATERIAL TESTING, TRACE METALS ANALYSIS, MICROBIOLOGY 1240 Sugg Parkway / Greenville, NC 27834 / 252-752-3800 / www.metricsinc.com
PAUL GILLIGAN/GETTY IMAGES
Agent-in-PlAce
All Systems Slow Cautionary Tales from the Files of “Control,” a Senior Compliance Officer
PharmTech.com/aip PharmTech.com/aip
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
Pharmaceutical Technology
January 2012
“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?
Pfizer’s Got It. Pfizer CentreSource delivers innovative, high quality services that leverage Pfizer's awardwinning leadership in biologics development and manufacturing, including a host of GMP custom fermentation options. And with Pfizer's advanced facilities, regulatory track record, and experienced biotherapeutics professionals, you get Operational Excellence in Bioprocessing and Fermentation Services in a way that benefits your product, and your bottom line.
Contact Pfizer CentreSource for: Industry-leading protein expression technologies and biological product characterization Extensive drug product and cold chain operations Experience with a broad variety of products and host organisms Full US and EU cGMP compliant manufacturing Expertise in culture improvement, fermentation process optimization, and recovery improvement
The Americas: +1.269.833.5844 Europe/Middle East/Africa: +32.2.714.6502 Asia Pacific: +65.6419.0248 centresource.info@pfizer.com www.pfizercentresource.com Pfizer's Project Pegasus Bio 7 Manufacturing Facility in Strängnäs, Sweden, is a 2011 Facility of the Year Award (FOYA) winner for Operational Excellence.
In the Field
18 .....Market Report from Europe 22 .....Brazil’s Pharma Market Expectations 20 .....Corporate Social Responsibility 24 .....FDA–EMA Inspections
Sean Milmo
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
18
Pharmaceutical Technology
MONTH 2012 JANUARY 2012P h PahramTe r mTe c hc.hc.ocm om
PHOTO: IMAGE SOURCE / GETTY
The European Union market takes steps toward continuous processing and modular facilities.
^ĞůĞĐƚƚŚĞ ŶƚĞƌƉƌŝƐĞYƵĂůŝƚLJΘŽŵƉůŝĂŶĐĞ DĂŶĂŐĞŵĞŶƚ^ŽfƚǁĂƌĞ^ŽůƵƚŝŽŶ Biotechnology Quality Assurance
cGxP
FDA Regulations FMEA eValidation
Medical
21 CFR Part 1270
Device
Medical Device CFR 11
GxP
Quality MedWatch Plus
Risk Management ISO 14791 21 CFR 11
FDA GMP eMDR
Risk FMEA
GxP FMEA Good Manufacturing Practice
Change
Quality
Pharmaceuticals Change Management
eMDR GMP
Life Sciences Regulatory Compliance FDA Submissions FMEA
Complaint Handling
FDA GMP
Medical Device FMEA
Risk
Life Sciences Blood Services 21 CFR 11 eValidation
FMEA
FDA Regulations Biotechnology Electronic Submissions
eVal GxP ISO
Quality Assurance Software Good Manufacturing Practices
FDA
Pharmaceuticals 21 CFR Part 1271
CFR 11
Risk Management FDA Submissions Medical Device Regulatory Compliance
21 CFR Part 11
ISO
Life Sciences
eMDR
Medical Device FMEA MedWatch Plus
GMP
FDA
Blood & Tissue
cGMP
FDA 21 CFR
cGMP
FMEA GxP
ISO 14791
ISO FDA CFR GMP
Quality Assurance
Life Sciences
Quality
GxP
FMEA
Blood & Tissue
Blood
cGMP Biotech
eVal 21 CFR
eValidation
ISO Electronic Signatures Change Management
eValidation ISO 14791
Pharma Quality
Risk Assessment Pharmaceuticals
Regulatory Compliance
FDA Regulations Quality Assurance Software
ISO
cGMP
Biotechnology
Med Watch
21 CFR 11
21 CFR Part 1270 cGMP FDA Submissions
ISO
Quality Assurance Software Change Management Pharmaceuticals Risk Management Quality
cGxP Quality
eMDR ISO 13485 Compliance
Biotechnology GxP 21 CFR
Blood
Complaint Handling eValidation
cGMP
eValidation Failure Mode Effects Analysis CFR
Failure Mode Effects Analysis ISO 14791
FDA Compliance
Medical Device Reports 21 CFR Part 11
Pharmaceuticals Biotechnology
Medical Device 21 CFR Part 1271 Compliance
Regulatory Compliance Software Failure Mode Effects Analysis
FDA Compliance Good Manufacturing Practices MedWatch Plus 21 CFR Part 1271 Risk Assessment Quality Assurance
GMP
CFR 11
Risk Assessment
ISO 13485
21 CFR 11
FDA
ISO
FDA cGxP
FDA Submissions Blood Services Regulatory Compliance Software Complaint Handling
FDA
ISO 14791
FDA ISO
eMDR
Quality
Compliance 21 CFR Part 1271
Quality Assurance Software ISO 13485 Electronic Submissions Quality CFR
MedWatch
Risk Change Management
ĞƐƚWƌĂĐƟĐĞƐ: Integrated modules for Quality and FDA Compliance Management: ŽĐƵŵĞŶƚŽŶƚƌŽůZĞƉŽƌƟŶŐƵĚŝƚƐdƌĂŝŶŝŶŐEŽŶĐŽŶĨŽƌŵĂŶĐĞ WŚĂŶŐĞDĂŶĂŐĞŵĞŶƚZŝƐŬƐƐĞƐƐŵĞŶƚ...and more!
ǁŝƚŚƚŚĞŵŽƐƚVALUE
Risk Management/ĚĞŶƟĮĞƐŵŝƟŐĂƚĞƐĂŶĚƉƌĞǀĞŶƚƐŚŝŐŚƌŝƐŬĞǀĞŶƚƐ ŝŶƚŚĞYƵĂůŝƚLJ^LJƐƚĞŵ Flexible>ĞĂĚŝŶŐĞĚŐĞŇĞdžŝďůĞǁŽƌŬŇŽǁĂĚĂƉƚƐƚŽĂůůďƵƐŝŶĞƐƐ ƉƌŽĐĞƐƐĞƐǁŝƚŚŽƵƚƉƌŽŐƌĂŵŵŝŶŐ /ŶƚĞŐƌĂƟŽŶ/ŶƚĞŐƌĂƚĞƐǁŝƚŚϯrdƉĂƌƚLJďƵƐŝŶĞƐƐƐLJƐƚĞŵƐ ScalableZĞĂĚŝůLJĂĚĂƉƚƐƚŽĞŶƚĞƌƉƌŝƐĞĞŶǀŝƌŽŶŵĞŶƚƐĂŶĚŵƵůƟƐŝƚĞ deployments FDA ComplianceŽŶĮŐƵƌĂďůĞƐŽůƵƟŽŶĨŽƌƌĞŐƵůĂƚĞĚĐŽŵƉĂŶŝĞƐϮϭ &ZWĂƌƚϭϭĐŽŵƉůŝĂŶƚ Business Intelligence ŶƚĞƌƉƌŝƐĞƌĞƉŽƌƟŶŐƚƌĂĐŬƐ
