OCTOBER 2013 Volume 37 Number 10

Volume 37 Number 10 37 Number Volume USP on Plastic Maintaining Tracking Quality in PLUS: Packaging Systems the Cold Chain Drug Manufacturing Advancing Development & Manufacturing

PharmTech.com PHARMACEUTICAL TECHNOLOGY

Seeking Solutions in Tablet Sticking OCTOBER 2013 Screening methods and predictive models

address tenacious tablet-sticking problems

PharmTech.com

PEER-REVIEWED A Risk-Based Approach to Monitoring Elemental Impurities in Leachable Studies

DRUG DELIVERY EMERGING MARKETS API SYNTHESIS & MANUFACTURING Strategies for Oral Absorption Myanmar, Middle East, and North Africa Overcoming Challenges in Fluorine-Based Chemistry Let’s t

Parenteral Contract Manufacturing Service of Hospira Com

Let’s talk at

iCSE/CPhI 2013 Frankfurt, Germany October 22-24, 2013

AAPS 2013 C San Antonio, Texas November 10-14, 2013 O BIO-Europe 2013 Vienna, Austria NORTH November 4-6, 2013 AMERICA McPherson, USA PDA Europe Universe of Pre-fi lled Syringes & Injection Devices 2013 Basel, Switzerland November 5-6, 2013

Call +1-224-212-2267 or +44 (0) 1926 835 554 or e-mail [email protected] talk about the benefi ts of mplementary Capabilities

Biologics & small molecule fill & finish

Clinical & commercial supply to 45+ local markets

On-site development and bio-analytical expertise Zagreb, Croatia Liscate, Italy Advanced lyophilization capabilities EUROPE

Flexible labeling and packaging

Cold chain management

QP Release services

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P13-4132/R1-Aug.,13

Expertise, Resources and Technology Brought Together for Your Success

Visit us at CPhI Worldwide Booth #42G03 and AAPS at Booth #2312

Parenteral Development and Manufacturing We Deliver Quality and Results – Again and Again

Whether you’re an emerging company in need of clinical Large molecule or small, Patheon brings together the development expertise, or an established leader seeking technologies, services and experience you need for a reliable commercial supply, Patheon understands your needs successful parenteral product. and delivers results. We have it all, so you get exactly what you need. t 1,100 SKUs manufactured for more than 60 countries Each available in a wide array of formats and sizes. t 98%* Right First Time and On-Time performance t NEW Prefilled Syringes t Multiple European Outsourcing Awards for tech transfer t NEW Cartridges t Liquid Small Volume Parenteral (SVP) Patheon is in constant pursuit of innovative ways to achieve t Liquid Large Volume Parenteral (LVP) your scientific and business goals, like our new state-of-the-art t Lyophilized Vials manufacturing suite for prefilled syringes and cartridges.

Move Your Sterile Project Along the Right Path

+1 866.PATHEON t www.patheon.com t [email protected]

* 12 month average through May – Data on File

©Patheon Inc. All rights reserved. Published 7/13 PATH0335R0 EDITORIAL Editorial Director Rita Peters [email protected] Executive Editor Patricia Van Arnum [email protected] Managing Editor Susan Haigney [email protected] Scientific Editor Adeline Siew, PhD [email protected] Manufacturing Editor Jennifer Markarian [email protected] &RQWUDFW3DUWLFOH6L]H5HGXFWLRQIRU Community Editor Melanie Sena [email protected] WKH3KDUPDFHXWLFDO0DUNHWSODFH Multimedia Editor Reid Paul [email protected] Art Director Dan Ward Contributing Editors Jill Wechsler [email protected]; Jim Miller [email protected]; Hallie Forcinio [email protected]; Susan J. Schniepp [email protected]; Eric Langer [email protected]; and Cynthia A. Challener, PhD [email protected] Correspondents Hellen Berger (Latin/South America, [email protected]), Sean Milmo (Europe, [email protected]), and Jane Wan (Asia, [email protected])

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 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. Below is a partial list cGMP Markets: Capabilities: of the Pharmaceutical Technology brand editorial advisory members. The full board, which includes advisory $3,¶V 0LFURQL]DWLRQ members from Pharmaceutical Technology Europe, can be found online at PharmTech.com/EAB. ([FLSLHQWV 0LOOLQJ &RQWUROOHG 3RZGHU&ODVVL¿FDWLRQ 6XEVWDQFHV 3DUWLFOH6L]H James P. Agalloco R. Gary Hollenbeck, PhD Garnet E. Peck, PhD President, Chief Scientific Officer, Professor Emeritus of Industrial +LJKO\3RWHQW$3,¶V &KDUDFWHUL]DWLRQ Agalloco & Associates UPM Pharmaceuticals Pharmacy, Purdue University See us at AAPS, Larry L. Augsburger, PhD Ruey-ching (Richard) Hwang, PhD Wendy Saffell-Clemmer Booth 3841 www.powdersize.com Professor Emeritus Senior Director, Director, Research University of Maryland Pharmaceutical Sciences, BioPharma Solutions 3DFL¿F'ULYH_4XDNHUWRZQ3$ Pfizer Global R&D 3KRQH_)D[ David H. Bergstrom, PhD Gurvinder Singh Rekhi, PhD COO, NovaDel Pharma Inc. Mansoor A. Khan, PhD Department of Pharmaceutical and Director, FDA/CDER/DPQR Biomedical Sciences, Phil Borman The University of Georgia College QbD Lead & Data Management & Russell E. Madsen of Pharmacy Analysis Manager President, The Williamsburg GlaxoSmithKline Group, LLC Susan J. Schniepp Vice-President, Quality and Rory Budihandojo Heidi M. Mansour, PhD Regulatory Affairs, Allergy Director, Quality and EHS Audit, Professor, Laboratories, Inc Boehringer Ingelheim Shanghai College of Pharmacy, Pharmaceuticals Co. (China) University of Arizona–Tucson David R. Schoneker Director of Global Regulatory Affairs, Todd L. Cecil Jim Miller Colorcon Vice-President President, Compendial Science PharmSource Information Eric B. Sheinin, PhD United States Pharmacopeia Services Bio/Pharmaceutical President, Outsourcing Report Sheinin and Associates Metin Çelik, PhD Aloka Srinivasan President, Colin Minchom, PhD Principal Consultant, Pharmaceutical Technologies Vice-President, Particle Design PAREXEL International International (PTI) Hovione Heinz Sucker, PhD Zak T. Chowhan, PhD Christine Moore, PhD Professor Emeritus, Consultant, Pharmaceutical Deputy Director for Science and Pharmaceutical Institute, Development Policy, Office of New Drug Quality University of Bern Assessment, CDER, FDA Suggy S. Chrai, PhD Scott Sutton, PhD R. Christian Moreton, PhD President and CEO, Microbiology Network Chrai Associates, Inc. Vice-President, Pharmaceutical Sciences, Finnbrit Consulting Roger Dabbah, PhD Read board members’ Principal Consultant, Fernando J. Muzzio, PhD biographies online at Tri-Intersect Solutions Director, NSF Engineering PharmTech.com/eab. Research Center on Structured Tim Freeman Organic Particulate Systems, Managing Director, Dept. of Chemical and Biochemical FreemanTechnology Engineering, Rutgers University Sanjay Garg, PhD Moheb M. Nasr, PhD Professor, Vice-President, CMC Regulatory See us at AAPS, Pharmaceutical Sciences, Strategy, Global Regulatory Affairs, University of South Australia Booth 4527 GlaxoSmithKline

Pharmaceutical Technology’s eNewsletter Team: t
ePT, Editor Melanie Sena, [email protected] t
Sourcing and Management, Editor Patricia Van Arnum, [email protected] t
Equipment & Processing Report, Editor Jennifer Markarian, [email protected] t
Send product releases to [email protected] 4 Pharmaceutical Technology OCTOBER 2013 PharmTech.com For more than 30 years, VAI has pioneered the design and manufacture of hundreds of clean room solutions. t Cleanest wipe t Saturated wipes in the industry are made with WFI t Asepti-Fill® closed t Lot Specifi c fi lling system Documention t Laundered in Class 1 for all wipers t Laser cut sealed edges Quadruple Bagged using the ABCD Introduction System®

No other company off ers this broad a range of wipers…

STERI-PEROX® HYPO-CHLOR® DECON-Clean® ALCOH-Wipe® STEEL-BRIGHT® DAS-Wipe® WIPE Wipe Wipe Wipe

Dry cleaning wipe 70% USP IPA Saturated Saturated Sodium Removes residue Saturated with Stainless Steel Stainless Steel in Water for Hydrogen Hypochlorite Wipe from disinfecting DECON-AHOL® Cleaning wipe cleaning and Injection Peroxide Wipe agents WFI 70% USP lubricant wipe saturated wipe Isopropyl Alcohol

www.sterile.com 1-888-4-STERILE GETTING MORE VALUE OUT OF™ SALES MICRONIZATION Publisher Mike Tracey [email protected] As the world’s leading name Director of Sales Paul Milazzo [email protected] in micronization, Mid-West Sales Manager Irene Onesto [email protected] we’re helping Eastern Sales Manager Cheryl L. Wall [email protected] pharmaceutical companies European Sales Manager Chris Lawson [email protected] across the globe achieve their European Sales Manager Debbie Taylor-Higgins [email protected] challenging particle size European Sales Executive Christine Joinson [email protected] reduction requirements. Display, Web, Classified, and Recruitment Representative Tod McCloskey [email protected], /
FDA-inspected cGMP Executive Assistant Barbara Sefchick [email protected] facilities in the US and UK 485 Route One South, Building F, First Floor, Iselin, NJ 08830, USA /
Micronization, milling & classifying options Tel. 732.596.0276, Fax 732.647.1235 /
R&D to commercial quantities PharmTech.com /
Custom-designed containment capability Vice President Sales Russ Pratt [email protected] for highly potent compounds Sr. Production Manager Karen Lenzen /
Full-contract analytical lab for material International Licensing Maureen Cannon [email protected], characterization, release & stability tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255 testing, method validation & development Audience Development Manager Kristina Bildeaux [email protected] /
Humidity-controlled processing See us at AAPS, Booth 3523 www.microntech.com Joe Loggia, Chief Executive Officer Tom Florio, Chief Executive Officer Fashion Group, US +1 610-251-7400 Executive Vice-President Tom Ehardt, Executive Vice-President, Chief Administrative UK +44 (0)1322 425200 Officer & Chief Financial Officer Georgiann DeCenzo, Executive Vice-President Chris DeMoulin, Executive Vice-President Ron Wall, Executive Vice-President Rebecca Evangelou, Executive Vice-President, Business Systems Julie Molleston, Executive Vice-President, Human Resources Tracy Harris, Sr Vice-President Francis Heid, Vice- President, Media Operations Michael Bernstein, Vice-President, Legal J Vaughn, Vice-President, Electronic Information Technology

©2013 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 informa- PARTNERING FOR tion 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 SUCCESS 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. Contract development, manufacturing, and For uses beyond those listed above, please direct your written request to Permission Dept. fax 440.756.5255 or packaging since 1979 email: [email protected]. Advanstar Communications Inc. provides certain customer contact data (such as customers name, addresses, Liquid and Semi-solid Solid Manufacturing phone numbers, and e-mail addresses) to third parties who wish to promote relevant products, services, and other Manufacturing and Packaging and Packaging 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 s Creams, Gels & Ointment s Tablets & Core Tableting hours of 7:30 a.m. and 5 p.m. CST and a customer service representative will assist you in removing your name from Tube Filling s Capsules & Double Advanstar’s lists. Outside the US, please phone 218.740.6477. s Creams, Gels & Ointment Encapsulation Pharmaceutical Technology does not verify any claims or other information appearing in any of the advertise- Jars & Container Filling s Aqueous & Enteric Coating ments contained in the publication, and cannot take responsibility for any losses or other damages incurred by s Syrups, Liquid & Suspension s Cold & Thermoformed Blisters Bottling readers in reliance of such content. s Bottling s Plastic Ampoules Pharmaceutical Technology welcomes unsolicited articles, manuscripts, photographs, illustrations, and other materials but cannot be held responsible for their safekeeping or return. s Suppositories Single issues, back issues: Call toll-free 800.598.6008. Outside the US call 218.740.6480. Reprints of all articles in s In-house QC Testing this issue and past issues of this publication are available. Call 877-652-5295 ext. 121 or email bkolb@wrightsmedia. com. Outside US, UK, direct dial: 281-419-5725. Ext. 121. Direct mail lists: Contact Tamara Phillips, Marketing See us at AAPS, Booth 2805 Partnering for Success 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, www.confab.com | [email protected] | 1-888-826-6322 tel. 440.891.2742 or toll-free 800.225.4569 ext 2742, fax. 440.756.5255, [email protected]. To subscribe: Call toll-free 888.527.7008. Outside the U.S. call 218.740.6477.

6 Pharmaceutical Technology OCTOBER 2013 PharmTech.com DRAW ON EXCEPTIONAL FACILITIES

ABBVIE CONTRACT MANUFACTURING Biologics | Potent | Drug Product | APIs Prefi lled Syringe | Fermentation

If you had the opportunity to draw your ideal CMO, we’re confi dent your vision would look like AbbVie Contract Manufacturing. We have ten facilities across North America and Europe, including some of the world’s most technically advanced for their respective specialties. Partner with us and benefi t from a high degree of fl exibility, scale and wide-ranging capabilities.

Advance your project quickly and reliably. Contact AbbVie at +1 847 938 8524 or visit www.abbviecontractmfg.com

The prior Proprietary Pharmaceuticals business of Abbott Laboratories is now AbbVie. October 2013 Volume 37 Number 10 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 52 Tablet-Sticking Solutions Screening methods and predictive models address tenacious tablet-sticking problems. the cover Illustration by Dan Ward Images: Martin Botvidsson/Getty Images On FEATURES DEPARTMENTS/ ON PHARMTECH.COM

DRUG DELIVERY PRODUCTS Free eNewsletters Visit PharmTech.com/enews for: 60 Evaluating Strategies 18 Product Spotlight for Oral Absorption 96 Pharma Capsules t
ø
ePT: Weekly eNewsletter Enhancement keeps you current with industry Formulation scientists tackle the 98 AAPS 2013 Company Profiles news and business notes. challenges of improving drug absorption across the gastrointestinal membrane. 116 Industry Pipeline t
ø
Sourcing and Management: A monthly eNewsletter to help you TROUBLESHOOTING 120 Showcase/Marketplace maintain a healthy supply chain. 66 Helium Integrity Testing 125 Ad Index of Single-Use Vessels t
ø
Equipment & Processing Report: Monthly reports on cutting-edge Helium integrity testing can prevent failures in single-use bioprocessing vessels. techniques and technologies.

API SYNTHESIS & MANUFACTURING 70 Overcoming Challenges in Fluorine-Based Chemistry Recent advances seek to overcome the challenges of selective and late-stage insertion of fluorine into small molecules.

PEER-REVIEWED RESEARCH

ELEMENTAL IMPURITIES 82 A Risk-Based Approach to Monitoring Elemental Impurities in Leachable Studies The authors discuss a strategy for integrating the toxicological assessment of the elemental impurities found during extractable testing.

VISIBLE RESIDUE LIMITS 86 Ruggedness of Visible Residue Limits for Cleaning— Part III: Visible Residue Limits for Different Materials of Construction Risk of a cleaning failure due to visual failure for different materials of construction can be mitigated or eliminated using complementary cleaning validation studies.

Continued on page 10

PharmTech.com Helping people iswhatyoudobest.LetJubilant HollisterStiertakecare ofthedetailsgettingthere. Spokane, WA, USA • Montreal,Quebec, Canada•Roorkee, Uttarakhand, India•Salisbury, Maryland, USA Visit usatAAPS, Booth1218 Annabel doesn’t care doesn’t Annabel that her her that zero absences this school year. year. school this absences zero She doesn’t realize the the realize doesn’t She her mom smeared on that cat scratch scratch cat that on smeared mom her prevented an ugly infection. ugly an prevented And she doesn’t know that a special special a that know doesn’t she And imaging agent imaging Poppa’s cancer early so he could be be could he so early cancer Poppa’s here to see her off to third grade. third to off her see to here Full ServiceContractManufacturing Annabel doesn’t think about these these about think doesn’t Annabel Annabel is the daughter of a JHS employe JHS a of daughter the is Annabel things, but we do we but things, flu shot flu …Clin …Multiple DosageForms helped her have have her helped . ical toCommercial

helped find her her find helped Ointment, Cream&Liquid ointment ointment Capabilities Video scan QRcode

e

Solid Dosage • Non-Sterile Topicals & Liquids • Sterile Ophthalmics & Otics • Sterile Injectable Fill/Finish Continued from page 8 NEWS & ANALYSIS REGULATION &

GUEST EDITORIAL COMPLIANCE 12 Changing the US REGULATORY WATCH ASK THE EXPERT Dynamic of CROs 28 FDA Seeks 126 Ensuring Compliance External partnering Metrics to Define with Drug Accountability expands an organization’s Drug Quality Requirements capabilities and challenges. Manufacturing standards Kurt Lumsden, Director Client considered key to preventing Services at Perceptive Informatics, drug recalls and shortages. a subsidiary of PAREXEL, discusses CONVERSATION & COMMUNITY regulatory requirements for the drug accountability process. 14 Taking the Pulse of the Industry REGULATION & COMPLIANCE » Speeding imports » High hopes for malaria vaccine CONVERSATION & COMMUNITY » FTC continues campaign against brand-generic deals » Hitting the Headlines » China challenges FDA » Industry News and manufacturers » Readers Think That... » Harmonizing QbD filings On the Blog » » Industry expands third-world Pharmaceutical Technology is access to AIDS therapies selectively abstracted or indexed in: » Biological Sciences Database (Cambridge Scientific Abstracts) » Biotechnology and Bioengineering BIO FORUM INSIDE USP Database (Cambridge 20 Elucidating Biosimilars 36 USP Seeks Scientific Abstracts) Input on Standards » Business and Management Characterization Practices (RDSI) for Plastic Industry experts discuss the » Chemical Abstracts (CAS) importance of characterization studies Packaging Systems » Current Packaging Abstracts during biosimilars development USP seeks input from stakeholders » DECHEMA and related analytical methods. on new and revised standards to mitigate extractables and leachables » Derwent Biotechnology Abstracts (Derwent Information, Ltd.) in plastic packaging systems. » Excerpta Medica (Elsevier) PACKAGING FORUM » International Pharmaceutical Abstracts (ASHP) Maintaining QUALITY INSIGHTS 78 » Science Citation Index (Thomson) and Verifying 40 Tracking Quality in Pharmaceutical Technology is proud to the Cold Chain Drug Manufacturing be a member of DCAT, IPEC, and PDA. Tools and services A review of recent FDA enforcement provide thermal protection and activity of drug manufacturers reveals prove cold-chain compliance. issues with vial-filling, adequacy of quality- control/quality-assurance procedures, PHARMACEUTICAL TECHNOLOGY (Print ISSN: 1543-2521, particulate matter in inhalation powders Digital ISSN: 2150-7376) is published monthly, except two issues in June, by Advanstar Communications, Inc., 131 W. OUTSOURCING OUTLOOK and injectables, and drug labeling. First St., Duluth MN 55802-2065. Subscription rates: US and 92 The Expense possessions — 1 year (13 issues), $70; 2 years (26 issues), of Vision in $125. Canada and Mexico — 1 year, $95; 2 years, $145. All EMERGING MARKET REPORTS other countries 1 year, $135; 2 years, $250. International Outsourcing price includes air-expedited service. Single-copies (prepaid Practicality of implementation 44 Report from Myanmar only) — US, $8; outside the US, $10. Back issues (if available): should be a part of vision in the Foreign companies zero in on Myanmar US and possessions — $21; all other countries — $25. bio/pharmaceutical industry. with the hope of securing a foothold Include an additional $6.50 per order plus $2 per additional in its pharmaceutical market. 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 48 Report from Middle send address changes to Pharmaceutical Technology, PO East and North Africa Box 6188, Duluth, MN 55806-6188. PUBLICATIONS MAIL The pharmaceutical industry grows AGREEMENT NO. 40612608, Return Undeliverable Canadian despite conflict in the Middle East. Addresses to: IMEX Global Solutions, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian G.S.T. number: R-124213133RT001. Printed in the U.S.A.

PharmTech.com Your Power for Health

;HPSVY4HKL:VS\[PVUZ^P[O,_WLY[PZLHUKPassion

 0UQLJ[PVUTV\SKPUNMVYKPHNUVZ[PJZ  WOHYTHJL\[PJHSPUK\Z[Y`HUKTLKPJHSZLJ[VY

 7SHZ[PJSHI^HYLWSH[LZHUKZHTWSLJVSSLJ[PVU  Z`Z[LTZ

 *VH[PUN[LJOUVSVN` Z\YMHJL[YLH[TLU[Z

 >VYSK^PKLTHU\MHJ[\YPUN ^HYLOV\ZPUN

 8\HSP[`JLY[PÄJH[PVUHJJVYKPUN[V  +05,50:6 HUK+05,50:6 

.LYTHU`4HPUVMÄJL!.YLPULY)PV6UL.TI/PUMV'KLNIVJVTS(\Z[YPH!.YLPULY)PV6UL.TI/VMÄJL'H[NIVJVT )LSNP\T!.YLPULY)PV6UL)=)(:793PUMV'ILNIVJVTS)YHaPS!.YLPULY)PV6UL)YHZPSVMÄJL'IYNIVJVTS*OPUH!.YLPULY)PV6UL:\UZ*V3[KVMÄJL'JUNIVJVT -YHUJL!.YLPULY)PV6UL:(:PUMVZ'MYNIVJVTS1HWHU!.YLPULY)PV6UL*V3[KPUMV'QWNIVJVTS5L[OLYSHUKZ!.YLPULY)PV6UL)=PUMV'USNIVJVT <2!.YLPULY)PV6UL3[KPUMV'\RNIVJVTS<:(!.YLPULY)PV6UL5VY[O(TLYPJH0UJPUMV'\ZNIVJVT ^^^NIVJVTIPVZJPLUJL GUEST EDITORIAL

Changing the Dynamic of CROs PharmTech.com/forum IMAGES GREUEL/PHOTODISC/GETTY JORG

Anthony DeStefano External partnering expands an organization’s capabilities and challenges.

artnering is a crucial component to execute the broad range of studies, marketed products, the logic behind it of the development and commer- manufacturing, testing, distribution, applies to any external arrangement. Pcialization of any new drug prod- and marketing necessary to bring drugs Ultimately, the owner of the drug is re- uct or medical device. Partnering takes to market on their own. External stra- sponsible for assuring and demonstrat- many forms, from the formation of tegic partnering is important to large ing at any stage of development that internal teams to the development of companies as well, as they focus their the drug meets its quality standards external relationships needed to move in-house efforts on core capabilities and and is manufactured and tested to the drug discovery, development, or com- work with external resources to provide applicable cGMP standards. Written mercialization forward. much of the rest. agreements serve to assure that respon- Models for internal partnering have sibilities are clear, no crucial compo- evolved and improved over time as the nent falls through the cracks, and that groups that bring a drug from discovery External partnering procedures for dispute resolution are to market become better integrated and has evolved ... in place. effective teams. Achieving this integra- Through its educational and net- tion requires that the members of each to a model that working opportunities, the American group become effective and efficient at Association of Pharmaceutical Scien- their job and become familiar with the is much more tists (AAPS) plays an important role needs of the groups (internal or external) in partnering throughout the drug- with which they interact. Good intra- strategic. development and commercialization group execution combined with manag- process. Webinars, workshops, short ing inter-group interactions results in ef- This increase in external focus has courses, sessions at the annual meet- fective hand-offs and efficient processes. led to a changing dynamic and an in- ing and exposition, discussion- and External partnering has evolved in crease in the number of consultants focus-group interactions provide ven- scope over the past several years, ex- and contract research organizations ues for scientists to develop and hone panding from targeted, tactical out- (CROs). The roles of CROs have in their individual skills and to interact sourcing or insourcing designed to many cases expanded from provid- with individuals that are facing similar provide specific missing capacity or ing services for one part of the drug- work-related challenges. Networking at expertise, to a model that is much more development effort to, in the extreme, the annual meeting, regional meetings, strategic. For small companies, the need becoming full-service providers. and cross-group interactions with reg- for strategic partnering is clear, because Demonstration of the continuity of ulatory scientists, CRO members, and resources are not available for them systems and processes and adherence members representing their individual to cGMPs is typically straightforward technologies, provide venues to better for internal efforts but can be difficult understand the needs of other groups when dealing with external partners. and develop a broader understanding For post-market contract manufac- of the context in which one works. turing arrangements for drugs, FDA AAPS is committed to furthering its Anthony DeStefano, has issued a guidance outlining the educational and networking offerings PhD, is 2013 president of the American Association reasoning for, and the components of, and to working with its members to be of Pharmaceutical quality agreements for these arrange- a key resource in making partnering at Scientists (AAPS). ments. While this guidance applies to all levels more effective. PT

12 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Smarter from the start It’s a fact that early testing can make all the difference in the long run.

That’s why global pharma leaders are discovering BilcareOptima™ - the winning formula for faster speed-to-market and reduced packaging costs.

This unique service is available in multiple versions, depending on your specific needs. In just 4 – 6 weeks, our team of experts will perform sensitivity profiling to identify degradation causes and effects so that you can select the most affordable and effective packaging option before you move into validation testing.

Your competition might call that an unfair head start. We just call it BilcareOptima.

Call 302.416.0974 or email [email protected]

JÐlÚ4¬Ÿåܘ¬¨ÓÚaÚ.•JУJÚ.JbžJ˜¨Ú¨¨¬ëJܘ¬¨ÓÚaÚ4»vb˜JŸÜîÚ4¬Ÿåܘ¬¨Ó Delaware City, DE www.BilcareOptima.com PHARMA CONVERSATION & COMMUNITY

HEADLINES ON PHARMTECH.COM/NEWS READERS THINK THAT... t
"
GFEFSBM
KVEHF
IBT
BQQSPWFE
B
DPOTFOU
EFDSFF
PG
QFSNBOFOU
JOKVODUJPO
BHBJOTU
4IBNSPDL
.FEJDBM
4PMVUJPOT
(SPVQ
8IBU
BOUJDPVOUFSGFJUJOH
UPPMT
BSF
IBWJOH
UIF
NPTU
-FXJT
$FOUFS
0IJP
BOE
GPVS
PG
JUT
DPSQPSBUF
PGGJDFST
BOE
TJHOJGJDBOU
FGGFDU
PO
SFEVDJOH
UIF
OVNCFS
PG
DPVOUFSGFJU
FNQMPZFFT
GPS
DPOUJOVFE
ESVH
NBOVGBDUVSJOH
BOE
MBCFMJOH
QIBSNBDFVUJDBMT
JO
UIF
MFHBM
TVQQMZ
DIBJO WJPMBUJPOT
UIBU
SFTVMUFE
JO
UIF
EJTUSJCVUJPO
PG
NJTMBCFMFE
ESVHT
'%"
SFQPSUFE
4FWFSBM
WJPMBUJPOT
XFSF
GPVOE
BU
UIF
GBDJMJUZ
JODMVEJOH
GBJMVSF
CZ
UIF
RVBMJUZ
DPOUSPM
VOJU
UP
GVMMZ
GPMMPX
JUT
PXO
RVBMJUZ
DPOUSPM
QSPDFEVSFT
BOE
UP
FYBNJOF
QBDLBHFE
BOE
MBCFMFE
QSPEVDUT
UP
FOTVSF
DPSSFDU
MBCFMJOH
t
5IF
$PPSEJOBUJPO
(SPVQ
GPS
.VUVBM
3FDPHOJUJPO
BOE
%FDFOUSBMJTFE
1SPDFEVSFTo)VNBO
B
NFEJDJOFT
SFHVMBUPSZ
CPEZ
SFQSFTFOUJOH
UIF
&6
.FNCFS
4UBUFT
IBT
FOEPSTFE
UIF
SFDPNNFOEBUJPO
UP
TVTQFOE
UIF
NBSLFUJOH
BVUIPSJ[BUJPO
PG
/VNFUB
(&
CFDBVTF
PG
B
SJTL
PG
IZQFSNBHOFTBFNJB
/VNFUB
(&
XIJDI
JT
HJWFO
JOUP
B
WFJO
UP
QSFNBUVSF
CBCJFT
UP
QSPWJEF
OVUSJUJPOBM
TVQQPSU
XJMM
SFNBJO
TVTQFOEFE
VOUJM
B
SFGPSNVMBUFE
QSFQBSBUJPO
JT
NBEF
BWBJMBCMF 1BDLBHJOH
BOE
MBCFMJOH
BVUIFOUJDBUJPO
BOE
UBNQFS
FWJEFODF 6OJRVF
ESVHQSPEVDU
EFTJHO
PS
BVUIFOUJDBUJPO
QSJOUFE
EJSFDUMZ
PO
B t
5IF
$FOUFST
GPS
%JTFBTF
$POUSPM
$%$
BOE
1SFWFOUJPO







TPMJEEPTBHF
QSPEVDU SFMFBTFE
B
SFQPSU
"OUJCJPUJD
3FTJTUBODF
5ISFBUT
JO
UIF
4PDJBM
NFEJB
BOE
JNQSPWFE
DPOTVNFS
FEVDBUJPO 6OJUFE
4UBUFT

XIJDI
QSFTFOUT
B
TOBQTIPU
PG
UIF
*ODSFBTFE
SFHVMBUJPO
BOE
FOGPSDFNFOU CVSEFO
BOE
UISFBUT
QPTFE
CZ
BOUJCJPUJDSFTJTUBOU
HFSNT
IBWJOH
UIF
NPTU
JNQBDU
PO
IVNBO
IFBMUI
UIF
$%$
7JFX
NPSF
QPMM
SFTVMUT
BU
www.pharmtech.com/polls BOOPVODFE
"DDPSEJOH
UP
UIF
SFQPSU
NPSF
UIBO
UXP
NJMMJPO
QFPQMF
JO
UIF
64
FBDI
ZFBS
HFU
JOGFDUJPOT
UIBU
BSF
SFTJTUBOU
INDUSTRY NEWS UP
BOUJCJPUJDT
BOE
BU
MFBTU
 
QFPQMF
EJF
BT
B
SFTVMU t
"FTJDB
1IBSNBDFVUJDBMT
B
$%.0
TQFDJBMJ[JOH
JO
t
5IF
#JPNBOVGBDUVSJOH
3FTFBSDI
1SPHSBN
BU
.BTTBDIVTFUUT
GPSNVMBUFE
QSPEVDUT
BOE
"1*T
IBT
CVJMU
B
OFX
IJHI *OTUJUVUF
PG
5FDIOPMPHZ
IBT
SFDFJWFE

.JMMJPO
GSPN
UIF
DBQBDJUZ
NBOVGBDUVSJOH
GBDJMJUZ
BU
JUT
6,
TJUF
JO
%FGFOTF
"EWBODFE
3FTFBSDI
1SPKFDUT
"HFODZ
%"31"
UP
2VFFOCPSPVHI
,FOU
5IF
DPNQBOZ
JOWFTUFE
b
EFWFMPQ
OFX
UFDIOPMPHJFT
BOE
NBOVGBDUVSJOH
QMBUGPSNT
NJMMJPO
UPXBSET
UIF
 
N
FYQBOTJPO
PG
UIF
OFX
UIBU
XJMM
QSPWJEF
BO
FNFSHFODZ
TVQQMZ
PG
NFEJDJOFT
GPS
GBDJMJUZ
XIJDI
IBT
CFFO
DPOTUSVDUFE
TQFDJGJDBMMZ
GSPOUMJOF
NJMJUBSZ
NFEJDT
5IJT
QSPKFDU
JT
QBSU
PG
%"31"T
GPS
UIF
QSPEVDUJPO
PG
TPMJEEPTF
NFEJDBUJPOT
#JPMPHJDBMMZEFSJWFE
.FEJDJOFT
PO
%FNBOE
QSPHSBN
VTFE
JO
UIF
USFBUNFOU
PG
UZQF
**
EJBCFUFT XIJDI
BJNT
UP
NBOVGBDUVSF
CJPMPHJD
ESVHT
PO
EFNBOE
JO
B
GPSXBSE
PQFSBUJPOT
TFUUJOH
XIFSF
SFTPVSDFT
BSF
PGUFO
t
5IFPSFN
$MJOJDBM
3FTFBSDI
IBT
GPSNFE
BO
BMMJBODF
MJNJUFE
BOE
NBLF
UIFTF
ESVHT
BWBJMBCMF
JO

IPVST
XJUI
$IBSMFT
3JWFS
-BCPSBUPSJFT
UIBU
XJMM
QSPWJEF
DMJFOUT
XJUI
BO
JOUFHSBUFE
TPMVUJPO
GSPN
OPODMJOJDBM
UFTUJOH
BOE
BOBMZTJT
UISPVHI
DMJOJDBM
EFWFMPQNFOU
BOE
Join our online community SFHJTUSBUJPO
5IF
OFX
BMMJBODF
QSPWJEFT
OPODMJOJDBM
UFTUJOH
XXX1IBSN5FDIDPN-JOLFE*O QSPHSBNT
JO
UIF
BSFBT
PG
CJPBOBMZTJT
JNNVOPHFOJDJUZ
XXXQIBSNUFDIDPNUXJUUFS BOE
JNNVOPMPHZ
UP
TVQQPSU
DMJOJDBM
USJBMT

14 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Deep roots. Steady growth. *
&
/')+ *
%
+ %&#&0
+)%*)*
%
%
/'% %
)%
&
-)+ ##0 %+)+
*&#,+ &%*
)
!,*+
*&$
&
+ 
)*&%*
. 0
 )$

%,*+) *
*
&%* *+%+#0
 &*%
*


#&%+)$
*+)+ 
')+%)
)&$
*,''#0
  %
$%$%+
%
&)$,#+ &%
+&
),#+&)0
&$'# %
%
(,# +0
&%+)&#
.
&)
* %#*&,)
*&#,+ &%*
0&,
%
+),*+
#,*
*
+ 
.&)#
#)
%
' )$*
'&.)
')&,+*

*

* %,#)
&,*
&%
)&.+ yours.

&%+)+ ) $)0
% ,*+&$ %,+,) % &%)0
" % &# %

&.) '*,# #++ % &++# % % +
&* # *+) '*
%  # ,*+&$ #% %  ## % "* #&*,)* - * &++#*

  
1
...' )$+ &$ &0*+&%
&) 
1
% &%
 **&,) PHARMA CONVERSATION & COMMUNITY

ON THE BLOG

,FZ
JTTVFT
BSF
XIFUIFS
NPSF
TQFDJBMJ[BUJPO
.BOZ
CFMJFWF
UIBU
UIF
CSJCFSZ
TDBOEBM
“JO
'%"
JOTQFDUJPO
BOE
DPNQMJBODF
GVODUJPOT
“JOWPMWJOH
#JH
1IBSNB
JT
KVTU
UIF
UJQ
PG
UIF
XPVME
CF
CFOFGJDJBM
BOE
IPX
SJTLCBTFE
JDFCFSH
UP
UIF
NBOZ
QSPCMFNT
JO
$IJOB NPEFMT
BOE
QFSGPSNBODF
NFUSJDT
NBZ
JNQSPWF
Adeline Siew ” PWFSTJHIU
BOE
DPNQMJBODF
PVUDPNFT The Truth Behind China Bribery Scandals Jill Wechsler ” FDA CDER Weighs Organizational Changes See more posts at blog.PharmTech.com

EVENTS

Validation Week 0DUPCFS

 4BO
%JFHP
$"
64" XXXDCJOFUDPN

CPhI Worldwide 0DUPCFS

 'SBOLGVSU
(FSNBOZ XXXDQIJDPN

ISPE 2013 Annual Meeting /PWFNCFS

 8BTIJOHUPO
%$
64" XXXJTQFSHBOOVBMNFFUJOH

AAPS Annual Meeting /PWFNCFS

 4BO
"OUPOJP
$"
64" XXXBBQTPSH

LINKEDIN DISCUSSION POINTS

t

8IBU
BEWBODFT
EP
ZPV
XJTI
UP
TFF
JO
TJOHMFVTF
UFDIOPMPHZ
UP
JNQSPWF
UIF
QFSGPSNBODFT
PG
CJPQIBSNBDFVUJDBM
NBOVGBDUVSJOH
QSPDFTTFT

t

8JUI
UIF
JODSFBTF
JO
TJOHMFVTF
WFTTFMT
JEFOUJGZJOH
EFGFDUT
FH
IPMFT
PS
MFBLT
BU
KPJOUT
JT
CFDPNJOH
FWFO
NPSF
JNQPSUBOU
8IBU
NFUIPE
BSF
ZPV
VTJOH
UP
UFTU
UIF
JOUFHSJUZ
PG
TJOHMFVTF
TZTUFNT

Join the discussion at www.PharmTech.com/LinkedIn

16 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Your Resource for: Aseptic Fill/Finish Biologics Fermentation Clinical & Commercial Lyo Cycle Development

Realizing Quality of Life in NEW SERVICE! Every Single Dose.

For over 30 years CANGENE bioPharma has successfully entered into cooperative arrangements to produce over 20 commercial and 200 clinical products for customers in more than 43 countries. Our record of regulatory compliance with strict US, EU and Japanese guidelines means CANGENE bioPharma is the right partner to help you take your product from clinical trial to commercial production.

To ramp up your production capabilities quickly, contact CANGENE bioPharma today, your complete fill to finish solutions provider.

1-800-441-4225 [email protected] www.cangenebiopharma.com PRODUCT SPOTLIGHT: ANALYTICAL INSTRUMENTATION

Editors’ Picks of Pharmaceutical Science & Technology Innovations THE LATEST IN ANALY TICAL INSTRUMENTATION

busyRheocalcT LCMS-8050 Mass Software Tests Spectrometer Parameters and Increases Quality Data Collection Analysis

RheocalcT The LCMS-8050 Software allows triple quadrupole the operator to mass spectrometer automate viscosity can perform both positive and negative ion analysis in a single run testing from a PC for faster throughput. The LCMS-8050 achieves high sensitivity when using the DV3T Touch Screen Rheometer and the DV2T Touch through a patented ion optics system, a designed heated ESI probe, Screen Viscometer. The user interface for RheocalcT has a range of and UFsweeper III Collision Cell. The LCMS-8050 offers multiple choices for test method creation and data gathering/analysis. Loop reaction monitoring (MRM) speeds of 555 ch/sec and maintains functions allow performance of repetitive tasks on test samples that spectrum quality, sensitivity, and accuracy at scan speeds up to require viscosity measurement at multiple rotational speeds, different 30,000 μ/sec. The Synchronized Survey Scan function allows users temperature set points, and discreet time intervals. Viscosity data to obtain MRM data while simultaneously performing qualitative averaging is possible for individual tasks within a test step or over MS/MS scans. The LCMS-8050 provides 5-millisecond polarity multiple steps in the total test program. Advanced data analysis to switching and maintains ion intensity during polarity switching assess yield stress and pseudo plastic index can be performed with a at high speeds. The ion source features a cable-free, tubeless choice of math models: Bingham, Casson, NCA/CMA Casson, Power housing when switching from ESI to APCI or dual-ionization mode. Law, IPC Paste, and Herschel-Bulkley. Shimadzu Scientific Instruments Brookfield Engineering www.ssi.shimadzu.com www.brookfieldengineering.com

Video Capture and Software Improves Synchronisation Monitoring of System Pharmaceutical Ingredients A video system provides texture analysis data Dissolution and analysis capabilities Workstation Software for pharmaceutical provides updated data and supplement integration, method manufacturers. change control, and The Video Capture instrument monitoring and Synchronisation System can record tests and replay them for controlling multiple dissolution systems. The software supports frame by frame simultaneously with their corresponding force- laboratory capabilities to build, edit, search, retrieve, execute, distance-time graphs. The system includes a moveable video and archive all dissolution methods and test reports from a single camera, a transparent test platform, and an optional light interface. The software consolidates and maintains electronic data in attachment. To conduct a test, the camera is positioned in one location, with options for exporting information into a laboratory the most appropriate location for testing. As the TA.XT plus information management system or into business tools such as SAP texture analyser begins collecting data, a signal is relayed to Crystal Reports or Microsoft Excel. Dissolution Workstation Software the Video Capture Interface, which initiates recording at up organizes, executes, and manages methods and information for to 50 frames per second. Data is collected and analyzed by all Agilent dissolution equipment, including the Agilent 708-DS, Exponent Stable Micro Systems’ proprietary software. 709-DS, BIO-DIS, Apparatus 7, and dissolution sampling systems.

Stable Micro Systems Agilent Technologies www.stablemicrosystems.com www.agilent.com

18 Pharmaceutical Technology OCTOBER 2013 PharmTech.com

BIO FORUM

Elucidating Biosimilars IMAGE: STOCKBYTE/GETTY IMAGES IMAGE: Characterization PharmTech.com/bioforum Industry experts discuss the importance of characterization studies during biosimilars development and related analytical methods. he global market for biosimilar Early Clinical Development, Phar- cines are of very high molecular weight drugs has been forecasted to be macokinetic/Pharmacodynamic; and and complex structures depending on T$2.445 billion in 2013 according to John Patava, PhD, director, head of bi- the product. Biological molecules are a report by the British market-research osimilar intelligence and capabilities, also manufactured by processes involv- firm, Visiongain (1). The growth cor- ing living organisms, such as genetically responds to a 20% increase from last engineered bacteria, yeast, or mamma- year’s figures and accounts for ap- Biosimilar lian cells, and although these processes proximately 2% of the overall biologics medicines should can be well-defined, they are subject to market. Although narrowly focused on the variability inherent in living sys- only a small number of therapy areas never be assumed tems. The active ingredient for biolog- at present, the biosimilars market is ics can only be considered similar, not set to expand over the next decade to be exact copies identical. and beyond as a result of two major Proteins produced in different factors: the impending patent expi- of the originator mammalian cell lines, or under differ- ries on blockbuster biologics and the ent environmental conditions, may be financial environment that is driving molecule. expressed with subtle but important payers to push for wider adoption of differences with respect to character- biosimilars to manage the escalat- —Quintiles istics such as glycosylation. For this ing costs of healthcare. While many reason, biosimilar medicines should companies are keen on getting a share all at Quintiles (collectively referred to never be assumed to be exact copies of in the biosimilars market, bringing as Quintiles thereafter) about the im- the originator molecule. In recognition these complex molecules from bench portance of characterization studies of this inherent variability, regulators to launch can be a challenge, not just during biosimilars development and have determined that a unique pathway during the development stage but also related analytical methods. is required for the testing and registra- in terms of the manufacturing process tion of biosimilar medicines. involved. The complex nature of biosimilars NIBRT: Differences regarding the ap- Pharmaceutical Technology spoke PharmTech: Why are biosimilars proval process for small molecules as with Jonathan Bones, principal in- not considered identical to their compared to recombinant protein ther- vestigator at Ireland’s National Insti- original biologic products? apeutics are reflected in the complexity tute for Bioprocessing Research and Quintiles: Biosimilars are not ap- that must be considered when compar- Training (NIBRT); Reg Shaw, PhD, proved using the same pathway as ge- ing small-molecule APIs with biolog- CEO of NIBRT (collectively referred neric medicines because of the sheer size ics, molecules that are often many to as NIBRT thereafter); Kamali and complexity of the molecules that orders of magnitude larger. For ex- Chance, PhD, head of global biosimi- make up biological medicines. Generic ample, the cholesterol-lowering agent lars regulatory strategy, Biosimilars medicines are copies of relatively small, atorvastatin has a chemical formula of

Strategic Unit; Colin Vose, PhD, vice- well-characterized molecules with low C 33H35FN2O5 and a molecular weight of president, Centre for Integrated Drug molecular weights produced using well- 558.64 g/mol. Compare this compound Development; Doris Weilert, PhD, defined processes involving chemical with the monoclonal antibody trastu- senior research pharmacokineticist, synthesis. As such, the active ingredient zumab, which has a reported chemi-

of generic copies and the original medi- cal formula of C 6470H10012N1726O2013S 42 and a Adeline Siew, PhD, is scientific editor of cines are for all intents and purposes, molecular weight of 145531.50 g/mol, Pharmaceutical Technology. identical. In contrast, biosimilar medi- approximately 260 times the size of

20 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Ceolus™ UF’s extraordinary compactibility and flow allow formulation and tablet efficiency to take flight... CEOLUSTM Microcrystalline Cellulose USP/NF, EP, JP

Their unique morphology gives the Ceolus UF microcrystalline cellulose Together we can make your grades an unparalleled combination of compactibility and flow. Formulating formulation take flight... with Ceolus UF delivers smaller, harder, more efficient tablets than you ever thought possible.

Ceolus UF-711 – for direct compression of poorly ASAHI KASEI AMERICA, INC. compactible, high-dose actives using gravity feeding. 535 Madison Avenue, 33rd Floor New York, NY 10022, USA Ceolus UF-702 – for the greatest flow improvement P (855) 4-CEOLUS and remarkable tablet hardness via direct compression www.ceolus.com [email protected] Visit us at AAPS, Booth 633 Bio Forum the small molecule API and ultimately As companies generating biosimi- The importance of characterization more structurally complex. lar molecules do not have access to the PharmTech: Why is it important to Because we’re dealing with rela- intellectual property regarding the in- characterize amino-acid sequence and tively simple chemical species when novators’ manufacturing process, the carbohydrate structure? we consider small-molecule API ge- process for generating the biosimilar NIBRT: Characterization of the nerics, the approval process has been molecule will have, by nature, inher- amino-acid sequence—normally using tried and tested effectively over recent ent differences. Therefore, it is inap- LC–MS-based approaches, either top- decades and is now well established. propriate to say that two molecules down or peptide-centric bottom-up Rather than requiring full clinical are identical; substantive analytical, methods—is important to verify that trials, generic drug manufacturers biochemical, and if necessary, clinical the product produced is that as ex- are requested to demonstrate phar- comparison between the biosimilar pected from the engineered gene se- maceutical equivalence to show that and the innovator molecules will have quence. Data from such experiments their medicine contains the same ac- to be demonstrated. facilitate the determination and com- tive pharmaceutical ingredient at the parison of the experimental versus the same purity and same dose and with Bioequivalence testing predicted mass of the product. De- the same administration route as the PharmTech: Can you explain the proce- viations are indicative of post-trans- innovator product. dures for testing the bioequivalence of lational or other modifications. Such Application of the same approval ap- biosimilars and how it differs from bio- modifications, if present, can then be proach for large biological therapeutics equivalence testing for generic drugs? localized when using peptide-centric is not so straightforward due to the com- Quintiles: The principles of pharma- LC–MS methods, or sequence variants plexity of these large structurally com- cokinetic bioequivalence testing for can also be verified at the peptide level. plicated molecules. Despite advances in proteins are essentially very similar to Data from such studies can then be analytical chemistry and instrumenta- those for classical medicinal-chemistry used to evaluate whether the presence tion, the direct assessment of compa- small-molecule products and are based of a particular modification is impor- rability from analytical data is limited. on a comparison of peak concentra- tant with regard to the structure–func- Using liquid chromatography–mass tion, time-to-peak concentration, area tion relationship of the molecule, or spectrometry (LC–MS) methods, we can under the concentration–time curve; whether for safety or efficacy purposes, determine and confirm the primary se- however, depending on the mechanism it may be necessary to engineer out the quence, the presence and identity of post- of action of the protein, such a study modified amino acid. translational modifications and perform may need to be done in patients. Al- Similarly for carbohydrates, charac- protein structural analysis using ad- though it may be possible to carry out terization of the glycosylation present vanced experiments such as hydrogen– such a study in healthy volunteers, the with regard to monosaccharide analysis deuterium exchange MS. Comparison of products are “foreign” proteins that and structural characterization of the N- analytical data forms the case for proving may produce an immune response and O-linked oligosaccharides present whether two molecules are structurally on repeated administration. In ad- is important to ensure that the desired similar or not; however, data from cell- dition, some proteins, for example, glycosylation is present and that poten- based potency and bioequivalence assays monoclonal antibodies, have half- tially immunogenic epitopes are absent. will also be required. Ultimately, it will lives of weeks. These proteins would, Characterization of the glycosyl- be up to the regulatory agency to decide, therefore, require sample collection ation present on recombinant proteins based upon the presented evidence, for many weeks to accurately define is particularly important as the glycans whether a biosimlar candidate is similar the pharmacokinetics and a washout attached to the molecule can modulate enough to be approved. period of some months between treat- the stability and ability of the molecule The inherent analytical complexity ments with the originator product and to elicit its desired effector response, arises from the fact that recombinant biosimilar. Thus, a classical random- particularly in the case of monoclonal proteins are expressed in cellular sys- ized crossover design as used for small antibodies (1). Because glycosylation tems under defined bioprocess condi- molecules is not appropriate on safety is cell-line specific and also affected tions rather than using stepwise chem- and logistics grounds. Such studies, by the environmental conditions that ical synthesis. The cellular machinery therefore, are most likely to use a par- a cell finds itself in, it is necessary to that expresses the recombinant protein allel-group design, in which each sub- routinely characterize the oligosaccha- is sensitive to the physiochemical envi- ject only receives one of the products rides present to make sure that the ex- ronment of the cell, the availability of being compared. Such an approach pressed protein is being produced with nutrients, and removal of toxicants and increases the variability and thus, the consistent and reproducible glycosyl- inhibitory compounds. All of these fac- number of subjects needed to achieve ation. Furthermore, characterization of tors can affect the quality and quantity the required power to demonstrate the glycosylation present is important of the expressed protein. pharmacokinetic bioequivalence. to verify the presence or the absence

22 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Chemic Laboratories, Inc.

Who We Are Services Offered Chemic Laboratories, Inc. is a full service cGMP/GLP contract analytical Chemic Laboratories, Inc. offers a chemistry laboratory. Chemic provides an array of R&D and cGMP wide array of cGMP/GLP contract contract testing services including; Extractables/Leachables analysis, testing services including: CMC Method Development & Validation, Quality Control analysis, Release testing, Raw Materials analysis, Compendial testing, Bioanalysis, • Quality Control Testing Organic Synthesis/Formulation Development & ICH Stability testing. of raw materials, API’s Chemic continually strives to exceed the requirements and expectations and finished products of our sponsors. We are committed to providing quality services • Monograph Testing to our clients in support of their product development needs. (USP, EP, BP and JP) • CMC Method Development Major Markets & Validation Chemic Laboratories, Inc. is located in Canton, Massachusetts • Degradate Quantitation and provides cost-effective outsourcing solutions to a broad • Extractables and spectrum of global clients in the pharmaceutical, medical device and Leachables Analysis biopharmaceutical industries. We are committed to developing long • Container Closure Assessment term strategic alliances with our clients. Chemic offers the ideal blend of expertise and experience that is critical to our clients’ success. • ICH Storage and Accelerated Stability Studies • Bioanalytical Services 480 Neponset Street, Building 7, Canton, MA 02021 • GLP Method Development Tel. 781-821-5600 and Validation Fax 781-821-5651 • Organic Synthesis and www.chemiclabs.com Formulation Development Visit us at AAPS, Booth 3243 Bio Forum of potentially immunogenic epitopes that facilitate the deduction of linkage using currently available analytical such as galactose-_1–3-linked galac- and positional analysis of the oligosac- techniques. This means that confirm- tose motifs and the nonhuman mono- charides. There have also been signifi- ing similarity of two proteins requires saccharide N-glycolyl neuraminic acid. cant advances in associated informat- the use of a wide range of analytical Characterization of glycosylation is ics platforms for the annotation of both techniques. still a significant analytical challenge LC and MS data in recent years. Functional binding of molecules can although recent advances in analyti- Furthermore, the issues of glycan be tested using microarray analysis. cal instrumentation and separation micro- and macroheterogeneity must This technique enables the biosimilar chemistries have benefited the field also be considered. Performing a global developer to test the binding of the considerably. Glycans are tradition- glycosylation screen informs us of the protein to a large number of targets ally analyzed using either liquid-phase identity and relative abundance of the to determine binding and eliminate separation techniques such as liquid types of oligosaccharides attached to potential cross reactivity. In many chromatography or capillary electro- the molecule. However, combination cases, this functional binding may phoresis with optical or fluorescence with glycoproteomics is often neces- be adequate if the effect of the medi- detection or mass spectrometry. As oli- sary to identify the sub-populations of cine is simply to neutralize its target. gosaccharides lack inherent chromo- glycans present at each glycosylation Where the protein-based medicine acts phores or fluorophores, they must be site. through some cellular signaling path- way, there are tools for assessing these Ion-mobility spectrometry–mass modes of action such as cell-based ki- nase assays. spectrometry is emerging as a new and Tools for characterization powerful technology. —NIBRT PharmTech:What techniques are used to compare the structure of biosimilars derivatized to facilitate detection, fluo- The combination of analytical tech- and biologics? rescent reagents, such as 2-amino-ben- niques in an orthogonal manner is rec- NIBRT: LC–MS is an extremely valu- zamide, 2-aminobenzoic acid, 2-ami- ommended to impart confidence to the able tool for the analysis of biosimi- nopyridie or 2-aminoacridone, have analytical data. It is not recommended lars and biologics due to its ability to been widely reported as derivatiza- to analyze the glycosylation using a sig- separate many components in complex tion reagents used in glycan analysis. nal technique; generally, a minimum of mixtures and determine the mass of When using capillary electrophore- two approaches is recommended. those components in both a qualita- sis, charged fluorescent labels such as Quintiles: The amino-acid sequence tive and quantitative manner. LC–MS 1-aminopyrene-3,6,8-trisulfonic acid of a biosimilar molecule is one of the is routinely used for the characteriza- (APTS) or 8-aminonaphthalene-1,3,6- starting points in determining simi- tion of biologics using top-down ap- trisulfonic acid (ANTS) are used to larity to the originator medicine, with proaches wherein the intact mass of impart electrophoretic mobility to the the draft guidance from FDA imply- the molecule is determined, middle- labeled oligosaccharides and also to ing that a biosimilar molecule needs down approaches wherein subunits facilitate highly sensitive laser induced to have the same amino-acid sequence or domains of the molecule are sepa- fluorescence detection. as the originator medicine. Some pro- rated and independently analyzed, Mass spectrometry (MS) has also teins, such as monoclonal antibodies, and bottom-up approaches following been widely used for glycan analysis, are glycosylated (i.e., they have carbo- digestion of the therapeutic protein either using matrix-assisted laser- hydrate molecules attached to them). into its constituent peptides through desorption ionization (MALDI) or The extent and the exact structure of the action of a suitable protease. Such electrospray ionization (ESI). A caveat carbohydrates attached to a protein approaches facilitate verification of with the use of MS is its inability to may affect its binding to its target re- the primary sequence of the molecule, distinguish isobaric monosaccharide ceptor, its clearance from the body, identification and characterization of residues or isomeric oligosaccharides; and potentially, its immunogenicity. post-translation modifications, espe- therefore, it is more a compositional The manufacturing process (e.g., cell cially wherein the combined use of analysis. MS/MS based methods can line used) can influence the exact na- collisional-induced dissociation (CID) facilitate glycan sequencing when per- ture and extent of glycosylation of the and/or electron-transfer dissociation formed on [M+H]+ ions formed during protein, and thus potentially, its ac- (ETD) fragmentation strategies are positive ionization. MS/MS of [M-H]- tivity and safety. It is not possible to employed. As mentioned previously, ions formed when using negative ion- definitively determine the structure of LC, MS, and LC–MS approaches are ization is considerably more informa- a large protein, such as a monoclonal widely used for the characterization of tive as it can provide diagnostic ions antibody of approximately 150,000 Da, the glycosylation present.

24 Pharmaceutical Technology OCTOBER 2013 PharmTech.com the sky’s the limit

Whether it’s one small test for man or one giant drug development project for mankind, our breadth of testing capabilities and regulatory expertise support your most challenging product launch. From discovery to market, Bio/ Pharmaceutical firms are over the moon with our results. Together, there’s no limit to what we can do.

www.LancasterLabsPharm.com

Winner of the 2012 CRO Leadership Award for quality, regulatory, reliability, productivity and innovation.

Leading experts in: Global Services: Chemistry Molecular & Method Development/Optimization Raw Materials Testing Cell Line Characterization Cell Biology Validation/Qualification/Transfer Impurities & Residuals Testing Viral Clearance Biochemistry Virology Product Release Testing Characterization Bioassays Microbiology Stability Storage & Testing Cell Banking Professional Scientific StaffingSM Bio Forum

The combination of generated data All of the aforementioned methods equate patient exposure to the biosimi- from the analysis of the primary se- provide information regarding the lar medicine beyond the initial efficacy quence with additional analytical plat- molecules structural similarity; how- testing phase. forms is often required to provide an ever, to determine similarity of func- insight into the impact of alterations tion or efficacious effect bioequiva- Defining biosimilarity in the primary sequence or post-trans- lence assays must be performed. PharmTech: How do you define ‘simi- lation modifications on the secondary, lar’ when comparing a biosimilar with tertiary, or quaternary structure of the Safety considerations a reference product, given there will be protein. Traditional techniques such PharmTech: What are the safety issues differences caused by the manufactur- as X-ray crystallography and nuclear that must be considered when develop- ing process? magnetic resonance (NMR) spectro- ing a biosimilar product? NIBRT: The definition of similarity is scopy can be used for protein structure Quintiles: The most significant con- complicated by nature of the fact that determination; however, the applica- cern, from a safety perspective, with biologic products are expressed in living tion to comparability studies can be biosimilar medicines, is the risk of elic- expression systems and differences re- complicated. Other methods for study- iting an inappropriate immunogenic garding the manufacturing processes, be ing higher order protein structure such response. It is difficult to predict, based it cell lines used, media used, differences as calorimetric methods, analytical ul- on in-vitro characterization alone, in downstream processing or process- tracentrifugation, circular dichroism, whether a biosimilar product will be ing between the innovator and the bi- and fluorescence are capable of pro- more or less immunogenic than the osimilar process will undoubtedly exist. viding information regarding overall originator molecule. In-vivo studies Furthermore, there is currently a lack of alterations or differences in the protein in animal models are also not particu- appropriate reference standard material structure, but generally, are incapable larly useful for determining immuno- for the development of analytical meth- of localizing the area within the se- genicity of a protein in humans. This is ods for the evaluation of comparability quence of structural difference. Newer especially so for recombinant human and similarity. While batches of drug methods such as hydrogen–deuterium proteins, or ‘humanized’ antibodies product are often used, it should be con- exchange (HDX) MS are valuable tools (antibodies that have a significant part sidered that the formulation of the drug for detecting small changes in specific of their protein amino-acid sequence product may interfere in the subsequent regions of the protein structure. HDX– from human origin), as they are highly comparability/similarity study and at- MS is also more sensitive that other immunogenic in most animal models. tempts to deformulate the drug product technologies requiring much smaller For this reason also, animal models are may unknowingly introduce modifica- sample amounts and is also automated. not particularly useful in determining tions into the molecule, which compli- Ion-mobility spectrometry–mass pharmacokinetics of biosimilar medi- cates the study from the offset. It is inap- spectrometry is also emerging as a cines because the immune response propriate to say that two molecules are new and powerful technology to allow they stimulate accelerates their clear- identical due to the inherent complexity for the elucidation of protein structure ance from the animal. of the manufacturing process. Indeed, it based upon comparison of the mole- Pharmacokinetic profile and safety has been demonstrated that measureable cules collisional cross-sectional (CCS) testing of a biosimilar medicine, with differences exist between different lots area in the gas phase. If the overall the knowledge that this product has of an innovator product (3). The terms protein structure, say between inno- been well-characterized and deter- comparable, similar, and highly simi- vator and biosimilar, is different, the mined to be highly similar to the origi- lar require definition by the regulatory molecules may have differences in drift nator medicine, needs to be conducted authorities. Analytical chemistry gener- time and associated CCS value, which in humans. As a starting point to these ates the data that forms or backs up the may be indicative of a conformational studies, it should be understood that argument regarding comparability or change between the molecules. most biological medicines will lead similarity; however, it will always be the With regard to aggregation analy- to an immunogenic response in some decision of the regulators as to whether sis, size-exclusion chromatography patients. Immunogenicity rates of be- they believe the data are sufficient to jus- (SEC), often with multi-angle light- tween less than 1% to more than 20% tify such claims. scattering detection, is widely used for have been reported for human proteins the determination of aggregates. Other and humanized therapeutic monoclo- References methods employed include asymmetric nal antibodies (2). Therefore, clinical 1. F. Nimmerjahn and J.V. Ravetch, Nat Rev flow field flow fractionation (A4F) or studies need to be designed to show, Immunol 8 (1) 34-47 (2008). 2. FDA, “Prescribing Information,” www. analytical ultracentrifugation (AUC), not only the similarity in efficacy of accessdata.fda.gov/scripts/cder/drug- often as an orthogonal technique to the biosimilar medicine to the origina- satfda/index.cfm, accessed Aug. 10, 2013. SEC to increase overall analytical con- tor, but also its immunological profile. 3. M. Schiestl et al., Nat Biotechnol, 29 (4) fidence and interpretation. This assessment is done by ensuring ad- 310-312 (2011). PT

26 Pharmaceutical Technology OCTOBER 2013 PharmTech.com

REGULATORY ROUNDUP

Speeding imports NBOVGBDUVSFST
JU
BMTP
JT
EFMBZJOH
FGGPSUT
CZ
'%"
UP
JODSFBTF
'%"
JT
JNQMFNFOUJOH
JUT
MPOHEJTDVTTFE
4FDVSF
4VQQMZ
$IBJO
JOTQFDUJPOT
BOE
SFHVMBUPSZ
BDUJWJUJFT
JO
UIBU
DPVOUSZ
'%"
44$
JOJUJBUJWF
XIJDI
BJNT
UP
FYQFEJUF
UIF
JNQPSU
PG
ESVHT
BOE
XBOUT
UP
FYQBOE
JUT
QSFTFODF
PO
UIF
HSPVOE
JO
$IJOB
CVU
IBT
"1*T
GPS
NBOVGBDUVSFST
UIBU
NFFU
DFSUBJO
RVBMJUZ
TUBOEBSET
5IF
SVO
JOUP
QSPCMFNT
PCUBJOJOH
WJTBT
GPS
BEEJUJPOBM
JOTQFDUPST
BHFODZ
JT
MPPLJOH
GPS

NBOVGBDUVSFST
BOE
JNQPSUFST
UP
TJHO
'%"
IBT

TUBGGFST
QPTUFE
JO
#FJKJOH
4IBOHIBJ
BOE
VQ
GPS
B
QJMPU
UP
UFTU
UIJT
FYQFEJUFE
FOUSZ
QSPHSBN
BT
PVUMJOFE
(VBOH[IPV
JODMVEJOH
$IJOFTF
TVQQPSU
TUBGG
BOE
XBT
SFDFOUMZ
JO
BO
"VH


Federal Register
FR
OPUJDF
 
'%"
JOJUJBMMZ
BVUIPSJ[FE
UP
TQFOE

NJMMJPO
NPSF
GPS
BEEJUJPOBM
ESVH
BOOPVODFE
UIF
44$
QJMPU
JO
+BOVBSZ

BOE
UIF
FR
OPUJDF
BOE
GPPE
JOTQFDUPST
#VU
UIF
$IJOFTF
BSF
UBLJOH
UIFJS
UJNF
JO
FYQMBJOT
IPX
NBOVGBDUVSFST
DBO
BQQMZ
GPS
UIF
QSPHSBN
UP
DPWFS
QFSNJUUJOH
B
MBSHFS
64
SFHVMBUPSZ
QSFTFODF VQ
UP
GJWF
BQQSPWFE
ESVHT
PS
"1*T
'%"
XBOUT
JOGPSNBUJPO
PO
IPX
B
DPNQBOZ
XJMM
NBJOUBJO
DPOUSPM
PG
QJMPU
ESVHT
GSPN
QSPEVDUJPO
Harmonizing QbD filings UP
EFMJWFSZ
JO
UIF
64
5IF
BHFODZ
QMBOT
UP
FYBNJOF
SFDPSET
BOE
'%"
BOE
UIF
&VSPQFBO
.FEJDJOFT
"HFODZ
&."
IBWF
BHSFFE
BVEJU
TIJQNFOUT
QFSJPEJDBMMZ
BOE
NBZ
ESPQ
B
QJMPU
QBSUJDJQBOU
UIBU
PO
B
OVNCFS
PG
QPMJDJFT
GPS
QBSBMMFM
BTTFTTNFOU
PG
RVBMJUZCZ GBJMT
UP
NFFU
TUBOEBSET
"QQMJDBUJPOT
TIPVME
CF
GJMFE
FMFDUSPOJDBMMZ
EFTJHO
2C%
FMFNFOUT
JO
NBSLFU
BQQMJDBUJPOT
VOEFS
B
UISFF CZ
%FD


BOE
BSF
BWBJMBCMF
BU
XXXGEBHPW"CPVU'%" ZFBS
QJMPU
QSPHSBN
UIBU
DPODMVEFT
OFYU
ZFBS
5IF
"VH


3FQPSUT.BOVBMT'PSNT'PSNTEFGBVMUIUN
BOOPVODFNFOU

JOEJDBUFT
UIBU
TJODF
UIF
DPMMBCPSBUJPO
CFHBO
JO
.BSDI

UIF
SFHVMBUPSZ
BHFODJFT
KPJOUMZ
SFWJFXFE
UIF
2C%
New field force director FMFNFOUT
JO
B
OFX
ESVH
BQQMJDBUJPO
BOE
BMTP
QSPWJEFE
TDJFOUJGJD
.FMJOEB
1MBJTJFS
IBT
CFFO
OBNFE
'%"
BTTPDJBUF
DPNNJTTJPOFS
BEWJDF
UP
NBOVGBDUVSFST
5IJT
IBT
MFE
UP
BHSFFNFOU
PO
IPX
GPS
SFHVMBUPSZ
BGGBJST
BOE
IFBE
PG
UIF
0GGJDF
PG
3FHVMBUPSZ
BQQMJDBOUT
TIPVME
TVCNJU
JOGPSNBUJPO
PO
RVBMJUZ
UBSHFU
QSPEVDU
"GGBJST
03"
BGUFS
B
ZFBS
BT
iBDUJOHw
BTTPDJBUF
DPNNJTTJPOFS
QSPGJMFT
DSJUJDBM
RVBMJUZ
BUUSJCVUFT
BOE
UIF
NBOVGBDUVSJOH
BOE
NPSF
UIBO

ZFBST
JO
PUIFS
UPQ
03"
BOE
BHFODZ
QPTJUJPOT
QSPDFTT
5IF
SFHVMBUPST
SFKFDUFE
BO
BQQMJDBOUT
QSPQPTBM
GPS
4IF
SFQPSUT
UP
UIF
EFQVUZ
DPNNJTTJPOFS
GPS
HMPCBM
SFHVMBUPSZ
B
UISFFUJFS
DMBTTJGJDBUJPO
GPS
RVBMJUZ
BUUSJCVUFT
BOE
QSPDFTT
PQFSBUJPOT
BOE
QPMJDZ
B
QPTJUJPO
UIBU
IBT
OPU
CFFO
GJMMFE
TJODF
QBSBNFUFST
CVU
BHSFFE
UP
FWBMVBUF
PO
B
DBTFCZDBTF
CBTJT
OFX
%FCPSBI
"VUPS
EFQBSUFE
NPOUIT
BHP
XBZT
UP
EFGJOF
BOBMZUJDBM
UBSHFU
QSPGJMFT
BOE
NFUIPE
PQFSBUJPOBM
EFTJHO
SBOHFT
'VSUIFS
EJTDVTTJPO
PG
EFTJHO
TQBDF
WFSJGJDBUJPO
High hopes for malaria vaccine DPOUJOVPVT
QSPDFTT
WFSJGJDBUJPO
BOE
DPOUJOVPVT
NBOVGBDUVSJOH
&BSMZ
DMJOJDBM
TUVEJFT
BSF
HFOFSBUJOH
VOVTVBM
FOUIVTJBTN
BNPOH
PUIFS
2C%SFMBUFE
UPQJDT
BSF
PO
UIF
BHFOEB BCPVU
B
OFX
XIPMFQBSBTJUF
WBDDJOF
UP
QSFWFOU
NBMBSJB
VOEFS
EFWFMPQNFOU
CZ
.BSZMBOECBTFE
CJPUFDI
4BOBSJB
5IF
JOJUJBM
QIBTF
Industry expands third-world access to AIDS therapies 
USJBM
JOWPMWFE
MFTT
UIBO

QBUJFOUT
CVU
UIPTF
XIP
SFDFJWFE
UIF
5IF
.FEJDJOFT
1BUFOU
1PPM
.11
JT
HBJOJOH
NPSF
TVQQPSU
GSPN
UFTU
QSPEVDU
HBJOFE
TJHOJGJDBOU
QSPUFDUJPO
GSPN
JOGFDUJPO
5IF
QIBSNBDFVUJDBM
NBOVGBDUVSFST
BT
B
XBZ
UP
NBLF
DSJUJDBM
"*%4
QSPEVDUJPO
QSPDFTT
JT
USJDLZ
BT
JU
JOWPMWFT
JSSBEJBUJOH
NPTRVJUPFT
UIFSBQJFT
NPSF
BGGPSEBCMF
GPS
QBUJFOUT
JO
"GSJDB
BOE
PUIFS
UP
XFBLFO
UIF
NBMBSJB
QBSBTJUF
JO
UIFJS
CPEJFT
XIJDI
JT
UIFO
EFWFMPQJOH
SFHJPOT
3PDIF
BHSFFE
JO
"VHVTU
UP
B
GJWFZFBS
SFNPWFE
BOE
GPSNVMBUFE
JOUP
B
WBDDJOF
-BSHFS
TUVEJFT
BSF
QMBOOFE
EFBM
UIBU
XJMM
SFEVDF
UIF
QSJDF
JO

DPVOUSJFT
GPS
7BMDZUF
JO
5BO[BOJB
BOE
.BMJ
QSPWJEFE
UIF
EFWFMPQFST
DBO
PWFSDPNF
WBMHBODJDMPWJS
IZESPDIMPSJEF
B
LFZ
USFBUNFOU
GPS
B
WJSBM
JOGFDUJPO
TJHOJGJDBOU
IVSEMFT
JO
QSPEVDUJPO
USBOTQPSU
BOE
BENJOJTUSBUJPO UIBU
SFEVDFT
WJTJPO
JO
"*%4
QBUJFOUT
5IF
3PDIF
BHSFFNFOU
GPMMPXT
B
.BSDI
EFBM
CFUXFFO
.11
BOE
NBOVGBDUVSFST
7JJ7
)FBMUIDBSF
FTC continues campaign against brand-generic deals (MBYP4NJUI,MJOF
BOE
1GJ[FS
UP
CSPBEFO
BDDFTT
UP
;JBHFO
5IF
'FEFSBM
5SBEF
$PNNJTTJPO
'5$
JT
QSPUFTUJOH
B
iOPBVUIPSJ[FE BCBDBWJS 
1SJPS
UP
UIJT
POMZ
(JMFBE
4DJFODFT
IBE
MJDFOTFE
BOZ
HFOFSJDw
BHSFFNFOU
CFUXFFO
8ZFUI
1IBSNBDFVUJDBMT
OPX
)*7
UIFSBQJFT
UP
UIF
QSPHSBN
*O
B
QPTUJOH
PO
UIF
Pharmalot CMPH
PXOFE
CZ
1GJ[FS
BOE
HFOFSJDESVH
NBLFS
5FWB
5IF
DBTF
CFGPSF
B
PO
"VH


.11
FYFDVUJWF
EJSFDUPS
(SFH
1FSSZ
FYQMBJOFE
GFEFSBM
%JTUSJDU
$PVSU
JO
/FX
+FSTFZ
XBT
CSPVHIU
CZ
ESVH
SFUBJMFST
UIBU
UIFTF
SFDFOU
BHSFFNFOUT
SFGMFDU
NPOUIT
PG
EJTDVTTJPOT
QSPUFTUJOH
UIBU
UIF
EFBM
EFMBZFE
HFOFSJD
DPNQFUJUJPO
GPS
8ZFUIT
XJUI
NBOVGBDUVSFST
BMPOH
XJUI
FGGPSUT
UP
QFSTVBEF
HFOFSJDESVH
FYUFOEFE
SFMFBTF
BOUJEFQSFTTBOU
&GGFYPS
93
CFDBVTF
JU
DBMMT
GPS
NBLFST
UP
BCJEF
CZ
TVCMJDFOTJOH
BHSFFNFOUT
VOEFS
UIF
QSPHSBN 8ZFUI
UP
ESPQ
QMBOT
GPS
JUT
PXO
BVUIPSJ[FE
HFOFSJD
WFSTJPO
PG
UIF
ESVH
5IF
'5$
DMBJNT
UIBU
TVDI
B
NPWF
SFEVDFT
DPNQFUJUJPO
BOE
References MFBET
UP
IJHIFS
QSJDFT
BOE
UIBU
UIF
+VOF
4VQSFNF
$PVSU
SVMJOH
JO
1. FDA, Federal Register, Vol. 78, No. 161, pp 51192-51194 (Aug. 20, 2013). FTC v. Actavis
TVQQPSUT
$PNNJTTJPO
JOUFSWFOUJPO
JO
UIF
DBTF 2. EMA, EMA-FDA Pilot Program for Parallel Assessment of Quality-by-Design Applications: Lessons Learnt and Q&A Re- China challenges FDA and manufacturers sulting from the First Parallel Assessment (EMA, Aug. 20, 2013), 8IJMF
UIF
$IJOFTF
HPWFSONFOU
JT
FYQBOEJOH
JUT
JOWFTUJHBUJPO
http://www.ema.europa.eu/docs/en_GB/document_library/ PG
BMMFHFE
iFDPOPNJD
DSJNFTw
CZ
MFBEJOH
QIBSNBDFVUJDBM
Other/2013/08/WC500148215.pdf PT

28 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ) "$
3
/%+(

& (#+*!"

* $%"% /
()%+( Controlled-release Formulation Solutions

1
Introducing directly compressible Benecel™ DC hypromellose (HPMC) for: – Increased content uniformity – Improved flow over existing controlled-release and directly compressible grades – Lowered manufacturing costs – Reduced development time !*
%,(

/()
%
.&(!$
) "$
$
#*
/%+(
%$*(%""(")
%(#+"*!%$
$)
/
&(%,!!$
* 
(%)*
($ 
%
.!&!$*)
$
* $%"% !)
)
-""
)
&%"/#(
.&(*!)
$
* $!"
)+&&%(*
(%#
$ *%&
*%
%##(!"!0*!%$ +(
&(%+*)
%(
#%!4
$
)+)*!$(")
%(#+"*!%$)
!$"+ 1
+)*%##%"+"(
-! *
$"2

1
! ,!)%)!*/
()
%
"+"2

%(
)+)*!$
(")
$
!5+)!%$
%$*(%" 1
"/(")
$*(!
(
'+(!+)2
%*!$
)/)*#)
)
%$
#* (/"!
!* /"
(/"*
%&%"/#( 1
.*$(")
'+(!+)

%*!$
)/)*#)
)
%$
'+"%$2
 
%(
+)
-!*
%( $!
)%",$*) For more information, please contact your local Ashland Specialty Ingredients representative or visit us at ashland.com/pt/pharmaceutical.

 



"
#


 
  

#
 


® Registered trademark, Ashland or its subsidiaries, registered in various countries 2 Trademark, Ashland or its subsidiaries, registered in various countries * Registered trademark owned by Wacker Chemie AG. Ashland Inc. acts as a distributor for Wacker © 2013, Ashland AD-12380.1 With good chemistry great things happen.™ Jill Wechsler JT
Pharmaceutical Technology’s
8BTIJOHUPO
FEJUPS
UFM

KXFDITMFS!BEWBOTUBSDPN
3FBE
+JMMT
CMPHT
BU
1IBSN5FDIDPNXFDITMFS FDA Seeks Metrics to Define Drug Quality

Manufacturing standards considered key to preventing drug recalls and shortages.

SJUJDBM
ESVH
TIPSUBHFT
BOE
DPOUBNJOBUFE
DPNQPVOEJOH
PG
-POHFS
DZDMF
UJNFT
NBZ
TJHOBM
NPSF
FSSPST
BOE
QSPEVDU
$TUFSJMF
JOKFDUBCMFT
IBWF
IFJHIUFOFE
QVCMJD
DPODFSO
BCPVU
GBJMVSFT
UIBU
NVTU
CF
JEFOUJGJFE
EPDVNFOUFE
JOWFTUJHBUFE
ESVH
RVBMJUZ
BOE
TBGFUZ
%FTQJUF
B
EFDBEF
PG
FODPVSBHFNFOU
SFNFEJBUFE
BOE
DMPTFE
CFGPSF
B
MPU
PS
CBUDI
DBO
CF
SFMFBTFE BOE
HVJEBODF
GSPN
'%"
NBOVGBDUVSFST
IBWF
GBJMFE
UP
BEPQU $POWFSTFMZ
B
TIPSUFS
DZDMF
UJNF
NBZ
JOEJDBUF
UIBU
B
GBDJMJUZ
B
iDPOUJOVPVT
JNQSPWFNFOU
NPEFM w
BDDPSEJOH
UP
+BOFU
PQFSBUFT
JO
B
IJHI
TUBUF
PG
DPOUSPM
1SPDFTT
BOE
QSPEVDU 8PPEDPDL
EJSFDUPS
PG
UIF
$FOUFS
GPS
%SVH
&WBMVBUJPO
BOE
QFSGPSNBODF
JOEFY
1QL
WBMVFT
TJNJMBSMZ
DBO
CF
B
TJHO
PG
BO 3FTFBSDI
$%&3 
'%"
JT
TFFLJOH
OFX
TUSBUFHJFT
UP
TQVS PQUJNBM
DPOUSPM
TUSBUFHZ
TVQQPSUFE
CZ
JOEFQUI
VOEFSTUBOEJOH
DPNQMJBODF
XJUI
(.1T
BOE
UP
MJNJU
ESVH
QSPEVDUJPO
FSSPST PG
UIF
DBVTFT
PG
WBSJBCJMJUZ
GPS
CPUI
QSPEVDUT
BOE
QSPDFTT UIBU
MFBE
UP
TVQQMZ
QSPCMFNT
8PPEDPDL
FYQMBJOFE
BU
B
+VMZ
"
iCBUDIFTSJHIUUIFGJSTUUJNFw
NFBTVSF
CBTFE
PO
OVNCFS


TFNJOBS
PO
i6OEFSTUBOEJOH
D(.1Tw
TQPOTPSFE
CZ
PG
MPUT
SFMFBTFE
DPNQBSFE
UP
MPUT
JOJUJBUFE
TJNJMBSMZ
DBO
UIF
'PPE
BOE
%SVH
-BX
*OTUJUVUF
'%-* 
"DIJFWJOH
ESVH
RVBMJUZ EFNPOTUSBUF
UIBU
QSPDFTTFT
BSF
SPCVTU
BOE
QSPEVDUT
BSF
NBEF IBT
CFDPNF
NPSF
DPNQMFY‰BOE
NPSF
WJUBM‰XJUI
JOEVTUSZ
DPOTJTUFOUMZ
JO
B
TUBUF
PG
DPOUSPM HMPCBMJ[BUJPO
TIF
BDLOPXMFEHFE
FNQIBTJ[JOH
UIF
JNQPSUBODF
PG
NBOVGBDUVSFST
QSPEVDJOH
RVBMJUZ
QSPEVDUT
CBUDI
BGUFS
CBUDI 5P
GVSUIFS
FODPVSBHF
RVBMJUZ
QSPEVDUJPO
'%"
TFFLT
UP
FTUBCMJTI
DMFBS
XSJUUFO
DMJOJDBMMZ
SFMFWBOU
QVCMJD
TUBOEBSET
FDA wants to know how UIBU
JU
DBO
FOGPSDF
UISPVHI
SFWJFX
BOE
JOTQFDUJPOT
5IJT
FGGPSU
JT
TVQQPSUFE
CZ
UIF
'%"
4BGFUZ
BOE
*OOPWBUJPO
"DU
'%"4*"
manufacturers use quality XIJDI
SFRVJSFT
'%"
UP
ESBGU
B
TUSBUFHJD
QMBO
GPS
QSFWFOUJOH
BOE
NJUJHBUJOH
ESVH
TIPSUBHFT
1PMJDZ
NBLFST
XBOU
UP
LOPX
JG
metrics internally to '%"
DPNQMJBODF
BDUJPOT
MFBE
UP
TVQQMZ
QSPCMFNT
BOE
IPX
UIF
BHFODZ
DBO
CFUUFS
JOGPSN
IFBMUI
QSPGFTTJPOBMT
BOE
UIF
QVCMJD
monitor production. PO
QPUFOUJBM
TIPSUBHFT

Seeking metrics -FBEJOH
JOEJDBUPST
PG
NBOVGBDUVSJOH
RVBMJUZ
NBZ
DPWFS
B
*O
DSBGUJOH
UIF
TIPSUBHFT
QMBO
BO
'%"
%SVH
4IPSUBHFT
SBOHF
PG
DPNQBOZ
BDUJPOT
BOE
QPMJDJFT
TVDI
BT
BEFRVBUF
5BTL
'PSDF
IBT
CFFO
FYBNJOJOH
NPSF
CSPBEMZ
IPX
ESVH
JOWFTUNFOU
JO
NBOVGBDUVSJOH
GBDJMJUJFT
TVGGJDJFOU
GVOEJOH
GPS
NBOVGBDUVSJOH
QSPCMFNT
NBZ
QSFDJQJUBUF
QMBOU
DMPTJOHT
BOE
SPVUJOF
NBJOUFOBODF
BOE
TVQQPSU
GPS
USBJOJOH
QSPHSBNT
QSPEVDU
EJTDPOUJOVBUJPOT
BOE
XIBU
TUSBUFHJFT
QIBSNBDFVUJDBM
0SHBOJ[BUJPOBM
IFBMUI
BMTP
DBO
CF
BTTFTTFE
UISPVHI
XPSLFS
DPNQBOJFT
VTF
UP
USBDL
BOE
QSFWFOU
TVDI
GBJMVSFT
.PTU
TBGFUZ
FNQMPZFF
TBUJTGBDUJPO
TUBGG
SFUFOUJPOUVSOPWFS
PCWJPVT
BSF
SFQPSUT
PG
DPNQBOZ
SFDBMMT
QPPS
JOTQFDUJPO
BOE
USBJOJOH
FGGFDUJWFOFTT
DPNNFOUT
UIF
1BSFOUFSBM
%SVH
PVUDPNFT
BOE
BEWFSTF
FWFOUT
UIBU
BSF
WJTJCMF
UP
'%"
BOE
DBO
"TTPDJBUJPO
1%" 
1SFEJDUJWF
PS
GPSFDBTU
NFUSJDT
JODMVEF
JOEJDBUF
CSPBEFS
EFGJDJFODJFT
JO
NBOVGBDUVSJOH
QSPDFTT
BOE
NBJOUFOBODF
CBDLMPHT
DPNQMBJOU
USFOET
JOUFSOBM
BVEJUT
DPOUSPM
TUSBUFHZ
BOE
UIF
GJOEJOHT
PG
SFHVMBUPSZ
JOTQFDUJPOT
:JFME
BOBMZTJT
*O
BEEJUJPO
'%"
XBOUT
UP
LOPX
IPX
NBOVGBDUVSFST
VTF
PS
BCOPSNBMJUJFT
PG
QSPEVDU
QFS
CBUDI
PWFS
UJNF
DBO
CF
BO RVBMJUZ
NFUSJDT
JOUFSOBMMZ
UP
NPOJUPS
QSPEVDUJPO
BOE
UP
BEWBODF
TJHO
PG
PUIFS
QSPDFTT
PS
SBX
NBUFSJBMT
QSPCMFNT
TFMFDU
DPOUSBDU
NBOVGBDUVSFST
*O
B
'FC


Federal *O
JUT
DPNNFOUT
1GJ[FS
EFTDSJCFT
GPVS
MFWFMT
PG
RVBMJUZ
Registerr
OPUJDF

'%"
TPMJDJUFE
TVDI
JOGPSNBUJPO
BOE
QFSGPSNBODF
JOEJDBUPST
TUBSUJOH
XJUI
TUBGGJOH
BEFRVBDZ
NBOVGBDUVSFST
BOE
JOEVTUSZ
USBEF
BTTPDJBUJPOT
TVCNJUUFE
XPSLMPBE
BOE
JODSFBTFE
UVSOPWFS
'VSUIFS
TJHOBMT
PG
QPUFOUJBM
DPNNFOUT
EFTDSJCJOH
B
WBSJFUZ
PG
JOEVTUSZ
TUBOEBSET
BOE
RVBMJUZ
PS
DPNQMJBODF
JTTVFT
NBZ
BQQFBS
BT
JODSFBTFE
RVBMJUZ
BTTVSBODF
BQQSPBDIFT
 
5IF
GJMJOHT
JOEJDBUF
UIBU
EPDVNFOUBUJPO
FSSPST
VOQMBOOFE
RVBSBOUJOF
TIJQNFOUT
PS
QIBSNBDFVUJDBM
BOE
CJPUFDI
DPNQBOJFT
SFHVMBSMZ
NPOJUPS
DPNQMBJOUT
QFS
VOJUT
QSPEVDFE
5IF
OFYU
MFWFM
DBQUVSFT
IJHIFS
FSSPS
SBUFT
GPS
FYBNQMF
UP
JEFOUJGZ
OPODPOGPSNBODFT
BWFSBHF
EJTQPTJUJPO
DZDMF
UJNFT
PS
PQFSBUPS
FSSPST
QFS
CBUDI
EJTDSFQBODJFT
BOE
EFWJBUJPOT
IJHI
FSSPS
SBUFT
BSF
DPOTJEFSFE
%PDVNFOUFE
RVBMJUZ
FWFOUT
PWFSEVF
SFHVMBUPSZ
DPNNJUNFOUT
FWJEFODF
PG
QPPS
QSPDFTT
DPOUSPM
QPPS
USBJOJOH
PG
PQFSBUPST
PS
BO
JODSFBTF
JO
SFKFDUFE
CBUDIFT
NBZ
TJHOBM
UIF
OFFE
GPS
MBY
PWFSTJHIU
CZ
TVQFSWJTPST
QPPSMZ
NBJOUBJOFE
FRVJQNFOU
BDUJPO
UP
NBJOUBJO
QSPEVDU
RVBMJUZ
DPOUSPM
BOE
GBDJMJUJFT
PS
QPPS
QSPEVDU
BOE
QSPDFTT
DIBSBDUFSJ[BUJPO
5P
BTTFTT
DPOUSBDU
NBOVGBDUVSFST
1%"
OPUFT
UIBU BDDPSEJOH
UP
UIF
(FOFSJD
1IBSNBDFVUJDBM
"TTPDJBUJPO
(1I"
QIBSNBDFVUJDBM
BOE
CJPUFDI
DPNQBOJFT
VTF
NFUSJDT
TVDI
BT
BOE
UIF
1IBSNBDFVUJDBM
3FTFBSDI
BOE
.BOVGBDUVSFST
PG
TVQQMZ
BTTVSBODF
PWFS
UIF
QBTU

ZFBST
SFEVOEBOU
GBDJMJUJFT
"NFSJDB
1I3." 
NJOJNVN
SBX
NBUFSJBM
TUPDLT
BOE
DPOUJOHFODZ
QMBOT
GPS
"DU

30 Pharmaceutical Technology OCTOBER 2013 PharmTech.com CMIC specializes in development and cGMP commercial services for oral solid dose products.

CLINICAL www.cmiccmousa.com

ANALYTICAL CMIC CMO USA Corporation FORMULATION Cedar Brook Corporate Center 3 Cedar Brook Drive Cranbury NJ 08512 609-395-9700

COMMERCIAL

For the fastest path to approval... shift to CMIC!

Visit us at AAPS, Booth 3013 PG(PE
TJUVBUJPOT
TVDI
BT
QBOEFNJDT
'JSNT
HFOFSBMMZ
DPOTJEFS
QBSUJDJQBUJPO
JO
TVDI
VOEFSUBLJOHT
PS
TPNF
LJOE
PG
HVBSBOUFFE
NFUSJDT
GPS
DPOUSBDUPST
TJNJMBS
UP
UIPTF
BQQMJFE
JOUFSOBMMZ
QVSDIBTF
QSPHSBN
JOEVTUSZ
JT
QFTTJNJTUJD
BCPVU
UIBU
BQQSPBDI
CVU
BMTP
XFJHI
TVQQMZDIBJO
TFDVSJUZ
TUFSJMJUZ
BTTVSBODF
BOE
1%"
OPUFT
JO
JUT
DPNNFOUT
UIBU
DFSUBJO
SFHVMBUPSZ
BDUJPOT
QSPEVDU
BOE
QSPDFTT
LOPXMFEHF
NJHIU
FODPVSBHF
NBOVGBDUVSFST
UP
FYQBOE
DBQBDJUZ
TVDI
BT
FYQFEJUFE
SFWJFX
PG
OFX
NBOVGBDUVSJOH
MJOFT
BOE
QPTU BQQSPWBM
DIBOHFT
UP
JNQSPWF
QSPDFTT
DBQBCJMJUJFT
0UIFS
JEFBT
Production quality metrics BSF
GPS
'%"
UP
XBJWF
1SFTDSJQUJPO
%SVH
6TFS
'FF
"DU
1%6'"
FTUBCMJTINFOU
GFFT
GPS
SFEVOEBOU
QSPEVDUJPO
TJUFT
JNQMFNFOU
could help establish a TIFMGMJGF
FYUFOTJPO
QPMJDJFT
BOE
SFEVDF
QSFBQQSPWBM
SFRVJSFNFOUT
GPS
TJUF
USBOTGFST
BTTBZ
JNQSPWFNFOUT
BOE
more rigorous way of FYUFOEFE
DPNQBSBCJMJUZ
QSPUPDPMT
QBSUJDVMBSMZ
GPS
iHPPE
BDUPSTw
JO
(.1
DPNQMJBODF

evaluating facilities during 'SPN
UIF
BHFODZT
QFSTQFDUJWF
QSPEVDUJPO
RVBMJUZ
NFUSJDT
DPVME
IFMQ
FTUBCMJTI
B
NPSF
SJHPSPVT
BOE
PCKFDUJWF
XBZ
PG
inspections. FWBMVBUJOH
GBDJMJUJFT
EVSJOH
JOTQFDUJPOT
TBJE
%PVHMBT
4UFBSO
EFQVUZ
EJSFDUPS
GPS
QPMJDZ
BOE
BOBMZTJT
JO
$%&3T
0GGJDF
PG
Boosting capacity $PNQMJBODF
BU
UIF
'%-*
DPOGFSFODF
4VDI
TUBOEBSET
DPVME
8IJMF
NBOVGBDUVSFST
TFF
WBMVF
JO
RVBMJUZ
NFUSJDT
UIFZ
BSF
MFTT
QSPWJEF
B
MPPL
BDSPTT
B
DPNQBOZ
BOE
JOEVTUSZ
UP
CFUUFS
BTTFTT
FOUIVTJBTUJD
BCPVU
QSPQPTBMT
UIBU
'%"
FODPVSBHF
SFEVOEBOU
NBUFSJBMJUZ
BOE
DMJOJDBM
SFMFWBODF
PG
B
(.1
JTTVF
BOE
UP
BWPJE
NBOVGBDUVSJOH
TJUFT
BT
B
TUSBUFHZ
GPS
QSFWFOUJOH
TIPSUBHFT
'%"
FOGPSDFNFOU
BDUJPOT
UIBU
BHHSBWBUF
ESVH
TIPSUBHFT
'%"
-BOHVBHF
JO
'%"4*"
QSPQPTFT
UIBU
'%"
JEFOUJGZ
B
MJTU
PG
iRVBMJGJFE
SFDPHOJ[FT
UIBU
UIFSF
BMXBZT
JT
UFOTJPO
CFUXFFO
FOTVSJOH
NBOVGBDUVSFSTw
XJUI
DBQBCJMJUZ
BOE
DBQBDJUZ
UP
QSPEVDF
WJUBM
UIBU
ESVHT
BSF
OPU
DPOUBNJOBUFE
BOE
QSPWJEJOH
BDDFTT
UP
MJGF ESVHT
SBQJEMZ
#VU
XJUIPVU
GVOEJOH
UP
TVQQPSU
NBOVGBDUVSFS
TBWJOH
NFEJDJOFT

We create chemistry that provides platforms for your success.

Meeting market needs with platform solutions.

Visit BASF at the AAPS Annual Meeting and Exposition in Booth 2705. For more information on BASF Pharmaceutical Ingredients and Services visit: www.pharma-ingredients.basf.com

32 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Visit us at AAPS, Booth 219 "
OFX
0GGJDF
PG
1IBSNBDFVUJDBM
2VBMJUZ
JO
$%&3
DPVME
TVQQPSU
UIFTF
FGGPSUT
CZ
DPMMFDUJOH
QFSGPSNBODF
NFUSJDT
BOE
DPOEVDUJOH
USFOE
BOBMZTJT
UP
JEFOUJGZ
CPUI
DPNQMJBOU
PQFSBUJPOT
BOE
PVUMJFST
"O
VQHSBEFE
*5
QMBUGPSN
DPVME
DPNQJMF
JOGPSNBUJPO
GSPN
BMM
TPVSDFT
PO
TJUFT
BOE
QSPEVDUT
UP
TVQQPSU
B
TUSFBNMJOFE
SJTLCBTFE
JOTQFDUJPO
QSPDFTT
5IJT
JOJUJBUJWF
BMTP
DPVME
FWBMVBUF
'%"
QFSGPSNBODF
TVDI
BT
JO
JTTVJOH
DJUBUJPOT
BOE
FOGPSDFNFOU
MFUUFST
UP
TFF
JG
UIF
BHFODZ
NFFUT
JUT
PXO
TUBOEBSET 8PPEDPDL
BDLOPXMFEHFE
BU
UIF
'%-*
NFFUJOH
UIBU
JOUFOTJWF
SFHVMBUJPO
PG
ESVH
NBOVGBDUVSJOH
JT
QBSUJBMMZ
UP
CMBNF
GPS
JOEVTUSZT
SFMVDUBODF
UP
JNQMFNFOU
JOOPWBUJWF
RVBMJUZ
TUSBUFHJFT
8IJMF
QSPEVDFST
PG
GPPE
QSPEVDUT
BOE
GJOF
DIFNJDBMT
IBWF
FOHJOFFSFE
QSFDJTF
DPOUSPMT
UIBU
ZJFME
EFGFDU GSFF
QSPEVDUT
TIF
GJOET
UIBU
QIBSNBDFVUJDBM
DPNQBOJFT
+PPQXCVKPIVJG GPDVT
NPSF
PO
DPNQMZJOH
XJUI
SFHVMBUJPOT
'PS
'%"
IPXFWFS
UP
FGGJDJFOUMZ
BTTFTT
BOE
BQQSPWF
IVOESFET
PG
BQQMJDBUJPOT
+PFWUVT[5VCPFCTF GPS
OFX
HFOFSJD
ESVHT
UP
NFFU
UJHIU
SFWJFX
UJNFGSBNFT
NBOVGBDUVSFST
OFFE
UP
FOTVSF
UIBU
QSPEVDUT
DPOTJTUFOUMZ
NFFU
IJHI
RVBMJUZ
TUBOEBSET
5P
NPWF
NPSF
CSFBLUISPVHI
ESVHT
RVJDLMZ
UISPVHI
UIF
BQQSPWBM
QSPDFTT
QIBSNBDFVUJDBM
BOE
CJPUFDI
DPNQBOJFT
OFFE
UP
FTUBCMJTI
IJHI
RVBMJUZ
QSPEVDUJPO
D[  TZTUFNT
FBSMZ
JO
EFWFMPQNFOU
5IFTF
JNQFSBUJWFT
QVU
ESVH
2TQXKFKPI RVBMJUZ
IJHI
PO
'%"T
SBEBS
TDSFFO

3FGFSFODFT 8GTUCVKNKV[ 1. FDA, Federal Register, Vol. 78, No. 29, p 9928-9929, Feb. 12, 2013. 2. Comments available at the Federal eRulemaking Portal: KP$NGPFKPI www.regulations.gov, Docket No. FDA-2013-N-0124. PT HTQO (QTOWNCVKQPVQ 2KNQV5ECNG Join PT’s community +PJO
UIF
1IBSN5FDI
HSPVQ
PO
-JOLFE*O™
BOE
TUBSU
EJTDVTTJOH
UIF
JTTVFT
UIBU
NBUUFS
UP
ZPV
XJUI
ZPVS
QFFST (P
UP
PharmTech.com/linkedin

5IF
MJOLFE*O
MPHP
JT
B
SFHJTUFSFE USBEFNBSL
PG
-JOLFE*O
$PSQPSBUJPO BOE
JUT
BGå
MJBUFT
JO
UIF
6OJUFE
4UBUFT BOEPS
PUIFS
DPVOUSJFT $QQVJ $QQVJ 2 B & C Janine Place, New Brunswick, NJ 08901 5P
TUBZ
VQ
UP
EBUF
XJUI
UIF
MBUFTU
IFBEMJOFT www.globepharma.com E:[email protected] GSPN
BDSPTT
UIF
CJPQIBSNBDFVUJDBM
JOEVTUSZ T: (732)296-9700 F: (732)296-9898 www.globepharma.com GPMMPX
VT
PO
5XJUUFS
BU
XXX1IBSN5FDIDPN'PMMPX

34 Pharmaceutical Technology OCTOBER 2013 PharmTech.com 0LNDUWLVWKH&RQWUDFW'HYHORSPHQWDQG0DQXIDFWXULQJ 2UJDQL]DWLRQ &'02 WKDWGHOLYHUVWKHVHUYLFHV\RX QHHGSOXVWKHVSHHGDQGUHVSRQVLYHQHVV\RXZDQW

:K\SXWXSZLWKLQቹH[LEOHSURFHGXUHVDQG XQUHWXUQHGFDOOV"$W0LNDUW\RXKDYHRXU IXOODWWHQWLRQ$QGZH·UHTXLFNWRUHVSRQG ZLWKSHUVRQDOL]HGVROXWLRQVWKDWJHW\RXU SURMHFWVFRPSOHWHGIDVWHUDQGWR\RXU LQGLYLGXDOUHTXLUHPHQWV 7KH&XUH)RU &'02 $WWHQWLRQ'HILFLW'LVRUGHU

2XUSURIHVVLRQDOVHUYLFHVLQFOXGH)RUPXODWLRQ'HYHORSPHQW &OLQLFDO7ULDO6XSSOLHV5HJXODWRU\)LOLQJ6XSSRUWSOXV0DQX IDFWXULQJDQG3DFNDJLQJVROXWLRQV

7RH[SHULHQFHMXVWKRZUHVSRQVLYHZHFDQEHFRQWDFW XVDW0,.$57RUVHQGXVDQHPDLOWR LQIR#PLNDUWFRP

5HDG\5HVSRQVLYH 5LJKWIRU

0LNDUW,QF_&KDWWDKRRFKHH$YHQXH_$WODQWD*$ ZZZPLNDUWFRP_0,.$57 Desmond Hunt, PhD, is senior scientific liaison, General Chapters, US Pharmacopeial Convention.

USP Seeks Input on Standards for Plastic Packaging Systems

USP seeks input from stakeholders on new and revised standards to mitigate extractables and leachables in plastic packaging systems.

refilled syringes, parenteral drugs, and many therapeutic Plastic materials are used in a variety of ways within Pbiologics delivered through infusions are contained in plastic the pharmaceutical sector, from packaging systems and packaging systems. Packaging systems must protect and be medical devices to tubing and single-use components compatible with the drug product and not compromise the used in the manufacturing process. A question faced by stability, efficacy, or safety of the drug product. In turn, the the manufacturer is, “What ultimate impact does a plastic ingredients of a drug product should not be absorbed onto the material or component have on the drug product?” Because surface or migrate into the body of the plastic packaging system. the makeup of most packaging materials is proprietary, drug manufacturers must rely on their own testing for extractables and leachables to determine if a material is suitable. With a USP is actively seeking robust compendial standard, knowledge of a material can be obtained that will provide the manufacturer with an ability feedback from drug to make more informed decisions about materials during the drug-development process, which ultimately saves time and manufacturers, packaging effort. USP introduced a biocompatability standard for plastic materials in 1965 and physiochemical standards in 1970. manufacturers, and Improvements in analytical techniques in recent years have prompted pharmaceutical manufacturers to take a closer look suppliers. at potential risks associated with plastic materials used to package pharmaceutical products, and therefore, a need to The US Pharmacopoeial Convention (USP) is currently update the standards. revising its existing quality standards and developing new standards for plastic packaging systems. Because these USP’s standards standards will have a significant impact on drug manufacturers Plastics used in packaging systems are composed of polymers and packaging-material suppliers, USP is actively seeking with a range of molecular weights and contain additives such feedback from drug manufacturers, packaging manufacturers, as antioxidants, stabilizers, lubricants, colorants, and other and suppliers as well as other stakeholders who may be additives. The nature and amount of additives for packaging affected by the new standards. systems are dictated by the type of polymer used, its application, and the process used to convert that polymer into Extractables and leachables components, containers, or packaging systems. Plastic-packaging systems can include not only the container As drug products are manufactured, packaged, stored, that holds the drug product, but also gaskets, rubber stoppers, and administered, these drug products come into direct tubing, and other components that may be a part of the contact with packaging systems and their plastic materials overall system that delivers the drug to the patient. For the of construction. Because such contact may result in an manufacturer, understanding and mitigating risks associated interaction between the product and its packaging system, with extractable and leachable aspects (unintended migration it is important that both the drug product and the packaging into or out of packages) is an important part of ensuring the materials are not adversely affected by such interactions. The quality and safety of the medicine delivered to patients. use of well-characterized plastic materials of construction Extractables are chemical compounds that can be extracted in components, containers, and packaging systems and the from a material under laboratory conditions, which can include appropriate testing of packaging systems help to determine the use of solvents and/or extreme temperatures. Leachables if such adverse interactions are taking place and whether the are extractables that may migrate into the drug product packaging material of choice is suitable for its intended use. over the course of a drug product’s shelf life. Drug-product USP’s new and revised standards for plastic packaging leachables can affect the stability and efficacy of the product, systems have been proposed as a suite of interconnected and in some extreme cases, pose significant patient safety chapters in the United States Pharmacopeia—National risks. Formularyy (USP–NF):

36 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Shift Your Development Into High Gear - Wurster Coating Services

Leading pharmaceutical companies worldwide depend RQ&RDWLQJ3ODFHIRUUHOLDEOHÀXLGEHGSURFHVVLQJDQG

>> Nano Particle Milling >> Bead Layering >> Extrusion/Spheronization >> Blending and Granulation >> Capsule Filling and Tableting

Depend on our unsurpassed knowledge and expertise when your project requires PLFURHQFDSVXODWLRQRISRZGHUVJUDQXOHVDQGFU\VWDOVIRU >> Taste masking >> Moisture or oxygen barrier applications >> O ral delivery for controlled, delayed, sustained, or enteric release >> Patented time release ion resin suspensions Visit us at AAPS, Booth 2700

Ask us about our unique coating capabilities using solvent or aqueous formulations. EMAILINFO ENCAPCOMs  s#OATING0LACE )NC "OX 6ERONA 7ISCONSIN53!sWWWENCAPCOM

LQIR#FRDWLQJSODFHFRP‡   t
General Chapter <661> Plastic Packaging Systems and their Materials of Construction
t

1MBTUJD
.BUFSJBMT
PG
$POTUSVDUJPO
t

1MBTUJD
1BDLBHJOH
4ZTUFNT
GPS
1IBSNBDFVUJDBM
6TF t
General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems t
General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/ Delivery Systems
t

0SBMMZ
*OIBMFE
BOE
/BTBM
%SVH
1SPEVDUT General Chapter <661> Containers—Plastics is being revised and will be titled Plastic Packaging Systems and Their Materials of Construction. The chapter will provide the testing rationale for plastic materials of construction and packaging systems used for the pharmaceutical industry. USP recognizes that the use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suited for its intended use as the properties and characteristics of the materials can be matched to the performance requirements of the packaging system. USP recognizes that the use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suited for its intended use.

/FX
(FOFSBM
$IBQUFS

1MBTUJD
.BUFSJBMT
PG
Construction will help determine whether a material is deemed well characterized by establishing its identity, biocompatibility (biological reactivity), general physicochemical properties, additives, and extractable metals. The objective of <661.1> is to provide tests, procedures, and acceptance criteria for plastic materials of construction used in pharmaceutical packaging systems, because proper characterization of these materials facilitates the identification and use of appropriate materials in pharmaceutical systems. The testing of packaging systems to establish that they are suitable for their intended use is addressed in new General $IBQUFS

1MBTUJD
1BDLBHJOH
4ZTUFNT
GPS
1IBSNBDFVUJDBM
Use. The applicant who seeks regulatory approval of a packaging system or packaged pharmaceutical product is responsible for establishing that the product’s packaging TZTUFN
NFFUT
UIF
FYQFDUBUJPOT
PG
 
5IJT
DIBQUFS
establishes what is meant by “appropriately tested,” which includes the requirement that the packaging system has been established to be safe by way of appropriate chemical testing,

38 Pharmaceutical Technology OCTOBER 2013 PharmTech.com which could include extractables testing, leachables testing, Seeking input and appropriate toxicological assessments. Revised General Chapter <661> and the suite of related new Screening the materials used in a packaging system and its chapters have been published for comment in the September– components for ingredients that are probable extractables 0DUPCFS

JTTVF
PG
Pharmacopeial Forum (PF), USP’s free- and possible leachables is an important step for establishing access, online publication for posting proposals and receiving TVJUBCJMJUZ
/FX
(FOFSBM
$IBQUFS

"TTFTTNFOU
PG
public comments to its developing standards. A 90-day Extractables Associated with Pharmaceutical Packaging/ comment period for receiving feedback to these chapters as Delivery Systems presents and describes best-demonstrated they appear in PF XJMM
FOE
PO
/PW


0ODF
GJOBMJ[FE
UIF
scientific practices for accomplishing an extractables general chapters will be published in USP–NF. However, USP’s BTTFTTNFOU
/FX
(FOFSBM
$IBQUFS

"TTFTTNFOU
PG
Packaging, Storage, and Distribution Expert Committee will Drug Product Leachables Associated with Pharmaceutical carefully review the comments received through PF during this Packaging/Delivery Systems outlines a framework for the period and further revisions to the chapters may result. design, justification, and implementation of assessments Like USP, the PQRI Extractables and Leachables Working for drug-product leachables derived from pharmaceutical Group is also working to develop guidelines, specifically for packaging and delivery systems. Accompanying <1664> packaging systems used for parenteral and ophthalmic drug is General Chapter <1664.1>, which addresses specific QSPEVDUT
0O
%FD
o

641
BOE
123*
XJMM
DPIPTU
B
considerations for leachables in metered dose inhalers, workshop, “Suitability and Compatibility for Packaging and nasal sprays, dry powder inhalers and inhalation solutions, Delivery Systems: Extractables and Leachables.” The workshop suspension, and sprays. General Chapter <1664.1> is will take place at USP’s headquarters in Rockville, Maryland, intended to incorporate into USP’s chapters specific best and both organizations invite stakeholders to provide input practice recommendations of the Product Quality Research on each organization’s developing work related to plastics Institute (PQRI) related to leachables in orally inhaled packaging systems. and nasal drug products, including the first safety-based For more detailed information on the December workshop thresholds for leachables characterization and safety and to access USP’s suite of proposed general chapter qualification. changes, visit uspgo.to/extractables-leachables. PT Filling flexibility from benchtop to production )RURYHU\HDUV)OH[LFRQᅣVH[SHUWLVHKDVRIIHUHGÀOOLQJDQGFDSSLQJVROXWLRQVWR XVHUVDVWKH\VFDOHXSIURPUHVHDUFKWRIXOOVFDOHÀOOÀQLVK2XUVLQJOHXVH WHFKQRORJ\KDVEURXJKWVLPSOLFLW\DQGVHFXULW\WRKLJKSXULW\OLTXLGÀOOLQJDSSOLFDWLRQV

%HQFKWRSÀOOLQJ Clinical scale 3URGXFWLRQ VHPLDXWRPDWLRQ scale ÀOOÀQLVK

wmpg.com 800-282-8823

Pharmaceutical Technology OCTOBER 2013 39 Patricia Van Arnum is Executive Editor of Pharmaceutical Technology

Tracking Quality in Drug Manufacturing

A review of recent FDA enforcement activity of drug manufacturers reveals issues with vial-filling, adequacy of quality-control/quality-assurance procedures, particulate matter in inhalation powders and injectables, and drug labeling.

uality is crucial to ensure drug safety. A review of FDA’s 4 x 1 single-dose kit (1 vial and 1 syringe) with an expiration date Qenforcement reports and related information from of Aug. 31, 2015. It was first distributed on July 12, 2013. The low September 2013 highlights issues relating to vial-filling, fills affect approximately 0.2% of the batch and range between adequacy of quality assurance/quality control (QA/QC) 30% and 75% of the labeled dose. No batches distributed in procedures, particulate matter in inhalation powders and other markets were affected, and the companies don’t expect injectables, and drug labeling. any supply issues. There is little evidence that patient safety would be compromised as a result of injecting an underfilled Underfilled vials vial, and any health consequences would likely be minimum, AstraZeneca and Bristol-Myers Squibb reported in September according to Bristol-Myers Squibb. 2013 that they voluntarily recalled approximately 92,000 vials Bydureon is part of the diabetes alliance between AstraZeneca of their jointly marketed Type 2 diabetes treatment, Bydureon and Bristol-Myers Squibb. Bristol-Myers Squibb acquired (exenatide extended-release injectable suspension), in several Bydureon through its 2012 acquisition of Amylin Pharmaceuticals. European countries because some vials were not fully filled. AstraZeneca and Bristol-Myers Squibb formed a diabetes alliance The affected batches were recalled in the United Kingdom, in 2007 for certain drugs and later expanded that collaboration Germany, Romania, the Netherlands, Ireland, Sweden, Finland, following Bristol-Myers Squibb’s acquisition of Amylin to include and Spain, according to Bristol-Myers Squibb. The Bydureon the diabetes portfolio of Amylin, including Bydureon. recall was issued after a review of manufacturing records indicated at least one of the batches may have had a very Adequacy of QA/QC procedures small number of underfilled vials, according to a Sept. 16, 2013 FDA issued an import alert under which US officials may detain alert distributed by the UK Medicines and Healthcare products at the US border drug products manufactured at Ranbaxy Regulatory Agency (MHRA). The affected batch (C164827) was a Laboratories’ facility in Mohali, India. The firm will remain on

FDA REVIEWS GUIDANCE STATUS Products—Updating Labeling in ANDAs”—issued February 2001 In August 2013, FDA announced that the Center for Drug t
“Inhalation Drug Products Packaged in Semipermeable Evaluation and Research (CDER) reviewed the status of Container Closure Systems”—issued July 2002. draft guidance documents issued before 2010 to determine CDER has identified guidance documents in the following what should be done with those guidance documents going topics and are developing a plan for revision or finalization: forward (1). In the review, CDER identified 23 draft guidance t
Biopharmaceutics documents for withdrawal in the areas of cGMP compliance, t
Chemistry, manufacturing, and controls development of antimicrobial drugs, abbreviated new drug t
Clinical pharmacology applications (ANDAs), labeling of ANDAs, and more. Guidance t
Combination products documents to be withdrawn include but are not limited to: t
cGMP compliance t
“Manufacturing, Processing, or Holding Active t
Development of antimicrobial drugs Pharmaceutical Ingredients”—issued April 1998 t
Drug advertisements t
“Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment”— t
Drug safety issued November 2003 t
Electronic submissions t
“Forms for Registration of Producers of Drugs and t
Labeling Listing of Drugs in Commercial Distribution”—issued t
OTC products May 2001 t
Pharmacology and toxicology t
“Disclosing Information Provided to Advisory t
Procedural guidance Committees in Connection With Open Advisory t
Radiopharmaceuticals. Committee Meetings Related to the Testing or Approval of New Drugs and Convened by CDER, Beginning on Reference January 1, 2000”—issued December 1999 1. FDA, “Retrospective Review of Draft Guidance Documents Issued Before t
“Labeling Over-the-Counter (OTC) Human Drug 2010; Withdrawal of Guidances,” Federal Register, August 7, 2013.

40 Pharmaceutical Technology OCTOBER 2013 PharmTech.com the import alert until the company complies with US cGMPs, with cGMPs. Ranbaxy is required to hire a third-party expert according to a Sept. 16, 2013 FDA statement. to conduct an inspection of the Mohali facility and certify FDA also ordered that the Mohali facility be subject to to FDA that the facilities, methods, processes, and controls certain terms of the consent decree of permanent injunction are adequate to ensure continuous compliance with cGMPs. entered against Ranbaxy in January 2012. The decree contains Once the agency is satisfied that Ranbaxy has come into provisions to ensure cGMP compliance at certain Ranbaxy compliance with cGMPs, Ranbaxy will be permitted to resume facilities, including in Paonta Sahib and Dewas, India, as manufacturing and distribution of FDA-regulated drugs at the well as provisions addressing data-integrity issues at those Mohali facility. two facilities. Ranbaxy’s Paonta Sahib and Dewas facilities have been on FDA import alert since 2008. FDA exercised its Particulate matter in inhalation powders authority under a provision in the consent decree permitting it Boehringer Ingelheim Roxane, based in Columbus, Ohio and to order that terms of the decree be extended to a Ranbaxy- a subsidiary of Boehringer Ingelheim, initiated a voluntary owned or operated facility if an inspection determines that the nationwide recall in the United States of certain lots of its facility is in violation of the Federal Food, Drug, and Cosmetic Spiriva HandiHaler (tiotropium bromide inhalation powder) Act or FDA regulations, including cGMPs. capsules, 18 mcg per dose (prescription only), according to In September and December 2012, FDA inspections identified FDA’s weekly enforcement report of Sept. 25, 2013. Spiriva is cGMP violations at Ranbaxy’s Mohali facility, including failure to used to treat chronic obstructive pulmonary disease. The adequately investigate manufacturing problems and failure to Class III recall was initiated on Aug. 30, 2013 due to the potential establish adequate procedures to ensure manufacturing quality. for extrinsic foreign particles in the API used to manufacture Under the decree, Ranbaxy is prohibited from manufacturing Spiriva Handihaler. The product distribution quantity was FDA-regulated drugs at the Mohali facility and introducing drugs 15,385,232 capsules, according to the FDA report. The recall into interstate commerce, including into the United States, applies to several products types: a 10-count blister (NDC 0597- from the Mohali facility until the firm’s methods, facilities, 0075-27), 30-count blister (NDC 0597-0075-41), 90-count blister and controls used to manufacture drugs at the Mohali facility (NDC 0597-0075-47), and 5-count blister physician sample (NDC are established, operated, and administered in compliance 0597-0075-75). A Class III recall refers to products that are

100% of the Fortune 500* pharmaceutical companies use TrackWise® for their quality and compliance needs. Learn why.

*2012 Fortune 500 annual ranking of America’s largest corporations by industry.

Trust. Safety. Efficiency. +1(609) 807-5100 | www.spartasystems.com | blog.spartasystems.com ©2013 Sparta Systems, Inc. All Rights Reserved.

Pharmaceutical Technology OCTOBER 2013 41 unlikely to cause any adverse health reaction, but that violate to a Sept. 18, 2013 FDA press statement. Shamrock Medical FDA labeling or manufacturing laws. repackaged and distributed solid and liquid oral nonsterile drug products for human use to hospitals throughout the United Mislabeled drugs States. FDA reported that inspections found several violations A federal judge approved a consent decree of permanent at the facility, including failure by the quality control unit to injunction against Shamrock Medical Solutions Group, Lewis fully follow its own QC procedures and to examine packaged Center, Ohio, and four of its corporate officers and employees and labeled products to ensure correct labeling. The FDA for continued drug manufacturing and labeling violations that previously had sent warning letters to Shamrock Medical for resulted in the distribution of mislabeled drugs, according violating cGMPs and distributing incorrectly labeled drugs. The September 2013 announcement followed an FDA alert issued in April 2013 advising healthcare providers to remove drugs distributed by Shamrock helium Medical from supply stock due to the 2 possibility that they were mislabeled. The warning covered many nonsterile medications and dosage forms, He including tablets, vials, ophthalmic and otic solutions, and patches. 4.0026 orine neon Particulate matter in injectable drugs FDA reported on Sept. 13, 2013 that 9 10 Hospira had initiated on July 12, 2013 a voluntary nationwide recall to the user Trust level for one lot of 0.25% bupivacaine F Ne HCl injection, USP (2.5 mg/mL), 30-mL isn’t listed single-dose vial (NDC 0409-1159-02). .998 20.180 An expanded recall was issued on orine argon on the Aug. 29, 2013 for one lot of 0.75% bupivacaine HCl injection, USP (7.5 17 18 periodic table. mg/mL), 30-mL single-dose vial(NDC 0409-1165-02). Bupivacaine is indicated for the production of local or regional You can’t measure it with tests. anesthesia or analgesia. Both recalls Cl Ar You can’t see it in a microscope. .453 39.948 were due to confirmed customer While scientifi c rigor and proven reports of particulate floating and/or mine krypton competence are the price of entry, embedded in the glass vial, according trust is the essential element in our to FDA. The particulate was identified 35 36 business. We never forget, when as stainless steel ranging in size from you choose a partner, you are 542 microns to 1700 microns in Lot trusting them with your brand. 18-136-DK (0.25% bupivacaine) and Br Kr as iron oxide with an average size of .904 83.798 2000 microns in Lot 23-338-DK (0.75% bupivacaine). dine xenon Hospira also initiated a voluntary 53 54 recall of propofol injectable emulsion, 1%, 200 mg/20 mL (10 mg/mL), packaged in 5 units x 20 mL single-patient infusion TOPICAL SEMI-SOLIDS & LIQUIDS vials per carton (prescription only), I Xe according to a Sept. 18, 2013 FDA Formulation, Development and Manufacturing 6.90 131.29 enforcement report. The Class II recall Diana Ritch was initiated on Aug. 14, 2013 due to atine radon Manager of New Customer Business visible particulate embedded in the glass 85 86 704.939.4329 vial being observed and confirmed in a www.eisolutionworks.com sample bottle during sample inspection. The product distribution quantity was At Rn 283,150 vials. PT 42 Pharmaceutical Technology OCTOBER 2013 PharmTech.com No Limits...No Compromises A New Standard of UHPLC/HPLC Excellence

Utilizing patented technologies, and driven by Shimadzu’s Nexera X2 HPLC/UHPLC features: customer input, Shimadzu has developed the Q New PDA detector: offers superior sensitivity and resolution, Nexera X2 Series to deliver superior, real-world achieving a 0.4×10-5 AU noise level for genuine UHPLC analysis performance across a wider application range, while Q Automated solvent blending and method scouting: ideal for delivering unparalleled flexibility and reliability in method development UHPLC/HPLC analyses. With newly added features, Q Intelligent Peak Deconvolution Analysis (i-PDeA) function: such as i-PDeA and i-DReC, Nexera X2 will improve unique software solution to separate and accurately integrate your productivity while assuring data quality. co-eluting peaks Nexera X2 is the next milestone in the evolution of Q Intelligent Dynamic Range Extension Calculator (i-DReC): liquid chromatography. extends the dynamic range so low concentration (trace or impurity compounds) and very high concentration samples can Learn more about Shimadzu’s Nexera X2. be accurately analyzed in a single injection Call (800) 477-1227 or visit us online at Q Ultrahigh-throughput and clean autosampler: perfect front- www.ssi.shimadzu.com/X2 end systems for any LCMS applications

Order consumables and accessories on-line at http://store.shimadzu.com Shimadzu Scientific Instruments Inc. 7102 Riverwood Dr., Columbia, MD 21046, USA Ultra High Performance Liquid Chromatograph Visit us at AAPS, Booth 3227 Report from: Myanmar

Foreign companies zero in on Myanmar with the hope of securing a foothold in its pharmaceutical market.

nternational pharmaceutical companies are flocking into showed interest in investing in Myanmar. Plans to open a branch IMyanmar to explore business opportunities in the country. office are already in the pipeline. The company has obtained Myanmar’s pharmaceutical market has attracted investors with approval to expand its pharmaceutical services and is in discussion the sector projected to be worth $100 to $120 million despite its with the Directorate of Investment and Companies Administration relatively small population of approximately 60 million people. (DICA) officials on the required legislations and regulations. “The country’s pharmaceutical industry is fuelled by the growing per capita income and a middle class that is seeking better Myanmar’s healthcare system healthcare,” Chris Woo, managing director of tax services at Myanmar’s healthcare system lacks funding and is primarily PricewaterhouseCoopers (PwC) Myanmar, told Pharmaceutical a self-pay system. Consequently, the market favors Indian Technology. “Currently, many employers do not provide any manufacturers who can offer lower-priced options compared health plans for its employees; however, the healthcare to players from developed countries. Potential investors should, landscape and relevant demand are set to change as more therefore, plan their market-entry strategies carefully, according international investors hire locals and establish international to Ghosh. “They should examine the option of partnering standards in the country.” with local players, investing in the development of local sales The advances made by Indian companies in Myanmar have also force and launching product portfolios that offer incentives for prompted foreign players to look into the potential investment purchases across its portfolios.” opportunities in the country. Indian companies constitute 35% Ghosh added, “At this stage, the country is facing uncertainties to 40% of the market followed by companies from Bangladesh, relating to the political landscape especially with rising ethnic China, Indonesia, Pakistan, Thailand, and Vietnam. “Given that the tensions, changes in regulations and the need for greater per capita pharmaceuticals expenditure is still rather low, generic infrastructure improvement. Therefore, it is advisable for and over-the-counter drug companies will stand to benefit more in international companies planning to penetrate the Burmese the short to medium term,” commented Abhijit Ghosh, healthcare market to collaborate with a local partner, particularly in the area and pharmaceutical leader at PwC Singapore, in an interview of distribution.” International industry players should also consider with Pharmaceutical Technology. “This is why many Indian investing in manufacturing plants in Myanmar and hiring or pharmaceutical companies such as Ranbaxy Laboratories and developing a local support team to further their business interest. Cipla continue to play a dominant role in the Burmese market.” Such plans will better position companies to take advantage of the In 1993, Haryana-based Ranbaxy Laboratories set up business expected future economic growth in Myanmar. in Myanmar after receiving its first drug approval from the local The good news is that the Burmese government is introducing Food and Drug Administration (FDA). The company then went on reforms to improve the healthcare sector. It is reallocating to establish a branch office in 1997 with more than 175 approvals budgets to an expanded national pharmaceutical formulary,

to date. Recently, Mumbai-based Sun Pharmaceutical Industries according to Varun Sethi, general manager of the Business Unit PERAWONGMETHA/FLICKR/GETTYATHIT IMAGES

44 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Lots of imitators. ONLY ONE TRUE INNOVATOR.

6eij^i Xdci^cjZh id WZ i]Z ^cYjhign aZVYZg ^c hda^Y hiViZ X]Zb^hign# Djg edanbdge]^hb! XgnhiVaa^oVi^dc! hVai! Xd"XgnhiVa VcY Vbdge]djh hXgZZc^c\ VcY hZaZXi^dc XVeVW^a^i^Zh ]VkZ aZY i]Z lVn i]gdj\] ]^\]"ZcY egdXZhh YZkZadebZci! bZi]dY YZkZadebZci! VcVani^XVa VcY >E hjeedgi# 6cY WZXVjhZ lZ¼gZ ValVnh add`^c\ [dg i]Z bdhi ZmeZY^i^djh VcY gZa^VWaZ dei^dch id hjeedgi ZVgan YZkZadebZci! lZ cdl d[[Zg 9^hXdkZg HXgZZch!ž V lZaa YZh^\cZY hZg^Zh d[ [Vhi! adl eg^XZY hXgZZch# Contact us today to learn more.

The Crystallization Experts®

lll#hhX^"^cX#Xdb™lll#Veij^i#Xdb ^c[d5hhX^"^cX#Xdb™ZmeZgi^hZ5Veij^i#Xdb -%%"(,*"'&,.dg &,+*")+("%&&'

Visit us at AAPS, Booth 2505 Healthcare at Diethelm Keller Siber Hegner (DKSH) Myanmar. with challenges in compliance and infrastructure. Therefore, the DKSH has been operating in Myanmar for more than 15 years selection of a trusted market-expansion services partner that and is one of the country’s most comprehensive distribution knows the local market is essential. There are plans to increase the infrastructures for pharmaceuticals, over-the-counter products, number of drugs as part of the government’s sponsored healthcare and medical devices. The company currently employs more scheme but implementation is still in its early stages,” said Sethi. than 550 employees in its business unit. The 2013 government Industry players have expressed mixed feelings about the budget has set aside $450 million in healthcare spending future of Myanmar’s pharmaceutical sector. “While some whereby a large portion would be allocated to pharmaceuticals are hopeful of the future, others harbor cynicism about the as part of the plan to make available the expanded national willingness of the past government who remain in the current formulary to public hospitals. Plans have been announced to political hierarchy to embrace meaningful reforms that would increase spending on pharmaceuticals from $0.20 per person drive further investment into the country’s infrastructure, per annum to $2 per person per annum in the next two years. healthcare, and education systems,” remarked Ghosh. “The If this proposal materializes, pharmaceuticals will account government, therefore, needs to embrace a policy of greater for approximately $125 million, which represents 27.4% of transparency, make additional investments in infrastructure to the 2012–2013 healthcare budget (1). Part of the budget will help improve connectivity, and facilitate further reforms that will also go towards increasing the number of doctors from local directly benefit people across this country.” medical schools. Other initiatives by the government include reorganizing and strengthening Myanmar’s FDA workforce to References build additional capabilities in the area of drug registration. 1. Health Intelligence Asia, “Healthcare in Myanmar 2013—Myanmar Pharmaceutical Market & Devices Market Survey Report,” www. Projected growth healthintelasia.com/product/myanmar-pharmaceutical-market- Moving forward, Myanmar’s pharmaceuticals sector is projected healthcare-in-myanmar-2013/#!prettyPhoto, accessed Sept. 9, 2013. to double from $430 million in 2012 to $660 million by 2015 with 2. Business Monitor International, “Myanmar Pharmaceuticals and the likelihood that branded products will gain popularity over the Healthcare Report Q3 2013,” www.marketresearch.com/Business- next two years (2). “However, the marketplace will remain highly Monitor-International-v304/Myanmar-Pharmaceuticals-Health- fragmented at both wholesale and pharmacy levels coupled care-Q3-7685877/, accessed Sept. 9, 2013. PT

Achieving new standards in performance takes years of innovative R&D. This is the result.

Vcaps® Plus hypromellose capsules for pharmaceutical products Secondary gelling agents and ionic gel promoters – used by other HPMC capsules – may slow down release of active ingredients. Capsugel’s Vcaps® Plus HPMC capsules are made through a proprietary manufacturing process that eliminates the need for gelling systems. They disintegrate and release their contents independent of pH and ionic strength of the test media. Download our free whitepaper Visit us at booth #2012 to discover how Vcaps® Plus capsules can optimize at AAPS 2013 in performance, improve product stability, and reduce drug San Antonio, TX development times.

© 2013 Capsugel Belgium NV All rights reserved. VcapsPlus.com 888-783-6361

46 Pharmaceutical Technology OCTOBER 2013 PharmTech.com “Researchers at the Population Council are working to protect women’s lives.”

The No.1 cause of death among women of childbearing age is now AIDS.* This tragic fact inspires Council staff working around the world to develop new techniques and practices to slow the epidemic. We’re proud to say that scientists in the Council’s New York lab are using a Ross Double Planetary mixer in their quest to create a microbicide that is safe for humans – and deadly for the virus that causes AIDS. Learn more. 1-800-243-ROSS www.mixers.com www.popcouncil.org

*World Health Organization, September 2009

Desmond Allen, Mechanical Engineer, Ross Employee Owner

Scan to learn more. Free Tag Reader: http://gettag.mobi Report from: Middle East and North Africa Jill E. Sackman

The pharmaceutical industry grows despite conflict in the Middle East. DOHA, QATAR

he Middle East and North Africa have been rocked in recent Tyears by upheaval ranging from moderate protest to full-scale The region shares a revolution, leading to a variety of changes in government with more changes to come. Medical products companies such as common thread: each GE Healthcare, however, have described the region as a “hidden jewel,” citing rapid spending growth by the various government country struggles with ministries, resulting in new and growing hospitals (1). On the pharmaceutical side, countries like Morocco have enacted balancing a shift toward legislation in the past decade to attract foreign investment in the country. While the Middle Eastern environment remains modernity with strong unsettled, the market for pharmaceutical products is still expected to grow in many countries across the region. traditions rooted in the

Middle East health and past. pharmaceutical market overview Many consider the Middle East to be a group of closely related, Levant includes Jordan, Lebanon, Syria, and Israel. North Africa culturally uniform states with relatively similar forms of is comprised of Algeria, Egypt, Libya, Morocco, and Tunisia. governance and levels of infrastructure. In fact, the region known GE’s observation that rapid spending growth in the Middle East as the Middle East contains a mixture of countries with significant has made it a “hidden jewel” is not merely anecdotal. Qatar, for differences in wealth, standard of living, and healthcare system example, went from spending US$1561 per capita on healthcare sophistication. The region, however, does share a common in 2010 to US$1920 in 2011, and the Ministry of Health’s Primary thread: each country struggles with balancing a shift toward Health Care Corporation has called for additional spending modernity with strong traditions rooted in the past. This effort is increases from now until 2022 (2). Qatar has also announced particularly evident in gender disparities in healthcare. plans to introduce a form of social health insurance by 2016. Geographically, the Middle East is divided into two main Other countries in the region, including those much poorer regions: Western Asia and North Africa. Western Asia includes than Qatar, have also begun working on increasing access to the Gulf Council countries of Bahrain, Kuwait, Oman, Qatar, health insurance. Morocco, for example, launched a program Saudi Arabia, and United Arab Emirates (UAE); these countries called Regime d’Assistance Medicale (RAMED) in 2012, offering are considered middle-income due to the influence of oil. The economic assistance to pay for medical care to 8.5 million

Persian Plateau includes Iran, Afghanistan, and Pakistan. The people (28% of the overall population) (3,4). WAJAHAT/FLICKR OPEN/GETTY IMAGES

48 Pharmaceutical Technology OCTOBER 2013 PharmTech.com A New Vision of Perfection. A New Class of Sterile Filtration.

www.sartorius-stedim.com/platinum turning science into solutions These two cases illustrate the vast difference in wealth across two countries as requiring review. In Algeria, PhRMA cites weak the region. The International Monetary Fund places the Gross patent protection, government-mandated price referencing, and Domestic Product based on purchasing power parity per capita importation restrictions as barriers to market access. The lobbying for Morocco at US$5265 in 2012, compared to US$102,211 in group does note that it is encouraged by the Minister of Health’s Qatar (5,6). Still, the governments in both countries are working announcement at a PhRMA meeting that the government would to improve access to care for their citizens. reduce the review time required for marketing authorization and In contrast, Jordan has served as a medical tourism increase intellectual property protection. destination for decades, but its healthcare system faces new In Lebanon, PhRMA notes some regulatory reforms that have challenges as a result of the Arab Spring. In 2010 and 2011, improved market access, but still argues that Lebanon needs to protests, government changes, and regional unrest led to make further changes. In particular, the group cites ineffective declining medical tourist numbers (7). More recently, refugees data protection, the lack of a regulatory system to monitor and from civil war-stricken Syria have overwhelmed the Jordanian confirm bioequivalence studies, and the existence of a “grey healthcare system. Jafar Hassan, Jordan’s minister of planning market” for medicinal products (11). and international cooperation, has expressed concern that resources in the country simply would not be enough to meet Implications for successful market the needs of the 2000 Syrian refugees coming into the country entry and in-region partnering every day (8). Jordan does serve as a major manufacturer of Despite regional conflict and social and economic upheaval in pharmaceuticals, exporting the majority of its drugs to other the Middle East, it is likely that there will be a surge in demand Arab countries (9). for healthcare products and services over the next few years. Socio-economic advancement, including increased disposable income and access to modern goods and services, is leading to Despite regional conflict changes in the region’s nutritional and lifestyle habits, increasing the frequency of lifestyle-related health concerns, such as obesity, and social and economic diabetes, and heart disease. As the standard of living in the region generally improves, upheaval in the Middle healthcare providers will face rising expectations for more and better quality services. These expectations, together East, it is likely that there with population growth and increasingly educated consumers (patients), will likely drive investment in hospitals and medical will be a surge in demand facilities, and increase demand for innovative drugs, healthcare services, and the latest medical technologies. for healthcare products Regionally, many countries (i.e., UAE, Qatar) are setting standards that provide state-of-the-art healthcare services, not and services over the next only for the growing local population, but also for expatriate workers and patients seeking high quality medical care. In few years. contrast, other countries in the region are struggling with overburdened government-run health systems and are turning Overall, according to the Central Intelligence Agency’s (CIA) to the private sector to provide much-needed investment and World Factbook, the population is growing in every Middle expertise (i.e., Kuwait). Eastern and North African country, and is generally younger than In light of predictions that the region’s healthcare market is the emerging markets of Southeast Asia and Korea. Demand expected to continue growing over the next few years (compared for healthcare products is growing as the population increases, to the low growth predicted in the mature markets of the US and but demographically, this region does not have the same health Europe), the Middle East seems like a good place to turn to for requirements as the aging populations characterizing many investment. developed markets in 2013 (10). Perhaps unique to the region is the social demand to make healthcare focused on serving the needs of the population rather Key regulatory considerations than strictly profit making. Zakat, the Islamic principle of charity, Regulations vary considerably across the region. Turkey, for is the driving force behind this perspective. Regional governments example, has introduced market exclusivity as part of its efforts to are interested in supervising and regulating the healthcare sector become a European Union (EU) member state and has introduced to ensure that private healthcare players fully understand, and other reforms to bring greater consistency with the rest of the EU. embrace, this concept and preserve the existing culture. Enforcement remains an issue, and the EU has rejected several of Turkey’s GMP certificates. Moving forward in the Middle East The Pharmaceutical Research and Manufacturers of America Population growth, rapid economic growth, and a willingness to (PhRMA) has flagged Algeria and Lebanon as being particularly invest in capital projects will likely make the Middle East a major concerning for manufacturers. In a report to the Office of the growth focus for the healthcare market over the next few years. United States Trade Representative, PhRMA called out these Some of the biggest opportunities will likely be in healthcare

50 Pharmaceutical Technology OCTOBER 2013 PharmTech.com 10. CIA, The World Factbook 2013-14 (Washington, DC: Central Intel- infrastructure initiatives, which has already attracted GE and ligence Agency, 2013). Siemens, both of which have large infrastructure businesses and 11. PhRMA, “Special 301 Submission 2013,” Pharmaceutical Research serve as major suppliers of healthcare IT and diagnostic imaging and Manufacturers of America (PhRMA) (2013). PT technologies. GE recently opened their new headquarters in Dubai Internet City, as well as a production facility in Saudi Arabia to —Jill E. Sackman, D.V.M., PhD, is a manufacture diagnostic imaging systems. senior consultant at Numerof & Associates, Inc. As the standard of living in the region generally Key Points improves, healthcare t
While the Middle Eastern environment remains unsettled, the market for pharmaceutical products is still expected providers will face rising to grow in many countries across the region. expectations for more and t
The Middle East contains a mixture of countries with significant differences in wealth, standard of better quality services. living, and healthcare system sophistication.

Creation of ‘free zones’ for foreign companies, including t
Regulations vary considerably across the region. full ownership and tax benefits, are likely to attract more organizations to the region. Recent increases in foreign direct t
The population is growing in every Middle Eastern and investment particularly in biotechnology research, is fueling North African country and is generally younger than growth in the market for biotechnology products. Leading the emerging markets of Southeast Asia and Korea. international biotech companies, including Amgen and Genzyme, have

Stability already set up operations in DuBiotech vaccines and biologicalsconditions available Storage - IntellimapNew Temperatureconditionsrooms, availableand Humiditychambers,- including FreezerCycling freezers testing CabinetStorage andservice warehouses - Intellimap New Temperatureconditionsrooms, availableand Humiditychambers,including StorageCycling freezerstesting serviceCabinetICH and conditions warehouses rooms, and chambers, and unique CalibrationHumidity conditionsfreezers and Cycling available warehousesTemperature Cabinet FreezerICH conditions Storage- A full and range unique of (Dubai Biotechnology & Research Park), Storage with smaller companies certain to join them. - A full range of ICH conditions and unique conditions for available tissues, vaccines and biologicals ® ® When you need a Vindon’s disruption-free validation for rooms, chambers, freezers Vindon’s and warehouses disruption-free validation for rooms, chambers, freezers and warehouses Freezer Storage- A full range of ICH conditions and unique conditions available

References for tissues, vaccines and biologicals Pharma -or Intellimap Biopharma

-80ºC Ultra-Low Temperature Freezer Storage -80ºC Ultra-Low Temperature Freezer Storage -80ºC Ultra-Low 1. N. Parmar, The National (Jan. 25, 2012). Cabinet outsourcing partner 2. F. Astorri, “Qatar Needs More Healthcare Validation and Calibration New Temperature and Validation and Calibration - including testing service you® can trust Vindon’s disruption-free validation for Staff, Funding,” arabianbusienss.com - including for testing tissues, service vaccines and biologicals disruption-free validation for rooms, chambers, freezers and warehouses (June 10, 2013). for tissues, 3. WHO, “Constraints and obstacles to We’ve got it covered social health protection in the Maghreb: Stability Storage the cases of Algeria and Morocco” (World Stability Storage Stability Storage Stability Storage Health Organization, October 2011). New Temperature and -80ºC Ultra-Low Temperature Freezer 4. “The King of Morocco Officially conditions available $
Stability Storage & Testing Launches the RAMED Plan for Medical - including testing service - including testing service New Temperature and Humidity Cycling Cabinet - Intellimap Validation - Intellimap Assistance,” The Maghreb Daily (Septem- Validation and Calibration $
-80ºC Ultra-Low Temperature Freezer Storage - A full range of ICH conditions and unique ber 2012). Freezer Storage

5. “Report for Selected Countries and Sub- - A full range of ICH conditions and unique - A full range of ICH conditions and -unique A full range of

® Vindon’s disruption-free validation for New Temperature and Humidity Cycling $
Temperature® and Humidity jects: Morocco,” International Monetary biologicals Vindon’s disruption-free validation for Humidity Cycling Cabinet for tissues, vaccines and biologicals for tissues, vaccines and biologicals Fund (April 2013). -80ºC Ultra- Cycling Testing 6. “Report for Selected Countries and Sub- -80ºC Ultra-Low Temperature for tissues, vaccines and Humidity Cycling Cabinet $
Validation and Calibration jects: Qatar,” International Monetary -80ºC Ultra-Low Temperature Validation and Calibration Validation and Calibration Fund (April 2013). New Temperature and 7. “Jordan: Managing Medical Tourism,” Low Temperature The Oxford Business Group (Feb. 2, - including testing - Intellimap 2012). Vindon 8. Sen, Ashish Kumar, “Official: Syrian service Stability Stability Vindon California $ Santa Fe Springs, Vindon Atlanta $ 300 Townpark Drive, - ® Refugees Straining Jordan’s Resources,” Vindon’s The Washington Times (Feb. 12, 2013). Orange County, California, 90670 Bld. 1, Suite 130, Kennesaw, GA, 30144 9 “Pharmaceutical Industry,” The Jor- Tel: +1 562 944 4466 Tel: +1 770 988-3095

danian Association of Pharmaceutical www.vindoncalifornia.com www.vindonscientific.com Manufacturers (August 2013).

Pharmaceutical Technology OCTOBER 2013 51 Cover Story: Tableting

Laboratory of Biophysics and Surface Analysis, both in the United King- dom, is developing a predictive tool to identify the best punch or die-coating solution to prevent sticking in a given formulation. The company says that the tool will provide quick guidance without time-consuming tests (2). TSAR-program researchers used atomic force microscopy (AFM) to map the adhesive forces on a tablet-punch face, such as the example shown in Figure 1. AFM can elucidate local chemical and mechanical properties, such as adhe- sion and elasticity, and even molecular Tablet-Sticking Solutions bond rupture strength, explains Rob Blanchard, research, development, and Screening methods and predictive models quality systems manager at I Holland. Such adhesion maps show differences in address tenacious tablet-sticking problems. adhesion caused by surface topography differences with various coatings at dif- Jennifer Markarian ferent humidities. The TSAR researchers also used X-ray photoelectron spectros- copy (XPS), Raman spectroscopy, and ablet sticking, in which material for damage or wear, repairing, measur- time-of-flight secondary ion mass spec- adheres to the surface of a tablet- ing to ensure that dimensions are main- trometry (TOF-SIMS) to visualize the Tpunch face, is an ongoing and tained, polishing, lubricating, and storing chemical distribution of selected ions on costly problem in pharmaceutical man- properly (1). the surface and better understand the in- ufacturing and is a significant issue for Microscopy can be used to assess teractions involved in sticking. Principle drug-product formulators. Analytical the surface of a punch. “You can’t see component analysis (PCA), a multivariate methods can be used to troubleshoot a 10-μ scratch with the naked eye, but statistical technique, is being used to ana- sticking problems and develop screen- 2-μ particles will stick to it. Suddenly, lyze these data and generate correlations ing methods. Experts are also seeking you have a film spot that acquires more to explain how the chemistry of a system to increase fundamental understand- powder and is then big enough to cause affects adhesion with different surface ing of the underlying causes of sticking defects,” explains Charles Kettler, di- coatings. This understanding of how the and to develop predictive models to rector at Natoli, a tooling and equip- formulation components behave and in- more quickly find solutions to specific ment manufacturer. “Microscopy teract to cause sticking will then be used sticking problems. allows you to see if the tool has a fun- to develop the predictive tool. The pre- Many variables affect tablet sticking, damental problem.” This type of analy- dictive tool will be validated using results including formulation (e.g., API, ex- sis could be used to identify a problem from compression experiments with vari- cipient, and other components), gran- with tool handling, such as whether a ous formulations and punch-tip coatings. ulation properties (e.g., particle-size polishing technique is more aggressive Although proper maintenance and distribution), tablet design (e.g., tablet than it should be. optimized coatings are essential, the shape), tablet-press conditions, tablet- Equipment suppliers have also de- root cause of sticking is often the for- tool properties, and tool maintenance. veloped special steel types and coat- mulation properties or particle size. If There are nearly as many possible solu- ings to prevent sticking. Finding the these properties are already set, man- tions as there are variables. best material, however, can be a time- ufacturers must find a solution in the consuming process that involves field tablet press or tooling. Ideally, however, Tooling solutions testing at a customer’s site and labo- the drug could be formulated to have a Tooling-equipment suppliers have found, ratory testing to identify a solution lower tendency for sticking. for example, that proper tooling and tool- to each unique problem. I Holland’s ing maintenance can help prevent stick- Tableting Science Anti-Stick Research Screening tools ing to a certain extent. I Holland cham- (TSAR) program, in collaboration with Various methods are available for as- pions a rigorous seven-step maintenance the University of Nottingham’s School sessing sticking problems and screen-

method that includes cleaning, assessing of Pharmacy and experts from the ing for sticking propensity, but the BOTVIDSSON/GETTY IMAGES; DAN WARD MARTIN

52 Pharmaceutical Technology OCTOBER 2013 PharmTech.com See us at AAPS Booth # 3541

NEXT GENERATION TABLETING TECHNOLOGY

NEW FE SERIES + Design – Simplicity as a key to efficiency + 360° accessibility + Guaranteed easy and safe operation www.fette-compacting.com

Fette Compacting America, Inc. 400 Forge Way Rockaway, N.J. 07866, USA Phone +1 973-586-8722 Fax +1 973-586-0450

www.fetteamerica.com Cover Story: Tableting

use of these tools has been limited by their complexity. Many instead rely Figure 1: An adhesion map shows different adhesive forces on a tablet-punch face. on subjective visual inspection, which 10 limits the ability to screen consistently. 45.00 To address this deficit, researchers at 39.38 33.75 Pfizer developed a simple, quantitative 8 28.13 screening tool for drug-product tablet- 22.50 sticking propensity that can be used to 16.88 rank the degree of sticking for many 6 11.25 5.625 formulations and their ingredients 0.000 using a custom tableting punch with a Force (nN) tip that can be removed to measure the 4 amount of adhered powder (3). “This (μm) Scan area gravimetric method has been success- 2 ful for classifying sticking severity during drug product design and has significantly reduced risk during scale 0 up,” says Matthew Mullarney, principal 0246810 scientist at Pfizer. “We can customize Scan area (μm) both our API and drug-product for- mulations to ensure they do not exceed in-house threshold values in the labo- can also be used to plan for manu- ing requirements) and to troubleshoot ratory before manufacturing any bulk- facturing campaigns (e.g., tooling/ the root cause of sticking problems in

FIGURE 1 IS COURTESY OF I HOLLAND. FIGURE 1 IS COURTESY tablet supplies.” The screening method tablet inspection frequency or clean- large-scale manufacturing.

External lubrication: A solution for tablet sticking Equipment suppliers are seeing increased interest in using external lubrica- the tooling can be used instead of external lubrication, adds Rob Blanchard, tion to eliminate tablet sticking, address excessive ejection forces, or provide research, development, and quality systems manager at I Holland. Lubricating an alternative to using a lubricant in the formulation if the lubricant causes systems will not be used for every formulation, but they are being used com- problems with dissolution or hardness. In this method, a lubricant (typically mercially as a solution for some problematic tablets. magnesium stearate) is suspended in air, and using a nozzle mounted near External lubrication also benefits products in which a lubricant in the formu- the tablet takeoff, a fine layer of the suspension is sprayed onto the exposed lation causes problems (e.g., with dissolution or hardness). Magnesium stearate upper and lower punch faces and die wall. is nonsoluble in water and, at concentration levels used in traditional tablet For some difficult products, this method can significantly reduce tablet formulations (0.5% to 2%), it can create hydrophobic bridges that can delay sticking or ejection forces. Tablet geometries with a large sidewall surface dissolution with a significant impact on the release profile of the API(s), notes area, for example, may have a high degree of friction between the tablet Michel. Because the external lubricant is sprayed directly where it is needed, it and the die wall. The external lubricant can be sprayed on the die wall to can be used at much lower levels (below 0.1%). External lubrication may thus reduce friction and eliminate the need for excessive ejection forces, which be helpful for some poorly soluble APIs. External lubrication is also frequently can potentially damage equipment, says Fred Murray, president of KORSCH used to produce effervescent tablets; reducing the amount of the poorly water- America, a tablet-press manufacturer. soluble magnesium stearate in the formulation avoids a “white film effect” Using external lubrication to reduce ejection force and scrape-off force upon dissolving in water, comments Michel. Research by Eurand (now Aptalis) helps lengthen the life of punch heads, punch faces, ejection cams, and found that external lubrication could be used to improve the dissolution and scrape-off bars used on tablet presses. It also helps reduce the amount of disintegration rate for orally disintegrating tablets (1). In some cases, inter- broken tablets, which minimizes downtime and production interruptions nal lubricants can degrade tablet hardness. Research done by Pfizer showed while maximizing yields, adds Nic Michel, general manager, North America that external lubrication can significantly improve tablet hardness compared for equipment manufacturer Pharma Technology Inc. (PTI). to internal lubrication over a range of compression forces (2). This research In some cases, external lubrication reduced ejection forces as much as 50%, found a consistent amount of magnesium stearate across the tablet surface and and lubrication was found to improve the integrity of the outer tablet edge, throughout the tablet run. adds Matt Bundenthal, direct sales manager at equipment manufacturer Fette References Compacting America. 1. Eurand, “Specialized techniques for developing ODT dosage forms,” Ap- Although external lubrication does not have a dramatic effect on every plication Note, www.americanpharmaceuticalreview.com/1488-White- Papers/120463-Specialized-Techniques-for-Developing-ODT-Dosage- product, in some it makes a big difference, comments Bundenthal. Lubricating Forms/, accessed Sept. 6, 2013. systems add cost and complexity, including additional cleaning requirements, 2. J.Nelson, et al., “Consistency of Magnesium Stearate Content Using Exter- nal Lubrication in Tablet Compression,” poster presentation at AAPS An- notes Murray. Manufacturers may choose an alternative solution. A coating on nual Meeting & Exposition (Atlanta, Georgia, 2008).

54 Pharmaceutical Technology OCTOBER 2013 PharmTech.com DĂŬĞƚŚĞSMART move ƚŽW&ͲϰͬKƌŐĂŶŝĐƐ

/ĚĂƚĂďĂƐĞƐĂƌĞƚŚĞŽŶůLJĐƌLJƐƚĂůůŽŐƌĂƉŚŝĐĚĂƚĂďĂƐĞƐŝŶƚŚĞǁŽƌůĚ ǁŝƚŚƋƵĂůŝƚLJŵĂƌŬƐĂŶĚƋƵĂůŝƚLJƌĞǀŝĞǁƉƌŽĐĞƐƐĞƐƚŚĂƚĂƌĞ/^KĐĞƌƟĮĞĚ͘

Standardized data More coverage All data sets are evaluated for quality RĞǀŝĞǁĞĚ͕ĞĚŝƚĞĚĂŶĚĐŽƌƌĞĐƚĞĚƉƌŝŽƌƚŽƉƵďůŝĐĂƟŽŶ TĂƌŐĞƚĞĚĨŽƌŵĂƚĞƌŝĂůŝĚĞŶƟĮĐĂƟŽŶĂŶĚĐŚĂƌĂĐƚĞƌŝnjĂƟŽŶ ĐŽŵƉƌĞŚĞŶƐŝǀĞĚŝīĐŽŵƉƌĞŚĞŶƐŝǀĞĚŝīƌĂĐƟƌĂĐƟŽŶĚĂƚĂďĂƐĞĨŽƌƉŚĂƐĞŝĚĞŶƟŽŶĚĂƚĂďĂƐĞĨŽƌƉŚĂƐĞŝĚĞŶƟĮĮĐĂƟĐĂƟŽŶ͕ŽŶ͕ ĨĞĂƚƵƌŝŶŐϰϳဓ͕ϮϳဒŽƌŐĂŶŝĐĂŶĚŽƌŐĂŶŽŵĞƚĂůůŝĐĐŽŵƉŽƵŶĚƐ͘ĨĞĂƚƵƌŝŶŐϰϳဓ͕ϮϳဒŽƌŐĂŶŝĐĂŶĚŽƌŐĂŶŽŵĞƚĂůůŝĐĐŽŵƉŽƵŶĚƐ͘

ICDD, the ICDD logo and PDF are registered in the U.S. Patent and Trademark Offi ce. Powder Diff raction File is a trademark of JCPDS—International Centre for Diff raction Data. Cover Story: Tableting

Equipment supplier Natoli finds this nership with Long Island University’s “Now that simpler tools are available gravimetric method useful for predicting Arnold and Marie Schwartz College for screening and classifying, both phar- the sticking tendency of formulations at of Pharmacy in New York. Laboratory maceutical companies and academic or prior to clinical-scale production and facilities for the institute are currently groups can focus on relating other mate- has tested small amounts of API with a being constructed at the university and rial properties, such as molecular struc- given formulation, tablet design, and tool are expected to open in late 2013 with ture, particle size, and mechanical prop- steel and coating for propensity to stick- fully qualified equipment, reports Ket- erties, to sticking and building models ing (2). Further work using this method tler. Various projects at the institute will that describe the sticking mechanism,” will be performed by researchers at the be used to further develop fundamental adds Mullarney. “We may soon find that Natoli Institute of Industrial Pharmacy understanding of tableting problems and sticking is multimechanistic, and a vari- Development and Research in part- formulation studies. ety of molecular chemistry, particle, and bulk-powder characterization tools and models will be needed to pa- rameterize the sticking mechanisms of different powders.” Once these Quality Products... mechanisms are understood, APIs and drug products can be designed Quality Service to reduce sticking propensity. Cur- rent work at Pfizer is focused on un- derstanding why some APIs appear stickier than others and investigating the contribution of a solid API’s mo- lecular attributes (e.g., surface chem- istry and morphology) to sticking. “Both computational models and experimental approaches will be necessary to get us closer to the root causes. Additionally, tooling designs Compact Multiport and surface treatments are also being studied,” notes Mullarney. ■ Unique Automation Model predicts tablet microstructure Concepts Work on building models to de- Steam Valve ■ Solution Driven scribe sticking is progressing. Mar- cial Gonzalez and Alberto Cuitino ■ Innovative Product at the Engineering Research Center Bonnet with Development for Structured Organic Particulate lockout device Systems (C-SOPS) at Rutgers, the ■ Customized State University of New Jersey, have Multiport Solutions developed mechano-chemical mod- ■ Pro-active Project els and computational methods that Management predict the evolution of microstruc- ture and interparticle forces during powder compaction. Because most properties of a compacted tablet can be attributed to its microstructure, 650 w/1235 the models can be used as tools to Tank Valve Illuminated Switch understand and predict how man- ufacturing process variables affect product performance. 3800 CAMP CREEK PKWY. The tendency of powders for #
 
>
!#"
 A""


  sticking and picking is described PHONE: 678-553-3400 by the adhesion of powder to die FAX: 678-553-3459 www.gemu.com walls and tool surfaces and can be explained by a competition mecha-

56 Pharmaceutical Technology OCTOBER 2013 PharmTech.com From Discovery to Clinical— Five Reasons to Choose MPI Research

Visit us at Speed ""14
CPPUI
 MPI Research takes your analytical project from first dose to final study in as little as 19 days—less than half the industry standard. That’s unprecedented among clinical research organizations. It’s an edge that we’re proud to offer our Sponsors in a highly competitive field. Quality MPI Research understands that each project is unique and that each Sponsor has distinctive needs. We work hand-in-hand with our Sponsors to custom-design studies to meet their highest standards. Our Sponsors can be sure that despite having the fastest turnaround in the industry, our commitment to quality is uncompromised. Compliance MPI Research is proud of its regulatory compliance record, and we are confident that ourS ponsors will be impressed with comparisons to any other CRO. t
0VS
GBDJMJUJFT
BSF
JO
GVMM
DPNQMJBODF
XJUI
JOUFSOBUJPOBM
&.&"
0&$%
*$)
+.)8
GFEFSBM
'%"
&1"
64%"
BOE
TUBUF
SFHVMBUPSZ
SFRVJSFNFOUT t
0VS
.BUUBXBO
GBDJMJUZ
IBT
JOUFSOBUJPOBM
"""-"$
BDDSFEJUBUJPO t
3FHJTUFSFE
RVBMJUZ
BTTVSBODF
2"
QSPGFTTJPOBMT
QSPWJEF
EFEJDBUFE
GVMMUJNF
2"
TFSWJDFT t
3FDFOU
'PPE
BOE
%SVH
"ENJOJTUSBUJPO
'%"
TVSWFJMMBODF
JOTQFDUJPOT
PG
CJPFRVJWBMFODF
TUVEJFT
TQFDJöD
UP
PVS
CJPBOBMZUJDBM
MBCT


yielded no Form 483 observations. &YQFSJFODF MPI Research staff has nearly 100 years of combined experience in customized development and validation of methods for small molecules and biologics. We are proud to employ some of the most knowledgeable TDJFOUJöD
FYQFSUT
JO
UIF
JOEVTUSZ Skill Set The science team at MPI Research applies the latest technology and methods that Sponsors will not find at the average CRO. The synergy of TUBUFPGUIFBSU
CJPBOBMZUJDBM
GBDJMJUJFT
DPNQSFIFOTJWF
FYQFSUJTF
USBEJUJPOBM
and elemental methods, high throughput, and rapid turnaround drives faster, better decisions.

For more information, visit www.mpiresearch.com.

® Cover Story: Tableting

nism between interparticle bonding Figure 2: A fully discrete model developed by the Engineering Research Center for Structured and particle–wall adhesion, explained Organic Particulate Systems (C-SOPS) at Rutgers, the State University of New Jersey, predicts Cuitino (2). If particle–wall adhesion is a compaction curve showing the pressure applied by upper/lower punches (black line) and the stronger than interparticle bonding, the pressure experienced by the die wall as a result of powder compression (blue line). The insert weaker interparticle bonds will break illustrates tablet microstructural details and interparticle and particle-wall forces (thicker lines when the tablet is ejected and cause depict larger forces). Sticking and picking tendency can be understood from these forces. sticking or picking. If particle–wall adhesion is weaker than most inter- 250 Upper/Lower punch particle bonds, internal cracks might occur. Ideally, if enough bond strength 200 was developed during compaction, no defects will occur. If the network

Pa) of particle–particle and particle–wall

m 150 forces are known, competing effects ( can be quantified, said Cuitino. Be- Die wall 100 cause this measurement is not possible Relative density = 1.00 with current experimental techniques, the researchers developed a nonlocal Pressure 50 Insert shows network of formulation of contact mechanics that forces and position of more accurately describes the powder deformed particles for 0 the compacted powder bed system (4). This fully discrete model is based on particle mechanics and de- 0.5 0.6 0.7 0.8 0.9 1 scribes every particle in the powder bed Relative density as an individual entity. “The collective STRUCTURED ORGANIC PARTICULATE SYSTEMS AT RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY. RUTGERS, THE STATE SYSTEMS AT STRUCTURED ORGANIC PARTICULATE rearrangement and deformation of the THE ENGINEERING RESEARCH CENTER FOR OF MARCIAL GONZALEZ AT FIGURE 2 IS COURTESY

Quality pharmaceuticals start with precise ingredient feeding. Trust Schenck AccuRate’s PureFeed® feeding equipment for optimal accuracy.

When it comes to precise ingredient feeding, Schenck AccuRate, a Schenck Process Group company, has spent over 40 years providing effective solutions for pharmaceutical manufacturing processes. We work closely with our customers to design products that meet specifi c application needs. The PureFeed® feeders were a result of customer input leading to a number of product features important to pharmaceutical manufacturers. They include: Ê UÊÀ>ۈ“iÌÀˆVÊ>VVÕÀ>VˆiÃʜvÊ´ä°ÓxÊ̜£¯ Ê UÊii`ÊÀ>ÌiÃÊ>ÃʏœÜÊ>ÃÊÓäÊ}À>“ÃÊ«iÀÊ œÕÀ Ê UÊÎÓʓˆVÀœˆ˜V Ê,>ÊwʘˆÃ iÃ Ê UÊ+ՈVŽÊ>˜`Êi>ÃÞÊ`ˆÃ>ÃÃi“LÞÊvœÀÊVi>˜ˆ˜}Ê>˜`ʓ>ˆ˜Ìi˜>˜Vi Ê UÊ6>Àˆ>LiÊëii`ÃÊ>˜`Ê œ««iÀÊ>}ˆÌ>̈œ˜Ê`i«Ì ÃÊvœÀʜ«Ìˆ“>Ê«Àœ`ÕVÌÊyʜÜ

Call us today for information on our ingredient feeding capabilities.

Schenck Process 746 E Milwaukee Street 7 ˆÌiÜ>ÌiÀ]Ê7ÊxΣ™ä * œ˜i\Ênää‡xxn‡ä£n{ E-mail: [email protected] Web site: www.accuratefeeders.com

58 Pharmaceutical Technology OCTOBER 2013 PharmTech.com powder bed is resolved by the fully discrete model and The PDA Training the microstructure of a compacted specimen is then pre- dicted,” explains Gonzalez. & Research These computational models are capable of resolving and Institute – tracking the micro-structural evolution of a powder bed com- pacted into relative densities close to 1 (i.e., into a solid tablet Where Excellence with porosities close to 0, which is typical of pharmaceutical Begins products). Figure 2 shows a compaction curve predicted by the model; the black line corresponds to the pressure applied by upper/lower punches in order to achieve a given relative density, and the blue line corresponds to the pressure expe- Turn your 60 classroom rienced by the die wall as a result of powder compression. knowledge into and lab courses The right-hand side of the insert in Figure 2 illustrates the action in one of designed to meet microstructure of the tablet with spherical particles of differ- the labs – the challenges ent sizes. In the left-hand side of the insert in Figure 2, lines you face – illustrate the network of interparticle forces and particle–wall  Microbiology forces predicted by the model, with stronger forces indicated  Biochemisty  Aseptic by thicker lines.  Cleanroom Processing  Biotechnology Experimental techniques, such as a tablet-press sim- Learn from  Environmental ulator and a tablet-hardness test, are used to calibrate industry Monitoring material properties employed by the model (e.g., elasto- experts who – plastic constants and fracture toughness of the particles).  Filtration  Developed it The model can be used to predict powder behavior and  Validation  Invented It properties for given tablet-press conditions (e.g., tooling  Quality Control  Tested It geometry and punch displacement) and powder formula-  Regulatory  Know It tion (e.g., the total mass and particle-size distribution of Affairs each component of the formulation). Other work in the early stages at C-SOPS uses to- Begin Your Excellent Experience mography to measure the density gradients across the Today at the PDA Training & tablet at different compressions. These measurements can identify internal cracks or other near-surface defects Research Institute. that cannot be detected visually. These defects can be correlated to the shape of the tooling (e.g., punch shape). www.pda.org/courses “Given this information, one can optimize the shape of Tel: +1 (301) 656-5900 | [email protected] the punch in order to minimize internal defects or avoid the formation of areas prone to chipping or capping,” Enter Campaign Code: TRIclasses on your explains Gonzalez. registration form Conclusion Current research is adding to the understanding of how adhesive forces and particle interactions cause sticking, and researchers are building models to elucidate sticking mechanisms. Results will be used to find better solutions to sticking problems by optimizing tooling and, eventu- ally, improving API and drug-product formulations. References 1. T. Higgins, Pharm. Tech. 37 (2) 36-37 (2013). 2. J. Markarian, Equipment & Processing Report (EPR), “Re- searchers Seek Solutions to Tablet Sticking”, online, Aug. 21, 2013, www.PharmTech.com/stickingsolutions, accessed Sept 6, 2013. 3. M. Mullarney, B. MacDonald, and A. Hutchins, Pharm. Tech. 36 (1) 57-62 (2012). 4. M. Gonzalez and A. M. Cuitino, J. Mechanics and Physics of Solids 60 (2) 333-350 (2012). PT

Pharmaceutical Technology OCTOBER 2013 59 Special Report: Drug Delivery

Metrics: Characteristics of the drug that influence absorption include particle size, solubility, lipophilicity, stability, ionization state (pKa), and polymorphism. Sometimes these characteristics work against each other to improve absorption. For example, a drug that is more lipophilic may increase permeability, but may result in lower solubility, thereby, decreasing the overall absorption. To overcome deficiencies of absorption due to drug properties, the dosage form may help improve absorption by altering the disintegration and dissolution time, increasing residence time in the intestine, and providing delayed release in the lower intestine instead of the stomach. Evaluating Strategies for The absorption of the drug through the GI tract is governed by either a Oral Absorption Enhancement simple passive diffusion or active transport with the aid of transporters located in the GI tract. For most drugs, Adeline Siew, PhD passive diffusion is the mode of trans- port. The amount of drug absorbed is dictated by the gradient created across Formulation scientists tackle the the membranes in the stomach and the small intestine as well as the chemical challenges of improving drug absorption structure of the drug molecule itself such as the size and degree of ioniza- across the gastrointestinal membrane. tion. Size and absorption usually have an inverse relationship. Most drugs ormulation scientists tasked with formulations must, therefore, be able to are weak acid or bases, therefore, the developing oral formulations often withstand the hostile acidic environment pH of the stomach and the intestinal Fface many challenges such as drug of the stomach and the high enzymatic tract affects the degree of ionization instability in the acidic and alkaline activity in the small intestine, circumvent of the drug, which directly affects the environments of the gastrointestinal the inherently impermeable intestinal solubility of the drug in the GI tract. (GI) tract and unsatisfactory absorption epithelial barrier and the binding The stomach has a pH of between variations of compounds with poor capacities of the resident mucus and 1 and 2 while the intestine has a pH physicochemical properties such as low luminal contents, escape the efflux ranging from 4 to 8. With this environ- solubility or low permeability. system that pumps substances back ment, the intestine provides a wide pH The primary function of the GI tract is into the lumen, and evade first pass range for drugs to exist in their ionized to digest and absorb nutrients and water metabolism by the liver (3). Pharma- state, which increases their solubility while at the same time impede the entry ceutical Technology spoke with Anshul compared to the more lipid-soluble, of potentially noxious luminal contents Gupte, PhD, senior formulation un-ionized state. such as harmful pathogens and toxins. scientist, and Michael DeHart, PhD, Most of the absorption takes place This function is accomplished by the development scientist, from the CDMO in the intestine mainly because the establishment of intestinal barriers Metrics, about the strategies used to intestine offers much greater surface formed by a continuous sheet of polarized enhance oral absorption and the area for drug uptake. The residence columnar epithelial cells that separate the challenges in developing oral formula- time of the drug in the stomach may external luminal environment from the tions for poorly permeable drugs. vary depending on the time for gastric internal environment of the body and PharmTech: What factors influence emptying. The latter is affected by food

exhibit selective absorption (1–3). Oral drug absorption in the GI tract? uptake, other drugs, and other factors. IMAGES MEDICALRF.COM/GETTY

60 Pharmaceutical Technology OCTOBER 2013 PharmTech.com A VARIETY OF MULTIPLE PROCESSES DOSAGE FORMS Aqueous & Solvent Solids, Creams and coating, encapsulating, Ointments, Bi Layer Compression, Suppositories granulation

COMMERCIAL MANUFACTURING API SERVICES Large & small Key Intermediates, High SCALE UP & TECH molecules, CI-CV, Value Active Ingredients TRANSFER Highly Potent Compounds, Modified Release

PRE-FORMULATION CLINICAL TRIALS & FORMULATION PACKAGING ACTIVITIES MATERIAL

ANALYTICAL PHARMACEUTICAL SERVICES DEVELOPMENT Method Development & Validation

From Concept to Commercialization. We can support you at any point on the journey.

Cutting-edge Pharmaceutical Development 30 North Jefferson Road Whippany, NJ 07981 and Commercial Manufacturing services to 973.428.4087 get you where you need to go. [email protected]

Building Partnerships For Life. halopharma.com Visit us at AAPS, Booth 519 Special Report: Drug Delivery

Due to the acidic nature of the stomach intestinal media is usually studied in vitro systems that generally incorporate a mucosa and the presence of enzymes to establish a relationship for the drug hydrophilic compound inside a lipid such as pepsin, drugs may be degraded in vivo. Additionally, the drug could membrane. Mucoadhesive polymers before they are absorbed. The presence be formulated into sustained-release, can be used to increase the residence of fatty foods can also lead to increased delayed-release dosage forms. time in the GI tract. Specific molecular gastric emptying time, which can lead PharmTech: What strategies are used weights and combinations of to degradation or reduced absorption to increase oral absorption of poorly polyethylene oxide, for example, of some drugs. permeable drugs? have been shown to exhibit excellent adhesive characteristics in vivo. Creating an esterified prodrug is Other methods include the forma- tion of bile salt complexes or using the most common way of increasing cyclodextrin inclusion complexes, which allows poorly soluble drugs to be permeability for a highly soluble drug. combined with cyclodextrins, thereby, creating a soluble complex. Lipinski’s rule of five has been used as Metrics: Creating an esterified prodrug Developing self-emulsifying drug- a preclinical tool to assess the bioavail- is the most common way of increasing delivery systems (SMEDDS) is another ability of a drug. According to Lipinski’s permeability for a highly soluble drug. strategy to increase oral absorption of rule of five, the molecular weight of the Prodrugs are reversible derivatives a poorly soluble drug. These systems drug has to be below 500 Da for it to be of drug molecules that undergo an are typically administered as soft a good candidate for oral absorption. enzymatic and/or chemical transforma- gelatin capsules. The drug is dissolved Additionally, Lipinski’s rule of five tion in vivo to release the active parent in the oil phase, and through careful states that the drug molecule should drug. Common functional groups that selection of surfactants, SMEDDS have less than five hydrogen-bond are employed for prodrug formation are able to promote GI absorption by donors and not less than 10 hydrogen- are amine, hydroxyl, sulfhydryl, and inhibiting bile secretion. In addition, the bond acceptors. The log P for the drug carboxyl moieties. A few examples surface area of cells exposed to certain should ideally be less than 5. A balance of the drug/esterified prodrugs are surfactants is increased. between the polarity and lipophilicity acyclovir/valacyclovir and melagatran/ PharmTech: What are the challenges of the drug is necessary so that the drug ximelagatran. Esterification of these when developing oral formulations for has sufficient solubility in the gastric drugs eliminates an ionized functional poorly permeable drugs? media as well as permeability through the gastric mucosa. One challenge is that a drug would be To optimize drug absorption, phar- maceutical scientists employ formula- soluble in the gastric media, but would tion strategies such as salt formation to increase drug solubility, micronization not get absorbed along the GI tract and is or particle size reduction to increase surface area, inclusion of surfactants subsequently eliminated from the body. and emulsion system to alter wetting and dispersibility, and addition of buffer group and increases the lipophilicity Metrics: One challenge is that a drug systems that alter the microenvironment of the drug molecule. When developing would be soluble in the gastric media, pH. Spray drying and conversion of the prodrugs, the pharmaceutical scientist but would not get absorbed along the drug into its amorphous, and thus, more must be careful that the increased GI tract and is subsequently eliminated soluble form is well established. In the permeability due to increased lipo- from the body. One must consider the case of a moderately or highly permeable philicity doesn’t result in reduced permeability change over the entire drug, the disintegration and subsequent solubility, whichcould offset any length of GI tract. Another factor dissolution from the formulation are increase in absorption due to increased to consider is whether the drug is a critical rate-limiting steps. In the case permeability. substrate for the active transport of an immediate-release formulation, Another approach is to use polymers system in the gastric mucosa. The the disintegration of the dosage form that, in general, mask the inherent strategy of creating SMEDDS can be is the critical step for the drug to be in hydrophilic nature of the API and undertaken by those companies that solution and subsequently absorbed. hence, lead to enhanced absorption. possess soft gelatin capsule technology. The dissolution of the formulation in Liposomes, nanoparticles, and micro- In some cases, there may be benefit of a the fed and fasted gastric media and spheres are all polymer-based delivery delayed-release formulation.

62 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Proven Steroid Technology at Globally Competitive Prices?

Pfizer’s Got It. Pfizer’s early-stage steroid bioconversion process World-class resources for analytical, regulatory, utilizes soybean-derived sterols and proprietary and technical support fermentation processes. The result: a manufacturer Outstanding chemical and bioprocess expertise able to offer the best of both worlds – innovative, and infrastructure high quality steroid technology, with the globally In-process and finished API analytical methods competitive pricing you require. development When it comes to reliable, trusted, and cost- Comprehensive regulatory/registration file preparation effective sourcing of steroid APIs and When you need the right balance of capabilities and intermediates, Pfizer CentreSource has what price in your sourcing strategy, you need Pfizer. you need: Call today to find out more.

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 Special Report: Drug Delivery

The two biggest hurdles in formula- can then be processed into tablets or a combination of immediate-release, tion development for a poorly perme- capsules with specific release profiles. extended-release, and delayed-release able drug are cost and time. Using newer Other techniques that generate amor- matrixes. The one-step drug coating technologies or equipment that have not phous material to improve absorption (OSDrC) Optidose technology, a been fully tested and validated as a com- are hot-melt extrusion, freeze drying, proprietary technology of Catalent, mercial option poses a risk. Therefore, and supercritical fluid drying. Each of can manufacture multiple layer proven methodologies such as the addi- these techniques has their own advan- tablets and a tablet-in-tablets with tion of functional excipients, particle size tages and disadvantages. multiple core placement to achieve reduction, modified-release tablets, or A more recent advancement in almost any desired pulsatile-release enteric coatings may offer the most prac- increasing oral absorption is the profile. In a similar fashion, capsules tical option to increasing permeability. advent of chronotherapeutics. Chro- containing beads with various polymer PharmTech: What are some recent notherapy uses the body’s natural, coatings can effectively deliver a drug advances in oral absorption enhance- circadian rhythms to improve absorp- using the body’s circadian rhythms. ment strategies? tion of drugs. For example, blood flow, Metrics: Spray drying to generate active versus resting state, and gastric References amorphous material to increase bio- mobility are a few things that change 1. A.L. Daugherty and R.J. Mrsny, Pharm. availability is becoming more prevalent. throughout the course of the day that Sci. Technol. Today, 4 (2) 144–151 (1999). Spray drying is a fast process where the could influence drug absorption. To 2. P.D. Ward, T.K. Tippin, and D.R. Thak- drug molecule and a stabilizer, usually effectively target the circadian rhythms ker, Pharm. Sci. Technol. Today, 3 (10) 346–358 (2000). a polymer, can generate a wide range of of the body, several techniques have 3. T.Y. Ma and J.M. Anderson, “Tight Junc- particle sizes to improve solubility (BCS been developed to offer pulsatile drug tions and the Intestinal Barrier,” in Phys- II and IV) or permeability (BCS III release. To achieve the pulsatile-release iology of the Gastrointestinal Tract, L.R. and IV). The spray-dried amorphous profile, tablets are generally formu- Johnson, Ed. (Academic Press, Burling- material generated from spray drying lated with multiple layers that contain ton, MA, 4th ed., 2006) pp 1559–1594. PT

We’re more than just a magazine...

The ePT weekly e-newsletter delivers critical information on *5283 recent contract awards, company mergers & acquisitions, ePT and fresh news of interest to a highly desired community of # pharmaceutical manufacturing professionals. + access to PT Sourcing & The PT Sourcing and Management monthly e-newsletter podcasts web seminars is the authoritative source on sourcing and managementA within the pharmaceutical’s global supply chain. dvancing surveys Management Development JULY & M 2012 Volume anufacturing 2

Equipment & Equipment & Processing Report focuses on pharmaceutical manufacturing process and Processing technology, providing manufacturing news, related Report regulatory issues, and current trends.

Pharmaceutical Technology Europe’s weekly electronic e-newsletter PTE e-Alert provides PTE e-Alert news, market developments, industry surveys and Get all this and more. information on up and coming trade events. Subscribe now at www.pharmtech.com PharmTech Digital provides readers around the world with Digital authoritative peer-reviewed research and expert analyses in the areas of process development, manufacturing, formulation Magazine and drug delivery, API synthesis, analytical technology, packaging, IT, outsourcing, and regulatory compliance. Extended R

64 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Optimizing Liquid Dosage Forms

High Purity Functional Excipients Super Refined® Range PEGs and Polysorbates Looking for a simplistic solution to your not-so-simple liquid dose formulation? Dimethyl Isosorbide When encountering challenging APIs or formulations requiring maximum purity Oleic Acid and Oleyl Alcohol profiles, look to Croda. Croda’s range of high purity functional excipients can offer Vegetable Oils you the solution needed for improved API stability, performance and delivery, Castor Oil and Etocas™ 35 improved overall formulation stability and reductions in gelatin crosslinking. (Polyoxyl 35 Castor Oil) For more information on how our ingredients can answer your pharmaceutical Propylene Glycol needs, contact your nearest Croda division High Purity HP Range HP Tween™ Range of Polysorbates HP Span™ Range of Sorbitan Fatty Alcohols Crodasol™ HSHP (PEG 660 12-Hydroxystearate) Synperonic™ PE Range of Poloxamers

North America email:[email protected] www.croda.com/healthcare Europe, Middle East & Africa email:[email protected] www.croda.com/healthcare Latin America email:[email protected] www.croda.com/healthcare Asia Pacific email:[email protected] www.croda.com/healthcare

Visit us at AAPS, Booth 3623 TROUBLESHOOTING Equipment and Processing Helium Integrity Testing GLOWIMAGES/GETTY IMAGES GLOWIMAGES/GETTY of Single-Use Vessels PharmTech.com/Troubleshooting Vishwas Pethe and Alex Terentiev

Helium integrity testing can prevent which is a significant improvement from standard pressure-decay testing limits of failures in single-use bioprocessing vessels. approximately 250 μm, but still risks al- lowing smaller defects to go undetected. ingle-use vessels drastically reduce contaminants into the vessel, thus ru- Clearly, this level of accuracy is not requirements for cleaning and vali- ining the entire batch. sufficient to guarantee sterility in a vessel Sdation compared to stainless steel or It is crucial that each vessel is tested prior being used in bioprocessing applications. glass tools, which saves a great deal of time to use to assure that there are no holes or ATMI LifeSciences conducted studies to and resources, such as water. The vessel ar- leaks in either the vessel’s walls, seals, or— find a reasonable cut-off point for the rives clean and validated and stays that way importantly—the joints and seals between bags used as bioprocessing vessels. The until it is plumbed into the process train. the valves and tubings that enter and leave studies began with guidance from the As long as the vessel has no holes, sterility the vessel. These joints are the most vulner- food sector, where it has been shown is assured. The downside of single-use ves- able points at which leaks can occur. that microbes can pass through holes as sels, however, is the possibility of defects small as 15 μm. Using 15 μm as a marker, in the plastic vessel (i.e., bag) or its seams. Historical integrity test methods ATMI coordinated independent, aerosol As the biopharmaceutical industry has For many years, the only nondestructive microbial-challenge laboratory studies. become more confident in using single- technique available for detecting leaks was These studies confirmed that microbes use technologies, the scale—and the the pressure-decay method. To conduct are unlikely to penetrate sterile vessels value—of what is contained in single-use this test, the vessel is filled with air to a with hydrophobic film surfaces through biovessels has grown. It is not uncommon predetermined pressure and left to stabi- any defects of 12 μm or smaller; microbes to see single-use vessels on the market lize for a set amount of time. The pressure proved to be unable to penetrate a vessel that accommodate up to 2000 L of prod- is then remeasured; a drop in pressure in- defect of 10 μm or smaller (1). uct. In these cases, the value of what is in dicates that some of the air has escaped the vessel could be more than hundreds from the vessel. The drop in pressure and Helium integrity testing of thousands or even millions of dollars. the time elapsed can be used to calculate A new solution was required to detect In these instances, if a defect were to be the total size of any defect(s) present in defects as small as 10 μm. ATMI devel- present in the bag, the potential financial the vessel through which the air escaped. oped a solution using helium tracer gas impact would be enormous, regardless of Typically, holes that are 250 μm (for a (HIT, ATMI). Unlike the pressure-decay whether the vessel is being used for stor- 200-L vessel) or 500 μm (for a 1000-L ves- method that measures pressure loss in a age or as a bioreactor. sel) can be identified in this way. vessel, this method measures the amount The rapid uptake of single-use ves- This technique is reasonably effective of tracer gas leaking through a defect. sels for use in bioprocessing applications when used on small vessels. In testing The amount of leaking gas can be cor- has made assuring integrity that much larger vessels, however, the accuracy level related to defect size. Although helium more crucial. Although major failures exponentially decreases because the ves- was well established in leak-testing pro- in the seams or large punctures in a ves- sels’ lack of rigidity means they can relax, tocols in the automotive, aerospace, and sel should be visible to the naked eye, therefore continually changing the pres- vacuum industries, ATMI’s method was the real problem lies in the potential sure within the vessel. This can be over- the first use of helium in integrity testing presence of microscopic holes. These come, to a certain extent, by constraining of flexible vessels used in the bioprocess- smaller imperfections are often unde- the vessel between two plates as it is pres- ing industry. Figure 1 shows the ATMI tected and can cause not only leaks, but surized. Holding the vessel in this manner HIT system. also the ingress of microbial or other makes it less likely to relax, which results To carry out HIT testing, the vessel is in a more steady pressure hold and, hence, placed inside a well-sealed, rigid cham- a greater sensitivity to any loss in pressure. ber and connected to a helium inlet Vishwas Pethe is a R&D scientist and In some instances, using this additional valve. The seals ensure no air or other Alex Terentiev, PhD, is R&D and engineering director, both at ATMI LifeSciences, constraint method, defects down to 100 gas can enter or leave while the test is in www.atmi.com/lifesciences. μm can be detected in a 200-L vessel, progress. All the air is then pulled from

66 Pharmaceutical Technology OCTOBER 2013 PharmTech.com NSF-DBA, NSF-Pharmalytica and Becker & Associates are changing their names to NSF Health Sciences on January 1, 2014.

Meet NSF Health Sciences at the AAPS, San Antonio Booth #3942.

Don't miss our scientific papers at the show!

NSF Health Sciences offers the same integrity, service and innovation, now enhanced by NSF International’s comprehensive range of global services and resources

NSF Health Sciences [email protected] www.nsf.org Troubleshooting

Figure 1: ATMI LifeScience’s patent- Figure 2: Helium leak rates of fully assembled finished good bags vs. fully pending HIT platform for helium assembled bags with 10-μm defects; 16 bags of each size were tested. integrity teting. 20

15 “Defective” bags

Box: 25%-75% data whiskers: min, max rate k

10 (Relative) elium lea H

5 Bags rejected when the leak rate through a bag is above this line the chamber with a vacuum until there is a negligible amount of helium in the “Good” bags chamber. A predetermined amount of helium is injected into the vessel. If there 0 1 5 102050 1 5 1020 50 are no defects in the vessel, the helium Volume of bag (L) will remain inside it. If there are any de- fects (e.g., holes or splits), the vacuum will cause helium to escape from the ves- storage container. These ports and con- systems from any supplier. On-site testing sel into the chamber. If this happens, the nectors are the most vulnerable part of enables processors to verify the integrity helium is detected using mass spectrom- the vessel in terms of leaks, holes, and of vessels at the point-of-use, immediately etry; the amount of helium detected cor- other defects. To run a constrained-plate prior to use, giving a further failsafe to relates precisely to defect size. pressure-decay test, however, all of these ensure that expensive batches of biophar- Figure 2 shows the results of tests at ports and inlets must be removed from maceutical products are not spoiled by ATMI on fully assembled bags of sizes the vessel before it can be placed between microbial contamination or lost through ranging from 1 to 50 L. For each size, 16 the plates. Therefore, not only does the a leak. HIT testing can currently be ap- bags were measured. The leak rates of de- constrained pressure-decay method offer plied to vessels up to 200 L, with plans to fective bags (with defects greater than 10 lower sensitivity, it also omits testing of extend this to 2000 L. μm) are statistically significantly higher the ports and inlets that have shown to than those of bags with no known de- be most likely to fail. In contrast, the HIT Conclusion fects, indicating that defective bags can method allows a fully assembled vessel As the penetration of single-use systems in be detected. to be tested. The entire vessel, including the marketplace continues to expand, the Defects down to 10 μm can be identi- the tubing sets, is placed inside the test need to assure the integrity of those sys- fied in this manner. In the rare case that chamber. If end connectors have porous tems has become more important. Supply- a lower detection limit is required, the membranes on the tube ends, the out- chain security and product integrity are HIT equipment can be designed to meet lets are blocked using a plug or sealing core components of biopharmaceutical those requirements, although it would mechanism to allow testing of the joints manufacturing success. Innovations like be more technically challenging to set between the tube and end connector. the HIT platform are important to ad- up. For these types of studies, the user In addition to being offered for the pre- vancing the potential of the industry as a must account for the influence of the tiny shipping validation of vessels and mani- whole, regardless of single-use provider. amount of background helium in the air. folds manufactured by ATMI, HIT tech- Detection limits of HIT, however, are nology is now available to end-users for Reference not the only advantage over the con- testing in their own facilities of single-use 1. ATMI, Internal research report. PT strained-plate method. In the real world, a single-use vessel is not just a vessel with Join the discussion a single inlet. It will have a number of dif- What method are you using to test the integrity of single-use systems? ferent inlet ports, all attached to connec- tors and tubes, particularly if it is being Post your comments on www.pharmtech.com/linkedin or click the QR code with your smartphone to go directly to the conversation. used as a bioreactor instead of a product- AUTHORS. THE OF COURTESY ARE FIGURES ALL

68 Pharmaceutical Technology OCTOBER 2013 PharmTech.com The EXPERIENCE

TO GO FROM CONCEPT The EXPERTISE TO CLINIC TO MARKET

The COMMITMENT

What separates one CDMO from another? At Metrics, we believe it comes down to experience, expertise and commitment. Like our formulators and analytical staff, who share decades of career experience and expertise. Or our commitment to continually surpass our clients’ expectations by offering new capabilities and technologies. Moving your project through the pipeline efficiently and cost-effectively is our number one priority. And that’s what separates us from the rest of the pack.

Potent Product Development. Veteran Expertise. 4:1 Ratio. Our state-of-the-art potent Our PhDs, Master and We offer a healthy balance development suites feature Registered Pharmacists and of four analytical chemists total containment Chemists average 17 years to every formulator to and no open processes. of professional experience. keep your project on track.

Pharmaceutical Development s Analytical Testing s CTM Manufacturing s Potent Products s Specialty Technologies Metrics / Greenville, NC / 252-752-3800 / www.metricsinc.com API Synthesis & Manufacturing ers reported that xylyl-phanephos) 2+ Pt in combination with XeF2 medi- ates the consecutive diastereoselective cation–olefin cyclization/fluorination of polyene substrates (5). The research- ers reported that isolated yields were typically in the range of 60–69%, and enantioselectivities reached as high as 87%. The researchers noted that the data were consistent with a stereoreten-

tive fluorination of a P2Pt–alkyl cation intermediate (5). The researchers de- tailed a [Pt]-catalyzed method for first cyclizing polyenes and then selectively Overcoming Challenges in fluorinating at the C3 position using

XeF2. The addition of TMS-OMe to Fluorine-Based Chemistry scrub adventitious HF provided a pro- cedure that gave isolated yields as high Patricia Van Arnum as 80% and enantioselectivities up to 87% (4, 5). The researchers proposed a mechanism by which the substrate un- dergoes a [Pt]-initiated cascade cycliza- Fluorinated molecules play an important role as tion to generate an intermediate [Pt]- alkyl, which is observed as the catalytic pharmaceutical compounds. Recent advances seek resting state. This compound reacted with XeF faster than ß-H elimination to overcome the challenges of selective and late- 2 to give the desired fluorinated product stage insertion of fluorine into small molecules. with a stereochemistry that is retentive at the original C3-Pt position (4, 5). luorine-based compounds play an searchers engineered two changes important role in pharmaceuticals. into Escherichia coli bacteria that had Palladium-catalyzed fluorination FIt is estimated that up to 20% of previously been engineered to make Tobias Ritter, a professor of chemistry pharmaceuticals on the market or in polyketides (2, 3). In their work, the in the Department of Chemistry and clinical development contain a fluo- researchers showed that a pathway for Chemical Biology at Harvard Univer- rine atom, and 30% of key blockbuster producing fluoroacetate can be used sity in Cambridge, Massachusetts, drugs contain fluorine (1). Given the as a source of fluorinated building and his team, recently reported on importance of fluorine-based mol- blocks for introducing fluorine into their work involving palladium(III)- ecules in drug development, chemists natural-product scaffolds. Specifically, catalyzed fluorination of arylboronic must overcome challenges associated they constructed pathways involv- acid derivatives. The researchers noted with fluorination of small molecules. ing two polyketide synthase systems that developing practical carbon−flu- and showed that fluoroacetate can be orine bond-forming reactions to pro- Polyketide synthase pathways used to incorporate fluorine into the vide aryl fluorides is challenging. The Researchers at the University of Cali- polyketide backbone in vitro. The re- researchers reported on a palladium- fornia at Berkeley and Stanford Uni- searchers further showed that fluorine catalyzed fluorination of arylboronic versity in California reported on their can be inserted site-selectively and acid derivatives, which allowed for an elucidation of engineered polyketide introduced into polyketide products operationally simple, multigram-scale synthase pathways as a means to in vivo. The researchers asserted that synthesis of functionalized aryl fluo- produce organofluorines (2). The re- their work shows the potential of pro- rides (6). The researchers proposed that ducing complex fluorinated natural the reaction mechanism involved a sin- products using synthetic biology (2, 3). gle-electron-transfer pathway involv- ing a palladium (III) intermediate that Patricia Van Arnum Catalytic enantioselective cyclization was isolated and characterized. Ac- is a executive editor of Pharmaceutical Technology, Researchers at the University of North cording to the researchers, the kinetic 485 Route One South, Carolina at Chapel Hill reported on studies suggested a mechanism distinct Bldg F, First Floor, their work involving catalytic enanti- from other known arene fluorination Iselin, NJ 08830 tel. 732.346.3072, oselective cyclization and C3-fluori- reactions without forming organopal-

[email protected]. nation of polyene (4, 5). The research- ladium species and offers an advantage IMAGES SCIENCE PHOTO LIBRARY/GETTY

70 Pharmaceutical Technology OCTOBER 2013 PharmTech.com THE BOLD DIFFERENCE in defining and protecting your brand

Sensient® Pharmaceutical Coating Systems leads the industry in the development and manufacture of innovative coatings and colors for the pharmaceutical and nutraceutical industries. Our patented, regulatory-compliant coatings define and protect brands while delivering application and production-efficiency benefits.

Servicing leading pharmaceutical companies from 35 locations globally, Sensient’s comprehensive range of versatile and novel coating systems offers visual and functional attributes necessary for brand definition, product identification and trademark protection.

Define and protect your brand with superior, high-quality coating systems. Visit sensientpharma.com.

SENSIENT ® PHARMACEUTICAL COATING SYSTEMS A unit of Sensient Technologies Corporation, a leading global PHARMACEUTICAL COATING SYSTEMS manufacturer of colors, flavors and fragrances

2515 N. Jefferson, St. Louis, Missouri 63106 | 800.325.8110 Manufactured in the USA ©2012 Sensient Colors LLC, all rights reserved. The SENSIENT trademark and the Sensient Technologies Corporation logo are owned and registered by Sensient Technologies Corporation. All rights in trademarks are reserved. API Synthesis & Manufacturing over other metal-catalyzed or -medi- is an active area of research by Ritter velop new methods for the synthesis ated arene fluorination reactions. The and his group. Carbon–fluorine bond of small-molecule tracers for positron researchers noted the reaction does formation is a challenging chemical emission tomography (PET), an imag- not produce side products from proto- transformation, particularly for func- ing method to study biological pro- demetalation, a common problem in tional group-tolerant, late-stage fluo- cesses in vivo. PET with the isotope 18F synthesizing aryl fluorides (6), but the rination of arenes (7). The researchers’ is currently limited by the absence of reaction had certain drawbacks, such approach uses high-valent transition general chemistry that can introduce as the inability to fluorinate heterocy- metal fluorides by means of oxidation fluorine into molecules at a late stage, cles and form constitutional isomers of aryl transition metal complexes with and carbon–fluorine bond formation for some electron-poor substrates (6). electrophilic fluorination reagents (7). using high-valent transition metal flu- Carbon–fluorine bond formation The group’s long-term goal is to de- orides via oxidation of aryl transition metal complexes with electrophilic fluorination reagents is one approach to resolve that challenge (7–9). Ritter and his team also developed an approach for silver-catalyzed late-stage fluorination using a cross-coupling reaction that attached fluorine atoms Stereoinversion of tertiary alcohols Researchers at The Scripps Research Institute (TSRI) recently reported on their work involving stereoinversion of tertiary alcohols to tertiary- alkyl isonitriles and amines. Their work is im- portant for organic chemistry in general and in synthesizing pharmaceutical compounds in overcoming the challenge of applying tertiary alcohols to stereoinverstion reactions. The researchers addressed a well-established

chemical transformation, the SN2 reaction (i.e., bimolecular nucleophilic substitution), which is used to join two smaller molecules together into a larger molecule or to exchange one functional group for another, but which does not tolerate tertiary carbon atoms (1). Although primary and secondary alcohols can be precursor substrates, tertiary alcohols and their derivatives usually fail to react or produce stereochemical mixtures of products (1). The researchers reported on the stereochemical inversion of chiral tertiary alco- hols with a nitrogenous nucleophile facilitated by a Lewis-acid-catalyzed solvolysis (1). “The basic idea is that you can take a tertiary alcohol with one stereochemical configuration and install nitrogen functionality, leaving it with the opposite stereochemical configura- tion,” said TSRI Research Associate Sergey Pronin, in a Sept. 11, 2013 TSRI release. The researchers hope to achieve stereoinversions See us at AAPS, of tertiary carbons to form carbon–oxygen, Booth 643 carbon–sulfur, and carbon–carbon bonds. Reference 1. S.V. Pronin, C.A. Reiher, and R.A. Shenvi, Nature 501 (7466) 195-196 (2013).

72 Pharmaceutical Technology OCTOBER 2013 PharmTech.com

API Synthesis & Manufacturing

onto aromatic substituents. The reac- fluorination reaction is the variety of using fluoroform (CF3H) in the direct tion used silver oxide to catalyze the functional groups that can be tolerated nucleophilic trifluoromethylation of fluorination of aryl tin compounds with and breadth of substrates used. The silicon, boron, sulfur, and carbon cen- the electrophilic fluorinating reagent researchers applied the cross-coupling ters (11). Fluoroform is a byproduct of N-chloromethyl-N-fluorotriethylenedi- reaction to fluorinate polypeptides, the manufacture of polytetrafluoroeth- ammonium hexafluorophosphate. The polyketides, and alkaloids and showed ylene (Teflon), refrigerants, polyvinyli- dene fluoride, and other products. Al- A silver-catalyzed fluorination reaction though fluoroform has little practical use, the trifluoromethyl (–CF3) func- broadened the variety of functional tionality is important for pharmaceu- ticals (11). The researchers elucidated groups and the breadth of substrates the conditions needed to convert fluo- used in carbon–fluorine bond formation. roform into useful reagents, including the silicon-based Ruppert–Prakash researchers asserted that the reaction tolerance by various functional groups, reagent for efficient (–CF3) transfer. was the first example of silver catalysis including vinyl ethers, dienones, alco- Fluoroform with elemental sulfur was for carbon–heteroatom bond formation hols, allylic alcohols, ethers, esters, and also converted to trifluoromethane- by cross-coupling chemistry (9, 10). oxetanes (9, 10). sulfonic acid, a widely used superacid, Carbon–fluorine bond formation by according to a Dec. 7, 2012 USC press transition-metal catalysis is difficult. Nucleophilic trifluoromethylation release. Specifically, the researchers re- Typically, transition metal-catalyzed G.K. Surya Prakash, professor of chem- ported on a direct trifluoromethylation fluorination reactions for synthesizing istry at the University of Southern Cal- protocol using close to stoichiometric functionalized arenes use palladium ifornia (USC) and director of the USC amounts of CF3H in common organic as the metal in the catalyst (9, 10). A Loker Hydrocarbon Research Institute, solvents, such as tetrahydrofuran, di- key benefit of the silver-catalyzed and his team reported on their work in ethyl ether, and toluene. The research- Resolution of ,QÀDPPDWLRQ"

WE SHARE YOUR METICULOUS APPROACH Immuno-Inflammation R&D Opportunities Do you want to be part of a team that’s driving change in the immuno-inflammation (II) therapeutic area? That’s pioneering medical discovery in everything from epigenetics to T-cell biology? If you’re an experienced scientist or physician, we share your meticulous approach to find treatments for the supposedly untreatable across II. To find out more about opportunities at GSK please visit www.gsk.com/careers searching under req ID 83534.

www.gsk.com/researchcareers See us at AAPS, Booth 1102

74 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Visit us at AAPS, Booth 1006 API Synthesis & Manufacturing ers reported that the approach can be lylsilane derivatives was achieved using ester group. The first reaction involved applied to a variety of silicon, boron, CuI and Togni’s reagents under mild the substitution of a hydrogen atom, on and sulfur-based electrophiles as well conditions. Specifically, the research- the carbon atom adjacent to the carbonyl as carbon-based electrophiles. ers developed a synthesis technique group, for a fluorine atom, resulting in that selectively and efficiently com- two enantiomers for which a palladium- Copper-catalyzed trifluoromethylation bined fluorine and amino acids into the based catalyst was used to preferentially Researchers at the RIKEN Advanced same organic molecule, according to a produce one of the enantiomers, thereby Science Institute in Wako, Japan re- Sept. 28, 2012 RIKEN Advanced Sci- making the reaction enantioselective. ported on their work on the copper- ence Institute press release. The start- The carbonyl group of the fluorinated catalyzed trifluoromethylation of allyl- ing materials were alpha-keto esters alpha-keto ester was then transformed silanes (12). Trifluoromethylation of al- that contained a carbonyl group and an to a hydroxyl group with two possible stereoisomers, for which one stereoiso- mer could be preferentially produced by using different reagents. The technique not only introduced fluorine, but two stereogenic centers to the molecule. Forming two stereogenic centers cre- ated the possibility of four different ste- reoisomers, which were subsequently isolated in separate reaction sequences. The researchers’ future interests involve widening the fluorination reaction to other starting materials, according to the release. References 1. D. O’Hagan, J. Fluorine Chem. 131 (11), 1071-10801 (2010. 2. M.C.Y. Chang et al., Science 341 (6150) 1089-1094 (2013). OUTWIT. OUTSOURCE. OUTSHINE. 3. R.F. Service, Science 341 (6150) 1052-1053 (2013). 4. M.R. Gagné, “Group Research High- lights: Catalytic Enantioselective Cycli- With the addition of a world class parenteral manufacturing facility, sation (University of North Carolina, Irvine's experts are now even better positioned to guide you through and Chapel Hill, NC ), www.chem.unc.edu/ people/faculty/gagne/?display=research_ expedite your time to market. display&show=all, accessed Sept. 20, 2013. 5. N.A. Cochrane , H. Nguyen and M.R. t 25 Years providing pharmaceutical/biopharmaceutical Gagné, J. Am. Chem. Soc. 135 (2) 628-631 analytical CMC support from preclinical to post-market (2013). 6. T. Ritter et al., J. Am. Chem. Soc. online, DOI: 10.1021/ja405919z, Sept. 16, 2013. t Formulation development 7. Ritter Group, “Research: Functional Group-Tolerant Late-Stage Carbon–Flu- t Manufacturing of small volume parenterals orine Bond Formation (Harvard Uni- and lyophilizates versity, Cambridge, MA), www.chem. harvard.edu/groups/ritter/research.html, Your single source for pharmaceutical development. accessed Sept. 20, 2013. 8. T. Ritter et al., Science 334 (6056) 639-642 Visit Us At (2010). The 2013 AAPS 9. P. Van Arnum, Pharm. Technol. 34 (12) Annual Meeting & Exposition 40-42 (2010). Booth 3913 10. T. Pingping, T Furuya and T. Ritter, J. Am. Chem. Soc. 132 (34) 12150-12154 OUTWIT. OUTSOURCE. OUTSHINE. (2010). 11. G.K. Surya Prakash, et al., Science 338 Visit www.irvinepharma.com or call 877.445.6554. (6112) 1324-1327 (2012). 12. M. Sodeoka et al., Angew. Chem. Int. Ed. Engl. 51 (19) 4577-4580 (2012). PT

76 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Ashland — your pharmaceutical technology resource Solubilization Solutions Ashland meets your solubility needs by providing the broadest t
*OUSPEVDJOH
"RVB4PMWF™
IZQSPNFMMPTF
BDFUBUF
TVDDJOBUF
range of excipients and technologies, as well as polymer expertise )1.$"4 1
GPS
ESVH
TPMVCJMJ[BUJPO
BOE
FOUFSJD
DPBUJOHT
GPS and technical support from benchtop to commercialization. o
*ODSFBTFE
TPMVCJMJUZ o
#SPBE
EFmOFE
TVCTUJUVUJPO
-
.
BOE
)
UZQFT We also understand the problems formulators face when using o
-PX
TPMVUJPO
WJTDPTJUZ
JO
NVMUJQMF
TPMWFOUT solid dispersions as an enabling technology. In fact, Ashland o
#SPBE
5

5
SBOHF has developed solid-dispersion formulations for over 100 APIs H E o
1FSGPSNBODF
NBUDIFT
NPOPHSBQIDPNQMJBOU
DPNQFUJUJWF
working with more than 50 pharmaceutical and biopharmaceutical QSPEVDUT companies worldwide. t
#SPBE
QSPEVDU
QPSUGPMJP
Work with Ashland as your formulation development partner to o
#FOFDFM™
)1.$
1MBTEPOF™
QPWJEPOF
1MBTEPOF
4
enhance the bioavailability of your APIs and improve your speed to DPQPWJEPOF
1PMZQMBTEPOF™
DSPTQPWJEPOF
1IBSNBTPMWF™
market. /NFUIZMQZSSPMJEPOF
BOE
$BWBNBY
$BWJUSPO™
t
&YUFOTJWF
FYQFSJFODF
XJUI
BMM
QPMZNFSJD
DBSSJFST
GPS
TPMJE
BOE
$BWBTPM
DZDMPEFYUSJOT dispersions 'PS
NPSF
JOGPSNBUJPO
QMFBTF
DPOUBDU
ZPVS
MPDBM

t
*OEVTUSZSFDPHOJ[FE
FYQFSUJTF
"TIMBOE
4QFDJBMUZ
*OHSFEJFOUT
SFQSFTFOUBUJWF
PS
WJTJU

– Spray drying and holt-melt extrusion VT
BU
BTIMBOEDPNQUQIBSNBDFVUJDBM 7JTJU
"TIMBOE
BU
$1I*
8PSMEXJEF
t
)BMM

#PPUI
# PS
""14
t
#PPUI


¥

3FHJTUFSFE
USBEFNBSL
"TIMBOE
PS
JUT
TVCTJEJBSJFT
SFHJTUFSFE
JO
WBSJPVT
DPVOUSJFT ™
5SBEFNBSL
"TIMBOE
PS
JUT
TVCTJEJBSJFT
SFHJTUFSFE
JO
WBSJPVT
DPVOUSJFT

3FHJTUFSFE
USBEFNBSL
PXOFE
CZ
8BDLFS
$IFNJF
"(
"TIMBOE
*OD
BDUT
BT
B
EJTUSJCVUPS

GPS
8BDLFS 1
"RVB4PMWF
"4™
)1.$"4
JO
UIF
6, ª

"TIMBOE

"% PACKAGING FORUM Maintaining and

Verifying the Cold Chain TETRA IMAGES/GETTY IMAGES PharmTech.com/pack Hallie Forcinio Tools and services provide thermal protection and prove cold-chain compliance. emperature-sensitive pharmaceuti- Another option for clinical trials, Figure 1: The Intelsius reusable BioCarrier cals and biologics depend on a variety the reusable BioCarrier courier transit courier transit case maintains payloads at of services and technologies to estab- case from Intelsius shown in Figure 1, T 2–8 ºC for more than 12 hours. lish, maintain, and verify proper storage is specifically designed for local courier and transport conditions. Table I lists routes, multiple site sample collection, temperature ranges for frozen, refriger- and “home visit” injectable transport. ated, and controlled-room-temperature A rugged polymer outer with expanded (CRT) products. With regulations evolv- polypropylene (EPP) liner maintains ing regarding thermal protection of these payloads at 2–8 °C for more than 12 h products, proof of compliance is gaining (up to 18 h with dry ice). A clasp closure attention. Fortunately, it is becoming easier secures the lid, and cases can be stacked to automate data collection, analysis, and and locked together. All three sizes are compliance reporting for controlled-tem- regulatory compliant with preprinted perature shipping and storage. In addition, UN3373 labels for the shipment of Cat- solutions increasingly offer sustainability egory B biological samples. and shipping weight. The configurations attributes such as reusability, recyclability, For greater distances and longer travel simplify and expedite assembly and lower or derivation from renewable materials. times, Intelsius offers its next generation total cost of ownership. ORCA 2.0 controlled-temperature ship- Sonoco ThermoSafe also offers options Maintaining conditions per. It thermally protects the payload for for CRT shipments. “A regulatory focus on Protecting temperature-sensitive prod- at least 170 h. Like many temperature- strict compliance to storage temperature ucts from point of manufacture to point controlled shippers, it relies on advanced limits has increased the demand for CRT of use typically involves integration of phase change material (PCM) that ex- shipping solutions,” explained Russell hardware such as insulated shippers and tends the protective period in extreme Grissett, vice-president, Sonoco Thermo- data loggers with software for manage- hot or cold environments with simple Safe (2). To address this emerging market ment, data collection, analysis, and proof preconditioning. A variety of PCM panel need, Sonoco Thermosafe designed the of compliance. Clinical Reference Labo- configurations increases the range of Certis Silver Universal CRT series. The ex- ratory, a provider of testing services for shipments served and reduces costs. To panded polystyrene (EPS) foam containers clinical trials, molecular diagnostics, and help optimize container configuration, and PureTemp PCM reportedly maintain toxicology, relies on hardware and soft- ATMOS analytical thermal modeling pharmaceuticals and biologics at 15–25 °C ware from Cryoport for a major clinical software, also from Intelsius, quickly as- for up to four days (for an 11-L payload), trial being conducted in four European sesses the suitability of a design for the regardless of the season. countries. Dry-vapor, liquid nitrogen intended route and payload. A Passive Vaccine Storage Device, de- shipping protects patient samples while To simplify specification, a number of signed to deliver vaccines in undeveloped a web-based logistics management portal suppliers have begun to offer prequali- tracks and documents all shipments. fied temperature-controlled shippers. We’ll be seeing more ... One recent introduction, the Aeris series HallieFo rcinio from Sonoco ThermoSafe, maintains its t
Controlled-temperature is Pharmaceutical payload at 2–8 °C for at least 54 h. The shipments Technology’s shippers are developed specifically to ad- Packaging Forum t
Sustainable designs for shippers editor, 4708 dress the European Union’s good distri- Morningside Drive, bution practice (GDP) guidelines, which t
Automated documentation of Cleveland, OH 44109, took effect on Sept. 8, 2013 (1). Four sizes, compliance tel. 216.351.5824, fax 216.351.5684, ranging from 2.5 to 24 L, are optimized t
Harmonized regulatory action

[email protected]. to minimize the number of components INTELSIUS. OF COURTESY IS 1 FIGURE

78 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Packaging Forum

areas, combines insulation technologies developed for space exploration and stor- Table I: Temperature ranges for product storage and distribution. age of cryogenic fluids with ice and data Storage type Temperature range (ºC) logging to overcome poor infrastructure Frozen -20 to 0 and unreliable power supplies (see Figure Refrigerated 2 to 8 2). Invented by Global Good, a collabora- Controlled room temperature (CRT) 15 to 25 tion between Intellectual Ventures and Microsoft founder Bill Gates to invent manufacturing and distribution in technology that improves life in devel- 2014. Under an agreement announced Figure 2: The Passive Vaccine Storage oping countries, the system maintains in July 2013, AUCMA, a refrigeration Device invented by Global Good 300 doses at the required temperature company based in Qingdao, China, is designed to deliver vaccines in for more than 30 days. Vials can be re- will manufacture and distribute the undeveloped areas. trieved as needed without jeopardizing device to strengthen the vaccine sup- the remainder, and the chamber can be ply chain in underserved regions. restocked and redeployed in the field. An onboard data logger monitors location, Enhancing sustainability internal temperature, and the number of To reduce waste, Fairview Pharmacy Ser- times vaccines have been removed. These vices has switched from EPS coolers to in- data can be communicated via daily text sulated shippers made of biodegradable, messages and downloaded via a USB port cornstarch-based Green Cell Foam mate- to help plan future vaccination campaigns. rial. The conversion to the compostable The super-insulated device success- shipper from StarchTech will keep about fully completed field trials in Senegal 44,000 EPS coolers out of landfills in 2013. plifies disposal for the estimated 12,500 in 2013 and will undergo additional Because EPS is rarely included in curbside patients who receive temperature-sensitive

TABLE I IS COURTESY OF THE AUTHOR AND FIGURE 2 IS COURTESY OF INTELLECTUAL VENTURES. field testing in Africa before broader recycling programs, the shipper also sim- medications from the pharmacy each year.

The ultra-flexible CAPSULE FILLER designed for R&D and lab-based operation

The FlexaLab R&D Capsule Filler

Designed for R&D, lab, clinical trials, small batches and special productions Can handle several dosing units simultaneously, enabling multiple product combinations in one capsule Up to 3,000 capsules/hour Continuous or intermittent motion AAPS Booth #307 Self-contained 100% Net weight check available See us at

mgamerica.com 866-962-3090

Pharmaceutical Technology OCTOBER 2013 79 Packaging Forum

messaging to automate documentation goods are compromised. Two-way wire- Figure 3: MadgeTech’s VTMS vaccine of conditions in storage environments less technology permits remote starting, temperature monitoring system and support compliance with regula- stopping, and downloading of the device. remotely monitors conditions in tory requirements. “Many of the people Data can be transmitted in real time to a refrigerators, freezers, and coolers and we have talked to have complained about central personal computer or downloaded records and transmits data. the difficulty of staying compliant with periodically. Accompanying MadgeTech manual temperature monitoring and in- 4 software preserves original records and ventory checks but are not ready to move includes customizable analysis and re- to a fully automated system because they porting tools. only have one or two refrigerators,” ex- To monitor air shipments, the wireless plained Dick Fettig, executive vice-pres- Sentry FlightSafe system from OnAsset ident of FreshLoc (3). Once deployed, the Intelligence combines sensors for environ- FreshLoc SA software sends a phone or mental conditions such as temperature, email message to remind the operator to humidity, pressure, shock, and vibration record the temperature or make the in- with GPS, wireless transmitters, and ana- ventory date check. The operator inputs lytical software to collect environmental Enhancing the sustainability of refrig- the data on a Smartphone, tablet, or per- data and track location in real time. En- erated truck trailers, Emerald Technology sonal computer and sends it in real time virotainer is testing the Sentry FlightSafe Partners has launched the patent-pending to a server where it can be accessed at any system on its RKN e1 and RAP e2 air Wedway refrigeration power system. The time. Each entry is signed with an email cargo containers, which are equipped system replaces fossil fuel with kinetic or text-message address for 21 CFR Part with compressor-based cooling and elec- power and eliminates related emissions. 11 compliance. The reminders reduce tric heating. Successful tests will lead to A WedLink temperature monitoring and the chance that scheduled checks will be commercialization of integrated systems management system from InTouch Tech- missed or product will experience tem- and required approvals and certifications. nologies makes it possible to view trailer perature abuse and become unusable. Until now, data on shipment conditions location in real time and remotely man- If the reading entered is out-of-specifi- were gathered continuously but not avail- age all refrigeration and mechanical sys- cation, the system issues an immediate able for review until a container reaches tems from any computer or mobile device alert and suggests corrective action. specific destinations. With the patented, equipped with an Internet connection. A fully automated system, the VTMS Federal Aviation Administration-compli- vaccine temperature monitoring system ant FlightSafe communications platform, Confirming conditions from MadgeTech, shown in Figure 3, the RKN e1 and RAP e2 containers trans- It’s not enough to establish and maintain provides continuous, remote monitoring mit location, condition, and environmen- frozen, refrigerated, or CRT conditions; of sensitive products such as vaccines or tal information whenever the containers data must be collected to confirm pa- pharmaceuticals in refrigerators, freez- are on the ground. Immediate access to rameters were met or provide a warning ers, and coolers. The system provides the data provides peace of mind regarding that a deviation occurred so a decision tools needed to comply with the Cen- product condition throughout transit and can be made about the viability of the ters for Disease Control and Prevention helps supply-chain partners take action product. Wireless devices are gaining (CDC) guidelines for storage and tem- if conditions drift out-of-specification or popularity for this task. perature monitoring of refrigerated vac- maintenance is needed. This knowledge One example, the Automated Tem- cines, which stipulates accuracy of +/- 0.5 also can expedite returns. perature Monitoring System (ATMS) °C and specifies use of a glycol-encased, Once fully deployed, The Sentry from Cargo Data Corp., relies on radio detachable probe along with a digital data FlightSafe system will provide Envi- frequency (RF) technology to automate logger to provide temperature-buffered rotainer’s Active Container Data and collection, retrieval, and archiving of in- readings and prevent false alarms (4). Transport Evaluation services with posi- transit temperature data captured by the MadgeTech’s VTMS consists of an NIST tion and sensory data for each shipment. company’s data loggers. The ATMS au- traceable RFTCTemp2000A data logger These enhanced information services tomatically posts the data to Cargo Data’s equipped with two-way wireless com- will help supply-chain partners verify website, where any interested party may munication plus a thermocouple and supply-chain performance and confirm view and print it, so that supply-chain part- glycol bottle. A liquid crystal display on product quality. ners do not need to manually download or the data logger displays minimum, maxi- UPS provides similar proactive ship- distribute temperature-recorder data. mum, average, and current temperature ment monitoring and risk management Another wireless device, FreshLoc readings. Alarms light up and sound if capabilities with its UPS Proactive Re- SA mobile temperature monitor from temperature drifts above or below the sponse Secure service. The service helps FreshLoc Technologies, works with a safe range. E-mail or text alerts also can ensure temperature-sensitive shipments

calibrated thermometer and text or email be sent so action can be taken before achieve timely arrivals at their destina- FIGURE 3 IS COURTESY OF MADGETECH.

80 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Packaging Forum tions and guarantees up to the retail value, Automating reporting specific job functions. For example, the se- plus other costs, when unexpected events As regulatory guidance and requirements nior management dashboard might pres- (including weather delays) occur. “This is evolve, so does the need for compliance ent the financial impact of any excursions the highest level of service we offer,” says reporting. However, data gathering and in the cold chain. Bill Hook, vice-president of UPS Global analysis can be cumbersome. The latest Healthcare Strategy (5). The 24-h/7-day cold-chain technology platform from References service provides end-to-end visibility and Dyzle BV not only automates the process, 1. EC, Guidelines on Good Distribution Practice of Medicinal Products for Human is available throughout the United States but documents the data to meet require- Use 2013/C 68/01 (Brussels, Mar. 2013). and Puerto Rico and for outbound ship- ments outlined in the European Union’s 2. Sonoco ThermoSafe, “Sonoco Thermo- ments to 12 countries in the European GDP guidelines (1). Safe Launches Certis Silver Universal Union. Other service enhancements for The open, independent platform collects CRT Design-Qualified Shippers,” Press Release, Mar. 14, 2013. temperature-controlled shipments include data from multiple sensors and monitoring 3. FreshLoc Technologies, “New Mobile Next Flight Out expedited delivery from systems, including proprietary and legacy Solution from FreshLoc Promotes Safety UPS Express Critical, installation of dry- devices, and provides automatic registra- and Prevents Non Compliance,” Press ice replenishment and refrigeration infra- tion and interpretation of environmental Release, Jan. 15, 2013. 4. Centers for Disease Control and Preven- structure at more destination locations, parameters like temperature, humidity, tion, “Guidelines for storage and tempera- and addition of UPS Proactive Response carbon dioxide, and energy consumption ture monitoring of refrigerated vaccines,” control towers in Europe and Asia. in real time. “With one view, we provide www.cdc.gov/vaccines/recs/storage/toolkit/ SenseAware, a sensor-based logis- complete end-to-end visibility of the cold toolkit-resources.pdf, accessed Sept. 6, 2013. 5. UPS, “UPS Launches Industry-First Ser- tics system from FedEx, uses sensors chain on any Internet-enabled device, en- vice for High-Value Time- and Tempera- to detect temperature, light, humidity, abling automatic registration that is needed ture-Sensitive Shipments,” Press Release, barometric pressure, and location. The to meet the new GDP guidelines,” explains June 26, 2013. system communicates these data in near Bert Zandhuis, CEO of Dyzle (6). Another 6. Dyzle BV, “Dyzle’s Latest Version of Proven Cold Chain Solution Sets the real-time so supply-chain partners can benefit of the software is its ability to orga- Standard for Global GDP Compliance,” take action as needed. nize data into dashboards customized for Press Release, June 18, 2013. PT

Introducing a Commercial Facility for Today’s Market

UPM Pharmaceutical’s new 500,000 square foot commercial facility in Bristol, Tennessee serves customers with large-scale manufacturing capabilities for solid oral dosage tablets and capsules, as well as semi-solid creams and ointments.

WINNER

INNOVATION PRODUCTIVITY REGULATORY To learn more, visit www.upm-inc.com or call +1 410 843 3738.

Pharmaceutical Technology OCTOBER 2013 81 PEER-REVIEWED

A Risk-Based Approach to Monitoring Elemental Impurities in Leachable Studies

Kathleen Kelly and Nancy Lewen

he determination of elemental impurities is one of the Tstandard tests performed as part of leachable and extractable studies for a final container-closure system (CCS). The Code of Federal Regulations (21 CFR 211.94) (1) states “drug product containers and closures shall not be reac- tive, additive, or absorptive as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.” To ensure that the CCS does not alter the performance of the product, nor that anything is being introduced into the final drug product, extractable and leachable testing is performed. FDA’s Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics (2) recommends that extraction studies be con- ducted for the critical components of the packaging system. The determination of elemental impurities is one of the standard tests performed as part of leachable Extractable and leachable studies and extractable studies for a final container- An extractable study is initiated with all the components closure system. The authors discuss a strategy of the CCS that will be in direct contact (i.e., the primary for integrating the toxicological assessment of component) with the drug product. For example, in a vial/ the elemental impurities found during extractable stopper system, the vial and stopper are examined, but not testing with the United States Pharmacopeia, the metal seal that secures the stopper to the vial. For a European Pharmacopoeia, and the European ready-to-use syringe, the syringe barrel, needle, needle shield, Medicines Agency guidelines to develop a risk-based and stoppers are tested, but not the plunger. Oral products approach for testing of elemental impurities in have blister packs, plastic bottles, or heat seals as contact leachable studies. surfaces. These primary components are examined indi- vidually and are subjected to a variety of conditions, such as extremes of temperature, pH, organic solvents, and placebo. The exact conditions are based upon the drug-product for- mulation and storage conditions. The extractable study is designed to provide a worst-case scenario to determine what impurities, if any, can be extracted from the components of the CCS. Studies are designed to minimize any degradation of the extracted compounds that might occur to provide an accurate profile of the extraction products. The leachable study is designed to provide an estimation of the Kathleen Kelly*, PhD, is a principal scientist and Nancy Lewen is a principal scientist, both with Bristol-Myers Squibb, 1 Squibb extent that any of the extractable impurities actually leach into Drive, New Brunswick, NJ, tel. 1.732.227.7613, the drug product during normal shelf life and storage conditions. [email protected]. To design the leachable study, a toxicological assessment of the compounds identified in the extraction study is performed to *To whom all correspondence should be directed. determine the safe level of exposure based upon the route of Submitted Mar. 28, 2013. Accepted June 24, 2013. administration. Based on this toxicological assessment, target

limits are established for the extractable compounds, methods MARIA TOUTOUDAKI/GETTY IMAGES 82 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Elemental Impurities

are developed and validated for quantitation, and the leachable been provided with a complete listing of the limits for all ele- study is initiated. The leachable study is performed with the ments that have the possibility to negatively impact patient actual drug product (or placebo) in the CCS that is to be the safety should they find their way into pharmaceutical prod- final commercial presentation using materials obtained from ucts. Because the listing of elements and limits have been the targeted commercial suppliers. The leachable studies are thoroughly vetted by a cadre of toxicologists from around the generally performed using the long-term stability study supplies. world, this information can be used to establish a risk-based approach for assessing elemental impurities in the context of Requirements for elemental impurity analysis leachables studies. The extractable studies will include any elemental impuri- Risk-based approaches are permitted by the EMA guideline, ties that may be extracted from the CCS components. The the Ph. Eur., and the USP and take into account the entire results of these studies identify which elements will be process, requiring good control on all aspects of manufacture, monitored in subsequent leachable studies. Recently, the including the supply chain of both raw materials and United States Pharmacopeial Convention (USP) issued in the packaging components. Using this approach, it is possible United States Pharmacopeia (USP) a new General Chapter to assess whether or not a specific test, or—in the case of <232> Elemental Impurities–Limits (3), which provides a elemental impurities—a specific element must be tested. listing of the elemental impurities of potential toxicological Given the acceptability of a risk-based approach, and concern as well as acceptable limits for those elements. USP the acceptable safety limits provided by the EMA General Chapter <232> applies to drug products. guideline, the Ph. Eur., and the USP, it is now possible to The European Medicines Agency (EMA) also issued identify target limits for elements of interest in leachable its Guideline on the Specification Limits for Residues of studies based on the context of those documents. Metal Catalysts or Metal Reagents (4), which addressed Table I provides a listing of the USP and EMA/Ph. Eur. elements of interest and maximum daily exposure limits elements of interest and limits. Although the permitted for patients. In establishing its listing of elements and their daily exposures (PDEs) provided in Table I assume a corresponding limits, EMA evaluated existing toxicological 10 g/day maximum daily dose, it is possible to calculate the information and based the final listing of elements and limits appropriate daily concentration limit (μg/g) for a product on patient safety. In 2012, the European Directorate for the with a different daily dose using the following equation: Quality of Medicines & HealthCare (EDQM) in the European Pharmacopoeia (Ph. Eur. ) adopted the EMA guideline as PDE (μg/day) Concentration limit (μg/g) = (Eq.1) a new chapter, 5.2.0 Metal Catalysts or Metal Residues (5), Maximum daily dose (g/day) publishing it verbatim and thereby adopting both the EMA’s listing of analytes of interest and their corresponding limits. Once the appropriate concentration limits are calculated, While the EMA guideline and the new USP General Chapter it is possible to use the listing of elemental concentration <232> are not completely harmonized, there is nonetheless, limits to determine whether or not to include a given a considerable amount of harmonization between the two elemental impurity in a leachable study. The example in documents. For both EMA and USP, patient safety was Table II illustrates how this risk-based approach would be the foremost reason for an element’s inclusion on the list used for an oral dosage form. The same approach may be of analytes of interest. These assessments are based on an used for other routes of administration, such as parenteral. assumed maximum daily dose of 10 g/day (of drug product) Use Equation 1 and Table I to calculate the appropriate and have factors built into them to assure that the limits are concentration limits for the analytes observed in the well within the safety limits for each elemental impurity. extractable study—silicon (Si), sulfur (S), boron (B), pallidum Historically, any elemental impurities that are seen in (Pd), iron (Fe), lead (Pb), chromium (Cr), arsenic (As), sodium extractable studies are further evaluated and followed during (Na), potassium (K), and mercury (Hg)—for an oral drug subsequent leachable studies. This testing is often done, product with a maximum daily dose of 200 mg. Where regardless of whether there is any toxicological data that the USP and EMA/Ph. Eur. limits differ, use the lower of would indicate a potential for impact on patient safety or the the two limits. For example, for iron, the USP and EMA contrary. As a result, costly and often unnecessary testing guidelines list the concentration limit as not applicable has been performed. Because the EMA and USP toxicological (N/A) and 13,000 μg/g, respectively, in Table I. Using assessments have conservatively established limits based on Equation 1, the appropriate concentration limit would be patient safety, it is appropriate to use those limits to make (13,000 μg/day)/(0.2 g/day) = 65,000 μg/g. Table II provides any decisions regarding the need (or lack thereof) to monitor those limits. elemental impurities during leachable studies. Because Si, S, B, Na, and K are not listed as elements of interest by either the USP or the EMA, they are, therefore, Risk-based approach for elemental not considered to be a safety concern, and, therefore, would impurity analysis in leachable studies not need to be monitored in a leachable study. The levels for With the publication of the EMA guideline, Ph. Eur. 5.20, and Fe, Cr, Pd, Pb, and Hg observed in the extractable study are USP General Chapter <232>, the analytical community has below the calculated concentration limits, and as a result, are Pharmaceutical Technology OCTOBER 2013 83 Elemental Impurities

Table I: Elements and permitted daily exposures (PDEs) permitted under provisions under the United States Pharmacopeia (USP), European Pharmacopoeia. (Ph. Eur.), and European Medicines Agency (EMA) guideline (References 3, 4, 5).

Element Oral exposure daily Parenteral exposure Inhalation exposure Large-volume parenteral PDE (μg/day) daily PDE (μg/day) daily PDE (μg/day) component limit (μg/g) USP EMA/Ph. Eur. USP EMA/Ph. Eur. USP EMA/Ph. Eur. USP EMA/Ph. Eur. Cadmium (Cd) 25 N/A 2.5 N/A 1.5 N/A 0.25 N/A Lead (Pb)5N/A 5 N/A 5 N/A 0.5 N/A Inorganic arsenic (As) 1.5 N/A 1.5 N/A 1.5 N/A 0.15 N/A Inorganic mercury (Hg) 15 N/A 1.5 N/A 1.5 N/A 0.15 N/A Iridium (Ir) 100 100** 10 10** 1.5 N/A 1.0 N/A Osmium (Os) 100 100** 10 10** 1.5 N/A 1.0 N/A Palladium (Pd) 100 100 10 10 1.5 N/A 1.0 N/A Platinum (Pt) 100 100 10 10 1.5 0.07*** 1.0 N/A Rhodium (Rh) 100 100** 10 10** 1.5 N/A 1.0 N/A Ruthenium (Ru) 100 100** 10 10** 1.5 N/A 1.0 N/A Chromium (Cr)*250 * 25 25 0.01 * N/A Molybdenum (Mo) 100 2501025 250 N/A 1.0 N/A Nickel (Ni)500 250 5025 1.5 0.10 5.0 N/A Vanadium (V) 100 2501025 30 N/A 1.0 N/A Copper (Cu) 1000 2500 100 250 70N/A25 N/A Manganese (Mn) N/A 2500 N/A 250 N/A N/A N/A N/A Iron (Fe) N/A 13,000 N/A 1300 N/A N/A N/A N/A Zinc (Zn) N/A 13,000 N/A 1300 N/A N/A N/A N/A * Not a safety concern. ** Subclass limit: total amount of listed metals should not exceed the indicated limit. *** Pt as hexachloroplatinic acid. N/A is not applicable (i.e., not included in the corresponding document).

therefore not considered to be a safety concern. As a result, Table II: Example for oral drug product with maximum using the risk-based approach, they would not need to be daily dose of 200 mg. PDE is permitted daily exposure. monitored in a leachable study. The results of the extractable N/A is not applicable. study that was performed yielded only one concentration Element Concentration found PDE Calculated in excess of the calculated elemental concentration limit in extractable study (μg/day) limit (μg/g) (As: 110 μg/g versus 7.5 μg/g). The As concentration in the (μg/g) extractable study would be considered a safety concern. A leachable study, therefore, would need to be performed; Silicon (Si)8 N/A N/A however, only As would need to be monitored. Sulfur (S) 22 N/A N/A There are instances where an element is not included Boron (B)5 N/A N/A found in the USP and/or EMA/Ph. Eur. listing of elemental impurities, or where, despite being present below a Iron (Fe) 225 13,000 65,000 toxicological limit of concern, it is necessary to monitor it for Lead (Pb) 3 5 25 product quality or stability reasons. Some biologic products, Chromium (Cr) 16 2500 12,500 for example, can be significantly affected by the presence Arsenic (As) 110 1.57.5 of metals. In these cases, it may be warranted to include these elements in either a leachable study or a separate Sodium (Na) 318 N/A N/A laboratory-scale experiment to assess potential product Potassium (K) 2315 N/A N/A quality impact even though they do not pose a patient- Mercury (Hg) 19 1575 safety concern. Pallidium (Pd) 15 100 500 contin. on page 94 84 Pharmaceutical Technology OCTOBER 2013 PharmTech.com PRESENTED BY: CONTAINMENT STRATEGIES IN HIGH-POTENCY MANUFACTURING SPONSORED BY: DATE: September 12, 2013 11am EDT

REGISTER FREE AT www.pharmtech.com/highpotency

EVENT OVERVIEW: PRESENTER: With the increasing use of high-potency APIs, containment strategies are becoming increasingly important. Systems must be designed to both protect safety of the workers and safety of the drug products. Applying a science- and risk- based approach to mitigate cross-contamination and ensure proper segregation of facilities and operations is crucial. This 30-minute webinar will focus on current best practices and John P. Farris, CIH strategies for containment in high-potency manufacturing. President & CEO SafeBridge Consultants, Inc. KEY LEARNING OBJECTIVES: • Learn how to optimize containment MODERATOR: in high-potency manufacturing Jennifer Markarian • Learn best practices to ensure operator safety Manufacturing Editor • Discuss best practices and various risk-mitigation Pharmaceutical Technology strategies, including the use of disposables. • Understand regulatory and industry guidance for high-potency manufacturing For questions contact Sara Barschdorf at WHO SHOULD ATTEND: [email protected] • Director, group leader, manager, senior scientist in QA/QC • Director, group leader, manager of regulatory affairs • Director, group leader, manager, senior personnel of manufacturing • Director, group leader, manager, senior scientist in analytical development PEER-REVIEWED

Ruggedness of Visible Residue Limits for Cleaning—Part III: Visible Residue Limits for Different Materials of Construction

Richard J. Forsyth, Keith Bader, and Kelly Jordan

Visible residue limits (VRL) have been established alidation or re-validation of a cleaning program requires for numerous APIs, excipients, and formulations Vtwo criteria to establish equipment cleanliness. The first on stainless steel. It is a question of considerable criterion is that there can be no carryover that will have an interest that the VRL would be different for different adverse impact on the patient (1). Setting a health-based materials of construction. The authors generated limit to assure patient safety can begin with the allowable VRL data for a variety of materials of construction daily exposure (ADE) of the API approach (2, 3), or with the and found that VRLs were higher on some materials 1/1000th of the therapeutic dose approach (1, 4). The health- of construction than on stainless steel, meaning the based limit is not only specific for the API but also for the same level of residue is visible on some coupons manufacturing equipment in the facility. but not visible on other material of construction The second criterion is that the equipment must be coupons. The relationship of the coupon, observer, visually clean (5). Visually clean equipment can involve either and light source was also different for other materials a qualitative assessment or quantitative assessment using a of construction, making optimal viewing conditions visible residue limit (VRL), which is the level below which an dependent on the material of construction and the API or formulation is not visible. VRLs have been established viewing background. Risk of a cleaning failure due to for use in clinical (6) and manufacturing (7) facilities. In Part I visual failure for different materials of construction of this series, the ruggedness of the VRL approach was can be mitigated or eliminated using complementary shown for hundreds of APIs, excipients, formulations, and cleaning validation studies. detergents (8). In Part II, ruggedness was also demonstrated regarding the presentation of the coupons to the observers (9); however, to date, all VRL data has been generated using stainless-steel coupons. Because stainless steel comprises the vast majority of pharmaceutical manufacturing equipment product contact surfaces, it was the logical material of construction (MOC) on which to concentrate. Determining VRLs for other materials of construction has been a question of considerable interest. Swab recovery studies have shown that a common recovery factor can be developed for the vast majority of different materials of construction (10); however, it is intuitive that the VRL for a given soil will differ from stainless steel to clear glass to the white background of polytetrafluorethylene (Teflon, DuPont). There are a variety of materials of construction to Richard Forsyth* is a senior consultant at Forsyth be considered for VRLs and depending on the equipment Pharmaceutical Company, 907 Shamrock Ct. Royersford, PA configuration, an alternate material of construction could 19468, Keith Bader is senior director of technology, and Kelly Jordan is an engineer, both at Hyde Engineering + Consulting, comprise the majority of the product contact surface area. 6260 Lookout Rd, Suite 120 Boulder, Colorado 80301, Once the VRL is established for a variety of MOC coupon types, [email protected]. which VRL to use going forward is the question. A distinct VRL for each material of construction is too cumbersome to * To whom correspondence should be addressed. develop, maintain, and assure compliance. Using the highest established VRL for the range of materials of construction Submitted: Feb. 1, 2013. Accepted: Mar. 3, 2013. is overly conservative unless the material of construction with the highest VRL is also the primary component of the 86 Pharmaceutical Technology OCTOBER 2013 PharmTech.com LOCAL SPEED GLOBAL POWER SGS LIFE SCIENCE SERVICES

When we say global, it means something. With  labs in 1 countries, we are the world’s largest Network of Contract Analytical Laboratories providing analytical development, biologics characterization, and quality control testing, in addition to Clinical Research Services.

Locally, four North American labs can handle virtually any of your development needs. Our SGS experts are reliable, current on regulatory issues, and can model processes for whatever capacities and capabilities you require. We promise immediate service, varied and available expertise, and seamless project management. Call us.

CONTACT US LOCALLY: OR GLOBALLY:

Fairfield, NJ West Chester, PA Europe: +32 10 42 11 11 + 1 888 747 8782 + 1 610 696 8210 Asia: +65 63790 111 [email protected] [email protected] [email protected]

Lincolnshire, IL Mississauga, ON +1 847 821 8900 + 1 905 364 3757 [email protected] [email protected]

SGS IS THE WORLD’S LEADING INSPECTION, VERIFICATION, TESTING AND CERTIFICATION COMPANY

Visit us at AAPS, Booth 2923

©20 SGS SA – All rights reserved WWW.SGS.COM/,)&%3#)%.#% Visible Residue Limits

was deposited on one of the Table I: Material of construction coupon types for visible residue limit (VRL) determination. coupons to serve as a negative control. Either 100 μL or 200 μL Coupons for VRL study Represented coupons of the suspension were spread Stainless steel Hastalloy, aluminum on the coupons. The final Glass Acrylic, polycarbonate resin thermoplastic (Lexan, SABIC Plastics) residue areas, concentrations, and observations of the five soils Polytetrafluorethylene Polypropylene, silicone, latex rubber, ethylene propylene diene (Teflon, DuPont) monomer, neoprene are shown in Table IV. For observation, the coupons were arranged first by soil Table II: Soil concentrations. and then sequentially by Soil Concentration Batch Expiration date concentration on the three Aspirin 81 mg/tablet 434549 Jan 2015 MOC coupon types. Observers Caffeine 200 mg/tablet 10671868 May 2013 independently viewed the coupons under well-defined, Calcium carbonate 600 mg/tablet X27234 Aug 2013 controlled conditions. The light Diphenhydramine 25 mg/tablet P75456 Dec 2014 level was between 350 lux to 400 Ibuprofen 200 mg/tablet 2KE1259A Jul 2014 lux. Data have shown that a light level of more than 200 lux lighting Table III: Soil dilutions for visible residue limit determinations. provides consistent results (6–8). Three observers viewed Spotting solution Residue spotted Target concentration the coupons from a distance preparation (20 cm2) of 2 ft at a viewing angle of 40 º 2 Solution A – 400 μg x 0.2 mL 80 μg 4 μg/cm and determined the level of Solution A – 400 μg x 0.1 mL 40 μg 2 μg/cm2 each soil that was visible on Solution B – 100 μg x 0.2 mL 20 μg 1 μg/cm2 the MOC coupon. Changing viewing parameters did not Solution B – 100 μg x 0.1 mL 10 μg 0.5 μg/cm2 significantly change the ability 2 Solution C – 50 μg x 0.1 mL 5 μg 0.25 μg/cm to see residue on stainless Solvent 0 μg 0 μg/cm2 steel, but the ability to detect residue on both glass and manufacturing equipment. The current study was conducted polytetrafluorethylene (Teflon, DuPont) was greatly influenced to generate data to provide a basis for addressing these issues. by the viewing parameters. The optimal viewing parameters for glass were similar to stainless steel, but highly dependent on Methods the background. Either dark or white backgrounds can make The VRL study was conducted to determine visual limits visual detection difficult. A medium, neutral color enhanced for a variety of soils on a range of MOC coupons using the residue detection. Alternatively, looking through the glass following parameters. Table I lists multiple MOC coupon with the light source behind and slightly offset as shown in types, which are commonly used in pharmaceutical and Figure 1 also afforded equivalent viewing parameters. Optimal biopharmaceutical manufacturing. A subset of coupon viewing conditions for glass are fairly restricted and need to be types was chosen as representative of the MOC coupon established for each facility. Residues on polytetrafluorethylene types. Stainless steel was chosen as representative of metal (Teflon, DuPont) are difficult to detect but viewing from a coupons; glass was chosen as representative of clear shallow angle as shown in Figure 2 seemed to give the best coupons; and polytetrafluorethylene (Teflon, DuPont) was chance of seeing the residue. The observers determined the chosen as the most difficult to see of the opaque coupons. VRL of each soil under optimal conditions on each material of Pharmaceutical soils included aspirin, caffeine, calcium construction as presented in Table V. carbonate, diphenhydramine, and ibuprofen tablets. The concentrations of the tablets are shown in Table II. The tablets Results and discussion were initially dispersed in several millimeters of distilled water. The MOC coupons chosen for the study were seen as repre- The soils were accurately diluted with isopropanol to the sentative of a wide variety of materials. A subset was also approximate concentrations listed in Table III. Isopropanol was chosen, rather than to attempt a comprehensive survey of chosen as the spotting solvent because it spreads easily due to materials of construction because the combination of soils its low surface tension, resulting in residues of approximately and materials of construction are typically restricted to a the same area, and it also evaporates quickly. single site. Implementation of this approach at a site should The soils were deposited onto individual coupons at include all soils on all materials of construction employed at the various concentrations in a serial order. Isopropanol the site unless an abbreviated approach can be justified. 88 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Visible Residue Limits

Figure 1: Optimal viewing of glass coupons. Figure 2: Optimal viewing of polytetrafluorethylene (Teflon, DuPont) coupons.

Residue

Light intensity (lux) Product contact surface Light intensity (lux)

Distance (meter) Angle (degrees) Distance (meter)

Residue Angle (degrees)

Product contact surface

The target residue concentrations as shown in Table III highest VRL of the residue as the overall limit for all materials were based on past experience with a wide variety of of construction; use the VRL for stainless steel and mitigate the pharmaceutical soils dissolved or suspended in methanol risk for other materials of construction. on stainless steel (8). The low surface tension of isopropanol Using a separate VRL for each material of construction is allowed the residues to spread out on the materials of a viable approach as long as the highest VRL is lower than construction. The resulting concentrations of the dried the acceptable cleaning limit (ARL) but it would be logistically residues are shown in Table IV. The combination of soils, challenging. Maintaining accurate records for each residue and MOC coupons, and solvents should be assessed for each material of construction as well as training site personnel would facility to ensure a uniform distribution of residues. require significant site resource expenditures. The larger issue Observations of the residues on the different MOC coupons would be in those instances where the VRLs for some materials varied based on the observation parameters. Residues on stainless-steel coupons were visible at a light level of > 200 lux, a viewing angle of > 30 º, and a distance of < 10 ft (3 m). Observations of residues on glass coupons were more challenging. Residues were visible when the viewing angle was at 30 º with the coupons laying flat on the viewing surface. Residues were not as visible at other angles. Residues were also highly visible when the glass coupons were viewed looking through the coupons with the light source at a slight offset behind the coupon. Under the optimal viewing conditions, the VRL on glass is comparable with the VRL on stainless steel. Residues on polytetrafluorethylene (Teflon, DuPont) coupons were not visible at the highest levels, > 5 μg/cm2. The observed VRLs for all of the residues tested on the three materials of construction are listed in Table V. The high VRLs of residues on polytetrafluorethylene (Teflon, DuPont) and similar materials of construction can be addressed using one of several options: use individual VRLs for each

ALL FIGURES ARE COURTESY OF THE AUTHORS THE OF COURTESY ARE FIGURES ALL material of construction; use the Pharmaceutical Technology OCTOBER 2013 89 Visible Residue Limits

Table IV: Soil residue concentrations and observations.

Aspirin Stainless steel Glass Amount Diameter Area Concentration Visible Diameter Area Concentration Visible (μg) (cm) (cm2) (μg/cm2) (Y/N) (cm) (cm2) (μg/cm2) (Y/N) 80 4.5 15.95.0 Y 4 12.66.4 Y 403.59.64.2 Y 4 12.6 3.2 Y 20 4 12.6 1.6 Y 4 12.6 1.6 Y 10 3.59.6 1.0 Y 3.59.6 1.0 Y 5 3.59.6 0.5 Y 4 12.6 0.4 Y Caffeine Stainless steel Glass Amount Diameter Area Concentration Visible Diameter Area Concentration Visible (μg) (cm) (cm2) (μg/cm2) (Y/N) (cm) (cm2) (μg/cm2) (Y/N) 80 4.5 15.95.0 Y 5 19.64.1 Y 40 4 12.6 3.2 Y 5 19.6 2.0 Y 20 4.5 15.9 1.3 Y 3 7.1 2.8 Y 10 4 12.6 0.8 Y 3.59.6 1.0 Y 5412.6 0.4 Y 4 12.6 0.4 Y Calcium carbonate Stainless steel Glass Amount Diameter Area Concentration Visible Diameter Area Concentration Visible (μg) (cm) (cm2) (μg/cm2) (Y/N) (cm) (cm2) (μg/cm2) (Y/N) 80 4.5 15.95.0 Y 4.5 15.95.0 Y 40 4.5 15.9 2.5 Y 5 19.6 2.0 Y 20 4.5 15.9 1.3 Y 4.5 15.9 1.3 Y 10 4.5 15.9 0.6 Y 4.5 15.9 0.6 Y 5 N/A N/A N/A N N/A N/A N/A N Dephenhydramine Stainless steel Glass Amount Diameter Area Concentration Visible Diameter Area Concentration Visible (μg) (cm) (cm2) (μg/cm2) (Y/N) (cm) (cm2) (μg/cm2) (Y/N) 80 4 12.66.4 Y 4 12.66.4 Y 40 4 12.6 3.2 Y 4 12.6 3.2 Y 20 2.54.94.1 Y 3 7.1 2.8 Y 10 2.54.9 2.0 Y 2.54.9 2.0 Y 5 23.11.6 Y 23.11.6 Y Ibuprofen Stainless steel Glass Amount Diameter Area Concentration Visible Diameter Area Concentration Visible (μg) (cm) (cm2) (μg/cm2) (Y/N) (cm) (cm2) (μg/cm2) (Y/N) 80 4 12.66.4 Y 4.5 15.95.0 Y 403.59.64.2 Y 3 7.1 5.7 Y 20 3 7.1 2.8 Y 3 7.1 2.8 Y 10 2.54.9 2.0 Y 2.54.9 2.0 Y 5 2.54.9 1.0 Y 23.11.6 Y

90 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Visible Residue Limits

struction can be mitigated or eliminated using complemen- Table V: Visible residue limits (VRL) tary developmental cleaning process and validation studies. VRL (μg/cm2) Part I of this series of articles examined the ruggedness of Residue Stainless Glass polytetrafluorethylene VRL viewing conditions and defined optimal viewing conditions steel (Teflon, DuPont) (8). In Part II, current detection methodologies were challenged Aspirin < 0.5 < 0.4 > 5 and the author discussed questions about the constant Caffeine < 0.4 < 0.4 > 5 parameters of VRL studies that remained to be answered (9). Calcium < 0.6 < 0.6 > 5 References Diphenhydramine < 1.6 < 1.6 > 5 1. FDA, “Guide to Inspection of Validation of Cleaning Processes,” (Division Ibuprofen < 1.0 < 1.6 > 5 of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs, July 1993). of construction are below the ARL, but the VRLs are higher than 2. D. G. Dolan et al., Regul. Toxicol. Pharmacol. 43, 1-9 (2005). the ARL for other materials of construction. In those instances, 3. R. J. Forsyth and D. V. Haynes, Pharm. Technol. 22 (9) 90-112 (1998). a secondary confirmation would be necessary for those 4. G. L. Fourman and M. V. Mullen, Pharm. Technol. 17 (4) 54- 60 (1993). materials of construction with the high VRL. This scenario would 5. Code of Federal Regulations, Title 21, Food and Drugs (Government be likely considering the high VRLs on polytetrafluorethylene Printing Office, Washington, DC) Part 211, Section 67.b.6. (Teflon, DuPont) compared to those on stainless steel and glass. 6. R. J. Forsyth, V. Van Nostrand and G. Martin, Pharm. Technol. 28 (10) 58-72 (2004). Use of the highest VRL as the overall limit is logistically 7. R. J. Forsyth and V. Van Nostrand, Pharm. Technol. 29 (10) 152-161 (2005). more manageable and is a viable approach as long as it is 8. R. J. Forsyth, Pharm. Technol. 33 (3) 102-111 (2009). lower than the ARL. The risk of a cleaning failure, however, 9. R. J. Forsyth, Pharm. Technol 35 (3) 122-128 (2011). becomes much greater the closer the VRL is to the ARL. This 10. R. J. Forsyth, J. C. O’Neill, and J. L. Hartman, Pharm. Technol 31 (10) approach could severely limit the application of VRLs for 102-116 (2007). cleaning determinations. 11. R. J. Forsyth, “Cleanability of Pharmaceutical Residues from Different Continued use of the established VRL on stainless steel Materials of Construction,” in press. would need to address the higher visible limits on other 12. A. J. Canhoto, et al., J Valid. Technol. 11 (1) 6-15 (2004). PT materials of construction or accept the risk that these materials are also clean. Acceptance of the risk that the materials with high VRLs are clean might be reasonable if the material of construction in question comprised a small percentage (i.e., < 5%) of the total product contact surface area of the manufacturing equipment, which would be the case for gasket material or sight glass material on a tank. However, it would be preferable to either mitigate or address the risk of higher VRLs. One approach to address higher VRLs would be to determine the relative cleanability of residues on the site materials of construction (11). If the residues rinse from the MOC coupons at the same rate as stainless steel or the cleaning cycle is longer than all of the cleanability times, it could then be concluded that if the stainless-steel product contact surfaces are clean, the other product contact surfaces are also clean. Although cleanability experiments are additional work, on top of strengthening a site’s visual-inspection program, they provide objective data to establish the hardest-to-clean residue at the site. For a site with a large number of residues, a paper exercise (12) could group and/or eliminate a majority of the residues prior to performing the laboratory cleanability studies.

Conclusions VRL have been established for different materials of con- struction. VRLs were higher on some materials of construc- tion than on stainless steel. The relationship of the coupon, observer, and light source was also different for other materials of construction, making optimal viewing condi- tions material of construction dependent. Risk of a cleaning failure due to visual failure for different materials of con- Pharmaceutical Technology OCTOBER 2013 91 OUTSOURCING OUTLOOK

The Expense of EVANS/PHOTODISC/ JONATHAN IMAGES GETTY Vision in Outsourcing PharmTech.com/outsource

Jim Miller Practicality of implementation should be a part of vision in the bio/pharmaceutical industry.

ision is one of the most sought- when Microsoft CEO Steve Ballmer moves, most notably its withdrawal after and admired qualities of a announced his retirement. Ballmer from its biosimilar joint venture with Vcorporate executive. The Oxford delivered enormous profits over a 12- Teva, and the restructuring of its mi- Dictionary (online edition) defines vi- year period and successfully positioned crobial fermentation business. Those sion as “the ability to think about or the company in some key businesses initiatives were originally set in mo- plan the future with imagination or such as databases, gaming, and Skype. tion by Lonza’s previous CEO, Stefan wisdom;” and as “a mental image of Borgas, who clearly had a vision to what the future will or could be like” (1). position Lonza in the forefront of the When a CEO’s vision is aligned with The contract major biotechnology trends sweeping what really happens in the business services business over the bio/pharmaceutical industry. environment, it can bring great cor- Borgas engineered the acquisition of porate success and great admiration has had its share Cambrex’s biologics assets in 2006, for the CEO. The classic example in re- which gave Lonza significant positions cent times of a corporate leader with a of visionaries, but in bioscience-based research tools, mi- spot-on vision is Steve Jobs, whose un- crobial fermentation, and cell therapy. derstanding of the promise of mobile their track record Another acquisition gave Lonza capa- technology yielded some of the most bilities in virus-based products. Borgas successful product launches of all time. has not been good. established the biosimilars joint venture Vision has become such an admired with Teva, which linked Lonza’s large, quality in corporate leadership that it Despite that performance, Ballmer was mammalian cell-culture capacity with has come to overshadow other quali- widely criticized for Microsoft’s late and Teva’s experience in developing and ties, including operating skill. The troubled response to mobile technology, marketing generic injectables. He also excitement generated by a corporate and the company’s stock went up when established Lonza’s presence in China vision can drive up the valuation of his retirement was announced. by building a small-molecule manufac- a company (i.e., its stock price) even The bio/pharmaceutical contract turing facility in Nanjing and added ca- when operating results are poor; just services business has had its share of pabilities for antibody-drug conjugates look at the performance of Amazon’s visionaries, but their track record has at the company’s main manufacturing stock, which has rocketed up despite not been good. Their efforts to respond site in Visp, Switzerland. marginal earnings. to clear trends in the bio/pharmaceuti- Borgas’s strategic moves undoubt- With technology companies, the cal industry such as the re-engineering edly positioned Lonza directly in the story often trumps the actual perfor- of R&D, the growing role of biophar- path of major trends driving the bio/ mance. That point was driven home maceuticals, and the expanding role pharmaceutical industry, but they were of emerging markets in the supply expensive, requiring extensive capi- Jim Miller is president chain have often come to naught, over- tal expenditures and investments in of PharmSource whelmed by the realities of profitability R&D and acquisitions. Whatever their Information Services, and cash flow. long-term promise, the initiatives hurt Inc., and publisher of Bio/Pharmaceutical Lonza’s near-term profitability and the Outsourcing Report, Lonza’s vision heavy reliance on contract manufac- tel. 703.383.4903, The practical difficulties of realiz- turing made it difficult to hit stated Twitter@JimPharmSource, [email protected], ing a vision were evident when Lonza earnings targets. When the EU debt www.pharmsource.com. announced a series of retrenchment crisis struck and the Swiss franc shot

92 Pharmaceutical Technology OCTOBER 2013 PharmTech.com COUNT ON US

FROM GEL S AND CREAM S TO OINTM ENTS AND AEROSOL S

FROM NON-STERIL E TO STERIL E

FROM CONCEPT TO COMMERCIAL I Z ATION

FROM VIRTUAL TO LARGE P H ARM A

Z See us at CPhI Worldwide at Booth 42M10, Hall 4.2 / Oct. 22-24

Work with the leaders at bringing semi-solids and liquids to life.

www.dptlabs.com COUNT ON USTM Outsourcing Outlook up in value, Lonza’s profitability was ing for the corner to be turned, and them vulnerable to the volatility of severely hurt, and Borgas was replaced. the business might actually run out of venture funding and capital markets. The new executive team has focused on cash before the vision is realized. Tak- Many CMO and CRO executives restoring predictable, near-term prof- ing those kinds of risks will generally have seen the contract services busi- itability and retreated from some of be unpalatable and unwise for other- ness model as one that can transform those strategic initiatives. wise successful businesses. the bio/pharmaceutical industry and Other examples of failed visions in help it adapt to new market realities. Lessons learned the contract services industry point to In the clinical research sector, that In hindsight, Borgas’ vision for Lonza the fact that customer behavior often has indeed been the case, especially seems well founded: the trends it was takes much longer to change than the as CROs have leveraged the power of based on are in fact reshaping the bio/ visionary expects. This situation has information technology to streamline pharmaceutical industry. The Lonza been especially true for the integrated clinical trials. CROs have been able to experience, however, shows that reality services model, often referred to as the make the investment in information has a habit of impinging on the vision, “one-stop shop.” Companies that have technology without undermining their and that pursuing a vision is inher- pursued this model did so with the near-term profitability and perfor- ently risky. Reality struck in the form understanding that small companies mance. CMO and CDMO executives of the European financial crisis and lacked the sophistication to buy ser- will be well served to follow that more the longer-than-expected time it has vices individually, and that bio/phar- incremental approach to pursuing taken to clarify a path for biosimilars maceutical companies of all sizes are their long-term visions. in the US. looking to shorten development times The risk comes in part because and reduce costs. Those visionaries, Reference pursuing a vision by definition means however, underestimated the reluc- 1. Oxford Dictionaries, “Definition of vision being ahead of the market and giving tance of the large bio/pharmaceutical in English,” (Oxford University Press), people what they want before they companies to change the way they do online, http://oxforddictionaries.com/ know they want it. Stockholders and things, and their reliance on smaller us/definition/american_english/vision, investors may run out of patience wait- bio/pharmaceutical companies made accessed Sept. 17, 2013. PT

Peer-Reviewed—Elemental Impurities contin. from page 84

Conclusion reduce cycle times, and maintain drug-development costs By using the list of elemental impurities and their accepted while ensuring the highest level of patient safety and drug- PDE limits provided by the USP and EMA/Ph. Eur., it is possible product quality. to develop a risk-based approach, based on patient safety and toxicology, to determine the need to include elemental impu- Acknowledgments rities analyses in leachable studies. This approach has the The authors gratefully acknowledge the contributions of potential for considerable savings in terms of time and money, Wendy Luo, manager, quality/toxicology with Bristol-Myers thereby reducing the cost of developing drugs and lowering Squibb. costs to patients. This approach was applied to a leachable study that included five elements that had been observed in References the extractable study. Based on the outsourcing costs associ- 1. CFR, Title 21 Part 211.94 (Government Printing Office, Washington, DC), ated with the method development, validation, and sample Revised April 2013, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ analysis for all five elements for the course of the 36-month CFRSearch.cfm?fr=211.94, accessed Sept. 18, 2013. study, a cost savings of $68,000 (26% overall) was achieved. 2. FDA , Guidance for Industry: Container Closure Systems for Packaging The emphasis of the recently issued USP Chapter <232> Human Drugs and Biologics—Chemistry, Manufacturing, and Controls and EMA’s Guideline on the Specification Limits for Residues Documentation (Rockville, MD, May 1999). of Metal Catalysts or Metal Reagents/Ph. Eur 5.20 on the 3. USP 35–NF 30 General Chapter <232>“Elemental Impurities—Limits,” toxicological concerns for patient safety provides a scientific (US Pharmacopeial Convention, Rockville, MD, February 2013), p. 5633. basis for the development of a risk-based analytical strategy 4. EMA , Guideline on the Specification Limits for Residues of Metal Catalysts for the selection of elemental impurities to be included in or Metal Reagents (London, 2008). leachable studies of CSS. The use of this approach provides 5. Ph. Eur. Supplement 7.7, General Text 5.2.0, Metal Catalysts or Metal the industry the ability to more effectively use its resources, Residues (EDQM, Strasbourg, France, 2012), p. 5285. PT

94 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Optimizing Bioavailability: Enhancing Pharmaceutical Productivity ON DEMAND WEBCAST Register free at www.pharmtech.com/productivity

EVENT OVERVIEW: Who Should Attend: Enhancing bioavailability of APIs has been a large and growing ■ Pharmaceutical R&D scientists challenge for the pharmaceutical industry. It is estimated in ■ Pharmaceutical R&D formulators the literature that 40% of marketed drugs and more than 70% of drugs in development according to the BCS classification ■ Pharmaceutical process engineers have challenges associated with poor aqueous solubility. This ■ Pharmaceutical clinical trial executives/ 60-minute webinar will address several approaches to enhance managers solubility, and thus, bioavailability, through hot-melt extrusion ■ Life-cycle executives/managers technology. Highlights will include: ■ Supply-chain executive/managers

■ ■ Boehringer Ingelheim Vice President of Pharmaceutical Marketing/Brand executives/managers Development US highlighting trends and challenges associated responsible for life-cycle growth with bioavailability enhancement, technology applications, pros/ strategies cons, and pitfalls. ■ BASF scientific expert describing considerations and data Presenters comparisons for optimizing solubility of formulation polymers Dr. Keith Horspool when applying hot-melt extrusion technology. Vice President Pharmaceutical Development US ■ Catalent Pharma Solutions scientific expert describing processing Boehringer Ingelheim and scale-up parameter considerations when applying hot-melt extrusion to optimize product profiles, including downstream final Dr. Nigel Langley dosage form considerations. Head of Marketing and Technical Sales Pharma Ingredients and Services Key Learning Objectives: BASF

■ Gain insight on the issues, options, and pitfalls when optimizing Ron Vladyka bioavailability for compounds Principal Scientist Advanced Delivery Technologies ■ Understand hot-melt extrusion polymer selection considerations Catalent Pharma Solutions to enhance bioavailability ■ Learn about hot-melt extrusion process parameters and Moderator approaches to enhance development efficiency and the Patricia Van Arnum probability of development success at all stages of drug Executive Editor development Pharmaceutical Technology

Presented by Sponsored by

For questions, contact Sara Barschdorf at [email protected] PHARMA CAPSULES

& with Catalent Appoints The 10,000-ft2 two-story Q A Imaging Center is the latest joint First President of effort between MPI Research, Amie Gehris, Technical Service Manager , INVICRO, and 3D Imaging, which Healthcare and Specialty Nutrition, Dow Water Catalent Asia Pacific have collaborated on more than Catalent Pharma Solutions 100 imaging projects to date. and Process Solutions has named David Heyens as The multimillion-dollar project PharmTech: Abuse-deterrent drugs have president of Catalent Asia will employ INVICRO’s molecular come into prominence with the recent issu- Pacific. Reporting directly imaging informatics team and ance of FDA draft guidance. What is meant to Catalent’s president and 3D Imaging’s radiopharma- by an abuse-deterrent drug and what role CEO, John Chiminski, Heyens ceutical group. Many of the does the formulation play? will assist Catalent’s growth expanded imaging solutions, Gehris: Whether intentional or uninten- in the region following the including nonhuman primate tional, the abuse of certain drugs can be life company’s recent expansion PET and CT imaging capabilities, threatening. One of the best known types into China and will build became available in July 2013. of deliberate drug abuse is that of opiates, on Catalent’s operations such as oxycodone, which has been linked to numerous deaths. in Japan, Australia, and However, unintentional abuse—chewing sustained-release for- Singapore. “This appointment Capsugel Expands mulation drugs, for example—is also potentially lethal. Loading an comes at an important API onto a resin to create a resinate can slow the release of a drug Manufacturing sufficiently to reduce or eliminate the potential for lethal concen- moment in our business, as trations of active drugs in the body. The API remains bound within we launch our two new joint for Finished the resin, so the rate of absorption is reduced. This technology is ventures in China for softgel Dosage Forms used to reduce the high risk associated with intentional abuse, technologies and clinical Capsugel’s Dosage Form thus reducing the likelihood of overdose and making illicit extrac- supplies, and focus more Solutions business unit tion more difficult and less efficient. growth resources in Asia reported upgrades and Pacific,” said Chiminski. expansions to three of its PharmTech: What are specialized considerations in formulating an abuse-deterrent drug, including excipient functionality? Replacing Heyens as the manufacturing facilities in the president of Catalent Softgel US and Europe, increasing the Gehris: Based on the new FDA standards for controlled sub- Technologies will be Aris Gen- company’s finished dosage stances, new formulations must have abuse-deterrent features, including a crush-proof component. Historically, the controlled nadios, PhD. Also reporting to form capabilities as part of its release of the drug was the matrix tablet ingredients themselves. Chiminski, Gennadios will be LIPIDEX technology platform. When the controlled-release mechanism of the tablet was com- resonsible for the softgel devel- The investments broaden the promised by crushing, the drug was immediately available in a opment, delivery, and supply company’s global capabilities large dose. The current drug-delivery system has a crush-proof business with 10 manufacturing to handle hormonal as well component that prohibits dose dumping from the controlled- facilities that deliver a share of as high-potent compounds release formulation. This is the standard by which FDA is basing its pharmaceutical, generic, and for soft gelatin and liquid-fill criteria for accepting generic formulations into the US market. consumer health softgel prod- hard capsules, responding to a Functional excipients, such as ion-exchange resins, have a ucts to markets worldwide. growing demand. direct impact on the availability of the API. Ion-exchange resins The Ploermel facility in modify the release of drugs and reduce the immediate availability MPI Introduces France increased containment of the API, whether or not the integrity of the tablet thas been capacity to handle hormonal compromised. There are commercial examples of ion-exchange resins being used successfully in suspension formulations to mod- Imaging Center as well as high-potent com- ify the release of APIs over a period of time. A coating strategy is MPI Research, in partnership pounds in softgel manufac- typically employed in these instances. Also, ion-exchange technol- with INVICRO and 3D Imag- turing. Capsugel’s Livingston ogy reduces the dose-dumping effects when alcohol is present, ing, has introduced its new facility in the UK has installed making them useful for abuse-deterrent formulations. Imaging Center, set to open the latest generation CFS 1500 in spring 2014 at the MPI capsule filling and sealing PharmTech: What testing is used in formulating an abuse-deter- Research global corporate machine, and a proprietary rent drug? headquarters in Mattawan, lipid expert system has been Gehris: Slight modifications of standard testing may be neces- Mich. When the facility opens, incorporated into the finished sary when employing an ion-exchange strategy to a formulation. pharmaceutical researchers dosage form development Typical dissolution testing, either static or dynamic, can be used. will have access for the first process. In addition, its Green- Dissolution media may have to be altered slightly to achieve ac- time to a cyclotron facility di- wood, South Carolina facility in ceptance criteria for quality-control release protocols by increas- rectly connected to a vivarium, the US commissioned and vali- ing the ion background. Also, assay testing includes removing the permitting drug radiolabeling dated a new commercial-scale drug from the resin before testing with typical analytical methods and in-depth studies across a liquid-fill encapsulation unit for by displacing it with salt, acid, or a combination of those materials. variety of animal models. pharmaceutical applications.

96 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Advancing Development & Manufacturing

GLOBAL LAUNCH OF PharmTech.com NEW eBOOK SERIES

What you need to know about Analytical and Bioanalytical Testing

A FORMAT FOR EVERYONE This new e-book is available for the iPad or for a standard computer web browser

FREE Download

Analytical methods Specifi c topics covered include:

development and testing are ➤ Multiple reaction monitoring-mass crucial for ensuring product spectrometry for biopharmaceutical analysis quality of pharmaceuticals. ➤ I mpurity profi ling using convergence This supplement offers chromatography and mass spectrometry case-study analysis of ➤ Atomic force microscopy and topographic the chromatographic, and Raman imaging of drug-delivery systems spectroscopic, and imaging ➤ Simultaneous quantitative and qualitative methods used in the measurements for primary drug metabolism investigations identifi cation, characterization, and quantifi cation of drug ➤ I dentifi cation and quantifi cation of trace-level impurities in biotherapeutics substances and drug products ➤ as well as impurity analysis. HPLC using small-particle columns in pharmaceutical analysis ADVERTISER PROFILES

Asahi Kasei 535 Madison Avenue, 33rd Floor New York, NY 10022 tel. 212.371.9900 AbbVie Contract 855.4CEOLUS Manufacturing fax 212.371.9050 [email protected] 1401 Sheridan Road North Chicago, IL 60064 USA +1 847 938 8524 Description [email protected] Asahi Kasei is a global supplier of www.abbviecontractmfg.com microcrystalline cellulose and other specialty pharmaceutical excipients. AbbVie continues a legacy Our products are known for their premium quality and are supported reflecting more than a century at with first-rate technical service. the forefront of pharmaceutical Our newest products are Swelstar development and manufacturing. MX-1, WB-1, and PD-1. These are AAPS For 25 years, the company has novel grades of pregelatinized starch, offered contract manufacturing all of which meet the monograph services that today comprise specifications in the NF, EP, and JPE. t
Swelstar MX-1 is a gel-matrix biologics, potent, drug product, excipient. MX-1’s unique prop- Company prefilled syringes, fermentation, erties allow well-controlled and high quality active pharma- drug release even under high ceutical ingredients (APIs). ionic-strength conditions. Profiles t
Swelstar WB-1 is a binder for AbbVie Contract Manufacturing wet granulation. Its unique core has a portfolio of 10 state-of- and shell structure imparts the-art facilities, offering a broad excellent binding and disinte- grating properties to tablets. range of capabilities in North t
Swelstar PD-1 is a super dis- America and Europe. AbbVie integrant with high swelling Contract Manufacturing handles properties. It also provides 2013 partners’ projects with the same excellent drug stability. dedication it shows its own Asahi Kasei’s core product products and clients also gain line includes: access to the unique capabilities t
Ceolus KG-802, KG-1000, UF-711, of a highly experienced and UF-702 – Highly compact- developer and manufacturer. ible MCC for tablet size reduc- tion, pressure-sensitive API’s and multiparticulate tablet systems. t
Celphere MCC spherical cores 2013 AAPS Booth #3005 – a superior alternative to sugar spheres for higher production rates, lower agglomeration, bet- ter dissolution control, and all- around more robust formulations.

AAPS booth 633

98 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Bilcare Research BioPharm International 1389 School House Road 485 Route One South Delaware City, DE 19706 Bldg F, Second Floor Ashland Inc. tel. 302.838.4000 Iselin, NJ 08830 Ashland Specialty Ingredients fax 302.838.3222 www.biopharminternational.com [email protected] 8145 Blazer Drive Volume 26 Number 6 www.bilcaresolutions.com INTERNATIONAL Wilmington, De 19808 BioPharm

June 2013 The Science & Business of Biopharmaceuticals www.biopharminternational.com PARENTERAL PACKAGING Tel: +1 (800) 345-0447 USING PLASTIC FOR PARENTERAL CONTAINERS

PEER-REVIEWED

A GENERIC GROWTH TEST METHOD FOR IMPROVING QUALITY CONTROL OF Fax: +1 (302) 992-7507 DISPOSABLES IN INDUSTRIAL CELL CULTURE

PLUS:

DRUG APPROVAL TRENDS FLEXIBILITY IN Email: [email protected] BIOMANUFACTURING EMERGING MARKETS www.ashland.com INTEGRATING A PREFILLED SYRINGE PLATFORM APPROACH FOR VACCINE DEVELOPMENT Ashland offers an unparalleled range of cellulosic and vinyl Description pyrrolidone polymers to meet Bilcare Research is a packaging solu- Description the needs of pharmaceutical tions provider that partners with the BioPharm International covers the and nutraceutical formulators. global pharmaceutical and health- entire biopharmaceutical develop- Ashland is your full-service care industries to improve patient ment, manufacturing, and business solid-dosage resource for outcomes. The company is among spectrum. We provide practical, peer- tablet binding, film coating the world’s leading manufacturers of reviewed technical solutions to enable pharmaceutical and medical blister and disintegration; as well as biopharmaceutical professionals to films and foils, supplying a full range excipients for controlled release perform their jobs more effectively. of thermoforming films, Alu-lid foils, and drug solubilization. BioPharm International readers and cold-form foils. are involved in product and process Delivering pharmaceutical development, manufacturing, quality Bilcare Research’s offerings include: control/quality assurance, analytical performance since the 1950s, t
ECOmply™, an eco-friendly technologies, regulatory affairs, plant Ashland creates value for its blister combining biodegrad- and project engineering and design, customers through applications ability and product protection and corporate management for the knowledge, regulatory stability entire scope of biopharmaceutical support, and a powerful products, including therapeutic pep- product portfolio: AquaSolve™ t
Bilcare Protect™, a specialty tides, proteins, nucleic acids, and cells blister film that fights counter- hypromellose acetate succinate, for cell therapies and regenerative feiting via embedded images Klucel™ hydroxypropylcellulose, medicine, as well as both therapeutic nearly impossible to duplicate Benecel™ hypromellose, and prophylatic vaccines. Aquarius™ coating systems, For information on advertising t
BilcareOptima™, the first Natrosol™ hydroxyethylcellulose, and special projects, please contact scientific method for develop- Aqualon™ ethylcellulose, Publisher Mike Tracey (732.346.3027 ing optimum packaging for Aqualon and Blanose™ sodium or [email protected]). To make pharmaceutical products. carboxymethylcellulose, an editorial contribution, please con- Polyplasdone™ crospovidone, tact Editorial Director Plasdone™ S-630 copovidone Rita Peters (732.346.3038 or rpeters@ and Plasdone providone. advanstarcom). AAPS booth 3423 AAPS Booth 3023

Pharmaceutical Technology OCTOBER 2013 99 ADVERTISER PROFILES

Brookfield Engineering CANGENE Laboratories, Inc. bioPharma, Inc. 11 Commerce Blvd. 1111 S. Paca St. Middleboro, MA 02346 Baltimore, MD 21230 Tel. 800.628.8139 / 508.946.6200 tel. 800.441.4225 Fax 508.946.6262 fax 410.843.4414 [email protected] [email protected] www.brookfieldengineering.com www.cangenebiopharma.com

Description CANGENE bioPharma is a leading provider of high quality fill/finish services in sterile liquids (vials and syringes) and lyophilized products. CANGENE bioPharma has an out- standing regulatory profile, including Description excellent regulatory compliance with US, EU, and Japanese regulations. We Brookfield viscometers/rheometers have helped produce over 20 com- have been the world standard in mercial and 200 clinical products for viscosity measurement and control customers for distribution worldwide. of liquids and semi-solids for almost 80 years. Quality, affordability, Services ease of use, and customer service t
Lyophilization Cycle Development are just some of the reasons why t
Fill/Finish of Vials and Syringes manufacturers have continuously t
Liquid & Lyophilized Products used Brookfield equipment in the t
Aseptic Processing QC and R&D departments. t
Terminal Sterilization Brookfield is also a leading t
Biopharmaceutical Manufacturing manufacturer of texture analyzers/ t
Process Development testers for tension and compression t
Fermentation testing. Brookfield also has a line of t
Fractionation/Purification instrumentation for quick and easy t
Clinical & Commercial Scale analysis of powder flow behavior in industrial processing equipment. AAPS booth 2843 Brookfield manufactures and services a full range of viscometers and rheometers, texture analyzers, and powder flow testers.

AAPS booth 4428

100 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Capsugel Catalent 535 North Emerald Rd. Pharma Solutions Greenwood, SC 29646 14 Schoolhouse Rd. tel. 888.783.6361 Somerset, NJ 08873 fax 888.783.6360 tel. +1 888 SOLUTION (765 8846) [email protected] [email protected] www.capsugel.com www.catalent.com

Description Capsugel is a global leader in provid- ing innovative, high-quality dosage forms and solutions for the health Description care industry. With more than 100 From drug and biologic development years of experience, we provide a services to delivery technologies to comprehensive array of advanced supply solutions, we are the catalyst solutions to pharmaceutical and nu- for your success. With over 75 years tritional customers from formulation of experience, we have the deepest through clinical and commercial sup- expertise, the broadest offerings, and ply. From hard gelatin, liquid-filled the most innovative technologies to and vegetarian capsules, to product help you get more molecules to development and manufacturing ser- market faster, enhance product vices, we help our customers improve performance and provide superior, their product profiles and accelerate reliable manufacturing results. development and commercialization timelines. Catalent. More products. Better treatments. Reliably supplied.™ AAPS booth 2012 AAPS booth 1612

Pharmaceutical Technology OCTOBER 2013 101 ADVERTISER PROFILES

Chemic Laboratories, Inc. Cirrus Pharmaceuticals, Inc. CMIC CMO USA 480 Neponset St., Building 7 511 Davis Drive, Suite 100 Corporation Canton, MA 02021 Durham, NC 27713 3 Cedar Brook Drive tel. 781.821.5600 PO Box 14748 Cranbury, NJ 08512 USA fax 781.821.5651 Research Triangle Park, NC 27709 tel. 609-395-9700 [email protected] tel. 919.884.2064 fax 609-395-8824 www.chemiclabs.com fax 919.884.2075 [email protected] www.cmiccmousa.com [email protected] www.cirruspharm.com

Description CMIC is a contract manufacturing Description organization that helps our Description Cirrus Pharmaceuticals, Inc. is now a pharmaceutical clients develop, Chemic Laboratories, Inc. is a full Kemwell Company. Together, Cirrus receive regulatory approval and service cGMP/GLP contract ana- and Kemwell provide a more com- commercially manufacture oral solid lytical chemistry laboratory. Chemic plete range of pharmaceutical product dosage drugs. We specialize in provides an array of R&D and cGMP development services and cGMP multiparticulate and modified contract testing services including; Ex- manufacturing with facilities in India release technologies. tractables/Leachables analysis, CMC (Bangalore), Sweden (Uppsala), and CMIC CMO USA is a member of the Method Development & Validation, the United States (North Carolina). CMIC Group, a full service contract Quality Control analysis, Release test- pharmaceutical company, with over ing, Raw Materials analysis, Com- Cirrus provides product development 4,500 employees in 6 countries pendial testing, Bioanalysis, Organic services to the pharmaceutical, bio- worldwide. CMIC is the largest CRO Synthesis/Formulation Development technology, consumer healthcare, and and 2nd largest CMO in Japan. & ICH Stability testing. animal health companies worldwide. Capabilities include physical/chemical Services AAPS booth 3243 characterization, analytical method CMIC is your full-service partner in development and validation, formula- solid oral dosage forms for: tion development, device selection t Formulation development and evaluation, process development, t Analytical development and testing scale-up/technology transfer, GLP t Feasibility trials batch manufacturing, and stability t Scale up storage and testing. Dosage forms t GMP clinical trial manufacturing include inhalation, oral liquids, par- t GMP validation enterals including lyophilization, and t GMP manufacturing. topicals, with solids to be added soon. AAPS booth 3013 Products developed at Cirrus can be transferred/manufactured to state-of- the-art cGMP manufacturing facilities in Bangalore for clinical supplies and commercial manufacturing.

AAPS booth 421

102 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Coating Place, Inc. Croda Inc 200 Paoli St. 300-A Columbus Circle Verona, WI 53593 Edison, NJ 08837 tel. 608.845.9521 tel. 732.417.0800 fax 608.845.9526 fax 732.417.0804 [email protected] [email protected] www.coatingplace.com www.croda.com/healthcare

Description Description Coating Place has developed and Croda is a manufacturer of a com- manufactured modified release oral plete range of high purity excipients dosage products since 1976. We are and delivery aids, offering superior the leading provider of Wurster fluid quality for the global pharmaceutical bed microencapsulation. CPI pro- market. Croda excipients are ideal for vides services from bead layering, multiple dosage forms: topical, par- extrusion / spheronization, and roller enteral, oral and ophthalmic formu- compaction to capsule filling and lations as well as advanced delivery tableting. Our experience makes us systems. the industries choice. Featured products include ingredients Products and services which have been Super Refined® via t
Formulation development solid a proprietary process which removes dosage forms polar and oxidative impurities. t
Commercial manufacturing t
SUPER REFINED® t
Analytical method development t
Oils t
Stability studies t
Arlasolve™ DMI t
Method and process validation t
PEGs t
Immediate and controlled release t
Polysorbates products t
Propylene Glycol t
Encapsulation services t
Castor Oil t
Tablet compression t
CRODASOLS: High and pan coating Purity solubilizers t
Clinical scale manufacturing t
CRODAMOLS: A wide range t
Ion resin suspension of ester solvents and vehicles time release products t
POLAWAX: Compendial, t
Schedule II-V controlled self-emulsifying wax substance drug manufacturing t
Solvent and aqueous based AAPS booth 3623 coating formulations

AAPS booth 2700

Pharmaceutical Technology OCTOBER 2013 103 ADVERTISER PROFILES

DPT Laboratories Dr. Reddy’s 318 McCullough Laboratories Inc. San Antonio, TX 78215 200 Somerset Corporate Blvd. tel. 210.476.8100 Bridgewater, NJ 08807 fax 210.227.5279 tel. 908.203.4932 www.DPTLabs.com fax 908.203.4914 [email protected] www.drreddys-cps.com

Description Description Dr. Reddy’s Custom Pharmaceuti- DPT is a contract development and cal Services (CPS) offers a variety of manufacturing organization (CDMO) programs specifically geared to solve specializing in sterile and non-sterile your development or commercial semi-solid and liquid dosage forms. needs. We can help you extend your DPT provides fully integrated devel- product life cycle by leveraging gener- opment, manufacturing and packag- ic assets, by utilizing effective chiral ing solutions for biopharmaceutical chemistry solutions for asymmetric and pharmaceutical products. DPT is problems, by providing the right the source for semi-solid and liquids facilities and technologies for high — from concept to commercializa- potent, steroidal or prostaglandin tion and beyond. products, or by utilizing the variety Drug development services range of formulation technology platforms from pre-formulation, formulation that we have at our disposal for dif- and biopharmaceutical development, ficult and sophisticated formulation analytical development and valida- needs. With our vast experience in tion, through process development. custom solutions, we have the techni- Production capabilities include cal and industry experiences required five cGMP facilities, clinical trial ma- to provide the right solution services terials, full scale commercial produc- for you. tion, controlled substance registration Class II – IV and complete supply AAPS booth 1006 chain management. Packaging services encompass en- gineering and procurement resources necessary for conventional and spe- cialized packaging.

AAPS booth 2805

104 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Fette Compacting America GE Healthcare 400 Forge Way Bio-Sciences Rockaway, NJ 07866 P.O. Box 643065 Eurofins Lancaster tel. 973.586.8722 Pittsburgh, PA 15264-3065 Laboratories, Inc. fax 973.586.0450 Postal Address www.fetteamerica.com 800 Centennial Avenue 2425 New Holland Pike P.O. Box 1327 Lancaster, PA 17601 [email protected] 717-656-2300 Piscataway, NJ 08855-1327 [email protected] tel. + 1 800.526.3593 www.lancasterlabspharm.com fax + 1 877.295.8102 Email: [email protected] Description www.gelifesciences.com With a proven track record of pro- viding quality scientific solutions for the largest pharmaceutical and biopharmaceutical companies in the world, Eurofins Lancaster Laboratories is a global leader in bio/pharmaceutical laboratory Description services providing comprehensive, innovative, and timely solutions to Fette Compacting America, North Description streamline all of your CMC testing America’s leader in precision tablet GE Healthcare Life Sciences offers requirements. press technology, is a subsidiary of Ger- technologies and services for the man manufacturer Fette GmbH. Fette manufacture of biopharmaceuti- With facilities in Lancaster, PA; Compacting America offers customers cals such as recombinant proteins, Portage, MI and Dungarvan, in the United States, Canada, and antibodies, and vaccines. Our Xcel- County Waterford, Ireland, and a Puerto Rico a variety of services, lerex portfolio provides innovative global capacity of over 300,000 including new and used machine sales, biomanufacturing products and square feet, Eurofins Lancaster technical assistance, machine installa- solutions that transform the speed Laboratories has the capacity and tions, training and seminars, valida- and economics of producing qual- breadth of capabilities to meet ity therapeutic proteins, including all of your product testing needs. tion, maintenance, spare parts, and All of our facilities offer cGMP- tooling. biosimilars and vaccines. compliant laboratory services and Products operate under the same strict qual- Our Xcellerex portfolio includes XDR ity control program and utilize the Fette Compacting America’s ground- Single-use stirred-tank bioreactors, same LIMS system. breaking FE Series of tablet presses XDM Quad and XDUO Quad Single- delivers unprecedented levels of pro- Use Mixing systems, and related Clients can choose from five service ductivity, flexibility, and availability. single-use assemblies. Xcellerex prod- models, including the award- Details include: ucts are tried and tested, and to date, winning Professional Scientific t
Easily-detachable, FDA-certified more than 20 therapeutic proteins SM Staffing (PSS) and Full Time high-performance polymer and vaccines have been manufactured Equivalent (FTE) programs, to t
360º access includes for clinical trials using Xcellerex determine the most efficient and unique filling system for cost-effective service solution for technology. simple, safe feeding their project. Eurofins Lancaster Labs also provides secure 24-hour t
Innovative filling system for data access via LabAccess.comSM. easy, reliable feeding and increased product output AAPS Booth #3223 t
Fast format and product changeover t
Maximum yields, minimum product loss, and easy changeover

AAPS booth 3541

Pharmaceutical Technology OCTOBER 2013 105 ADVERTISER PROFILES

GlobePharma, Inc. Halo Pharmaceutical, Inc. Hospira One 2 One™ 2B & C Janine Place US Office: 30 North Jefferson Road 275 North Field Drive New Brunswick, NJ 08901 Whippany, New Jersey 07981 D-0988, Bldg. H-1 T: (732)296-9700 F: (732)296-9898 tel. 973-428-4000 Lake Forest, IL 60045 E: [email protected] Canada: 17800, rue Lapointe tel. US: 1.224.212.2267 Web: www.globepharma.com Mirabel, Québec tel. Europe: +44 (0) 1926 835 554 Canada J7J 1P3 fax US: 1.224.212.3210 [email protected] [email protected] halopharma.com www.one2onecmo.com

Parenteral Contract Manufacturing Service of Hospira Description Established in 1993, GlobePharma Description has been Innovating the Industry Hospira’s One 2 One™ business is a Standard & providing excellent Description customer support for 20 years. Halo Pharmaceutical is a contract world leader in the custom develop- GlobePharma has introduced development and manufacturing ment and manufacture of injectable & patented several products. organization that provides scientific, products packaged in vials, prefilled Our products are used by pharma- regulatory, and development expertise syringes, and cartridges. Hospira has ceutical companies worldwide. as well as a wide spectrum of manu- extensive experience with injectable GlobePharma offers a variety of facturing services to help customers drug commercialization, and One 2 unit-dose & bulk samplers for bring their products to market quickly, One™ has over 20 years of contract powders, liquids & semi-solids, effectively and on budget. Halo offers manufacturing experience serving Remote Swabbing Sampling Tools, fully integrated capabilities in a variety bio/pharmaceutical companies. Cleaning Validation Coupons, of dosage forms including tablets, Product/service information POWDEREX™ Accelerated Powder capsules, powders, liquids, creams, t
Sterile filling and lyophiliza- Segregation Tester, R&D & Pilot Scale sterile and non-sterile ointments, and Blender with interchangeable tion facilities in North America, suppositories. Halo Pharmaceutical’s V-Shells, Bins, Double-Cones all Europe, and Australia. capabilities in the areas of tech trans- with high-speed Intensifier Bars, t
Manufactured over 25 large fer, process and product development, SimpleBlend™ stand-alone blender, molecules, 10 cytotoxic products production, scale-up and validation, Patented SIFT-N-BLEND™, cGMP and 10 beta-lactam products. and analytical method development Valves,Manual Tablet Press,Rotary t
Extensive product devel- allow us to partner with clients from Tablet Press, Instrumentation, opment experience with development through commercializa- High Shear Granulators, Dedusters, complex formulations. tion or at any point along the way. Polishers,Empty Capsule Eliminators, t
Practical knowledge of 70 mar- Cone Mills and more to be kets, including expert regulatory introduced soon! filing strategies for the Ameri-

cas, Europe, and Asia Pacific. AAPS Booth 3329

AAPS booth 519

106 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

International Centre for Jubilant HollisterStier Diffraction Data Contract Manufacturing & Services Division 12 Campus Boulevard U.S.A. – Canada – India Newtown Square, PA 19073 3525 N. Regal St. tel. 610.325.9814 Spokane, WA, U.S.A. 99207 fax 610.325.9823 tel. 800.655.5329 [email protected] Irvine Pharmaceutical [email protected] www.icdd.com Services, Inc. jublHS.com 10 Vanderbilt, Irvine CA 92618 Toll: (877) 445-6554 Tel: (949) 951-4425 Fax: (949) 951-4909 [email protected] www.irvinepharma.com Description ICDD, a not-for-profit corporation, is Irvine is your single source for Description dedicated to the collecting, editing, pharmaceutical development, Jubilant HollisterStier Contract Man- and publishing of the Powder Diffrac- offering high quality scientific ufacturing is an integrated contract tion File (PDF). Our mission is to be solutions to the pharmaceutical, manufacturer, able to manufacture the world center for quality diffraction biotechnology, and medical sterile injectable, solid and semi solid and related data to meet the needs of device industries. dosage forms. Our facilities across the technical community. North America and India provide Over the past 25 years, Irvine specialized manufacturing services ICDD’s PDF-4/Organics 2014 database has earned its reputation for for the pharmaceutical and biophar- featuring 479,278 entries is designed outstanding analytical testing maceutical industries. We provide for rapid materials identification. Its in all dosage forms from small a full-range of support and services design allows for easy interface with molecules to biologics. With the to streamline the manufacturing diffractometers and data analysis addition of a new manufacturing process. systems of leading software developers facility staffed by some of the and manufacturers of X-ray equip- industry’s most experienced t
Sterile Injectable Fill/Finish ment. The database is useful for scien- formulation scientists, Irvine (clinical to commercial) tists working in consumer products, guides its clients and expedites t
Lyophilization (clinical catalysis, forensic science, analytical their time to market. to commercial) labs, drug discovery, and production. t
Sterile Ophthalmics & Otics t
Non-Sterile Topicals & Liquids AAPS booth 3304 Irvine’s GMP services include: parenteral manufacturing (lyo/ t
Solid Dosage liquid), formulation development, t
Multiple Formats (vials, analytical chemistry, analytical ampoules, tablets, capsules, development, biopharmaceutical bottles, tubes, jars, applicators) development, microbiology, stability, structural chemistry, and Jubilant HollisterStier is registered with such Regulatory authorities as the drug delivery technologies. FDA (CDER, CBER) EMA, ANVISA, PMDA, and Health Canada. Visit www.irvinepharma.com or call (877) 445-6554. AAPS booth 1218

OUTWIT. OUTSOURCE. OUTSHINE.

Pharmaceutical Technology OCTOBER 2013 107 ADVERTISER PROFILES

Metrics, Inc. MG America 1240 Sugg Parkway 31 Kulick Rd. Greenville, NC 27834 Fairfield, NJ 07004 tel. 252.752.3800 tel. (973) 808.8185 fax 252.758.8522 fax (973) 808.8421 www.MetricsInc.com [email protected] www.mgamerica.com

Description MG America is a recognized leader in Description the supply of processing and packag- Metrics Inc. is one of the most respect- ing machinery to the pharmaceuti- ed contract pharmaceutical develop- cal, nutritional, cosmetic, food, and ment and manufacturing companies general packaging industries in the in the United States. Metrics is a full- United States, Canada, and Puerto service provider of quality pharmaceu- Rico. MG America offers equipment tical formulation development; First designed for flexibility, compact Time In Man formulations; CTM for operation, ease of use and maximum Phase I, II and III trials; commercial reliability. manufacturing; and analytical method development and validation services. Metrics has particular exper- tise in FTIM and Phase I, II, and III Products and services CTM manufacturing. t
1BDLBHJOH
.BDIJOFSZ including Globally, Metrics provides a broad case packers, cartoners, ther- spectrum of CMC services to support moforming machines, blister IND, NDA and ANDA submissions packaging machines, aseptic to regulatory agencies. Metrics’ spe- filling lines, powder microdos- cialty services include: ing, washing machines, pallet- t
Potent and Cytotoxic izers, inspection systems, and t
Formulation syringe assembly machines. t
Manufacturing t
Analytical t
$BQTVMF
'JMMJOH
.BDIJOFSZ to t
Stability Storage handle R&D, scale-up, intermit- t
Microbiology tent and continuous motion. Speeds range from 6000 to Specialty Technologies 200,000 capsules per hour. Dos- Metrics offers product development age forms include powders, pel- using proprietary technologies in the lets (beads), tablets, and liquids. areas of customized controlled release drug delivery; bioavailability enhance- AAPS booth 307 ment for poorly water-soluble drugs; and improved palatability for liquid and solid presentations.

AAPS booth 1202

108 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Micron Technologies Mikart, Inc. MPI Research 333 Phoenixville Pike 1750 Chattahoochee Ave. 54943 North Main Street Malvern, PA 19355 Atlanta, GA 30318 Mattawan, MI 49071 tel. 610.251.7400 tel. 404.351.4510 +1.269.668.3336 fax 610.251.7499 fax 404.350.0432 +1.269.668.4151 [email protected] [email protected] [email protected] www.microntech.com www.mikart.com www.mpiresearch.com

Description Micron Technologies provides con- tract particle size reduction and ana- lytical services for the pharmaceutical industry. We offer micronization, MPI Research, with global mechanical milling and classification, Description headquarters in Mattawan, for enhancing bioavailability, improv- Since 1975, Mikart has been a rec- Michigan, provides discovery, ing content uniformity, and refining ognized leader in providing contract safety evaluation, bioanalytical, the delivery of inhalation pharmaceu- manufacturing, product develop- surgical services, medical device tical products. ment, and packaging services to evaluation, and analytical services the pharmaceutical industry. The to the biopharmaceutical, biotech, Products and services company specializes in solid dose and medical device, animal health, Micron is capable of micronizing liquid oral dose products. and chemical industries. R&D to bulk production scale quanti- Mikart offers more than 37 years ties, as well as highly potent com- of experience and knowledge to take MPI Research is a high-quality pounds and controlled substances. products from formulation develop- organization that is committed Our contract analytical laboratory ment through full-scale commercial to bringing safer and more provides material characterization, production. effective products to the world. release testing, stability testing, We exceed expectations method development and method Products and services through consistency and validation. Our facilites in the US and t
Formulation development quality, with a commitment to UK are FDA inspected, we operate t
Analytical methods development communication and innovation, according to cGMP regulations, and t
Methods and process validation delivering benefits throughout we are committed to being the indus- t
Stability testing all phases of development. try’s “Provider of Choice.” t
Clinical supplies packaging t
Immediate- and controlled- Learn how we can go beyond for AAPS booth 3523 release tablet manufacturing you at www.mpiresearch.com. t
Capsule manufacturing t
Oral liquid manufacturing t
Schedule II–V controlled drug manufacturing t
Film coating t
Solid dose and liquid bottle packaging t
Laminated foil pouch packaging AAPS Booth 527 t
Blister packaging t
Regulatory services

Pharmaceutical Technology OCTOBER 2013 109 ADVERTISER PROFILES

Patheon Pfizer CentreSource Pharma Tech Industries 4721 Emperor Blvd. Suite 200 7000 Portage Rd. 545 Old Elbert Rd. Durham, NC 27703 Kalamazoo, MI 49001 Royston, GA 30662 USA North America/South America: tel. 706.246.3555 tel. 919.226.3200 tel. 269.833.5844 fax 706.246.3330 [email protected] fax 269.833.3604 www.pharma-tech.com www.patheon.com Europe/Middle East/Africa: tel. +32.2.714.6502 fax +32.2.749.5509 Asia/Pacific: tel. +65.6419.0248 fax +65.6419-0022 www.pfizercentresource.com Description Patheon is a leading provider of Description contract development and commercial The largest pharmaceutical con- manufacturing services to the global tract manufacturer and packager of pharmaceutical industry for a full powder products in the world, PTI array of solid, and sterile-dosage has served global pharmaceutical forms. Through the company’s recent and personal-care companies with acquisition of Banner Pharmacaps—a turnkey product development, manu- market leader in soft gelatin capsule facturing, and packaging services for technology—Patheon now also 40 years. PTI’s two facilities produce includes a proprietary products and over 300 SKUs of powders, efferves- technology business. Description cent, and solid-dose products, plus Pfizer CentreSource offers world- cotton swabs and injection-molded Patheon provides the highest wide expertise and capacity in fine components. quality products and services to chemicals and finished dosage form approximately 300 of the world’s manufacturing. A recognized indus- Services leading pharmaceutical and try leader in steroid synthesis and t
Contract manufacturing—in- biotechnology companies. The production, we also provide advanced cluding powder blending, solid- company’s integrated network facilities that meet or exceed GMP dose compression, effervescent consists of 16 locations, including 13 standards for contract manufacturing products, capsule filling, and commercial contract manufacturing sterile dosage forms (including high cotton swab manufacturing facilities and 9 product development potency) as well as product devel- t
Contract packaging—including centers across North America and opment, process development, and bottle filling, stick packs, pouch Europe. Patheon enables customer advanced manufacturing for high (unit-dose) filling, cartoning, products to be launched with potency drug product. labeling, and custom packaging confidence anywhere in the world. t
Contract molding of caps, bot- Services tles, components, and devices AAPS Booth 2312 The company supplies high quality t
Technology transfer, includ- and high value APIs and intermedi- ing transfer of late-stage R&D, ates from its chemical synthesis, cus- dedicated large- and small-scale tom fermentation, and bioprocessing operations, and niche processes capabilities. PCS also provides high t
On-site, full-scale test- quality solutions in aseptic filling and ing including microbial and a suite of highly potent drug product analytical capabilities. development, manufacturing, and packaging services. AAPS booth 3141

110 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Pharmaceutical Powdersize, Inc. PYRAMID Technology 20 Pacific Dr. Laboratories, Inc. 485 Route One South Quakertown, PA 18951 3598 Cadillac Avenue Bldg F, Second Floor tel. 215.536.5605 Costa Mesa, CA 92626 Iselin, NJ 08830 fax 215.536.6630 Tel 714.435.9800 www.PharmTech.com [email protected] Fax 714.435.9585 www.powdersize.com [email protected] FDA on GMP USP on Fixed-Oil Pharmacopeial APRIL 2013 Volume 37 Number 4 PLUS: Inspection Trends Excipients Harmonization Advancing Development & Manufacturing www.pyramidlabs.com

PharmTech.com

Analyzing and Controlling Solid-Dosage Manufacturing Moving toward closed-loop control of continuous processing.

PEER-REVIEWED Miniaturization of a Simulated Gastric Fluid Dispersion Experiment On a Microfluidics System

API SYNTHESIS & MANUFACTURING: PACKAGING FORUM: STERILITY ASSURANCE: Ad i Fl Ch i t PiiPk i Iti St ilit fP tlPdt

Description For more than 35 years, Pharmaceutical Technology has published authorita- Description Description tive, reliable, and timely information As a leader in custom powder sizing, PYRAMID Laboratories, Inc. is on every aspect of applied pharma- Powdersize has optimized its tolling located in Southern California, ceutical science and biotechnology. services for improved yield, grinding United States. Our facilities are More than 38,000 professionals rely performance and process robustness. housed in three buildings coverings on Pharmaceutical Technology to stay By combining expertise in both equip- more than 70,000 ft. The combination ahead of the curve in manufacturing ment design and nearly two decades of of our manufacturing facilities and equipment and processes, formulation toll manufacturing, Powdersize deliv- state-of- the-art laboratory allows and drug delivery, active pharmaceuti- ers unique solutions to the challenges PYRAMID to offer the pharmaceutical cal ingredients and excipients, software of poor precision during feeding, and biotech industry both analytical and automation, validation and compli- product “blowback” and system loss and manufacturing support capabilities. ance, packaging and labeling, outsourc- associated with large surface areas, es- ing issues, and a host of related topics. pecially for small batch sizes necessary Products and services The industry’s premier editorial for early stage R&D studies or clinical PYRAMID provides contract Aseptic staff delivers unequaled double-blind, evaluation. Capabilities of reducing Manufacturing and Services for peer-reviewed research, authoritative product exposure down to 10 ng/m3 Sterile Injectable Drugs. technical articles, independent news via containment approaches has also PYRAMID provides expertise reports, and in-depth analyses. been added to address the challenges in formulation and process associated with handling cytotoxic development and aseptic filling Opportunity and/or highly sensitizing APIs. for vials and syringes, as well as Through regular and special issues, lyophilization applications for electronic publications, and custom clinical and commercials products. publishing services, Pharmaceutical In addition, PYRAMID now Technology reaches the readers who provides storage and distribution of make pharmaceutical manufacturing parenteral drug products across the run. For information on advertising and globe. PYRAMID has established special projects, please contact Publisher a reputation of exceptional quality, Mike Tracey (732.346.3027 or mtracey@ AAPS booth 3841 performance, and integrity. advanstar.com). To make an editorial contribution, please contact Editorial AAPS booth 219 Director Rita Peters (732.346.3038 or [email protected]).

AAPS booth 3423

Pharmaceutical Technology OCTOBER 2013 111 ADVERTISER PROFILES

Ross, Charles & Sartorius Stedim Son Company North America, Inc. 710 Old Willets Path 5 Orville Dr. Hauppauge, NY 11788 Bohemia, NY 11716 tel. 800.243.ROSS tel. 800.368.7178 fax 631.234.0691 fax 631.254.4253 [email protected] [email protected] www.powderinjection.com www.sartorius.us

Improve Dispersion with High-Speed Powder Injection Description In many plants, production can be Sartorius Stedim Biotech is a leading improved significantly by accelerating provider of cutting-edge equipment the dispersion of lightweight powders and services for the development, in a liquid vehicle. Using traditional quality assurance, and production batch mixing techniques, in which processes of the biopharmaceutical powders such as fumed silica are industry. The company’s integrated poured onto the surface of a liquid ve- solutions covering fermentation, hicle, the powder tends to float on the filtration, purification, fluid man- surface and resist wetting out – even agement, and laboratory technolo- in the presence of a strong vortex. gies enable the biopharmaceutical industry around the world to develop SLIM technology employs a specially and produce drugs safely, timely, and modified rotor/stator mixer to draw economically. powders directly into the high-shear Sartorius Stedim Biotech, a leading zone of the mixer, where they are wet- supplier of equipment and services ted, subjected to intense shear, and for the biopharmaceutical indus- dispersed instantly. try, offers bioreactors, fermenters, crossflow, integrity-test equipment, Learn more: housings, single-use fluid handing, www.PowderInjection.com and mixing technology. Consum- ables include crossflow cassettes, membrane adsorbers, depth filters, sterilizing and prefilter cartridges and capsules, mycoplasma, and viral filtration. Comprehensive validation and training services support the company’s products.

112 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Sensient® Pharmaceutical Coating Systems 2515 N. Jefferson Ave. St. Louis, MO 63106 Schenck Process tel. 800.325.8110 746 E. Milwaukee St. SGS LIFE SCIENCE SERVICES [email protected] Whitewater, WI 53190 75 Passaic Avenue Phone: 262-473-2441 www.sensientpharma.com Fairfield NJ 07004 Fax: 262-473-4384 Email: [email protected] 1-866-SGS-5003 Web site: www.accuratefeeders.com [email protected]

www.sgs.com/lifescience By working closely with its customers, Schenck Process has excelled at designing SGS Life Science Services is a weighing and feeding leading contract service organization systems for pharmaceutical providing clinical research, pharma- processes worldwide. ceutical development, biologics char- Whether it is sanitary level acterization, biosafety, and quality screw or disc feeders, Description vibratory feeders, weighbelt control testing. Delivering solutions feeders or bulk bag Sensient Pharmaceutical Coating Systems is for pharmaceutical, biologics, and discharging systems a global leader in the development and medical-device manufacturers, SGS Schenck Process has the manufacture of superior coating systems provides clinical trial management right bulk solids handling and brand-defining color solutions for the (Phase I to IV) and services encom- pharmaceutical and nutraceutical markets. solution for tablet coating, passing, data management, biosta- Servicing leading pharmaceutical compa- multi-ingredient batching, tistics, and regulatory consultancy. intermediate bulk packaging, nies from 35 locations globally, Sensient's SGS also offers GMP/GLP contract and jet milling. comprehensive range of versatile and novel coating systems offers the visual and laboratory services that include With operations in over 75 functional attributes necessary for brand analytical chemistry, microbiology, countries, 125 years of bulk definition, product identification, and stability studies, bioanalysis, extract- solids weighing and feeding trademark protection. ables and leachables, virology, cell experience, global service bank and virus seeds characteriza- and support, Schenck Products and Services tion, utilities qualification (gas, air, Process is prepared to meet Sensient partners with customers globally water), and protein analysis. Operat- your pharmaceutical and regionally to create market-defining processing equipment ing 28 facilities in 15 countries, SGS needs. opportunities and advanced product represents the broadest, wholly- solutions. Combining sophisticated owned, global network of contract technologies with our unique color analytical laboratories. expertise, we work with you to develop safe, high-performance coating systems AAPS BOOTH NUMBER 2923 with the visual, application, and production-efficiency benefits to better define and protect brands.

Pharmaceutical Technology OCTOBER 2013 113 ADVERTISER PROFILES

Shimadzu Suheung Capsule UPM Pharmaceuticals, Inc. 5EKGPVKƂE 16610 Marquardt Ave. 6200 Seaforth St. Instruments Cerritos, CA 90703 tel. 562.926.5685 Baltimore, MD 21224 fax 562.926.4272 tel. 410-843-3738 7102 Riverwood Drive [email protected] [email protected] Columbia, MD 21046 www.suheung.com www.upm-inc.com Phone: 800-477-1227 Fax: 410-381-1222 [email protected] www.ssi.shimadzu.com

Description Suheung Capsule’s founding in 1973 Description has solely focused on manufacturing UPM Pharmaceutical is a the highest quality capsules. Through Baltimore-based, independent Description our research and development, and provider of contract drug devel- technical investments Suheung is Shimadzu is a world leader opment, cGMP manufacturing the world’s leading manufacturer of in the analytical instruments and analytical testing services. hard capsules. Suheung’s dedication industry. Our instruments We specialize in oral routes of to quality is seen in each and every are used throughout the administration with a focus element, and every process of capsule pharmaceutical pipeline, on solid dosage forms., and production. from proteomics and semi solids. metabolomics research and Products Analytical Services drug discovery/development Suheung’s EMBO CAPS® Capsules t HPLC / UPLC Based to QA/QC and manufacturing, come in the following size’s #00EL, t Dissolution Testing providing a total solution to #00, #0EL, #0, #1, #2EL, #2, #3, #4. The t Full ICH Stability Testing researchers working within the capsules are made of gelatin (bovine, pharmaceutical industry. porcine & fish) or Hypromellose mate- Formulation Development Products rial. Patented Locking Mechanism/ t Complex Formulations variety of colors, print options/Kosher r*2.%7*2.% t Low Solubility Solutions and Halal certified/DMF No. 1521. ™ r.%/5/5 t

Bevi-Batch r788KU AAPS booth 4527 Clinical Manufacturing r(6+4 r)% t cGMP Manufacturing r)%/5/5 t Phase I - III r##+%2 t Direct API Fill into Capsules r61% r/#.&+ Commercial Manufacturing r$CNCPEGU t

FDA Inspected r2CTVKENG5K\G#PCN[\GTU t

Solid Oral Dosage Forms r6JGTOCN#PCN[\GTU t

Semi Solid Dosage Forms t

DEA Controlled Substances AAPS booth 3227 AAPS booth 3200

114 Pharmaceutical Technology OCTOBER 2013 PharmTech.com ADVERTISER PROFILES

Veltek Associates, Inc. Vindon Scientific (USA) Inc. Watson-Marlow Pumps 15 Lee Blvd. 300 Town Park Drive Group Building 1, Suite 130 Malvern, PA 19355 Kennesaw, GA 30144 37 Upton Technology Park tel. 888.478.3745 Tel: +1 770 988 3095 Wilmington, MA 01887 fax 610.644.8335 Fax: +1 770 988 3094 tel. 800.282.8823 [email protected] Email: [email protected] fax 978.658.0041 www.sterile.com Websites: www.vindonscientific.com [email protected] www.vindoncalifornia.com www.wmpg.com

Description: Vindon Scientific (USA) provides Description outsourced storage to clients in it’s Veltek Associates Inc. plays an in- Pharma and Biopharma storage suites Description novative role to the pharmaceutical, in California and Atlanta, encompassing Products from the Watson-Marlow biotechnology and medical device walk in rooms and chambers that Pumps Group Biopharmaceuti- industries by developing products provide a complete range of world cal Division provide many benefits and services to improve operations climatic ICH conditions as well as unique including filling validation, sterile and reduced costs associated with conditions. contamination. processes, traceability, superior flow rates and metering accuracy, scalable We focus on identification and 2013 has seen Vindon introduce their solutions, and reliable dispensing control of contamination in classified analytical and testing services to Phama performance. areas. We produce a complete range and Biopharma clients - including Watson-Marlow peristaltic pumps of sterile pharmaceutical grade dis- pharmaceutical stability testing - as well totally contain fluid to be pumped, infectants, sporicides, lubricants, and as DEA schedule I - V storage. buffer solutions; hand sanitizer and ensuring isolation from any source of contamination. Flexicon aseptic hands-free dispensers; Environmen- Services & Products: filling systems provide solutions from tal Monitoring Systems; In-line and ? Outsourced GMP compliant pharma laboratory bench to fully automatic Cage cleaners; and Core2Clean Spray/ storage and testing including stability aseptic filling, plugging, and capping Mop/Fog Systems. storage trials VAI Labs provides microbiological systems. The Watson-Marlow range of Biopharmaceutical-grade tubing testing ranging from the identifica- ? Outsourced GMP compliant for peristaltic dispensing delivers tion of microorganisms to antimicro- Biopharma storage, at temperatures consistent, accurate, and long-term bial effectiveness studies to prove the down to -80ºc, testing and analysis effectiveness of selected disinfectants. performance. In our state-of-the-art cleanrooms, we manufacture Pump- Aseptic Processing Inc. provides ? Validation and Calibration services sil, a premium quality platinum cured detailed consulting services. (IQ, OQ, PQ, CQ) silicone tube; Bioprene, a unique Thermoplastic Elastomer (TPE); and ? Controlled environment storage PureWeld XL, a high-quality weldable equipment TPE tube used in the biotechnology and pharmaceutical industries. Vindon has manufactured stability chambers for over 40 years and has provided storage services and equipment validation for more than 20 years.

AAPS Booth 1414

Pharmaceutical Technology OCTOBER 2013 115 INDUSTRY PIPELINE

MANUFACTURING EQUIPMENT & SUPPLIES

Sanitary Ross inline high powder feeder shear mixers The AccuRate The mixers are a versatile PureFeed AP-300 choice for general purpose feeder is designed mixing, powder wet-out, specifically for particle size reduction, pharmaceutical solubilization, emulsificat- processes and Controlled environment tion, and homogenization. includes the following customer driven This device features a four-blade rotor run- features; quick and easy disassembly, a storage suites ning within a close tolerance fixed stator at dual arm agitation system for maximizing Vindon’s controlled environment storage tip speeds in the range of 3,000-4,000 ft/min, material handling versatility, and an FDA suites in Georgia, California, the United with ultra-high shear designs running at tip compliant EPDM feed hopper that is Kingdom, and Ireland provide a complete speeds over 11,000 ft/min. disposable and recyclable. Feed rates from range of ICH conditions as well as unique Ross, Charles & Son, Hauppauge, NY t 0.5 to 150 Kg/hr. are achievable for the conditions and biological storage. www.mixers.com t tel. 800.243.ROSS PureFeed AP-300 as well. Vindon, Los Angeles, CA t Schenck AccuRate, Whitewater, WI t www.vindonca.com t tel. 562.944.4466 www.accuratefeeders.com t tel. 1.888.742.1249

MANUFACTURING EQUIPMENT & SUPPLIES

Storage Tablet press Vacuum-recovery containers The FE35 is a single- system Meissner’s rotary tablet press VAC-U-MAX’s Vacuum QuaDrum that uses up to 51 Recovery System for storage stations to produce Granular Activated containers over 367,000 tablets/ Carbon (GAC) conveys are available hr. The machine is the spent carbon in 50-, 100-, clad in easily detach- material from holding tanks to waste con- and 200-L volumes to support its One-Touch able, FDA-certified tainers. The VAC-U-MAX self-contained single-use biocontainer assembly portfolios. high-performance GAC delivery system is mounted on a The polyethylene storage containers are polymer panels, and self-contained skid. The system features a chemically resistant and easy to clean, and offers 360-degree access. The FE35 contains prepackaged, dilute-phase, pneumatic-con- are available with slotted or solid lid options geometrically optimized surfaces that are de- veyor system to deliver or remove GAC from to offer varying levels of accessibility. signed to offer the easiest-possible handling scrubber towers and holding tanks. The sys- Meissner Filtration Products, Camarillo, CA t and fast cleaning. Fette Compacting America, tem includes tubular probing wands, a con- www.meissner.com t tel. 805.388.9911 Rockaway, NJ t www.fetteamerica.com t vey hose, a filter receiver, a vacuum pump, tel. 973.586.8722 and a control panel. VAC-U-MAX, Belleville, NJ t www.vac-u-max.com t tel. 973.759.4600 OUTSOURCING & MANUFACTURING EQUIPMENT & SUPPLIES CONSULTING SERVICES

PTSE 12/36 EC PowerMix Brabender® Pharma planetary introduces the in- disperser novative 12mm PTSE The PowerMix 12/36 EC, a Stand- features a saw- Alone Table-Top tooth disperser Manufacturing Twin-Screw Extruder blade and a planetary stirrer. This agitator and raw-material testing especially designed combination handles viscous dispersions up Incorporating its Avrio parenteral manufac- for Hot Melt Extrusion applications. The clam- to around 2 million cP. After the mixing cycle, turing facility into the Irvine brand in January shell barrel with removable barrel liner offers the vessel is rolled over to the Discharge was the first step in Irvine’s three-prong quick cleaning, sterilization and easy analysis System. As the platen is lowered hydraulically initiative for aggressive yet stable growth: of the extrusion process. Segmented screw into the vessel, the finished product is forced more highly trained technical personnel, new elements offer numerous processing capabili- out within seconds. Various size and style instrumentation and increased capacity for ties and adaptability to specific needs. adaptors allow the operator to fill syringes formulation, biopharmaceuticals, and raw- Brabender Pharma, South Hackensack, NJ t and cartridges straight from the mix vessel. material testing. Irvine Pharmaceutical Services, www.brabender-pharma.com t Charles Ross & Son, Hauppauge, NY t Irvine, CA t www.irvinepharma.com t tel. 201.343.8785 www.mixers.com t tel. 631.234.0500 tel. 877.445.6554

116 Pharmaceutical Technology OCTOBER 2013 PharmTech.com INDUSTRY PIPELINE

OUTSOURCING & CONSULTING SERVICES

Contract Oral drug delivery development and The Catalent Institute manufacturing has produced a new services Oral Drug Delivery Guide, providing infor- Patheon is a provider of mation about underly- contract development ing pharmaceutical sci- Contract development and manufacturing ences and insights from and manufacturing services services to the global real-world product de- Halo Pharmaceutical is a contract develop- pharmaceutical industry, velopment experts. The manual is available ment and manufacturing organization that providing products and to download for free and covers key topics in provides scientific, regulatory and develop- services to approximately 300 of the world’s oral drug delivery, including Predicting Drug ment expertise and a wide spectrum of leading pharmaceutical and biotechnical Absorption, Solving Problems of API Degra- manufacturing services to help customers companies. Through its fully integrated dation, Drug Delivery Technology Solutions, bring their products to market quickly, ef- worldwide network, it ensures that customer Criteria for Use, and Patient Population Fo- fectively and on budget. Halo Pharmaceutical, products can be launched anywhere in the cused Drug Delivery Technology Strategies. Whippany, NJ t www.halopharma.com t world. Patheon, Research Triangle Park, NC t Catalent Pharma Solutions, Somerset, NJ t tel. 973.428.4087 www.patheon.com t tel. 905.821.4001 www.catalent.com t tel. 866.720.3148

OUTSOURCING & CONSULTING SERVICES

Peptide production Corden- Pharma provides ther- apeutic pep- Pharmaceutical services tides spanning WellSpring Pharmaceutical is a full-service all development phases from multi-gram to provider of clinical and commercial manu- multi-100 kg quantities. We provide flexible facturing and packaging, blinding, method High-potency micronization cGMP peptide production and development development, analytical testing, and distribu- Powdersize has added the capability to mi- capacities for solid-phase, hybrid, and high tion services. Highly qualified managers and cronize high-potency active pharmaceutical potency in our CordenPharma Colorado and technical professionals work at the compa- ingredients to containment levels of 10 ng/ CordenPharma Switzerland sites, as well ny’s 100,000-ft2 facility to ensure that clients’ m3. The company’s 2- and 4-in. jet mills can expanded liquid phase synthesis in our newly clinical and commercial products meet high scale to a 10-in. jet mill. Gram and kilogram acquired Peptisyntha facility in Brussels, standards. WellSpring Pharmaceutical Canada, quantities as high as 100 kg thus can be mi- Belgium. CordenPharma, Boulder, CO t Oakville, Canada t
www.wpcoutsourcing.com t cronized. Powdersize, Quakertown, PA t www.cordenpharma.comt tel. 800.868.8208 tel. 866.337.4500 www.powdersize.com t tel. 215.536.5605

OUTSOURCING & CONSULTING SERVICES

Solid dose high- containment capabilities Packaging research BilcareOptima is the first scientific method Pfizer Centre- for developing optimum packaging for phar- Source offers an maceutical products. BilcareOptima deter- end-to-end suite of mines packaging needs of drug formulations Turnkey tableting high-containment through studies such as forced degradation Pharm Tech Industries offers 100% turnkey services for oral solid analyses—which take into account the ef- tableting for effervescent and solid dose dose manufacturing. The company’s fa- fects of environmental factors such as tem- products. The service makes PTI one of a cilities include engineered containment perature, humidity and light—and formula- select few contract manufacturing organiza- models and segregation-based models. tion-specific dimensional sensitivities. Bilcare tions capable of taking raw powdered prod- Services include development support, Research can then develop product-specific uct through the entire formulation, finishing advanced manufacturing and packa g i n g . packaging based on barrier requirements. and packaging process under one roof within Pfizer CentreSource, Kalamazoo, MI t Bilcare Research, Delaware City, DE t
a low humidity environment. www.pfizercentresource.com t
www.BilcareOptima.com t tel. 302.416.0974 Pharma Tech Industries, Royston, GA t tel. 269.833.5844 www.pharma-tech.com t tel. 706.246.3555

Pharmaceutical Technology OCTOBER 2013 117 INDUSTRY PIPELINE

OUTSOURCING & CONSULTING SERVICES

Bioanalytical analysis MPI’s senior sci- entists develop Parenteral Contract Manufacturing Service of Hospira and validate as- Contract manufacturing services Contract manufacturing services says to support Hospira’s One 2 One business specializes in Through its predecessor, AbbVie has more development contract manufacturing of injectable prod- than 120 years of experience in developing from preclinical ucts packaged in vials, prefilled syringes, and producing pharmaceutical products. For to Phase I–IV cartridges, flexible containers, and ampoules. more than 25 years, the company has offered clinical research. Additional offerings include product devel- contract manufacturing to provide custom- The company’s specialized capabilities in- opment and fill–finish of clinical trial materi- ers with high-quality, innovative, cost-effec- clude mass spectrometry of small molecules, als, registration, and commercial batches. tive services in the area of biologics, potent, proteins, peptides, thermal analysis, immu- The company’s range of capabilities spans drug product, and bulk APIs to benefit the nochemistry, and residue analysis. biologics, potent drugs, vaccines, cytotoxics, companies that put their trust in us. MPI Research, Mattawan, MI t controlled substances, and lyophilization. AbbVie, North Chicago, IL t www.mpiresearch.com t tel. 269.668.3336 Hospira One 2 One, Lake Forest, IL t www.abbviecontractmfg.com www.one2onecmo.com t tel. 224.212.2267 CLEANROOM EQUIPMENT & OUTSOURCING & CONSULTING SERVICES SUPPLIES Specialty Contract Squeegees technologies analytical Perfex’s Twin- Metrics offers services Blade and product devel- SGS Life Sci- Quick-Dry Foam opment that ence Services Squeegees are leverages propri- offers analyti- constructed with etary technolo- cal chemistry, FDA-approved gies in the areas of customized controlled microbiology, materials. The release drug delivery; bioavailability en- stability studies, method development, pro- squeegees are hancement for poorly water-soluble drugs; tein analysis, and bioanalytical testing. With chemically resis- and improved palatability for liquid and the acquisition of M-Scan’s laboratories, tant and nonspar- solid presentations. Metrics scientists also SGS’s portfolio now includes the character- king, and will not rust or corrode. The 100% can formulate non-sterile liquids, creams ization of biologics with GLP–GMP contract polymer construction will resist water, oil, and gels, or manage technology transfer for analytical services, consulting, and training grease, detergents, sanitizers, and solvents. manufacturing and packaging. based on mass spectrometry and chroma- The sqeegees are designed for floor–chemi- Metrics, Greenville, NC t www.metricsinc.com t tography. SGS Life Science Services, cal applications, and wiping surfaces dry tel. 252.752.3800 www.sgs.com/lifescience t tel. 866.747.5003 and nearly streak-free. Perfex, Poland, NY t www.perfexonline.com t tel. 800.848.8483

CLEANROOM EQUIPMENT & SUPPLIES PACKAGING EQUIPMENT & SUPPLIES

Laboratory Compounding Capsule filler cleaning cleanrooms MG America offers the system Terra’s com- new FlexaLAB Capsule The Core2Clean pounding clean- Filler, which can produce Plus System rooms are suitable up to 3,000 capsules/ incorporates for compounding hr. Specifically designed spray, mop, and sterile inject- for R&D labs, clinical tri- fog capabilities ables and other als, small batch outputs into one unit. The preparations in and special productions, system provides a accordance with US Pharmacopeia <797> FlexaLAB can function at clean solution to the surface each time, thus standards. An ISO 5 (Class 100) primary pro- continuous or intermittent motion. Multiple eliminating cross contamination from dirtied cessing area with three HEPA filter–fan units dosing units can be utilized simultaneously, solutions. The system is designed to simplify provides a total of 1950 cfm (3315 m³/h) of enabling the FlexaLAB to manufacture cap- moving from one controlled area to another 99.99% particle-free air (measured at 0.3 μm sules with product combinations. MG America, t t by eliminating the requirement to make a diameter). Terra Universal, Fullerton, CA t Fairfield, NJ www.mgamerica.com new solution. Veltek, Malvern, PA t
www.terrauniversal.com t tel. 714.578.6190 tel. 973.808.8185 www.sterile.com t tel. 610.644.8335

118 Pharmaceutical Technology OCTOBER 2013 PharmTech.com INDUSTRY PIPELINE

LABORATORY EQUIPMENT & SUPPLIES

On-line TOC Trace-metals TC series baths analysis analysis Brookfield offers the To help phar- The Discover SP-D TC Series Circulating maceutical System from CEM Water Baths config- companies performs microwave- ured for use with improve qual- assisted closed vessel Brookfield viscometers ity and reduce digestions for trace and rheometers. TC costs, GE Analytical Instruments offers a sci- metals analysis in only Series baths feature: ence- and risk-based program for achieving 10 minutes, including touch screen technol- real-time release of pharmaceutical water. cool down. Automa- ogy, multiple languages, swiveling control The program streamlines a complex process tion options are available and the system head, stain and chemical resistant composite and helps companies move total organic car- can run unattended. The Discover SP-D is deck, and USB, Ethernet & RS-232 connectiv- bon testing from the laboratory to the pro- compact and offers temperature and pres- ity. Operating temperatures range from -20° duction floor in approximately six months. sure control, easy-to-use vessels, and docu- to 200°C. Four models are available with the GE Analytical Instruments, Boulder, CO t mentable results. The system also includes choice of digital or programmable control- www.geinstruments.com t tel. 800.255.6964 a guide for implementing USP Chapters 232, lers. Brookefield Enginneering Laboratories t 233, and 2232. CEM Corporation, Matthews, NC www.brookfieldengineering.com t t www.cem.com t tel. 800.726.3331 tel. 508.946.6200

CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS

API and excipients manufacturing Chemicals and laboratory products Pharmaceutical coating systems Roquette is a global manufacturer of phar- Spectrum Chemicals & Laboratory Products Sensient Pharmaceutical Coating Systems maceutical excipients and actives. The com- announces two new life sciences reagent specializes in high-quality coating sys- pany offers a range of polyol excipients that distribution agreements with bioWorld and tems, brand-defining color solutions, and is intended to combine chemical stability Accumedia. Spectrum is now the premier enhanced product performance for the with good taste, sugar-free sweetness, and distributor of bioWorld’s 4000+ affinity chro- pharmaceutical and nutraceutical markets. oral health benefits for a variety of pharma- matography, molecular biology, cell culture, The company provides complete coating and ceutical applications. Roquette’s portfolio and microbiology products and Accumedia’s visual-enhancement solutions in addition to includes: Pearlitol (crystalline/granulated complete line of dehydrated culture media. its personalized service. mannitol), Neosorb (sorbitol), SweetPearl All products are available online. Sensient Pharmaceutical Coating Systems, (maltitol), Xylisorb (xylitol), and Lycasin Spectrum Chemicals & Laboratory Products, New St. Louis, MO t www.sensientpharma.com t (maltitol syrups). Roquette America, Geneva, IL t Brunswick, NJ t www.spectrumchemical.com tel. 800.325.8110 www.roquette.com t tel. 630.463.9430 t tel. 800.772.8786

INFORMATION TECHNOLOGY & MISCELLANEOUS

Job-focused ICH Q3 D: Elemental Impurities— training How Prepared Are You? PDA’s Training and Research Date: October 25th 11AM EST Institute pro- GMP compliance software vides intensive, This webinar, presented by Janeen Skutnik EtQ’s GMP Regulatory Compliance Software job-focused training that clients can apply Wilkinson, VP of NFS Health Sciences Pharma is an integrated quality management and immediately. The curriculum is designed to Biotech, will teach you how to navigate the FDA compliance management software sys- foster professional development in areas ICH draft Guidance on Elemental Impurities, tem that has been designed to maintain com- such as aseptic processing, biotechnology, and help you learn how to understand and pliance with various regulatory requirements environmental monitoring, filtration, micro- interpret the guidance, how to work with and adapt to business processes. EtQ’s mod- biology, quality, regulatory affairs, training, your suppliers, what you need to know if you ules are tightly integrated to deliver a best- and validation. Courses can be customized are a supplier of APIs, Excipients, or Packag- in-class solution for the Life Science industry and provided at the client’s location. ing Components, and how to ensure you are and include eMDR, Complaint Handling, Parenteral Drug Association, Bethesda, MD t ready for implementation. CAPA, eValidator, Change Management, and www.pda.org t tel. 301.656.5900 NSF Pharma Biotech t www.nsf.org t more. EtQ, Farmingdale, NY t tel. 857.277.0060 www.etq.com t tel. 800.354.4476

Pharmaceutical Technology OCTOBER 2013 119 Go to: marketplace.findpharma.com PRODUCTS AND SERVICES SHOWCASE

EQUIPMENT & SUPPLIES

ELIZABETH_HATA :LHYJO

OUTSOURCING RESOURCES Content Licensing for Every Marketing Strategy

r
'%"JOTQFDUFE
D(.1
GBDJMJUJFT
JO
UIF
64
BOE
6, MICRONTECH r
.JDSPOJ[BUJPO
NJMMJOH

DMBTTJGZJOH
PQUJPOT :LHYJO r
3%
UP
DPNNFSDJBM
RVBOUJUJFT r
$VTUPNEFTJHOFE
DPOUBJONFOU
DBQBCJMJUZ
GPS
IJHIMZ
QPUFOU
DPNQPVOET Marketing solutions fit for: r
'VMMDPOUSBDU
BOBMZUJDBM
MBC
GPS
NBUFSJBM
DIBSBDUFSJ[BUJPO
SFMFBTF

TUBCJMJUZ
UFTUJOH


NFUIPE
WBMJEBUJPO

EFWFMPQNFOU r
)VNJEJUZDPOUSPMMFE
QSPDFTTJOH Outdoor | Direct Mail www.microntech.com 64

 Print Advertising 6,

 
 Tradeshow/POP Displays OUTSOURCED RESOURCES Social Media | Radio & TV Non-Routine Investigative Leverage branded content from Testing Pharmaceutical Technology to create a more powerful and sophisticated statement about your product, service, or company in your k Competitive Product Analysis next marketing campaign. Contact Wright’s k Contaminant Identification Media to find out more about how we can k Material Characterization customize your acknowledgements k Deformulation and recognitions to enhance k Custom Synthesis your marketing strategies. k Litigation Support k FDA Registered For information, call Wright’s Media at 877.652.5295 or visit our website at 866.470.9602 www.wrightsmedia.com www.chemir.com

CH0028 04.13 Search for the company name you see in each of the ads in this section for FREE INFORMATION!

120 Pharmaceutical Technology OCTOBER 2013 PharmTech.com PharmTech.com LAB EQUIPMENT MANUFACTURING/PROCESSING EQUIPMENT

Airflow Diagnostic Tools Mixing/Blending/Drying CUSTOM TANKS & PRESSURE VESSELS MANUFACTURING Two ASME plants in the USA. 316/304 S/S & many alloys. All codes. Scan for plant locations Quick Ship & a free quote. Metal Detector Program Free Tag Reader: http://gettag.mobi In Stock 8 E-Z Tec® metal detector aperture heights 1-800-524-ROSS Available in 12, 18 and www.StorageVessels.com 24-inch widths  Food-grade polypropylene belt TRAINING

Hands-On HPLC & GC Training Courses

Purity.Eriez.com  888-300-3743 Method Development Fundamentals * Troubleshooting Sponsored by Agilent and ACS Featuring Dr. Lee N. Polite - Primary Instructor Cure for the Common Job. Proven relief from the signs and symptoms of Chronic Job Search (CJS) (312) 243-2153 Axion Analytical Laboratories, Inc. www.ChromatographyTraining.com Training Institute, Inc.

For Marketplace Advertising Contact Tod McCloskey to place your Marketplace ad at: 800-225-4569 ext. 2739 Tod McCloskey [email protected] (800) 225-4569, ext. 2739 [email protected]

Pharmaceutical Technology OCTOBER 2013 121 RECRUITMENT

For Recruitment Advertising 'SRXEGX8SH1G'PSWOI]EXI\XˆXQGGPSWOI]$EHZERWXEVGSQ www.pharmtech.com

122 Pharmaceutical Technology OCTOBER 2013 PharmTech.com PharmTech.com

STATEMENT OF OWNERSHIP, MANAGEMENT, AND CIRCULATION (Requester Publications Only) (Required by 39 USC 3685) 1. Publication Title: Pharmaceutical Technology 2. Publication Number: 1543-2521 3. Filing Date: 9/30/13 4. Issue Frequency: Monthly, except two issues in June 5. Number of Issues Published Annually: 13 6. Annual Subscription Price (if any): $70.00 7. Complete Mailing Address of Known Office of Publication: 131 West First Street, Duluth, St. Louis County, Minnesota 55802-2065 Contact Person: Kristina Bildeaux Telephone: 507-89 5-6758 8. Complete Mailing Address of Headquarters or General Business Office of Publisher: 2501 Colorado Avenue, Suite 280, Santa Monica, CA 90404. 9. Full Names and Complete Mailing Addresses of Publisher: Mike Tracey, 485F US Hwy 1S, Suite 210, Iselin, NJ 08830 Editorial Director: Rita Peters, 485F US Hwy 1S, Suite 210, Iselin, NJ 08830 Executive Editor: Patricia VanArnum, 485F US Hwy 1S, Suite 210, Iselin, NJ 08830 10. Thi s publication is owned by: Advanstar Communications Inc., 2501 Colorado Avenue, Suite 280, Santa Monica, CA 90404. The sole shareholder of Advanstar Communications Inc. is: Advanstar, Inc., whose mailing address is 2501 Colorado Avenue, Suite 280, Santa Monica, CA 90404. 11. Advanstar Communications Inc. is a borrower under Credit Agreements dated June 6, 2013, with various lenders as named therein from time to time. As of June 6, 2013, the agent for the lenders is: Goldman Sachs Lending Partners LLC, Administrative Agent, 30 Hudson St, 4th Floor, Jersey City, NJ 07302. 12. Does Not Apply 13. Publication Title: Pharmaceutical Technology 14. Issue Date for Circulation Data Below: Aug-13 15. Extent and Nature of Circulation

Average No. Copies Each Issue No. Copies of Single Issue During Preceding 12 Months Published Nearest to Filing Date A. Total Number of Copies 34,860 28,934 B. Legitimate Paid and/or Requested Distribution 1. Outside County Paid/Requested Mail Subscriptions Stated on PS Form 3541 27,445 21,278 2. In-County Paid/Requested Mail Subscriptions Stated on PS Form 3541 0 0 3. Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and Other Paid or Requested Distribution Outside USPS 1,691 1,501 4. Requested Copies Distributed by Other Mail Classes Through the USPS 0 0 C. Total Paid and/or Requested Circulation (Sum of 15b (1), (2), (3), and (4)) 29,136 22,779 D. Non-requested Distribution 1. Outside County Non-requested Copies Stated on PS Form 3541 4,583 5,304 2. In-County Non-requested Copies Stated on PS Form 3541 0 0 3. Non-requested Copies Distributed Through the USPS by Other Classes of Mail 0 0 4. Non-requested Copies Distributed Outside the Mail 770 580 E. Total Non-requested Distribution (Sum of 15d (1), (2), (3) and (4)) 5,353 5,884 F. Total Distribution (Sum of 15c and e) 34,489 28,663 G. Copies not Distributed 371 271 H. Total (Sum of 15f and g) 34,860 28,934 I. Percent Paid and/or Requested Circulation 84.48% 79.47%

16. □ Total circulation includes electronic copies. Report circulation on PS Form 3526-X worksheet. 17. Publication of Statement of Ownership for a Requester Publication is required and will be printed in the October issue of this publication. Name and Title of Editor, Publisher, Business Manager, or Owner: Anne Brugman, Audience Development Director Date: 09/30/13 I certify that the statements made by me above are correct and complete.

124 Pharmaceutical Technology OCTOBER 2013 PharmTech.com Ad Index COMPANY PAGE COMPANY PAGE COMPANY PAGE

AbbVie ...... 7 Eurofins Lancaster Laboratories ...... 25 Parenteral Drug Association ...... 59 Aptuit ...... 45 Excipient Fest ...... 123 Patheon Pharmaceutical Svc Inc ...... 3 Asahi Kasei ...... 21 Fette Compacting America Inc...... 53 Pfizer CentreSource ...... 63 Ashland Specialty Ingredients ...... 29, 77 Flexicon Liquid Filling ...... 39 Pharma Tech Industries ...... 15 BASF Corporation ...... 32, 95 GE Healthcare Life Sciences ...... 127 Powdersize ...... 4 Bilcare Research ...... 13 Gemu Valves Inc ...... 56 Pyramid Laboratories ...... 33 Brabender Pharma ...... 91 GlaxoSmithKline Inc ...... 74 Roquette America Inc ...... 73 Brookfield Engineering ...... 89 GlobePharma Inc ...... 34 Cangene Biopharma ...... 17 Greiner Bio-One ...... 11 Ross, Charles & Son Company ...... 47 Capsugel, A Div Of Pfizer ...... 46 Halo Pharmaceuticals ...... 61 Sartorius Stedim N America Inc ...... 49 Catalent Pharma Solutions ...... 128 Hospira One 2 One ...... Gatefold Cover Schenck Accurate ...... 58 CEM Corporation ...... 38 Intl Centre For Diffraction Data ...... 55 Sensient Pharmaceutical...... 71 Chemic Laboratories Inc ...... 23 Irvine Pharmaceutical Services ...... 76 SGS Life Sciences ...... 87 Cirrus Pharmaceuticals Inc ...... 19 Jubilant Hollister Stier ...... 9 Shimadzu Scientific Instrument ...... 43 CMIC CMO USA Corporation ...... 31 Kimberly Clark Corp ...... 85 Sparta Systems ...... 41 Coating Place Inc ...... 37 Meissner Filtration Products ...... 2 Spectrum Chemical Mfg Corp ...... 72 Confab Laboratories Inc ...... 6 Metrics Inc ...... 69 Suheung-America Corporation ...... 4 Corden Pharma Intl GmbH ...... 27 MG America Inc ...... 79 Croda Inc ...... 65 Micron Technologies Inc ...... 6 UPM Pharmaceuticals ...... 81 DPT Laboratories ...... 93 Mikart...... 35 Vac U Max ...... 16 Dr Reddy’s Laboratories Inc ...... 75 MPI Research ...... 57 Veltek Associates ...... 5 Ei A Pharmaceutical Solutions Works ...... 42 NSF Intl ...... 67 Vindon Scientific ...... 51

♦ CALL FOR PAPERS ♦ CALL FOR PAPERS ♦ CALL FOR PAPERS ♦ CALL FOR PAPERS ♦

Pharmaceutical Technology and Pharmaceutical Technology Europe cover all aspects of pharmaceutical drug development and manufacturing, including formulation development, process development and manufacturing of active pharmaceutical ingredients (both small molecule and large molecules) and finished drug-products (solid dosage, semisolid, liquids, parenteral drugs and topical drugs), drug-delivery technologies, analytical methods development, analytical testing, quality assurance/ quality control, validation and advances in pharmaceutical equipment, machinery, instrumentation, facility design and plant operations.

We are currently seeking novel research articles for our peer-reviewed journal as well as manuscripts for our special issues. For peer-reviewed papers, members of the Editorial Advisory Board of Pharmaceutical Technology and Pharmaceutical Technology Europe and other industry experts review manuscripts on technical and regulatory topics. The review process is double-blind. Manuscripts are reviewed on a rolling basis.

Our single-themed issues, which include literature reviews and tutorials, address excipients and ingredients, analytical testing, outsourcing, solid dosage and more.

Please visit our website, www.PharmTech.com/Authors, to view our full Author Guidelines. Manuscripts may be sent to Editorial Director Rita Peters at [email protected].

We look forward to hearing from you. Martin Barraud/OJO Images/Getty Images Martin Barraud/OJO

Pharmaceutical Technology OCTOBER 2013 125 ASK THE EXPERT

Ensuring Compliance with Drug Accountability Requirements

Kurt Lumsden, Director Client Services at Perceptive Informatics, a subsidiary of PAREXEL, discusses regulatory requirements for the drug accountability process.

How do I ensure my drug and tracking of paper records at every site. Process Q.accountability process is adequate? implementation for a specific trial will depend on a number of Although the need for drug accountability process factors, including but not limited to: A.compliance is essential, there are no clearly defined t
IP classification—This will determine whether paths for ensuring the process is adequate. Regulations do re-reconciliation is required not indicate a specific method or modality must be employed t
IP formulation—A liquid or gel vs. capsules or pills will (1). However, as with other investigational product (IP) determine if accountability required is quantitative or management processes and transactions, such as temperature qualitative excursion management and IP release or expiry update, t
IP route of administration (e.g., oral, intravenous, adequate drug accountability is crucial to trial success. subcutaneous—If the product or packaging could be Accountability should be demonstrated by having full considered hazardous, then destruction on site may be traceability of IMP/IP (investigational medicinal product) from necessary initial release, ordering, allocation, and dispensation through t
IP packaging and labeling (uniquely vs. non-uniquely return-to-site, accountability, reconciliation, and eventual numbered supplies)—Non-uniquely labeled drugs will only destruction. If adequate accountability in these areas cannot be traceable to the batch and quantity level in a blinded trial be demonstrated, trial results are at risk. t
Accountability process and documentation—Typically, According to 21 CFR 312.57(a), “a sponsor shall maintain accountability process and documentation involves the adequate records showing the receipt, shipment, or other following steps: disposition of the investigational drug. These records t

3FUVSO
PG
EJTQFOTFE
*1
UP
UIF
TJUF
JODMVEJOH
VTFE
PS
are required to include, as appropriate, the name of the partially used IP) by the patient (unless product was investigator to whom the drug is shipped, and the date, administered on site by a clinician) quantity, and batch or code mark of each such shipment” t

*1
BDDPVOUBCJMJUZ
DPOEVDUFE
CZ
UIF
TJUF
BOE
(2). Additionally, 21 CFR 312.62(a) states, “An investigator is confirmation of returned, lost, or damaged product required to maintain adequate records of the disposition of t

*1
SFDPODJMJBUJPO
DPOEVDUFE
CZ
UIF
NPOJUPS
XJUI
the drug, including dates, quantity, and use by subjects. If verification of the accounted product the investigation is terminated, suspended, discontinued, or t

%FTUSVDUJPO
POTJUF
PS
SFUVSO
PG
UIF
*1
UP
UIF
GJOBM
completed, the investigator shall return the unused supplies of destruction facility. the drug to the sponsor, or otherwise provide for disposition of Adequate drug accountability is crucial to drug trial success. the unused supplies of the drug under 312.59” (3). An adequate process should be clear and understood by Adequate drug accountability will provide transparency stakeholders, with seamless implementation and robust through the IP chain of custody. This involves maintaining compliance monitoring. Factors such as trial design, records that document past and current IP disposition with jurisdiction, and IP-designation configuration (4), or route of relevant dates and other details such as batch, allocated administration, influence the specific steps required for a trial. subject, and expiry. Electronic applications that track accountability can provide Use of electronic applications for collection and tracking of important benefits to effective trial management. accountability data may provide considerable benefits over paper records. One important benefit is enhanced visibility through References chain of custody by centralizing accountability trial data in a 1. ICH, Good Clinical Practice (E6 – 1996 section 4.63), May 1996. single system, which also improves reporting. This method allows 2. FDA, 21 CFR 312.57, April 1, 2013. demonstrated compliance with regulations and mitigates the 3. FDA, 21 CFR 312.62(a), April 1, 2013. likelihood of audit findings related to accountability. It also enables 4. FDA, 21 CFR 3.2(e), April 1, 2013. PT rapid completion of end-of-study documentation from one source. Furthermore, electronic applications help improve the Your opinion matters. monitoring of ongoing site compliance with accountability Have a common regulatory or compliance question? activities and error checking, and reduce the overall burden Send it to [email protected] and it may appear in a future column. created by the requirement for completion, collation,

126 Pharmaceutical Technology OCTOBER 2013 PharmTech.com GE Healthcare Life Sciences

5 years or 12 months

From design to GMP biomanufacturing. It’s your call. Why wait up to 5 years for a GMP facility when you can have your own FlexFactory™ in 12 months? FlexFactory offers far less risk and complexity than conventional biomanufacturing facilities. In only 12 months, this fully modularized and integrated single-use biomanufacturing platform deploys new production capacity at less than half the total cost of traditional stainless steel plants. Plus FlexFactory’s comprehensive portfolio of GMP services includes everything you need for a smooth transition to single-use manufacturing. Now, make more informed investment decisions, experience faster product changeovers, and rapidly expand capacity. Take the next big leap in biomanufacturing technology.

Xcellerex and you’re done

www.gelifesciences.com/xcellerex Download our white paper: The Flexible Factory: A rapid-deployment, reduced-capital model for biomanufacturing www.xcellerex.com/fl expaper

GE, imagination at work, the GE monogram, Xcellerex, and FlexFactory are trademarks of General Electric Company. © 2012 General Electric Company — All rights reserved. First published September 2012. ˝ 2013˝ Catalent 2013 Catalent Pharma Pharma Solutions. Solutions. All rights All reserved.rights reserved. OSDrCO isSDrC a registered is a registered trademark trademark of Sanwa of SanwaKagaku K Kagakuenkyusho Kenkyusho Co. Co. better outcomes. technologies. optimized delivery optigel lock optigel lock optigel bio optigel bio optishell optishell e e fill formulations fill formulations Solutions Solutions Scherer Scherer with with E E INNOVATIVE INNOVATIVE DELIVERY OPTIONS DELIVERY OPTIONS x x ve ve pertise pertise

versatile versatile ry m ry m

softgel softgel ™ ™

for for

for complex for complex ™ ™

o o ™ ™ for macromolecules for macromolecules

, ,

more more , , l l for abusedeterrence for abusedeterrence delivery delivery e e proven proven

technologies. technologies. c c u u

molecules molecules l l e e

RP RP h h

as as

technologies technologies

a a

ch ch a a ll ll optimelt optimelt + C + C zydis zydis dose dose rp scherersoftgel technologies rp scherersoftgel technologies Improved Improved permea permea E E B B from from enge enge N N I I ata ata 1 1 OAVA OAVA

HA HA 888 888

® ® forms. forms. development development and and nanotechnology nanotechnology l l ent ent . W . W b b N N ™ ™ lity. lity. hmetechnology hmetechnology

solu solu CED CED S S I I

relia relia . M . M LAB LAB

O O Integrated Integrated e e O O h h b b L L ptimized ptimized ility ility U U o o I I ave ave b b r r L L TI TI Visit usat AAPS, Booth1612

e e to to le le IT IT

and and pr pr ON ON

supply. supply.

Y Y supply supply

a a services services

o o final final

so so d d solutions solutions u u

l l c c ution ution ts ts

deliver deliver . B . B ette ette . . @ @

osd controlled releasetechnologies osd controlled releasetechnologies dosing dosing divida divida OP OP CO CO regimens regimens profiles. profiles. B B From From catalent.com catalent.com etter etter b b r r r r TI TI NTR NTR c c etter etter ® ® t t optidose optidose b b

r r

M M outcomes outcomes options options le le eat eat

orphan orphan A A

I I and and OLLED OLLED and and ZED ZED

wide wide

m m outcomes outcomes

pulsed pulsed target target ents ents : : ™ ™

com com tablets tablets range range

with with www.catalent.com www.catalent.com drugs drugs R R b b

. .

release release release. release. ELEASE ELEASE ination ination

Re Re

improved improved of of

l l

ia ia for for

to to

, , bly bly

b b payers payers

su su lock lock ppl ppl T T optigel micro optigel micro tablets &granules tablets &granules zydis zydis geriatric geriatric outcomes. outcomes. conditions conditions SOLU SOLU B B b b A A etter etter , , ie ie usters usters patients patients R R /b /b d. d. ® ® GE GE fast-dissolve fast-dissolve

adherence adherence ™ ™ etteroutcomes etteroutcomes TI TI

T T populations populations O O

POPULA POPULA , , and and Ideal Ideal N N our our ™ ™ technology technology S FO S FO

disease disease and and

for for

and and development development

pediatric pediatric

R R , , innovators. innovators.

specific specific patient patient

TI TI

areas. areas. O O N N

and and

S S