* DDT March 2009 Covers:DDT Cover/Back April 2006.qx 2/26/09 11:31 AM Page 2

March 2009 Vol 9 No 3 www.drugdeliverytech.com INTHIS ISSUE

INTERVIEW WITH DEPOMED’S PRESIDENT & CEO CARL A. PELZEL

Combination Devices 18 Abhijit Gokhale, PhD Excipient Sourcing 22 Alen Guy, PhD

Solid Dose 24 Charles Potter, PhD

Nanomedicine Market 32 Bill Martineau, MBA

FEATURING

Analytical The science & business of drug development in specialty pharma, biotechnology, and Testing Labs 62 Xiaochun Yu, Ms. Cindy H. Mr. Mike PhD Dubin Mesa Cardiology & From Battlefield to A New Approach to Proteins & Peptides: Oncology 68 Dependent On Backpack: Evolution Threshold Evaluation & of the Auto-Injector Stuart L. Cantor, PhD Quantitation of Advances in Drug Unknown Extractables Delivery? & Leachables Using HPLC/CAD 2-4 DDT March 09 front pages :DDT Frntmttr apr06 06.2-4.qx 2/26/09 11:33 AM Page 2 2-4 DDT March 09 front pages :DDT Frntmttr apr06 06.2-4.qx 2/26/09 11:33 AM Page 3 - D ac 9fotpgs:D rttrapr0606.2-4.qx2/26/0911:33AMPage4 Frntmttr :DDT pages front 09 March DDT 2-4

4 Drug Delivery Technology March 2009 Vol 9 No 3 o oeifraincnatRlhVtr t973-299-1200 at Vitaro Ralph contact information more For nutysol ulcto nieydevoted entirely publication only industry’s eparato h aktlc ihthe with marketplace the of abreast Keep n lc nSbcito Services Subscription on click and neo h est o a losubscribe also can you website the on Once ot www.drugdeliverytech.com to Go remi i [email protected] at him e-mail or odu eieyaddevelopment. and delivery drug to ooreNewsletter! our to tm o nenlo esnlue rteitra rproa s fseii let,i rne yDu Delivery Drug by granted is clients, MA specific Danvers, of Drive, Rosewood use 222 personal Clearance, be 750-4470. Copywrite or the (978) may internal with fax: registered recording, publication 750-8400, the photocopy, users (978) photocopy or this by other phone: to and use, including 01923; Authorization of publisher. libraries mechanical, personal US the for part or from the LLC or handling. electronic permission Technology No under internal means, written and reserved without any reserved. for shipping system, rights by retrieval items rights for or All and form order storage 07045. All information any NJ per address or Conventions. in Montville send $5.00 transmitted Copyright please Road, or Drug Add Postmaster: Changebridge reproduced Pan-American to: offices. countries. 219 mailing payment and Technology, other additional Send Delivery International and all banks. Drug 07045-9998 US in NJ (prepaid) to on United Montville, $24.00 copies changes the Single drawn at Mexico; outside 07045. 07045. Paid funds, year NJ and Postage US NJ 1 Montville Periodicals Canada, for in Road, Montville $153.00 Changebridge payable US, Mexico. Road, 219 are $15.00, Department, and Changebridge subscriptions subscription Canada, LLC States, 219 All Technology United Mexico. Delivery LLC, Technology the September, and in Delivery July/August, Technology year Canada, June, Drug Delivery May, 1 States, accept expressed. April, for Drug cannot opinion March, $99.00 February, publishers any rates: by January, Subscription for but safety 2009, November/December accuracy, or in the and times ensure for herein 10 responsibility to October, supplied published no taken information is assume is of 1944-818X) publishers (ISSN precaution accuracy the the Every but for manuscripts. care, responsibility or reasonable photographs, with artwork, handled of are submissions editorial All at&Midwest & East etCoast West International aln itRental List Mailing 1 hnerdeRa,Mnvle J07045 NJ Montville, Road, Changebridge 219 XCTV DTRA DIRECTOR EDITORIAL EXECUTIVE [email protected] 0 rnc tet ut 200 Suite Street, Oronoco Executive 103 Account - Stratos S. Cheryl Executive Account - Geis Victoria arnD Graff De Warren ap Vitaro Ralph ad Brecht Candy DIITAIESUPPORT ADMINISTRATIVE ac 2009 March EHIA OPERATIONS TECHNICAL OTIUIGEDITORS CONTRIBUTING PUBLISHER/PRESIDENT oprt/dtra Office Corporate/Editorial www.drugdeliverytech.com detsn ae Offices Sales Advertising DTRA SUPPORT EDITORIAL RAIEDIRECTOR CREATIVE a:(7)299-7937 (973) Fax: hlmrQ Eagel Q. Shalamar ihlsD Vitaro D. Nicholas e:(973)299-1200 Tel: a aio MSc Marino, Dan ahenKenny Kathleen ao McKinnie Jason er Bingham Debra id .Dubin H. Cindy ebeCarrillo Debbie akNewland Mark CONTROLLER ap Vitaro Ralph -al [email protected]: [email protected]: 548-3733 (703) Fax: 212-7735 (703) Tel: 22314 VA Alexandria, -al [email protected]: 721-0665 (415) Fax: 721-0644 (415) Tel: 94901 CA Rafael, 301 San Suite Avenue, 5th 818 Manager Regional Western -al [email protected]: 299-7937 (973) Fax: 299-1200 (973) Tel: 07045 NJ Montville, Road Changebridge 219 -al [email protected]: 549-6057 (703) Fax: 706-0383 (703) Tel: o o3 No 9 Vol 5-9 DDT March 2009 TOC pages:DDT April 06 TOC 5-9.qx 2/26/09 11:34 AM Page 5 5-9 DDT March 2009 TOC pages:DDT April 06 TOC 5-9.qx 2/26/09 11:34 AM Page 6

32 Nanomedicine in a Nanominute: A Market Brief Bill Martineau, MBA, predicts that all five groups of nanomedicines, spurred by expanding indications and a continuing flow of new products into the marketplace, will record strong growth in demand throughout the next decade and beyond.

36 Proteins & Peptides: Dependent on Advances in Drug Delivery? Contributor Cindy H. Dubin talks with some of the industry's leading protein and peptide manufacturers about how new drug delivery systems will improve next-generation drugs.

42 From Battlefield to Backpack: Evolution of the Auto-Injector Mike Mesa, using his company’s historical perspective, indicates that as auto-injectors continue to evolve, their safety, reliability, durability, and ease of use will remain critical considerations for researchers, physicians, and end-users.

50 A New Approach to Threshold Evaluation & Quantitation of “The increased use, development, and Unknown Extractables &

Vol 9 No 3 discovery of protein therapeutics will lead to Leachables Using HPLC/CAD increasing opportunities for drug delivery Xiaochun Yu, PhD, Steve Zdravkovic, Derek companies. Pharma companies need to use Wood, Chunyu Li, Yufei Cheng, PhD, and Xiaoya March 2009 these technologies to gain a competitive edge Ding, PhD, provide a case study involving the in an increasingly crowded therapeutic protein evaluation of the extractables of an elastomeric market. The protein therapeutic market is packaging component to demonstrate one of the largely immediate release, but there is a many applications of this new technique. trend moving toward increased sustained-

Drug Delivery Technology release formulations.” 6 p.36 5-9 DDT March 2009 TOC pages:DDT April 06 TOC 5-9.qx 2/26/09 11:34 AM Page 7 5-9 DDT March 2009 TOC pages:DDT April 06 TOC 5-9.qx 2/27/09 9:17 AM Page 8

Analytical Outlook 56 Depomed: Leader in Gastric Retention Technology “Overall, the ability to remain flexible to Drug Delivery Executive: Carl A. Pelzel, President different client needs is critical as we work and CEO of Depomed, discusses his company’s with contracting companies to create tailored innovative technology, its business model, and strategic goals. that enable them to accelerate development, meet critical milestones, or manage capacity. For contracting pharma 62 Analytical Testing Labs in the companies with defined project goals and Pharma Industry: Where Do They Stand? core areas of expertise, the ideal outsourcing Contributor Cindy H. Dubin leads a roundtable relationship may require a mode of discussion with executives from the industry's interaction that optimizes their ability to top contractors to learn how Specialty Pharma companies can get the most from their manage capacity overflow.” analytical lab partnership.

68 Cardiology & Oncology Drug Development & Regulation Stuart L. Cantor, PhD, and Kadriye Ciftci, PhD, discuss the road to development and regulatory approval associated with two of the leading therapeutic focus markets: cardiology and oncology.

DEPARTMENTS

Market News & Trends ...... 12 Combination Update ...... 18 Combination Devices to Protect Women From Sexual Transmission of HIV Vol 7 No 3 Vol 9 No 3 Excipient Update ...... 22 21st Century Pharmaceutical Quality: Are We There Yet? March 2007 March 2009 Advanced Delivery Devices ...... 24 A Solid Alternative to Needle & Technology Technology Showcase ...... 59 Drug Delivery Technology Drug Delivery Technology External Delivery ...... 74 8 p.62 Fear Factor of Phailure 5-9 DDT March 2009 TOC pages:DDT April 06 TOC 5-9.qx 2/26/09 11:34 AM Page 9 01 D ac 9Mre esLyu 2/26/0911:35AMPage10 1 News:Layout Market 09 March DDT 10-17

10 Drug Delivery Technology March 2009 Vol 9 No 3 inmesLLC Bionumbers Director Managing PhD Bossart, Josef Systems Delivery Drug 3M President Vice Division Vaughan James Corporation Genzyme Development Technology New President, Vice PhD Hoffmann, Peter AFPam Solutions Pharma BASF Manager Service Technical MSc PhD, Ali, Shaukat Schering-Plough Development Cycle Life & Delivery Drug Director, Senior MBA PhD, Monteith, David BD Delivery Drug Advanced Development Business of Director PhD Green, Philip Partners Valeo Partner Bingham Debra Ms. Pharma SPI Development Commercial & Marketing Global President, Vice MBA Chandar, Sarath Technology Delivery Drug Director Editorial Executive MSc Marino, Dan phrSihLaboratoriesUpsher-Smith Development PharmaceuticalDirector, MS PhD, Brown, A-S. Beth Solutions Pharma Catalent Process Business & Strategy VP, Stamoran Cornell Laboratories DPT Management Project & Marketing VP, MBA Iacobucci, Marc apl LLC Kappel, & Davidson Davidson, Partner Founding Esq. Davidson, M. Clifford Xcelience CEO & President MBA Hennecke, G. Derek Companies Lang The CEO & President Bermingham A. John Denver Colorado of University Sciences Pharmaceutical of Department Professor, PhD Kompella, B. Uday Development & Research Global Pfizer Formulations Research Director, PhD Horspool, Keith nvriyo Mississippi of University Pharmaceutics of Department Professor Associate & Chair DDS PhD, Repka, A. Michael hraetcl,Inc. Pharmaceuticals, SurModics Research President, Vice PhD Tice, Tom tAustin at Texas of University Pharmaceutics of Professor PhD McGinity, W. James Laboratories Research Merck Delivery Parenteral & Biopharmaceutics of Director MS PhD, Wu, Y. Henry oimInternational Corium CTO & President MBA PharmD, PhD, Cleary, W. Gary ono Johnson & Johnson Healthcare, Consumer McNeil Labs Technology, R&D R&D Fellow, Research PhD Lee, Der-Yang Colorcon Technologies Release Modified Director, Technical Global PhD Rajabi-Siahboomi, Ali Eurand America North President, Fraher John 10-17 DDT March 09 Market News:Layout 1 2/26/09 11:35 AM Page 11 01 D ac 9Mre esLyu 2/26/0911:35AMPage12 1 News:Layout Market 09 March DDT 10-17

12 Drug Delivery Technology March 2009 Vol 9 No 3 niae htDL2lpsmsaewl oeae.Oraiiyto ability Our tolerated. well are further DiLA2 weeks that 2 indicates for schedule Repeat every-third-day promising. an are on dosing Platform DiLA2 dose the repeat of and data acute tolerability formulations “The siRNA Polisky. of Dr. mg/kg added mice,” 9 in to up of dosing following systemic delivery repeat effective and safe demonstrate to platform continues the and are targets, that therapeutic PCSK9, important and potentially DGAT2 tissue, liver in genes two additional of knock-down achieved our Platform that DiLA2 announce proprietary to pleased are “We technology. delivery degradation. nuclease from as well protection providing as induction, cytokine surveillance with the associated escapes mechanisms monomer the of flexibility The flexible. conformationally analog structure nucleobase sugar unlocked in this change renders the activity Further, undesired strand. as passenger well the as of strand guide for the by potential effects the off-target minimizes UsiRNA within UNA activity. of RNAi Placement potent the for by provide recognized and fully machinery are RNAi UsiRNAs removed. carbon is adjacent ribose two of between atoms bond the which in (UNA), analogs nucleobase unlocked termed monomers, acyclic nucleotide effects.” minimizing side while potential genes silence a to have we construct believe siRNA and unique results significant are these We by response. encouraged cytokine in decrease yet substantial machinery a RNAi showed with compatible fully these were In UsiRNAs reduction. cases, both cholesterol for serum model and ApoB inhibition mouse message the in MDRNA. active of highly were Officer “UsiRNAs Scientific Chief PhD, Polisky, specificity,” Barry increasing said while siRNAs potent highly providing of Japan. in Tokyo, Conference Development Product and Peptide Technology Research, and Oligonucleotide TIDES Sciences Life inaugural Informa the at MDRNA, of Development and Pharmaceutical Michael Research by Discovery presented President, were Vice data PhD, Templin, V. The ApoB model. of rodent knockdown a 90% in to message up in resulted which response, dose M Data Delivery New Novel Reports Using Constructs; Models UsiRNA Animal in Targets Gene Silences Successfully MDRNA DN lorpre e nomto nisDL2Platform DiLA2 its on information new reported also MDRNA non- with modified are that siRNAs duplex are UsiRNAs means proprietary and novel a offer constructs UsiRNA “Our aao t rpitr sRAcntut eosrtn a demonstrating constructs UsiRNA proprietary its efficacy on vivo data in positive announced recently Inc. DRNA, h iN oeue hti xet ola osfradmore and safer to lead therapeutics. to RNAi-based effective expects it that molecule, siRNA within the (UNA) Analog Nucleobase Unlocked non- moiety the nucleotide incorporate that new UsiRNAs on as building such also technologies, is establishing It for partnerships. platform therapeutic versatile broad a and engine pipeline the clinical be its will for that platform discovery a drug to integrated expertise single, this applying is company The bioinformatics. and toxicology, pharmacology, chemistry, acid amino and alkylated peptide expertise, formulation biology, cellular molecular biology, includes capabilities of portfolio Its multidisciplinary options. therapeutic superior provide to delivery technologies drug liposomal-based and peptide- and proprietary compounds human improve RNAi-based novel to combining is by goal health Its (RNAi). interference RNA on based products therapeutic of commercialization and development and release. uptake endosomal cellular increase to for formulations peptides nanoparticle utilizing is MDRNA addition, delivery In of characteristics. variety other a and improve peptides to various molecules of targeting platform attachment the permit addition, to In designed interest. is for of tissue the target optimize the to to delivery order in acyl acids and amino linker, of charge, chains the tailor to The MDRNA acids. enables amino platform from systems delivery liposomal novel creating of expertise team. and scientific capability our the RNAi- and our engine discovery of depth drug and based breadth the a of represent demonstration results further recent The genes. those and targets silence effectively and gene safely multiple to against ability siRNAs deliver its efficiently in versatility its demonstrate Platform to DiLA2 continues our “Further, MDRNA. of Chief Officer and Executive President French, Michael J. RNAi-based stated of therapeutics," development the in forward potential step a major represent activity, off-target minimize that siRNAs delivery.” siRNA a improved of for development formulation the novel in platform advancement DiLA2 the significant that a belief represents our affirms targets of gene knockdown multiple achieving while hepatocytes to siRNAs deliver DN saboehooycmayfcsdo the on focused company biotechnology a is MDRNA for platform MDRNA’s proprietary is Platform DiLA2 The active highly constructs, UsiRNA novel and proprietary “Our 10-17 DDT March 09 Market News:Layout 1 2/26/09 11:35 AM Page 13 01 D ac 9Mre esLyu 2/26/0911:35AMPage14 1 News:Layout Market 09 March DDT 10-17

14 Drug Delivery Technology March 2009 Vol 9 No 3 ra,SesCmeca Partner Commercial Seeks Trial, Clinical II Phase of Completion Successful Announces CyDex rgmse iefrcin use. client for file master drug FDA and comprehensive CAPTISOL a its and for technologies, worldwide cyclodextrin and US the in patents maintains company The companies. biotechnology and pharmaceutical, specialty pharmaceutical, with leading partnering and its solutions using technology enabling products of pipeline own its developing is CyDex technology. CAPTISOL its licensing and products developing company pharmaceutical within commercialize Pharmaceuticals.” CyDex and develop, products retain, as to well intend as we license to products of a involvesdevelopment to strategy license ongoing to Our partner. intend we commercial one is product spray nasal azelastine budesonide Enabled Captisol The pharmaceutical company. specialty grow we formidable as a forward become company to the trial, propel clinical to II continue Phase will this by demonstrated as at development CyDex, and research ongoing “Our commented, a is development.” trial promising this very of completion the The in market. entrant rhinitis new allergic significant and strong a should we anticipate then efficacy, trials clinical clinical significant comparative show “If results. preliminary the review of Board Advisory AAOA the following , of School Pittsburgh of University Otolaryngology, of Department Professor, Associate MD, B.J. Ferguson, said delivery,” potentiating nasal by as sprays such steroid medications, of efficacy the increase may potentially beta-cyclodextrin, sulfobutylether environmental (EEC). an chamber in exposure rhinitis allergic of in treatment spray the nasal placebo against nasal (solution) spray Astelin plus () Aqua solution) Rhinocort (single and spray nasal azelastine Captisol-Enabled plus of budesonide efficacy relative patients the SAR compare 108 to in conducted was study cross-over way spray nasal product. combination this patent for PCT pending international application an has CyDex (SAR). allergic rhinitis seasonal for Captisol-Enabled spray its nasal of budesonide/azelastine trial clinical II Phase concept C ye hraetcl,Ic saspecialty a is Inc. Pharmaceuticals, CyDex CyDex, of CEO and President PhD, Odlaug, Theron modified chemically a CAPTISOL, “CyDex’s three- placebo-controlled, double-blind, randomized, A a ucsflycmltda al proof-of- early an completed successfully it has announced recently Inc. Pharmaceuticals, yDex 01 D ac 9Mre esLyu 2/26/0911:35AMPage15 1 News:Layout Market 09 March DDT 10-17 gemnswt hraetclcmaisi bu 5cutiswrdie n its abroad. achieved and totally worldwide, almost countries licensing are 35 signed sales about has in APR contract. companies pharmaceutical under party with or R&D directly third agreements to out on licensed carried as are well are technologies as that and activities own products its APR on The projects. value sustainable and new products create to systems, committed regulatory is and marketing APR its and know-how, on R&D Leveraging technologies. provides platforms, technology its also own on APR marketing. based and services distribution development for product development contract out-licenses of and stage technologies late proprietary at own them its using products medical OTC Rx, and develops devices, that Switzerland in headquartered company Development 700 over to included. increases are amount infections related this HSV-2 markets, and HSV-1 7 major if people million the million in 178 infections almost data, MedMarket from report suffer a Insights to Business according to worldwide, According cases study. million Diligence diabetic 30 and another venous, for pressure, account including wounds, ulcers, Chronic 2007. in cases million year. each injuries eye from million suffer 2.5 US almost commonly the references, most in same the people the is to each that According in billion procedure. surgery old ophthalmic cataract $3.4 years performed almost for 80 program spends government at Medicare people US the the the through year and of cataracts, half from almost suffer and US old the years 40 over people million 20.5 nanomaterials, in advances to due 2015 by trillion nanosystems. $1 and nanostructures, of excess to forecasted in turnover is a market drug nanotechnology pharmaceuticals, reach global in The advances monitoring. being including healthcare disciplines, are and that of delivery, sources range investment broad private a and government to applied from funds in billion $3 Galfetti. over Mr. concluded Balerna,” in based be will be and also Switzerland will in our s.a., headquartered of Nanotechnologies applications APR future named company, possible specifically new and company This nanotechnology. this new of a a development create platform the to technology to decided this dedicated APR of venture, inventors this the into give stake to substantial as well as portfolio R&D APR’s in studies clinical first the enter healing. cataract to been and ready has wound now wounds eye induced is surgically APR in results. excellent study with II performed Phase a positive Also, with results. efficacy process, promising and patented and safety, nano-coating toxicology, stability, the analysis, with chemical obtained its product including first the of features critical studied. this being of new also applications the are other from technology Several derived results. product promising first most the showed technology with eye made and tests skin initial and where wounds infections, induced surgically including wounds, infected acute unmet to areas.” solutions therapeutic therapeutic critical new several unlock “The in may APR. technology needs of new CEO this Galfetti, on Paolo based said products issues,” tolerability and or capabilities effects healing side powerful minimal totally with products to technology obtain nano-coating to on compounds based biological process a combining of potential disclosed. not were acquisition dermatology. the and ophthalmology of in terms products Financial developing resulting already the is of APR applications areas. specific therapeutic multiple of in treatment diseases the critical for several products biotechnology patent-protected new of preparation A Diseases Critical for Solutions Treatment Innovative for Platform Nanotechnology Delivery New Acquires APR P ple hraRsac ..i nitrainlDu eerh& Research Drug international an is s.a. Research Pharma Applied APR 100 over with world the in wounds prevalent most the are wounds Surgical-induced almost Ophthalmology, of Academy American the by cited references to According attracted have nanotechnologies Insights, Business of report 2008 a to According of expansion the in step important new this to focus right the give to order “In the studying tests preclinical vivo in and vitro in several performed already has APR and chronic, cataract, including injuries, eye of treatment the targeted first has APR great the understood we when technology platform new this acquire to decided “We ltomtcnlg ossigo aetdnn-otn rcs o the for process nano-coating new patented a a of of acquisition consisting the technology announced platform recently s.a. Research Pharma Applied PR

15 Drug Delivery Technology March 2009 Vol 9 No 3 01 D ac 9Mre esLyu 2/26/0911:35AMPage16 1 News:Layout Market 09 March DDT 10-17

16 Drug Delivery Technology March 2009 Vol 9 No 3 ainswt ytcfboi;adpelncldt niaigta a that indicating data preclinical and fibrosis; cystic in with found patients bacteria resistant highly novel kills company's technology the nanoemulsion that toxicitydemonstrating or data preclinical safety without concerns; but the drugs as effectively systemic as oral healing leading speeds product company’s labialis the herpes that topical indicating data IIb Phase including NanoBio, hs td o nitaaa esnlifunavaccine. influenza seasonal a intranasal and an for fibrosis, study cystic I for Phase therapy nebulized acne, a for on treatment studies topical preclinical novel a investigating study I Phase oadtedvlpeto h opn' aotttechnology NanoStat platform. company's directed the been of has development funding the in existingtoward million other $80 and over LLC date, Perseus To with investors. financing equity million B $12 series acquired in has it announced recently vaccines, intranasal N & Central in Expertise & Europe Infrastructure Eastern Enhance to AbCRO Acquire to PPD iloesePDsCnrladEsenErpa prtos Ms. operations. European Eastern and Central PPD’s oversee will systems.” and procedures PPD well- basic already on employees versed AbCRO the of many seamless with relatively integration, a many anticipate see We and clients. AbCRO our with synergies for our trials enhance global and conduct Europe to ability Eastern and Central strengthen in will foothold acquisition our “This PPD. Eshelman, of Fred Officer said Executive region,” Chief the in and reputation business solid research a clinical established regional strong a built has AbCRO 3 past the over PPD with years. extensively worked have whom professionals, of full-time many 230 than more employs regulatory AbCRO and affairs. identification, site recruitment, and patient management monitoring, trial clinical including services, clinical in Ukraine. operations and and Russia, staff Poland, existing PPD’s bolsters also and and infrastructure expertise, established with Croatia and Serbi,a Bulgaria, research. clinical emerging for high-growth, region a in will presence PPD’s which strengthen Europe, further Eastern and Central in operating organization aoi oprto ass$2Mlini eisBFinancing B Series in Million $12 Raises Corporation NanoBio P hsfnigflossvrlrcn rdc noneet by announcements product recent several follows funding This h eisBfnigwl eue ytecmayt opeea complete to company the by used be will funding B series The s ef he xctv fie n ofudro AbCRO, of Co-founder and Officer Executive Chief Leff, Ms. Pleasants, Christa and Leff A. Dana of leadership the “Under II-IV Phase of range full a provides AbCRO 2000, in Founded Romania, into entry immediate PPD gains acquisition The oaqieACRO,Ic ACO,acnrc research contract a agreement (AbCRO), an Inc. AbC.R.O., into acquire entered to has it announced recently Inc. PD, emtlgclpout,at-netv ramns and treatments, anti-infective products, developingdermatological company biopharmaceutical a Corp., anoBio n aoaoyfclte r oae nAnAbr Michigan. Arbor, Ann in located are facilities headquarters laboratory company's and The vaccines. intranasal a of and platform fibrosis, broad cystic acne, (cold fungus), labialis (nail onychomycosis herpes sores), for treatments are candidates company's product The lead platform. technology NanoStat patented its derived from vaccines intranasal and treatments anti-infective products, dermatological commercializing and developing on focused conditions.” economic challenging the despite participating financing to this respect in with there investors plans, from development interest future our significant was and data recent the our upon of “Based strength Corp. MD, NanoBio Jr, of Baker Chairman R. and James Founder said investors,” other company's the and currently of vaccines. injections approved two by times generated 20 those than than more higher ferrets in responses immune elicits influenza vaccine intranasal novel NanoBio's of administration single & netet n ceeaetedlvr fsf n effective and patients. safe their to of on therapeutics delivery returns the maximize accelerate partners and investments and R&D clients its help to quality commitment to a and expertise, therapeutic technologies, innovative applies PPD worldwide, professionals and 10,500 countries approximately 33 in offices With organizations. government and academic, device, include medical biotechnology, partners and pharmaceutical, clients Its programs. as partnering well compound as services post-approval and development, discovery, quarter. first the or of on end close the to about expected is and and conditions approvals, closing regulatory obtaining customary to subject America. is North acquisition and The Europe of Western density to lower compared a trials and clinical patients, reachable easily a of investigators, pool well-trained large offers CROs which largest region, the the of in one operating acquisition is its company through The Ltd. year InnoPharm, last of Ukraine and Russia in presence its director. senior a as UK the in operations clinical PPD’s region.” our this upon in build growth to immense resources global base PPD’s client with strong expertise our and combining to forward look We continued expansion. for grown possibilities has many Europe are Eastern there tremendously, in research clinical “While said, Leff aoi op sapiaeyhl ipamcuia company biopharmaceutical held privately a is Corp. NanoBio Perseus of support strong continued, the with pleased are “We P salaiggoa otatrsac raiainproviding organization research contract global leading a is PPD established and 1995 in region the in office first its opened PPD join will AbCRO, of Co-founder and Chairman Pleasants, Ms. 10-17 DDT March 09 Market News:Layout 1 2/27/09 9:25 AM Page 17

Sopherion Therapeutics Secures $55 Million in Series C Funding

opherion Therapeutics, LLC, a biopharmaceutical company President and CEO of Sopherion Therapeutics. “Zoticon's Sfocused on the development and commercialization of anti- experience in biotech is a great asset for us, and we look forward cancer therapies, recently announced a $55-million Series C to continuing to work closely together.” financing. The financing was led by Zoticon Bioventures, a global “Zoticon is very excited to be involved with Sopherion and the drug development and healthcare investment firm. Myocet program in North America. This investment underscores The company will use the funding to complete the pivotal Phase our strong, continued belief in the significant advances the III clinical development program for its lead product candidate, company is contributing to the field of oncology and to addressing Myocet. Myocet is a liposomal formulation of doxorubicin significant unmet medical needs,” added Asher Nathan, Managing designed to reduce the risk of cardiotoxicity while preserving Director of Zoticon and Chairman of the Board, Sopherion antitumor efficacy. Therapeutics, LLC. In January 2008, Zoticon Bioventures in-licensed Myocet and Sopherion Therapeutics, LLC is a privately held biotechnology provided funding of $20 million to Sopherion and subsequently company based in Princeton, New Jersey. The company is focused led an additional $35 million raise during 2008. Proceeds are to on developing novel anti-cancer therapies for patients suffering fund Sopherion and complete its global, registrational trial of from advanced cancer, particularly metastatic disease. Sopherion Myocet in combination with trastuzumab and paclitaxel versus is dedicated to the acquisition, discovery, development, and Vol 9 No 3 trastuzumab and paclitaxel for first-line therapy of patients with commercialization of novel anti-cancer therapies with unique metastatic breast cancer. Additional investors in the $35-million therapeutic activities that address unmet medical needs in and

round include TL Ventures, New Leaf Venture Partners/Sprout extend human life. In 2004, Sopherion entered into an exclusive March 2009 Group, ProQuest Investments, Canaan Partners, Devon Park licensing agreement with Zeneus Pharma Ltd., now Cephalon, Inc. Bioventures, Commerce Bank, and NewSpring Capital. for the future commercialization of Myocet in North America. “This funding is an important milestone for Sopherion and Zoticon is a privately held global drug development and represents continued validation for Myocet, which we believe has healthcare investment firm with a portfolio of life-sciences- the potential to become the standard of care for patients with focused companies. Zoticon's business model is to in-license novel

advanced breast cancer when used in combination with therapeutics, and continue their clinical development. Drug Delivery Technology

trastuzumab and paclitaxel,” said Ronald H. Goldfarb, PhD, 17 18-21 DDT MAr 2009 - Combination Update :Layout 1 2/26/09 11:36 AM Page 18

Combination Devices to Protect Women From Sexual Transmission of HIV By: Abhijit Gokhale, PhD; Jason McConnell, Andrew Loxley, PhD; and Mark Mitchnick, MD

uman immunodeficiency virus (HIV) is of F I G U R E 1 increasing concern at the global level. The US HFederal budget to counter HIV domestically and globally is rising at approximately 7% each year, with a proposed 2009 budget of just over $24 billion. Microbicides present a relatively new, promising area of alternative research and prophylaxis, and pharmaceutical formulators and scientists are developing various strategies aimed at vaginal drug delivery, such as , dissolving strips, and intravaginal rings (IVRs), as an effective method for microbicide delivery to the point of viral exposure IVRs (a) Commercially Available IVR (b) Dapivirine-Filled during vaginal intercourse. Developmental IVR

than directly from the matrix region. Over-coating matrix VARIOUS APPROACHES FOR devices in a layer of virgin polymer has become a popular VAGINAL DRUG DELIVERY tool for controlling the release of drugs from the devices, and generally yields near zero-order kinetics. Core sheath architectures are referred to as reservoir systems. Vaginal delivery of actives for local effect is a well- Gels have been on the market for some time as vaginal established practice, and the possibility for drug delivery to drug delivery vehicles. They are used to deliver, among the vaginal cavity using modern formulation approaches other things, contraceptives, antimicrobials, and labor has wooed scientists since the early 20th century.1 Various inducers.4,5 approaches have been investigated, with an emphasis on Therefore, gels naturally lend themselves to contraception. For example, T-shaped birth control devices investigation as drug delivery systems for microbicides, and (intrauterine systems, IUS) made of drug-free or drug- much of the early research in the field was focused on this vehicle. However, a device called the intravaginal ring loaded plastic were developed by the Population Council in (IVR), a rubber o-ring-shaped device that can be self- New York City, and have been used successfully in birth administered, offers the potential advantage of sustained- control.2 release and better compliance, and has therefore seen There are now several intravaginal devices on the Vol 9 No 3 significant developmental efforts.6,7 market serving various purposes. Implants, such as silicone discs and rods, were investigated for sustained-release of The IVR proved to be a breakthrough hormonal delivery strategy, and one that has more recently been acyclovir (ACV) to treat herpes simplex virus type-1.3 The March 2009 drug was uniformly compounded into the plastic from extended to the development of sustained-release which the discs and rods were prepared. Such products are combination devices for the delivery of microbicides to referred to as matrix devices, which tend to release drug reduce HIV transmission during heterosexual intercourse. with first-order kinetics. Coating the devices in silicone However, the wide range of physiochemical properties of rubber (providing a core sheath structure) proved to be an various microbicides presents a formulation challenge in the development of IVRs with well-controlled release of

Drug Delivery Technology effective technique to control the drug release, and zero- drugs. Ultimately, to successfully develop a sustained- order kinetics were observed as a result of diffusion from 18 release combination device product, a thorough the matrix region through the layer of virgin silicone, rather 82 D A 09-CmiainUdt :Layout12/26/0911:36AMPage19 Update Combination - 2009 MAr DDT 18-21 Implanon odvlpn iioebsdIVRs. silicone-based developing solutions to effective demonstrates clearly initial approach after This kinetics burst. release zero-order and state release, steady burst gave initial also the suppress to found as were such lactose compounds organic hydrophilic effect, no had practically (dimethylsiloxane) poly as such excipients hydrophobic Whereas kinetics. drug-release control to additives prpit rdst etrgltr requirements. regulatory meet the to in grades available appropriate is and delivery, drug intraocular implantables for even and as control) such birth devices, (hormonal other NuvaRing several for successfully used been EVA has microbicides. -based vaginal of early developmental and stage treatment HIV in used potent compound a antiretroviral microbicide, the EVA as Dapivirine from containing made polymer, IVR drug-eluting a developed company The grades. regulatory-appropriate of polymers from be prepared and IVR properties ideal mechanical The acceptable fashion. have zero-order should wide near a a release in could APIs of that variety and manufacture to easy was that NuvaRing called and Organon by marketed vivo. is in device weeks The 3 for micrograms/day) (15 estradiol and ethinyl micrograms/day) (120 provide etonogestrel and of device delivery control sustained birth a as marketed been have this for seen device. commonly of drug type of release burst initial weeks the 4 after for release zero-order show inhibitor) transcriptase reverse non-nucleoside (a Dapivirine microbicide necessary. is concern of API the to specific the factors and mechanism, drug-release the of understanding ees rgsae o eido years. 3 of period a for progestagen release otnosyfr6months. 6 mg/day) for (10 continuously progesterone hormone natural the countries delivers American and South was in that women elastomer lactating silicone for developed a on based IVR control birth h ema atceSine e u odvlpa IVR an develop to out set Sciences Particle at team The polymer (EVA) acetate vinyl ethylene an on based IVRs the containing IVRs reservoir-type Silicone-based RDC EEOMN STRATEGY DEVELOPMENT PRODUCT TM sasbuaeu mlnal eiedsge to designed device implantable subcutaneous a is 8 eea xiinswr netgtda IVR as investigated were excipients Several 8 10 Progering 11 TM sa is ® 9 . o h ia rdc dimensions. product custom-made final is the that for mold or a piston-type using a molder in injection product hydraulic IVRs the into and formed screws), then rotating is long, compound of pair a of flights between the additives with polymers molten that blends device uniformly more (a or compounder mixer, twin-screw batch a a in in preferably, molten performed in be is EVA could the Mixing where form. EVA, the of above point temperature, softening elevated the at mixed were polymer The and characterized. drug and prepared were different IVRs from various EVA vendors, of grades several injection- with an process, Using molding it. affect that to approaches implemented and be polymer, could the from drug the controlling of parameters diffusion the a of required understanding which scientific IVRs, sound the from zero- Dapivirine achieve of to release was order aim The polymer. the acetate vinyl of and/or content (VA) weight molecular the be changing can by EVA varied of properties physical The monomers. acetate al ees fDpvrn rmIR otiig13 2. mg) (23.4 1.3% Containing IVRs Dapivirine From Dapivirine of Release Daily oprsno hsclPoete fVrosIVRs Various of Properties Physical of Comparison EVA IVR 100mg Dapivirine EVA IVR 23.4mg D EVA 3.6mg IVR, Dapivirine Commercial IVR V sarno ooye fehln n vinyl and ethylene of copolymer random a is EVA R apivirine ing EUT DISCUSSION & RESULTS 2 E R U G I F 1 E L B A T For 0.548 0.444 0.399 0.570 5 ce mm Required to Bend the R N N N N 0.965 0.648 0.340 1.002 10 mm N N N N i ng by: (N) 1.555 1.132 0.983 1.815 20 mm N N N N

19 Drug Delivery Technology March 2009 Vol 9 No 3 18-21 DDT MAr 2009 - Combination Update :Layout 1 2/26/09 11:36 AM Page 20

F I G U R E 3 100 mg was found to be linearly dependant on the drug loading in the IVR (Figure 3). For IVRs containing a given mass of drug, release is relatively independent of the cross-sectional diameter of the device because the increased surface area available for release (a linear function of diameter) is offset by the reduced drug concentration in the device (a linear function of the square of the diameter). Conversely, IVRs containing the same concentration of drug show diameter-dependent daily drug release (data not shown). Surprisingly, we found that IVRs made from various EVAs differing in VA content (from 12% to 28%) and melt indices (from 3 g/10 min to 43 g/10 min) showed negligible

Daily Release of Dapivirine From 4 mm IVRs Containing Various Drug differences in drug-release kinetics, potentially allowing wide Loadings flexibility for tuning device processing and physical properties without affecting drug-release kinetics. Figure 1 illustrates a commercial IVR alongside an The IVRs were stored at 30°C/65% RH and 40°C/75% experimental Dapivirine-loaded IVR prepared by the scientists RH for 3 months and 6 months to determine their storage at PSI. Dapivirine release kinetic curves were generated by stability. Release kinetics from these IVRs were virtually testing IVRs in vitro under sink conditions in a mixture of identical to those of freshly prepared IVRs, indicating isopropanol and water. The medium was exchanged regularly promising storage stability of the devices. The bulk drug- for 30 days, and samples of the exchanged release fluid were loaded EVA compound was also found to be similarly stable, assayed for Dapivirine by HPLC. Figure 2 shows the in vitro indicating the potential for shipping compound globally to be release data for Dapivirine from IVRs made with a 4-mm molded into devices locally at the point of distribution. cross-sectional diameter containing 23.4 mg (1.3% w/w) of the drug. MICRORESERVOIRTM DEVICEFOR To a first approximation, drug release from IVRs is dependent on the drug concentration in the device and the ZERO-ORDERRELEASE surface area available for release. Dapivirine release from 4- In an effort to develop IVRs displaying a more constant mm diameter rings with a range of drug loadings from 3.6 to daily release of Dapivirine (eg, zero-order release kinetics), F I G U R E 4 the drug was microencapsulated in cellulose acetate phthalate (CAP), a polymer that is approved by the FDA for various dosage forms. The encapsulated drug/CAP particles form a free-flowing with an average particle size of

Vol 9 No 3 approximately 500 microns. This drug/CAP powder was compounded with the EVA and injection molded to make IVRs. The release kinetics of Dapivirine from these devices is

March 2009 shown in Figure 4. Essentially, the kinetics from devices containing microencapsulated drug are similar to those from reservoir devices: reduced initially burst release and constant daily release levels. In effect, each of the myriad drug-loaded microcapsules behaves like a “microreservoir” within the device. These IVRs were also evaluated for their storage Drug Delivery Technology Daily Release of Dapivirine from CAP MicroreservoirTM IVRs & Matrix IVRs stability at 40°C/75% RH for 3 and 6 months, with 20 Containing 1.3% Dapivirine satisfactory results (data not shown). 82 D A 09-CmiainUdt :Layout12/26/0911:36AMPage21 Update Combination - 2009 MAr DDT 18-21 1 i ,Wlt ,DwigA lo ,Ivn ,Shat .Vsa n ntmcotoe soitdwt posterior with associated outcomes anatomic and Visual D. Schwartz A, Irvine H, Bloom A, Dowling Contraception. R, data. Wolitz J, the Lim of overview an 11. Implanon: of efficacy and pharmacodynamics The L. Makarainen HB, G, Croxatto Page J, 10. Bitzer L, Oeyen, B, Karskov W, Urdl K, Gemzell-Danielsson M, Gomez C, Bastianelli and I, solubility Nisand elastomer H, silicone Ahrendt of Influence 9. D. Craig L, McAuley P, Tallon J, and Russell solubility D, elastomer Woolfson silicone K, Malcolm of Influence 8. D. Craig L, McAuley P, Tallon J, Russell D, Woolfson K, Malcolm 7. the determining for method mechanical dynamic A P. 2006;318:1-14. Tallon M, Pharmaceutics. Catney J D, Int Woolfson systems. S, delivery McCullough 1993;169:479-482. drug K, Gynecol. vaginal Malcolm Obstet as J Gels 6. Am MF. vaginosis. Bahia bacterial J, Neves of Das treatment the 5. for approaches New RL. Sweet long- 4. effective the for implant acyclovir an of Development B. Margulies T, Brennan M, Modugno R, 2005;10:977-985. Today Frey 1918;10:509-522. T, Discovery Pathol. Johnson Drug Pharmacol contraceptives. J 3. for vagina. options the Delivery through R. poisons Sitruk-Ware and drugs 2. of absorption The DI. Macht 1. presented. been has approach this based on microbicides for device delivery well sustained of controlled paradigm new A HIV. of against transmission women sexual of protection the a for are technology EVA, promising with here illustrated as elastomers, thermoplastic acceptance. should clinical hence similar show and IVRs, commercial to similar properties have physical investigation this during produced indicating IVRs ring, that vaginal available commercially IVRs a developmental to various compared for 1 data Table force distance. given bending a the shows through ring the force bend the to is required properties physical IVR A of comfort. measure and useful compliance affect may it as consideration, otaetv otiig3 irgaso tiy srdo n go rsieoe otaeto.20;4 451-457. 2006;74: Contraception. drospirenone. of mg oral 3 an and with estradiol compared ethinyl NuvaRing, of ring, contraceptive micrograms combined 30 the containing contraceptive of tolerability and acceptability 2006;90:217-225. Efficacy, Release. I. Controlled Milsom J rings. intravaginal from drugs of release vitro in 2003;90:217-225. the Release. on Controlled diffusivity J rings. intravaginal from drugs of release vitro in the on diffusivity rings. delivery drug intravaginal silicone in excipients 2002;23:3589-3594. pharmaceutical Biomaterials. and drugs of solubility elastomer silicone J Int mice. SKH-1 infected experimentally in and cells Vero in 2007;30:428-435. infection Agents. type-1 Antimicrobial virus simplex herpes of control term emn opiain fe accoi mln rcdrsi ainswt ISadctmglvrsretinitis. cytomegalovirus and 1998;127:288-293. AIDS with Complications. patients Implant Ganciclovir in procedures implant ganciclovir after complications segment 1998;58:915-975. nsmay Vsmd yijcinmligof molding injection by made IVRs summary, In important an also are IVRs of properties physical The HSCLPOETE OF PROPERTIES PHYSICAL OCUIGREMARKS CONCLUDING AIA RINGS VAGINAL REFERENCES adarc tTeNwYr optl onl eia Center. Medical Cornell Hospital, York in New trained The from was at MD He Paediatrics his School. and Medical University University Purdue BSc Georgetown from his Sciences earned Animal Mitchnick in Dr. ingredients. active of and stabilization encapsulation and care catheters, skin self-sterilizing international production, formulations, and nanoparticle US to pending related and patents issued 20 approximately holds Mitchnick Mark Dr. PhD the his Bristol. from and microencapsulation of Sussex on University of focusing Univeristy Chemistry the Physical from in Chemistry earned he in British-born, BSc and Ltd. his Corp., Synthomer EINK at at adhesives latex-based displays electrophoretic at Inc, batteries Systems ion A123 lithium next-generation in efforts development nanoparticle to rings. related vaginal an patents and is US processing He pending techniques. three traditional on with which inventor engineer substances, polymeric to bio difficult and are coating, drug and formation steCOo atceSine.D.Mitchnick Dr. Sciences. Particle of CEO the is B onn atce cecs eldthe led he Sciences, Particles joining to Prior delivery. siRNA gene-silencing to development microbicide and vaccine HIV from fields in proprietary nanotechnologies, and many novel projects, on of based variety a leads He development. formulation pharmaceutical in specializing PA, Bethlehem, in organization research a contract Inc., Sciences Particles at Technologies Loxley Andrew Dr. research. government and industrial,academic, in experience of 5 years over has delivery McConnell API Mr. other formulations. as well as rings vaginal of analytics and the development a on as focusing 2007 Chemist late Formulation in Sciences Particle joined He Pennsylvania. of University Kutztown McConnell Jason n niern set fnanoparticle of aspects engineering and scientific of covering field fluids, the supercritical in papers several published has Gokhale Dr. environments. andacademic industrial both in pharmaceutical experience years forms,8 dosage over other with and rings vaginal developmentfor product a on as focusing 2007 Chemist in Sciences Particle He Technology. joined of Institute Jersey New Gokhale Abhijit Dr. APHY H P RA G O I andhsB from BS his earned sDrco fNew of Director is andhsPDfrom PhD his earned

21 Drug Delivery Technology March 2009 Vol 9 No 3 22 D A 9-EcpetUdt 2:Layout12/26/0911:38AMPage22 Update Excipient - 09 MAr - DDT 22-23

22 Drug Delivery Technology March 2009 Vol 9 No 3 Rico). Puerto 22-23, (April 2009 Americas® ExcipientFest year’s this draw at to audiences expected large topics the of some are just these and industry, excipient the drive to helping are of excipients use co-processed the and strategies, sourcing (QbD), better Design by Quality like issues path. Now, the littered have excipients, quality poor and performance, drug impact excipients how about lack understanding a of decisions, purchasing in Shifts easy. dosage forms. solid of performance and safety, stability, processing, toward critically contribute excipients now that is established It well industry. $2.5-billion a is some claim what in a is just proof they The are commodity. longer No where used. affect are they they how and made, are they how functionality, their of understanding better a excipients: of importance T h xiins h auatrn process, manufacturing the making excipients, company the the of history learning the on about spent effort little world. is the There in anywhere can literally quest them their take motto, this by lowest Driven the price. at ingredients the Get simple: is directive of Their those agents. into purchasing and hands formulators’ of out fell decisions purchasing excipient when excipients. of the process manufacturing the with familiar intimately were companies time pharma a when Imagine excipients. those of the quality second-guessing no was there time when a Imagine supplier. with excipient basis their first-name a on actually were T HRI ISTEPOWER? THE LIES WHEREIN nutyeprstcl origadpoesn tteucmn ExcipientFest Contributor Dubin, upcoming H. the Cindy at Yet? By: processing There and We sourcing Are tackle experts Quality: Industry Pharmaceutical Century 21st etn oti on a o been not has point this to Getting httm ne bu 0yasago years 10 about ended time That formulators when time a Imagine nesadn bu the about understanding improved an been has there decade, past the hroughout Colorcon Affairs Regulatory Global of Director SchonekerDave ult fteecpet htg noa into product.” go drug that excipients the of quality the for responsible always ultimately is user pharmaceutical the necessary because is “This knowledge. a of in position pharma puts This standards. pharmaceutical- grade to made is product the sure making and controls, manufacturing understanding site, supplier’s says. less- he the suppliers,” for used necessarily not buy but they most, suppliers from of 20% the to for 10% place top in audits have will “Many companies use. to plan alternative they any excipients of quality the ensure programs to auditing improved use all should years.” few cases, past of the number during a in have and death, cause do can some excipients but Poor-quality cost, not. as well as fully quality which assess place, in programs great have companies pharma “Some Mr.Schoneker. says risks,” potential the to mitigate necessary is what they do price, always cheaper don’t a get can they that used. been historically has known who the supplier from excipient same different the be than might supplier new a from product the of make-up The compositional trouble. potential to up pharma companies opening is down going are Americas. ExcipientFest Changes Regulatory and Coming Legislative the on View IPEC’s - Sourcing Excipient in Strategies present Mitigation will who Colorcon, at Regulatory Affairs Global of Director and Chair, Americas IPEC former Schoneker, saysDave price,” on solely decision based a sometimes - use should they excipients what formulators telling they basically and are people, often chain are supply product by drug chosen a in used be to ingredient. the of quality the or uissol nld iiigthe visiting include should Audits generics and Pharma Big says He believe folks purchasing the “Once folks purchasing some that path The excipients of grade and origin “The at Risk t eetgieo xiin quality, excipient on guide newest its cost. low a at results the access to have can suppliers alternate from these purchasing anyone that so industry with reports cost these to share is effectively goal The suppliers. excipient of process certification third-party a to develop trying is (IPEC) Council Excipients 100%.” this believes FDA The accountable. they are therefore, material; alternative to the decision use the made lies They pharma. fully with responsibility the day, the of the end at earlier, stated As vision cloudy. Their becomes good. certain are are excipients they cheap but the it, in holes has really system control Their right. it’s themselves convince they badly, so something want “They Schoneker. Mr. continues (DOS),” Syndrome Outcome Desired call willing seller.” a be always will willing there a buyer, is there if applications, in excipients drug lower-quality of use the comes to it When applications. for drug problem certain a be could which practices, manufacturing certain realize of not impact may the they used, their be how will of product unaware is supplier the if but criminal, that’s adulterated, purposely are excipients the “If Schoneker. Mr. says grade,” pharmaceutical in than different are excipients past. the in many problems caused has be says, to he is This, excipient used.” an how about maker and the user the lack between a communication is of there times, in Many used products. be drug will selling are the they that excipients know even not do excipient manufacturers the cases, some “In supplier. excipient the not responsible, primarily is Mr. pharma typically, product, says drug Schoneker a in excipient an of ietro Business of Director hsps etme,IE released IPEC September, past This Pharmaceutical International The I what have industry the in “Many industrial-grade in “Impurities use the with arise do problems When lnGy PhD Guy, Alen Encapsulates Development ® mrcsConference Americas Balchem 22-23 DDT - MAr 09 - Excipient Update 2:Layout 1 2/26/09 11:38 AM Page 23

offering guidance to suppliers on how to at the upcoming ExcipientFest Americas process. The point is to co-process, not market their product to pharma, how pharma conference. “Second, the design and conveniently blend just to save money and can select the right excipient for specific formulation serve a purpose, and there is reduce risk.” intended use, and how to improve the more flexibility with the design of the While the benefits of co-processed communication between maker, distributor, dosage.” excipients are numerous - reduced number and user. IPEC has also developed a new Designing excipients specifically for and level of excipients, increased division, the International Pharmaceutical QbD is attracting industry interest. These are manufacturing throughputs, improved Excipients Auditing, Inc., to provide third- called co-processed excipients: two or more consistency, and increased robustness - party auditing services of excipient excipients specially processed together to industry regulators are slow in accepting manufacturers and distributors. interact with each other at the sub-particle them. There is a lack of USP monograph Federal regulators are also taking steps level, to minimize the variability of support, and until monographs are developed, to facilitate the communication process. The individual excipients, and to enhance their industry will not accept or invest in co- Food and Drug Administration Globalization performance. This enhanced functionality processed excipients, believes Dr. Guy. Act of 2009 has language that proposes would not normally be achieved by merely “Monographs are everything for many country-of-origin labeling and a registration blending the excipients, explains Dr. Guy. pharma industry gatekeepers.” This means fee to cover the cost of drug product and Major players in the market include JRS complexity for a pharma company trying to ingredient inspections. The draft also Pharma, BASF Corporation, Colorcon, and get a drug approved that exhibits co- proposes to increase the capacity of FDA to SPI Pharma. Up-and-coming players are Fuji processed excipients. “If a company can’t monitor foreign facilities. Health Sciences and Mallinckrodt Baker. cite a monograph, the regulatory work won’t Additionally, the draft Drug and Device “This represents a rapidly growing market go away,” says Dr. Guy. Accountability of 2009 aims to ensure the within the excipient industry with an “Until the FDA, industry and USP agree identity and source of drug ingredients. This increasing number of product launches and that co-processed excipients are here to stay, would involve various methodologies, giving new IP being generated annually,” says Dr. they won’t become mainstream,” he says. manufacturers responsibility for the quality Guy. He estimates the co-processed “Once they do become mainstream, and a of their drug ingredients, and ensuring excipients market for use in solid-dose forms framework is developed, critical mass will adherence to GMPs. to be around $30 million a year. build up. It is sound business practice to “The goal of all of these regulatory Excipient mixtures in co-processing are convert to them if they are better.” steps is to define what is good enough for produced to make use of the advantages of There is also that little matter of price. pharmaceutical uses,” says Mr. Schoneker. each component and potentially to overcome Mr. Schoneker says the cost of quality co- And industry is looking forward to their individual disadvantages. They are processed excipients might be more, but their formulators and developers playing a greater meant to enhance functionality and make a performance more than makes up for it. role in excipient acquisition in the future. more consistent product. A significant “Quality excipients are more expensive, “The gatekeepers we’ve come to know will number of co-processed excipients are but pharma needs to pay for them,” says Dr. diminish in this economic climate as specifically designed for use in a small set of Guy. “It means investing in a space many pharmaceutical companies strive to create circumstances, such as for orally don’t consider worth investing in. There their next blockbusters,” says Alen Guy, PhD, disintegrating forms. needs to be a better understanding of the Director of Business Development, Balchem “This trend has risen out of the pharma existing excipient base to innovate and take Encapsulates. “This can only be done by industry’s need to enhance brand lifecycle science further, and provide dosage forms producing better product and better dosage and produce dosage forms that improve that not only fit the QbD requirements as the forms with quality excipients.” patient compliance with their prescription,” pharma industry understands them, but also says Dr. Guy. Presently, only a small number the consumers’ needs to have they of co-processed excipients are aimed at more can take easily. Innovation leads to better CO-PROCESSING&QbD general formulation applications. performance. The goal is 21st century The individual identity of the excipient pharmaceutical quality.” N Overall quality of a finished product is not compromised in the process. “This is depends not only on the active ingredient but key to demonstrating that a new compound About ExcipientFest® Americas: This year, on the excipient and manufacturing as well, has not been developed,” says Dr. Guy. “That ExcipientFest Americas® will be held April so it is extremely critical that formulators can would be a negative outcome as the material 22-23 in the Grand Ballroom at the Puerto guarantee the safety and quality of the would need to undergo toxicity evaluation, Rico Convention Center in San Juan, Puerto ingredients being used in drug design. normally an expensive process.” Rico. In addition to the content presented in “We have seen an integration of Quality The actual process of combining the this article, attendees can visit sourcing and

by Design (QbD) and supply chain security, excipients is critical to their performance. Dr. science programs discussing IPEC’s Recent Vol 9 No 3 making sure the excipients purchased are Guy says if they are not processed the right Activities, Chemistry 101 for Non-Chemists, safe and have the greatest impact on the way, they won’t offer very much advantage. Managing Material Supply, Supplier attributes that affect drug release,” says Mr. “As a matter of fact, a co-processed excipient Relationship Management, Dynamics of Film Schoneker. can be reduced in functionality if the process Coating, Understanding Drug-Excipient March 2009 “Quality by Design is “hot” right now is not correct.” Interactions, SUPAC, Improving Solubility of and plays two very important roles. First, it Direct compression, wet granulation, Poorly Soluble Drugs, and many more. ensures a consistent, robust pharmaceutical and spray drying all have a place in Attendees will have the opportunity to visit manufacturing process from preclinical to producing co-processed excipients, but with excipient manufacturers and suppliers post-launch. Product performance will be the knowing which to choose will make all the on the expo floor. Please visit same every time,” says Dr. Guy, who will difference in product stability and quality. www.excipientfest.com for more information. Drug Delivery Technology present Co-Processed or Pre-Processed: “Often, we see companies make processing Highly Functional or Convenient Excipients choices based on risk,” says Dr. Guy. 23 “Ultimately, they wind up with a suboptimal 43-D a 9-Avne eiey2:Layout12/26/0911:39AMPage24 Delivery Advanced - 09 Mar - 24-31-DDT

24 Drug Delivery Technology March 2009 Vol 9 No 3 oi lentv oNel yig Technology Syringe & PhD Bennett, Needle Simon and Potter, PhD, Charles to By: Alternative Solid A niec fnel-tc nuisin injuries needle-stick of incidence N es fneedles. the of to reuse due year every die children 1.3 million WHO, the to According risk. one such is disease blood-borne of spread the risks. and challenges of a number are though, delivery of method this with Associated system. digestive the cope with cannot that those or urgency bloodstream with the into delivered be to need that drugs those for especially choice, of technique the remain still syringe and needle the formulations, suited not to are drugs some that mean issues solubility Whilst formulation. liquid using a syringe and needle traditional a via is administration of method cases, standard such the In needed. is action of onset rapid a if especially orally, administered be can drugs all not absorption, and solubility of reasons method. for this However, by delivered of fact 85% in and are tablet, drugs oral an via still is drugs methods. delivery oral and syringe and needle traditional the to alternatives current the discusses and vaccines, of administration the on focus particular a with biologics, and molecules, small areas, application two across delivery drug with associated issues the examines article This recognized. widely and understood well are injection of needle-free benefits The coming. in slow been has markets therapeutic and applications different of number a address feasibly N rs-neto ewe ainsand patients between Cross-infection most for route delivery preferred The nvra ouinta can that solution a universal but R&D, for focus a been long has injection eedle-free 1 diinly the Additionally, o8000ijre curn annually. occurring injuries 800,000 to 600,000 estimated an with attention, much received also has professionals healthcare service. healthcare the and health patient’s the for consequences long-term with drugs, of self-injection the to a deterrent be significant can needles of fear the necessity, a than rather preference personal a Although countries. industrialized in technology needle-free the of for development drivers main the of one doubt without is dislike common of this fear needles, a to admitting population the 10% of to up with Furthermore, agenda. the up further alternatives needle-free reliable and safe of development the pushed has disposal needle with associated burden and expense significant the and legislation new of introduction The 1 E R U G I F 2 nui.Hwvr ocrsrgrigthe regarding concerns However, insulin. of delivery the for developed recently more and drugs pulmonary for widely used been have example, vaccines. For and drugs all for options viable always not are methods delivery patch and nasal, pulmonary, oral, as such alternatives Nevertheless, technology. syringe and needle traditional of cost-effectiveness and reliability the with competitive are that solutions successful produce to innovation technological in surge a stimulated has in R&D investment significant years, 15 past the Throughout use. widespread for market the infiltrated really never and success limited had (1940s-50s), vaccination post-war for developed injectors” “jet- the as such technologies, injection rvosicrain fneedle-free of incarnations Previous ALTERNATIVES? HTAETHE ARE WHAT 24-31-DDT - Mar 09 - Advanced Delivery 2:Layout 1 2/26/09 11:39 AM Page 25 24-31-DDT - Mar 09 - Advanced Delivery 2:Layout 1 2/26/09 11:39 AM Page 26

long-term effects of delivering biologics to turn compresses the main driving spring of administration with the minimal of training, the lungs for systemic absorption have the actuator. When the preset force is providing a next-generation delivery method resulted in the withdrawal of current products achieved, the pushing action automatically with a distinctive competitive edge. What is and an arrest in development. actuates the delivery, with the dose itself as more, the Glide SDI is inexpensive to Other more recent innovations include the delivery vehicle penetrating the skin manufacture in high volumes. liquid and powder jet technologies from without the need for a traditional needle. This manufacturers, such as Equidyne Systems, process takes place in a smooth, almost Antares Pharma, BioJect Medical instantaneous, one-click action leaving the SELF-INJECTION OF SMALL Technologies, The Medical House, DCI, drug or vaccine to dissolve in the target MOLECULES & BIOLOGICS Zogenix, PharmaJet, and CrossJect, as well as tissue. This mechanism provides a more Anesiva and Pfizer, which are both based on consistent delivery, independent of skin type. A substantial market area for drug the PowderJect technology. However, these The solid dose formulation may contain one delivery technologies is the self- have not received the widespread acceptance or more active drug components, and the administration of biologics, for example, first anticipated. While the liquid jet injectors, excipients can be selected for immediate insulin for diabetes, parathyroid hormone developed as both single-use and multi-use and/or sustained release. This not only (PTH) for osteoporosis, and beta interferon systems, do not require the reformulation of provides the means to achieve the desired for the treatment of multiple sclerosis, drugs used with needle and syringe release kinetics, but also presents a delivery amongst others. Here, the needle-free technologies, there remain some issues solution that can accommodate a much administration, improved patient compliance, mainly attributed to the delivery mechanisms. broader portfolio of small molecules and and enhanced formulation stability provided A similar technology was developed by biologics. Needle-free operation, together by the Glide SDI would be of great benefit to PowderJect in 1993 to fire at with the disposable cassette technology, both the patient and the healthcare provider. supersonic velocities into the outer layers of improves user safety and eliminates the risk Glide Pharma is also building its own the skin using a helium-powered micro- of needle-stick injuries. The technology is pipeline of products for use with its Glide cylinder. Both liquid- and powder-based extremely convenient, safe, and easy to use, SDI based on the reformulation of off-patent technologies require a carefully controlled and as such, it is highly suitable for self- drugs, such as octreotide for acromegaly and power source to ensure the drug crosses the stratum corneum. This can be especially F I G U R E 2 challenging when working with different skin types and delivery sites, making accurate and consistent delivery very difficult. In addition, the power sources used often have significant cost implications and thus can outweigh the benefits of needle-free delivery.

NEW OPTION AVAILABLE Vol 9 No 3 The Glide SDITM (Solid Dose Injector) combines the benefits of a solid dose formulation, such as improved stability, with March 2009 a cost-effective, simple low-velocity delivery system. It comprises a simple pen-like, spring-powered actuator and a cassette (Figure 1) containing the pharmaceutical dose in a tiny, solid rod-shaped form. For the

Drug Delivery Technology delivery of the drug or vaccine, the cassette is gently pushed against the skin, which in 26 24-31-DDT - Mar 09 - Advanced Delivery 2:Layout 1 2/26/09 11:39 AM Page 27 24-31-DDT - Mar 09 - Advanced Delivery 2:Layout 1 2/26/09 11:39 AM Page 28

symptoms associated with neuroendocrine 27-gauge ). As patient two new pediatric vaccines were approved by tumors, fentanyl for breakthrough pain, and acceptance is key to maintaining compliance, the FDA - Pentacel from Sanofi-Aventis and sumatriptan for migraine. regular use, and long-term therapeutic Kinrix from GlaxoSmithKline. Investment is Non-clinical studies have demonstrated effectiveness, this is a distinct advantage. not just in R&D, but also in more bioequivalence for a range of drugs, eg, downstream areas, such as manufacturing. As sumatriptan (Figure 2), delivered in solid such, new facilities are now being dose form using the Glide SDI, compared to VACCINE DELIVERY constructed to increase global manufacturing conventional subcutaneous delivery of GSK’s capabilities, and the recent announcement of market product Imigran®/ Imitrex® with a Since their European introduction, when plans for a $200-million flu vaccine plant in needle and syringe. Furthermore, the Edward Jenner first trialed human small pox China from Canada's Microbix Biosystems is simplicity of the Glide SDI operation allows vaccinations using cowpox in the early 18th representative of this trend. for easy self-administration and means less century, vaccines have vastly increased in The growing global vaccine market time is spent on training. The ready-to-use, sophistication. As a consequence, the however is heterogeneous. Vaccines provide pre-loaded cassette is simply removed from vaccines of today are significantly safer and significant benefits to developing countries, the sterile packaging and attached to the mass produced to meet the demands of industrialized nations, and for emergency actuator prior to use. The “push-and-click” global populations and disease targets. use, but each of these markets has different system indicates that the dose has been However, the method of vaccine delivery has requirements (Figure 3). Providing a delivered and reassures the patient, and the essentially remained the same. Today, technology that could meet all the demands solid dose format eliminates the complicated vaccines constitute one of the fastest growing would be of great benefit to the industry, reconstitution steps that are often needed pharmaceutical markets and are receiving particularly in terms of acceptance and with biologics. Lastly, the disposable drug substantial investment. Analyst forecasts education. cassette is easily discarded in normal (EvaluatePharma - June 25, 2008) predict the domestic waste, and the pen-like actuator can vaccine market will grow at an annual rate of then be kept for repeated use. Results from a 14% (compared for example to an 11% DEVELOPING VERSUS Phase I human sensation study has growth for oncology), generating $35.1 INDUSTRIALIZED NATIONS demonstrated preference in 88% of billion in sales by 2012. Sanofi-Aventis has volunteers for this device over traditional pledged to invest $6 billion in vaccine Today, vaccines have been cited as the needle and syringe technology (a standard production, and in just 1 week in June 2008, most cost-effective tool for the prevention of death and disability in developing countries. They provide a means to combat the poverty F I G U R E 3 and economic underdevelopment that can result from the widespread disease and infection frequently observed in the developing world.3 The reality is that infectious diseases are thought to account for nearly 25% of deaths worldwide, with a 90%

Vol 9 No 3 mortality in developing countries, as compared with 10% in industrialized nations (WHO report 2003). As a consequence, organizations such as the International March 2009 Vaccine Institute are now exclusively dedicated to researching new vaccines for developing countries and to deploying these new-generation vaccines at affordable prices. This comes at a time when the Global

Drug Delivery Technology Alliance for Vaccines and Immunization (GAVI) Foundation, together with the Gates 28 24-31-DDT - Mar 09 - Advanced Delivery 2:Layout 1 2/26/09 11:39 AM Page 29

Foundation, are gearing up to vaccinate process and provide bespoke transportation applications need to allow long-term storage millions of children in developing nations. solutions tailored to the requirements of each of the vaccine, provide ease-of-use for mass Previously, issues associated with vaccine product and its destination, at a cost. But, is inoculation, and be cost effective in mass development, deployment, and success had this an investment that is affordable in the production. deterred investment and restricted the long-term? pipeline. Historically, a hindrance to a vaccine NEW TECHNOLOGIES FOR program’s success has been maintaining WHAT IS NEEDED? VACCINE DELIVERY patient compliance. For example, the delivery of many childhood vaccinations In developing countries, pharmaceutical Current alternatives to needle and across the developing world in the 1980s had pricing and access to new, cheaper syringe delivery of vaccines include proved successful and provided worldwide technologies are important factors. In , intranasal, and transdermal (via coverage of approximately 80% of infants. particular, sourcing technologies that can patches or solid dose injection) technologies. However, this statistic significantly changed improve product stability and remove the For example, FluMist® by MedImmune offers in the following years as recipients missed need for cold-chain storage would be the non-invasive delivery of a live trivalent their boost injections, leaving themselves extremely beneficial. Furthermore, with a flu vaccine, via intranasal administration, unprotected. For example, in 2000, less than high prevalence of infectious disease in many appealing to those in industrialized nations. 50% of infants in sub-Saharan Africa had developing nations eliminating the risks of However, required storage at 2°C to 8°C and received their third dose of diptheria-tetanus- cross-contamination, especially when a cost of $46 per dose mean this would be pertussis vaccine.4 To be able to administer immunizing large population sets, is hard to “roll out” for use in developing prime and boost simultaneously is the Holy extremely high on the agenda. The risk of countries. Other alternatives include a micro- Grail for the vaccine field, and to achieve needle-stick injuries and the re-use of needles needle patch, OnVax, developed by Becton such requires a technology that can deliver in these countries can hinder the safe delivery Dickinson (BD), and a similar Transcutaneus immediate- and time-controlled release of vaccines and contribute to the transmission Immunization (TCI) patch technology by formulations at the same time. of blood-borne disease. In slight contrast, for Iomai. The OnVax technology is based on an Traditional formulations typically industrialized nations, where the cost of array of very small vaccine-carrying silicon necessitate cold-chain storage to prevent vaccine production and thus purchase are teeth in a patch applied directly to the skin's product degradation. Yet, end-to-end significantly greater, the provision of a safe, surface. This allows the vaccine to penetrate temperature-controlled transportation effective, and viable alternative to current the skin over time and is proposed to reduce demands a series of integrated processes and delivery methods is more of a priority. the required dosage and eliminate the need extensive communication, starting from the for booster doses. This would be highly manufacturers, airlines, and government efficient in the case of an epidemic or organizations, through to local ground- VACCINES FOR EMERGENCY USE bioterrorism attack, hence BD is looking to handling teams, storage, and transportation develop this product with the anthrax and companies. This can be costly, logistically Increased focus and funding has smallpox vaccine. Iomai is also working on challenging, and labor intensive.5 Further provided the support and incentive that the an adjuvant immuno-stimulant (IS) patch to

complications can also arise from the biopharmaceutical industry requires in order improve the immune response to vaccine Vol 9 No 3 inaccessibility of a destination, the lack of to drive global vaccine development. The in- delivery in elderly patients. Both have the investment in local infrastructure, and a depth study of disease epidemiology has also potential for self-administration, and neither deficiency of technological expertise. For raised questions related to global security require cold-chain storage, thus making them March 2009 example, the expensive specialized heating and stimulated investment in the suitable for stockpiling and emergency use. and cooling containers often used for development of vaccines for potential However, as the microneedles are either transportation will not be carried by some bioterrorism threats. With the more recent coated with vaccine or filled to deliver the airlines if the local ground handling teams outbreaks of SARS and the avian flu strain vaccines through the needles themselves, are not technically equipped to deal with H5N1, stockpiling vaccines has moved up they are not cheap or easy to manufacture.

them. Today, new companies are emerging as the government agenda. As such, Drug Delivery Technology “handlers” to facilitate and oversee this formulations and delivery devices for such 29 43-D a 9-Avne eiey2:Layout12/26/0911:39AMPage30 Delivery Advanced - 09 Mar - 24-31-DDT

30 Drug Delivery Technology March 2009 Vol 9 No 3 euainadevrnetcnrlduring control environment and regulation temperature stringent less thus requiring altogether, chain cold the avoid potential to the with stable, more inherently is areas. remote more in those treating when especially patient, the for convenient more is and program a vaccination of costs and organization the simplifies greatly this professional, healthcare the to required visits fewer With lives. saving and programs vaccination of the success improving protection, full for the time at same doses follow-up and initial their both receive people ensuring compliance, with patient associated issues the avoid would This dose. one in vaccination, a “prime-and-boost” case, this in or formulations, release delayed- and fast-acting both combine to opportunity an presents also formulation solid-dose a Furthermore, use. emergency rapid for required when or administrations large-scale with unhelpful particularly product, lyophilized of reconstitution of steps complicated sometimes and time-consuming the for need the overcomes It disease. blood-borne of infection cross- the and injuries needle-stick of risk the eliminates SDI Glide The delivery. vaccine for benefits clear of number syringe. and needle with a injection standard a to compared when response immune enhanced an has produced SDI Glide the studies, preliminary In response. immune appropriate the stimulate and vaccine the release it to skin, dissolves the penetrated has it delivery Once the vehicle. is itself dose the but similar principle, a using works SDI Glide The epidermis. the of the properties of immunological advantage take to designed been have H DATGSO SOLID A OF ADVANTAGES THE OEFRVCIEDELIVERY VACCINE FOR DOSE motnl,teGieSIslddose solid SDI Glide the Importantly, a provides formulation dose solid A technologies new in advances Such ain,adeegnyuealike. use emergency and nations, industrialized and developing for vaccine delivery for as well as biologics, and molecules small of self-administration for suited ideally is and technologies syringe and needle with associated issues current the addresses successfully It molecules. small to vaccinations and peptides, proteins, from applications range delivery wide of a has SDI Glide The vaccines. and therapeutics of delivery the for technologies robust yet innovative requires industry the landscape, pharmaceutical .TmeaueCnrle hpet uaiainOutreach Humanitarian A Shipment; Controlled Temperature 5. goals: immunization global in Shifts S. Blume A, Hardon 4. developing into vaccines new Introducing L. Jodar J, Clemens 3. and Injuries Sharps and Needlestick of Incidence Guide: NIH 2. April Times. Hindustan Unsafe. are India in Injections Most 1. mrec use. for emergency or world, third the in vaccination mass outbreak, pandemic a as such scenarios for suitable particularly programs, vaccination standard in use in to is, addition SDI Glide the actuator, pen-like the and cassette drug preloaded easy-to-use, the With packaging. non-breakable wrapped, individually compact, in transported easily and sterile are cassettes SDI Glide The storage. on-site and transport rmTrnot ahet HMngrErp.Jl 2008, July 24-26. Europe. CHEManager Tashkent. to Toronto from 1984- Med. Sci Soc 2004;60:345-356. results. mixed and agendas unfinished 2005;11:S12-S15. Nature Medicine. complexities. and opportunities obstacles, countries: 2003. 18, November Workers. Care Health Non-Hospital Among Use, Availability. Device Safety Medical 2007. 29, oke bes ftechanging the of abreast keep To REFERENCES SUMMARY opn rwfo utfv mlye to 1000. employees over five just from grow company the saw he where Pharmaceuticals, PowderJect at years 6 nearly including companies, other start-up four successful in worked has He medical experience. extensive gained he where centre, cardiothoracic specialist a UK, Cambridge, Hospital, Papworth at Unit Transplant the within research undertaking 6 years spent Potter Dr. University. Cambridge aia-e udn rounds. venture funding several capital-led in role also pivotal has a and played deals commercial 40 over involved in been has He four applications. and patent articles scientific co-author 100 the over is of and Oxford and London Universities of the at educated Dr. was 2006. Bennett August in Pharma Glide joining before MedPharm and Solexa, Oxagen, at roles director development held business He companies. stage early and start-up several in positions management S E I H P A R G O I B Bennett Simon Dr. nldn senior including sciences, life in experience of years 17 over has He Pharma. Glide at Development Business President, Potter Charles Dr. niern from Engineering in PhD his earned He Pharma. Glide of CEO and founder and technology Glide the of inventor sthe is sVice is 24-31-DDT - Mar 09 - Advanced Delivery 2:Layout 1 2/26/09 11:39 AM Page 31 32-35- DDT Mar 2009-Market Brief :Layout 1 2/26/09 11:41 AM Page 32

MARKET BRIEF

Nanomedicine in a Nanominute:A Market Brief By: Bill Martineau, MBA

INTRODUCTION preparations for autoimmune and represent one of the fastest growing neurological disorders. Opportunities to classes of nanomedicines over the long- US demand for nanomedicines is reduce the side effects and enhance the term due to advances in chemotherapy forecast to expand 17% annually to $43 bioavailability of antiviral and protective agents as well as therapies billion in 2012. Technological antifungal drugs will keep the market for Crohn’s disease, ulcerative colitus, advances, changing healthcare for anti-infective nanomedicines and irritable bowel syndrome. approaches, and intensifying advancing at a strong pace. Replacement therapies for post- pharmaceutical industry competition In the area of cardiovascular drugs, menopausal symptoms and infertility will spur growth. Advances in nanomedicines will post long-term will emerge as the largest selling group pharmaceutical technologies will double-digit demand gains based of nanotechnology-based hormones increase the number of drugs adaptable largely on improved formulations of over the long-term. Monoclonal to nanomaterial delivery systems as cholesterol-reducing and thrombolytic antibodies for psoriasis, the prevention well as lead to the introduction of new agents. Strong growth in ophthalmic of transplant rejection, and, eventually, medicines based on monoclonal nanomedicines will evolve from the the prevention of cancer, along with antibodies and, eventually, gene increasing market penetration of delayed-release vitamins, minerals, and therapies. Changes in healthcare recently introduced monoclonal nutrients based on nanoparticles, will approaches will favor the use of antibodies and PEGylated drugs for comprise other nanomedicines medication over more expensive patient macular degeneration. Efficacy projected to fare well in the therapies. Nanomedicines that reduce advantages in the treatment of allergy- marketplace. the overall cost of treatment while related asthma and chronic obstructive Nanomedicines encompass improving patient outcomes will pulmonary disorder (COPD) will lead pharmaceuticals and biologicals generate strong growth opportunities to the rapid expansion of monoclonal composed of nanoscale active over the long-term. antibody and other nanomedicine sales ingredients or adapted to nanoparticle Opportunities for nanomedicines in respiratory indications. delivery systems. Monoclonal will extend into all therapeutic classes. Gastrointestinal agents will antibodies comprise the principal Anti-cancer agents will maintain the F I G U R E 1 leading sales position over the long-

Vol 9 No 3 term as existing and new pharmaceuticals based on monoclonal antibodies and nanopolymer

March 2009 formulations capture demand away from conventional chemotherapies that pose a high risk of adverse patient side effects. Growth in central nervous system nanomedicines will be spurred by the widening market penetration of Drug Delivery Technology recently commercialized and new 32 32-35- DDT Mar 2009-Market Brief :Layout 1 2/26/09 11:41 AM Page 33

MARKET BRIEF

nanoscale active ingredients now opportunities spurred by the flow of Based on direct tumor-attacking employed in therapeutic applications. As several new products into the marketplace. actions and improved side-effect profiles, of January 2009, 20 monoclonal antibody More than one-third of biotechnology monoclonal antibodies are emerging as the therapies have been approved for use by development projects are seeking to apply leading therapies for the treatment of the FDA. In addition, more than 150 new these proteins to new advanced treatments advanced cancers. The 9 monoclonal monoclonal antibody drugs are being for cancer, autoimmune disorders, antibodies approved by the FDA for tested in US clinical trials. Nanoparticle respiratory conditions, and numerous other cancer indications posted combined sales drug delivery agents in commercial use conditions. of $6.7 billion in 2007. consist of crystals, liposomes, and Based on an expanding range of high polymers. Dendrimers, fullerenes, value-added therapeutic compounds, micelles, nanoshells, and nanowires are combined demand for therapeutic POLYMER-BASED among the nanoparticle drug delivery monoclonal antibodies will increase 17% NANOMEDICINES agents in various stages of development. annually to $31 billion in 2012. Anti- Spurred by expanding indications and cancer agents will account for the largest The market for polymer-based a continuing flow of new products into the share of sales as existing and new products nanomedicines is forecast to grow over marketplace, all five groups of extend indications into a rising number of 20% annually to $8.2 billion in 2012. nanomedicines will record strong growth malignant conditions. Among other Although largely untapped, the vast in demand throughout the next decade and monoclonal antibodies expected to build potential of polymer-based nanomedicines beyond. Monoclonal antibodies will up large, rapidly growing demand are is beginning to make an impact in the remain the top selling group as advances compounds for asthma, Crohn’s disease, marketplace. In 2007, 9 therapies adapted in humanized and recombinant varieties macular degeneration, psoriasis, and to nanopolymer delivery systems posted lead to the development of breakthrough rheumatoid arthritis. In addition to new combined US demand of $3.3 billion, up therapies for many presently incurable introductions, most of the 20 monoclonal from $1.2 billion in 2002. conditions, including AIDS/HIV,asthma, antibody therapeutic agents now on the Seven of the 9 nanopolymer therapies atherosclerosis, COPD, hepatitis C, age- market will contribute to rising demand as on the US market are based on related macular degeneration, multiple acceptance and use expands among PEGylation technology. Included in this sclerosis, peanut allergy, psoriasis, medical providers. group are pegaptanib sodium for macular rheumatoid arthritis, systemic lupus The range of therapeutic monoclonal degeneration, pegvisomant for acromegaly, erythematosus, type 1 diabetes mellitus, antibodies on the market includes 9 anti- pegfilgrastim for chemotherapy-induced ulcerative colitis, and several forms of cancer agents, 3 anti-transplant rejection neutropenia, pegaspargase for leukemia, cancer. Polymer-based and other agents, 2 anti-arthritic agents, and 1 pegademase for severe combined immuno- nanomedicines will continue their rapid compound each for allergy-related asthma, deficiency disease, and two formulations penetration into the marketplace based on blood clot prevention, macular of peginterferon for chronic hepatitis C. Vol 9 No 3 new and improved product introductions degeneration, multiple sclerosis, plaque PEGylation technology encloses active with improved solubility, reduced toxicity, psoriasis, and respiratory syncytial virus drug ingredients in a shell composed of March 2009 and enhanced pharmacokinetics. (RSV). In addition, one of the anti- polyethylene glycol nanoparticles, which arthritic therapies (infliximab) is also increase circulating time, reduce toxicity, indicated for the treatment of Crohn’s and provide a more optimal release of MONOCLONALANTIBODIES disease, an inflammatory gastrointestinal active ingredients. disorder. Moreover, the anti-cancer The other two polymer-based Therapeutic monoclonal antibodies monoclonal antibody ritiximab serves a nanomedicines (glatiramer acetate and Drug Delivery Technology are projected to generate rapid growth rheumatoid arthritis indication. sevelamer hydrochloride) are nanoscale 33 32-35- DDT Mar 2009-Market Brief :Layout 1 2/26/09 11:41 AM Page 34

MARKET BRIEF

versions of macromolecular therapies, cup-shaped cyclic repeating polymers of regulatory obstacles to reach the which have been downsized to improve glucose known as cyclodextrins; commercial stage. their bioavailability and pharmcokinetic hydrogels, which form a versatile drug actions. Initially approved in December delivery system for many types of Crystalline Nanoparticle 1996, glatiramer acetate has evolved into a therapeutic compounds, including anti- Therapies leading treatment for relapsing-remitting cancer, anti-diabetic, and anti-infective Crystalline nanoparticle therapies are forms of multiple sclerosis. In 2007, the agents; and micellar nanoparticles based on a wet milling production process. compound recorded US sales of $1.1 consisting of hydrophobic drug This process reduces active drug billion. Glatiramer acetate is composed of ingredients enclosed in an outer shell or ingredients to nanoscale dimensions 50 a nanoscale L-glutamic acid polymer that composed of hydrophilic times smaller than ingredients produced contains the salts of three additional amino polymers, such as polyethylene glycol. through conventional micronization acids (L-alanine, L-lysine, and L-tyrosine). The strongest growth potential for techniques. Crystalline nanoparticle The compound interferes with the oral nanoparticle drug delivery systems technology creates drug particles with a pathogenesis of multiple sclerosis by exists in technologies based on cochleates. high surface area and rapid dissolution modifying certain immune processes Cochleates are lipid-based nanomaterials rates, which result in improved solubility, linked to the disease. that are being adapted to the encapsulation bioavailability, and overall Sevelamer hydrochloride is a of peptides, proteins, and other advanced pharmacokinetic actions. Moreover, the polymer-based nanomedicine that was therapies. The primary objective of these finished particles are adaptable to a nearly approved by the FDA in October 1998 for efforts is to create oral formulations of complete range of dosage formats, the reduction of serum phosphorus in drugs that presently must be administered including solid oral, liquid, topical, patients with end-stage renal disease. through injections. Although several years parenteral, inhalation, and transdermal. Elevated blood phosphorus levels in these away from commercialization, oral Four significant therapies based on patients can result in several life- nanocochleate technologies hold the crystalline nanoparticle technology are threatening complications, including tissue potential to revolutionize drug delivery by approved by the FDA for US marketing and vascular calcification and bone simplifying the treatment of cancer, (nanosized fenofibrate, sirolimus, deterioration. Sevelamer hydrochloride is a diabetes, and other major medical aprepitant, and megestrol acetate). In nanosized polymeric phosphate that binds conditions. terms of sales, a third-generation to phosphorus in the formulation of the cholesterol-reducing and eliminates it through the normal agent fenofibrate is the second most digestive process. End-stage renal disease OTHER NANOMEDICINES successful drug that has been reformulated afflicts an estimated 50,000 new patients as a nanomedicine. Approved by the FDA annually. Demand for other nanomedicines is in December 2004, the compound

Vol 9 No 3 In contrast to trends involving forecast to total $3.6 billion in 2012, up recorded US sales of $1.2 billion in 2007. therapeutic monoclonal antibodies, from $2.3 billion 2007. Compounds based The new formulation offers better developmental activities involving on crystalline nanoparticles, liposomes, solubility and bioavailability, which March 2009 polymer-based nanomedicines tend to albumin, and supercritical fluids will enhances its cholesterol-reducing action focus on commercializing broad divide most growth. Additionally, over the and absorption properties while reducing technologies. These technologies are then long-term, gene therapies are expected to dosage requirements. Unlike the previous adapted to new and existing products. contribute significant advances to the micronized version, nanofenofibrate can Some of the most notable efforts to quality and effectiveness of nanomedicine. be taken without food and adapted to more

Drug Delivery Technology develop nanopolymer therapies, However, these therapies will need to convenient dosing schedules. 34 formulations, and delivery systems include overcome formidable technical and 32-35- DDT Mar 2009-Market Brief :Layout 1 2/26/09 11:41 AM Page 35

MARKET BRIEF

Liposomes All Other Nanomedicines BIOGRAPHY Another group of nanomedicines on Four additional types of the market employ liposomes as drug nanomedicines have been approved for US Mr. Bill delivery agents. Liposomes, which range marketing, with numerous others in Martineau is from 80 to 100 nanometers in size, are various stages of development. The four an authority on synthetic lipid spheres composed of fatty approved products posted combined US the healthcare acids or polymers. In pharmaceutical sales of $370 million in 2006. Within this industry. He has applications, they are used to encapsulate group, a modified version of the anti- performed in- depth research in active drug ingredients that, if unmodified, cancer agent paclitaxel has achieved the biotechnology, would be vulnerable to destruction or most marketing success. The remaining pharmaceuticals, medical packaging, and cause toxicity during circulation. three offerings (an oil and water related areas, producing titles such as By carrying drugs to diseased sites form of the hormone estradiol for the U.S. Pharmaceutical Packaging, Cardiac intact, liposomes extend the time that treatment of post-menopausal symptoms; Implants, Nanotechnology in Healthcare, medication remains in the blood stream, a line of over-the-counter drugs based on Drug Delivery Systems, and Biochips. prolonging therapeutic actions and controlled flow cavitation; and a Prior to joining Freedonia, he was reducing toxic side effects. In addition, the nanodroplet-embedded multivitamin, Manager of Market Development at substances can be readily modified with multinutrient preparation) have yet to American Sterilizer Company, where he positive, negative, or neutral charges to demonstrate significant performance gained experience in healthcare research accommodate a wide range of advantages over conventional therapies. and strategic planning. At Invenex pharmaceuticals. The only shortcoming of In addition to the aforementioned Laboratories, he served as Product liposomes involves their difficulty in products, an inhaled form of insulin was Manager, responsible for the bypassing certain capillary cells in several adapted to a proprietary nanotechnology administration of a line of injectable organs. This problem, however, is being known as Advanced Pulmonary Delivery pharmaceuticals. He also served as Senior rectified through modification of the size Technology (APDT). APDT enabled the Health Care Analyst at Predicasts Inc. and composition of the lipid components. development of fine, uniform, and highly and Manager of Market Research at Life Current liposomal medicines dispersible particles for delivery deep Technologies Inc. (a division of The approved for US sales include three inside the lungs. These particles served as Dexter Corporation). Mr. Martineau formulations of the antifungal, antibiotic the active ingredients of the EXUBERA earned his BA in Management and his MBA in Marketing and Finance from Kent amphotericin B and single formulations of brand of inhaled powder insulin, which State University. the anti-cancer drugs daunorubicin and was approved by the FDA in January doxorubicin and the ophthalmic agent 2006. Although proven to be safe and verteporfin. Combined, these products effective in clinical trials, EXUBERA

recorded sales of $260 million in 2007, up failed to build up acceptance by patients Vol 9 No 3 from $242 million in 2002. All of the six and physicians and was withdrawn from currently available liposomal therapies are the market in January 2008. encapsulated in lipid nanospheres to March 2009 reduce their toxicity and lengthen their An in-depth report on this and other circulation time. related topics can be obtained by contacting the Freedonia Group at www.freedoniagroup.com. Drug Delivery Technology

35 36-41 - DDT March 2009 - DDT Special Feature:Layout 1 2/26/09 11:42 AM Page 36

PROTEINS & PEPTIDES: DEPENDENT ON ADVANCES IN

A column for large-scale peptide DRUG DELIVERY? purification at American Peptide Company, Inc. By: Cindy H. Dubin, Contributor

he success of protein and peptide therapeutics is revolutionizing the biotech and pharmaceutical market, Tspurring the creation of next-generation products with reduced immunogenicity, improved safety, and greater effectiveness, states a new report, Next Generation Protein Engineering & Drug Design. New technologies and genetic and chemical techniques will ensure a competitive edge in developing improved protein- and peptide-based therapeutics. The report points out that the protein engineering market in 2006 was worth almost $67 billion (10% of total pharma sales) and is forecast to rise to $118 billion (12% of pharma sales) in 2011. Despite their remarkable success, protein drugs continue to suffer from drawbacks, especially with respect to their delivery (subcutaneously or intravenously injected). The past 3 years have seen approvals of products for non-parenteral delivery, alongside advances in parenteral protein and peptide drug delivery. The increased use, development, and discovery of protein therapeutics will lead to increasing opportunities for drug delivery companies. Pharma companies need to use these technologies to gain a competitive edge in an increasingly crowded therapeutic protein market. The protein therapeutic market is largely immediate V l 6 N 8

Vol 9 No 3 release, but there is a trend moving toward increased sustained- release formulations. companies are researching and testing new delivery methods for While the majority of protein therapeutics on the market do not protein drugs, according to Market Research.

have devices available, this is a growing segment of the market, and Companies see the potential for improving the delivery S t b 2006 March 2009 Datamonitor expects the growth to accelerate. Datamonitor believes methods for protein- and peptide-based drugs. For some, this means companies should explore the use of devices to maximize the extending peptide half-life or improving manufacturing processes, potential of their products and differentiate them from competitors. while others are researching active coatings. Some companies on Improvements in protein drug delivery will increase patient the cutting edge of protein and peptide drug delivery include compliance and expand many drug markets. In addition, some new American Peptide, SurModics Pharmaceuticals (formerly

formulations may be patentable and can therefore extend a drug’s Brookwood Pharmaceuticals), Emisphere, PolyPeptide, and 3M D D li T h l Drug Delivery Technology life cycle. For these reasons, pharmaceutical and biotechnology Drug Delivery Systems. 3 36 36-41 - DDT March 2009 - DDT Special Feature:Layout 1 2/26/09 11:42 AM Page 37

AMERICAN PEPTIDE: F I G U R E 1 IMPROVING DELIVERY THROUGH SYNERGY

American Peptide Company, Inc. (APC) is a CMO offering Total Peptide Management to clients. The program is a customized service platform, which comprises a set of comprehensive services, including process development; scale-up production; analytical and process validation; stability studies; Chemistry, Manufacturing, and Controls (CMC); Drug Master Files (DMF) and regulatory support. Since the program’s launch early last year, APC has seen an increased collaboration between APC and clients in moving projects forward, explains Scott Caton, Director, GMP Quality Control at APC. Antibody-loaded PLG microparticles designed for 6-month delivery (SurModics In order to achieve the desired efficacy, Pharmaceuticals (formerly Brookwood Pharmaceuticals)). peptide drugs need to target the appropriate site and also have a therapeutic half-life. solution-phase synthesis methodologies, as SURMODICS PHARMACEUTICALS: Patricia Haller, PhD, Director, GMP well as hybrids, allows us to let a specific NEW-GENERATION ANTIBODIES Manufacturing and Process Development at target dictate the most appropriate synthetic APC, believes these challenges can be methodology. This ground-up process SurModics Pharmaceuticals (formerly overcome by engineering the peptide mapping allows us to accommodate a host of Brookwood Pharmaceuticals) is developing sequence or by conjugating the peptide to unnatural functionalities commonly found in injectable microparticle products for 4- to 6- carrier molecules, such as PEG or antibodies. state-of-the-art peptide therapeutics, ranging month delivery of proteins. Most recent American Peptide works with clients to from small molecule conjugates to polymer activities have been directed toward the supply engineered peptides so they can be modifications,” says Firuz Shakoori, Director delivery of new-generation, therapeutic screened for pharmacokinetic profiles and of Sales at APC. antibodies in several therapeutic areas. These efficacy. In addition, APC has expertise in “As we are in the midst of a global microparticles comprise antibody peptide conjugation and other difficult-to- economic downturn, the future of the peptide encapsulated within lactide/glycolide (PLG) manufacture peptides. industry in the coming years is far from excipient. Formulating and stabilizing these Since the acquisition by Otsuka certain,” Mr. Shakoori continues. “The API proteins without denaturation is a challenge Chemical Company (OCC) in September business is very dependent on research, that can result in the formation irreversible 2008, APC and OCC are creating new development, and outside sourcing from Big aggregates, explains Thomas R. Tice, PhD, synergistic opportunities in improving drug Pharma, biotech, and academia. This Vice President of Research, SurModics delivery that will benefit the pharma and situation notwithstanding, American Peptide Pharmaceuticals. biotech companies. will remain in an upbeat mode with current Surmodics’ low-shear APC’s target clients are pharmaceutical and future expansions and bring new microencapsulation process technology and and biotech companies using peptide-based technologies to enable the synthesis of a formulation compositions can maintain Vol 6 No 8 APIs for drug discovery and consumer wide-range of peptide-based compounds. protein integrity. Stability and release products development, explains Gary Hu, This is particularly important as the next kinetics can be improved with proprietary Vol 8 No 3 APC Vice President, Sales and Marketing. generation of peptide therapeutics will be microencapsulation technology involving Therapeutic focus areas are in cancer increasingly complex, far beyond naturally conjugation of protein to hydrophilic

September 2006 vaccines, neurodegenerative diseases, and occurring peptide hormones, and will be polymers. Further, Surmodics’ key strategic metabolic disorders. American Peptide has March 2009 critical to retain our competitive place in US- investment in construction of a state-of-the- developed proprietary technologies that allow based manufacturing. We anticipate that with art isolator manufacturing capability allows the company to quickly develop our expanded infrastructure and highly the production of commercial products economically viable, environmentally sound, skilled technical staff, APC will be well- aseptically. PLG microparticles offer a long scalable manufacturing processes for poised to partner with Big Pharma and safety record of PLGs as evidenced by the Drug Delivery Technology peptide-based APIs. biotech companies for the next 5 to 10

many examples of drug delivery products Drug Delivery Technology “Our expertise in both solid- and 34 years.” and medical device products that are on the 37 market, says Dr. Tice. 36-41 - DDT March 2009 - DDT Special Feature:Layout 1 2/26/09 11:42 AM Page 38

Quickly commercializing safe and advantages, this inevitably results in delays delivery systems. Proven drug delivery effective products to benefit patients and during formulation development, which could technologies, having gone through the rigors improve quality of life is the charter of most be avoided by simply choosing or designing of safety testing, regulatory review, product pharmaceutical and medical device the drug with controlled delivery in mind, approval, and demonstrated market companies. Many drugs, and in particular says Dr. Tice. acceptance, are greatly preferred to quickly peptide therapeutics, benefit from controlled Design for Peptide DeliverySM is a advance the product to market, explains Dr. delivery systems. While these delivery solution-oriented approach with the Tice. Using the Design for Peptide Delivery systems can significantly improve the SurModics and Genzyme Pharmaceuticals strategy, the SurModics/Genzyme team therapeutic product, peptides are not typically collaboration, which addresses peptide performs drug delivery-based screening on screened or optimized for properties that formulation issues early during development lead peptides in discovery to provide the would allow more effective implementation by screening lead compounds or assessing optimum peptide for use in controlled delivery. in controlled delivery systems. In the cases drug development candidates for their ability “We see a substantial growth area for where controlled delivery offers significant to be effectively implemented in proven drug the systemic and local delivery of therapeutic antibodies and related macromolecules,” says Dr. Tice. F I G U R E 2

The PolyPeptide Group utilizes solid-phase peptide synthesis (SPPS) for the manufacture of its many cus- EMISPHERE TECHNOLOGIES: tom and generic peptide-based APIs. NEW FRONTIERS IN DRUG DELIVERY

Emisphere’s core business strategy is to use its proprietary Eligen® Technology to develop novel oral forms of injectable drugs or poorly absorbed compounds. The broadly applicable Eligen® Technology and Emisphere’s current product candidates in the pipeline represent the foundation of the company’s value proposition and create significant opportunities for growth. Emisphere’s pipeline includes product candidates that have reached clinical development as well as a variety of preclinical research and development programs. Emisphere is currently active in the area of peptide delivery through partnerships with Novartis for the oral delivery of salmon calcitonin and parathyroid hormone, and with Novo Nordisk for delivery of its proprietary GLP-1 analogs. The Eligen® Technology is effective in delivery of biologically active agents with a range of molecular sizes and configurations.

Vol 8 No 3 The technology is supported by more than 4,000 carriers and 2,000 patents. Eligen®- based formulations can be implemented

March 2009 readily with new delivery candidates. An optimized commercializable formulation based on the existing technology can be typically achieved with a new drug candidate in a matter of a several months or less. Eligen® permits absorption of therapeutic Drug Delivery Technology

38 36-41 - DDT March 2009 - DDT Special Feature:Layout 1 2/26/09 11:42 AM Page 39

molecules directly through the gastric mucosa. “In contrast, a number of competing Development, North America, PolyPeptide “It is the only drug absorption technologies use paracellular transport Laboratories. technology ready for market that acts in this mechanisms based on short chain fatty acids. In the few cases where peptides can be manner,” says Dr. Gary Riley, Vice President, This approach may allow absorption of non- dosed orally, it is either because the structure Nonclinical Development and Applied target molecules and therefore raise potential of the peptides prevent enzymatic Biology, Emisphere Technologies. “It allows safety concerns,” says Dr. Riley. degradation in the upper gut or that they are drugs not otherwise bioavailable by the oral Emisphere markets its Eligen® administered in massive doses - a strategy route for reasons of poor permeability to be Technology to companies wishing to market that is not economically viable for most administered orally. It also provides oral dosage forms of drugs having a peptides. Injection is usually not well suited important advantages of safety and efficacy moderate therapeutic index. This includes for self-medication because of poor patient over other technologies designed to improve molecules as diverse as metal ions, proteins, compliance. oral bioavailability.” peptides, and oligonucleotides. As with other There are a number of delivery options An Eligen® carrier is co-formulated with drug delivery technologies, the driver for apart from the oral and injection route. These the molecule of interest to form a reversible adoption is not a single therapeutic focus but include oral, nasal, and buccal drug/carrier complex. After oral compatibility with the technology. Eligen is administration; a number of devices, such as administration in tablet form, the complex is compatible with many classes of molecules patches and needle-free injection devices; transported across the gastric mucosal other than proteins and peptides. Emisphere and externally or internally located membrane by the action of the carrier in is continuing to explore and optimize the administration devices. transiently altering gastric epithelial delivery of a wide class of organic and PolyPeptide Laboratories provides permeability. The only entities reaching the inorganic molecules. several strategies for peptide synthesis to circulation are drug and carrier. There is no “The Eligen® model of drug delivery support projects of any size. Peptide evidence that the complex circulates, and no continues to be most attractive and is synthesis is accomplished using either solid novel molecules are formed. The carrier is expected to continue to provide a suitable phase peptide synthesis (SPPS) or liquid not pharmacologically active. It has no platform for oral delivery of otherwise poorly (solution) phase synthesis (LPPS). Hybrid toxicity at the carrier doses used (typically absorbed drugs,” says Dr. Riley. “The current approaches involving fragments less than 300 mg/dose), and the carrier is surge in development of analogs of manufactured by SPPS and coupled in rapidly metabolized without accumulation. macromolecules having properties of solution phase are also used. The company is Eligen® carriers also protect molecules increased stability and decreased rates of adequately equipped to support both solid- from degradation in the GIT in the interval body clearance renders these classes of phase and solution-phase projects with before absorption occurs. This is a most molecules increasingly compatible with the material requirements in excess of hundreds important feature where proteins and Eligen® Technology.” of kilograms per year. peptides are concerned, says Dr. Riley. A major part of peptide manufacturing Several Eligen® formulations are in late is the purification and isolation procedures. development. A vitamin B12 formulation is POLYPEPTIDE LABORATORIES: PolyPeptide uses some of the largest state-of- expected to be marketed in 2010, and the PEPTIDE MANUFACTURING the-art equipment in the industry allowing for Novartis Eligen®/salmon calcitonin products OF ANY SIZE the manufacture of peptide APIs in single for osteoporosis and osteoarthritis are lots of up to about 10 kg, depending on currently in late Phase III testing in PolyPeptide Laboratories manufactures solubility and method of synthesis. For very approximately 6,000 patients. These products the peptide-based APIs that go into drug large manufacturing processes in which are expected to reach the market in delivery devices or formulations. Its lyophilization becomes a bottle-neck for the approximately 2012. customers develop novel delivery methods, isolation step, other procedures, such as “Eligen® formulations have the ability to which may involve molecular design of the spray-drying or, when appropriate, transform the market for poorly absorbed peptide, conjugation of the peptide to other precipitation, are being investigated. molecules,” says Dr. Riley. “Our products molecules, incorporation into polymeric The newly enlarged PolyPeptide Group Vol 8 No 3 simplify administration procedures for these matrices, formulation composition, the use of currently supports a large and diverse drugs and do so at a product cost that is less devices, etc. PolyPeptide can assist by selection of clients. This includes universities than the aggregate cost of parenteral manufacturing the custom-designed peptide and the full gamut of biotech and administration.” or by coupling the peptide to other non- pharmaceutical companies. March 2009 Eligen® acts as a drug molecule peptide moieties. “We do business with commercial chaperone, protecting macromolecules from “In the case of peptide-based organizations with less than 10 employees to degradation before absorption occurs. substances, we see the main challenge to the more than 50% of the top 20 Big Pharma Another benefit is passive transcellular drug drug delivery industry being that most companies, says Dr. Lax. “With our uptake. It does not allow uptake of peptides cannot be administered orally,” says comprehensive range of services, we can Drug Delivery Technology “bystander” molecules in the GIT. Dr. Rodney Lax, Senior Director of Business support customers with catalog material and 39 36-41 - DDT March 2009 - DDT Special Feature:Layout 1 2/26/09 11:42 AM Page 40

small-scale custom synthesis for research and F I G U R E 3 lead development through to GMP campaigns from gram to multi-10 kilogram quantities. 3M's sMTS Array for Systemic Delivery We have a range of generic peptide APIs approved in the US, Europe, and elsewhere. Most of our large-scale manufacturing is for the human and veterinary pharmaceutical market.” Historically, the main uses for peptides have been hormonal lesions and hormone- related disease, but today, they have applications in nearly every medical indication from hormonal/metabolic disorders, such as diabetes and obesity through pain management, bone disease, cancer, infection, imaging, and much more. There are hardly any areas of medicine that otherwise penetrate through the skin. The with a degree of sterility assurance that goes do not use or not developing peptide-based company is working on multiple variants of well beyond that of traditional transdermal APIs. the MTS technology to solve different products, and is often complicated by the “We see the peptide industry continuing delivery challenges, including solid incompatibility of proteins with radiation to grow for well over the next 5 to 10 years,” microstuctures coated with active (sMTS), sterilization.” says Dr. Lax. “The growth over the past few hollow microstuctures for fluid delivery The sMTS system may help address the years reflects rekindled interest in peptides (hMTS), and an MTS device in which the stability concerns through its solid-state due to their specificity and favorable safety microstructures are used as a pretreatment to coating, which for some protein and peptide profile. The cost of manufacturing has also facilitate subsequent delivery of active APIs, offers stability advantages over typical come down.” through the pretreated skin area. parenteral formulations. For some of these As the human genome continues to be 3M Drug Delivery recently announced a APIs, it may be possible to reduce the cold unraveled, the number of new targets co-development project with Vaxinnate Inc. in chain storage requirements, providing continues to increase. Peptide- (and protein)- which the company is using the MTS substantial advantage in the distribution of based drugs are building part of the arsenal of technology for delivery of a flu vaccine, and these medicines globally, but especially to the drugs to treat “previously untreatable” 3M is working on several other protein developing world. disease. As such, there is no alternative delivery projects using both the solid and With regard to the efficiency of API therapy, and the pharmaceutical industry is hollow versions of the MTS technology. utilization, 3M has demonstrated that both the under intense pressure to develop acceptable 3M also offers inhalation drug delivery sMTS and hMTS technologies are highly methods of administration that will ensure systems for delivery of proteins and peptides to efficient, providing bioavailability that is very patient compliance. the lungs. Most recently, 3M has added a range similar to with a range “There is no doubt that delivery of of dry powder inhalation (DPI) devices and of peptides and proteins from 1,000 to peptide drugs will continue to be an area of technologies that offer another solution for 150,000 MW. For vaccine delivery, the sMTS research, and PolyPeptide is excited to be pulmonary delivery of proteins and peptides, technology has been tested with a range of working with the industry to bring new particularly those with dosing requirements in antigens, and in some cases, has been shown peptide therapies to fruition,” says Dr. Lax. the 1- to 20-milligram range. A range of device to provide an equivalent immune response to formats are available, including a single-dose IM injection with up to a 10-fold reduction in disposable device that is well suited to delivery dose. This dose-sparing capability of sMTS Vol 8 No 3 3M: MEETING PROTEIN & PEPTIDE CHALLENGES of expensive protein and peptide APIs. may be further enhanced when the vaccine is “There are the usual challenges inherent co-administered with 3M’s toll-like receptor in protein/peptide formulation development, agonist vaccine adjuvants, allowing for up to

March 2009 3M Drug Delivery Systems has multiple such as maintaining physicochemical stability a 64-fold reduction in dose compared to IM delivery technologies that apply to the as well as the biological activity of the API administration. delivery of proteins and peptides. 3M’s throughout the product shelf-life, and A key advantage of 3M’s solid MTS Microstructured Transdermal System (MTS) ensuring efficient utilization of the often microneedle system is the ability to deliver a uses a molded plastic array to temporarily costly protein or peptide API throughout both range of biopharmaceuticals and vaccines, disrupt the normal skin barrier and allow the manufacturing and the delivery process,” systemically or intradermally. For Drug Delivery Technology intradermal delivery of many actives, says Tim Peterson. “We are also addressing pharmaceutical companies, sMTS fits well including proteins and peptides that would not 40 the challenge of developing MTS products with systemic delivery of potent small 36-41 - DDT March 2009 - DDT Special Feature:Layout 1 3/2/09 11:01 AM Page 41

molecules salts and proteins: it provides leveraged the microreplication and He adds that the development of protein bioavailability comparable to SC injection micromolding expertise to improve its MTS and peptide drugs will continue to accelerate and the potential to extend product life in arrays, optimizing the depth of penetration in the coming years, providing increasing more mature market segments. In addition, into the skin while simultaneously opportunities for alternative delivery systems sMTS enhances the efficacy of vaccines by simplifying the applicator systems required with a compelling value proposition. targeting the antigen to key antigen- for placement of the arrays. “Some of the first-generation injectable presenting cells within the skin, thereby “We are excited about the potential of products will likely also be developed in improving delivery efficiency and reducing our hMTS technology,” says Mr. Peterson. alternative delivery systems as a means to dose requirements. “This system consists of a wearable hollow provide product differentiation and stay ahead In addition, for 3M’s sMTS systems, microneedle array coupled to a liquid of biosimilars or other competitive products,” microstructures won’t fracture or break, reservoir for intradermal infusion of liquid says Mr. Peterson. “At 3M, with our sMTS eliminating risk of in situ fragmentation. For formulations. In the past year, we have and hMTS platforms, along with our patients, sMTS provides a simple-to-use, conducted a clinical study in which the inhalation technologies, we believe we offer a self-administration application with minimal hMTS device was used to rapidly deliver range of cost-effective and differentiated Vol 8 No 3 pain. high volume infusions (up to 1 ml) with solutions to meet the current and future “We have made a number of recent barely perceptible sensation to the subjects. challenges of protein and peptide delivery.”N advances in our sMTS technology,” says Mr. We have also conducted animal studies with Peterson. “Our formulation and coating a range of peptide and protein APIs, March 2009 technology has progressed to the point where including a polyclonal antibody fraction, we are achieving very precise and demonstrating a similar pharamacokinetic reproducible coatings on the profile to subcutaneous injection. This microstructures.” technology provides an easy-to-use and In many cases, these coatings release virtually painless alternative for many protein >90% of the protein or peptide API after less or peptide formulations currently given by Drug Delivery Technology than 5 minutes of wear time. 3M has also injection.” 41 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 42

AUTO-INJECTOR EVOLUTION

From Battlefield to Backpack: Evolution of the Auto-Injector By: Mike Mesa

INTRODUCTION in examining an eye injury.1 Treating combat injuries in the midst of a The glass , which enabled medics to quickly administer medication to injured chemical weapon attack may seem to be soldiers, was primitive by today’s standards for drug delivery devices. The early device worlds apart from treating allergy-induced consisted of a glass drug container with a rubber tube connected to its open end; a anaphylaxis. But both acute medical crises hypodermic needle was attached to the opposite end of the rubber tube. To administer the rely on a similar drug delivery device, which medication, the medic had to stab the needle into the victim’s leg and then continuously allows minimally trained individuals to self- squeeze and release the rubber tubing to milk the drug from the glass syrette or ampoule. inject potentially life-saving medication when emergency medical care may be absent or F I G U R E 1 remote. Originally developed for military use by Rodana Research Corporation, Inc., a forerunner of Meridian Medical Technologies, Inc., auto-injectors are prefilled, single-use devices designed for the quick administration of a precise dose of medication. The military has used auto-injectors for nearly 50 years to provide combat forces with the antidote for organophosphorous nerve agents as well as medications for other emergencies. The same auto-injector devices produced for the military have been sent into space and adapted for use in homeland security, acute medical care, and at-home management of chronic illness. The evolution of these types of drug delivery devices - from the battlefield to the backpacks of teenagers with severe allergies - is an interesting case study in how military innovations can influence the care of civilians.

FORERUNNERSTOTHECURRENT MILITARY AUTO-INJECTORS Vol 9 No 3 The first self-injectors carried by combat medics were glass prefilled with or . During World War I March 2009 (WWI), morphine was administered on the battlefield to manage pain associated with injuries, and atropine was one of several compounds used, somewhat unsuccessfully, to counteract the respiratory effects of chlorine and phosgene gas attacks launched by German

Drug Delivery Technology and Allied forces during that war.1,2 Atropine also causes pupils to dilate, which was useful 42 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 43 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 44

AUTO-INJECTOR EVOLUTION

Unfortunately, the devices were prone to bore to penetrate a membrane at the end of the In 1959, the US Army asked Rodana to breakage and difficult to use. The person sealed tube. The soldier or medic then removed provide atropine in the new auto-injection injecting the medication had to milk the the wire, stabbed the needle into the thigh, and delivery system, which was called the ACE ampoule until the syrette was emptied, which squeezed the metal tube until it was emptied. auto-injector. The new auto-injection system was difficult to accomplish, particularly in the While the metal syrette had obvious then replaced the metal syrette for the delivery midst of a battle. This method of drug delivery advantages over the glass version, there of antidotes to soldiers suffering from nerve also raised questions over dosing accuracy. remained drawbacks for soldiers. It still was agent poisoning. During World War II (WWII), medics difficult to ensure the entire dose was carried injectable morphine as well as drugs to administered, and many of the soldiers NEWFRONTIERSFOR counteract the effects of chemical weapons. reportedly were reluctant to stick themselves AUTO-INJECTORS However, nerve agents and other chemical with the needle, thereby presenting the military weapons attacks were less of a factor than in with concerns about soldier compliance.3 Because the ACE auto-injector permitted WWI; indeed, these agents were never soldiers to self-medicate on the battlefield with deployed against the United States Armed DEVELOPMENTOFTHE minimal training and little preparation of the Forces.3 AUTO-INJECTOR injector, its advantages were quickly recognized By the end of WWII, the need for an by another division of the US government. As easy-to-use, reliable device to deliver chemical The concept of the automatic syringe or the National Aeronautics and Space weapon antidote became more urgent. German auto-injector was the brainchild of Dr. Stanley Administration (NASA) prepared to launch its scientists had synthesized highly potent J. Sarnoff. At the time of his invention, Dr. Apollo space missions to the moon, NASA organophosphorous nerve agents during the Sarnoff was a scientist working at the Heart officials in 1966 enlisted Rodana to develop War and produced them for military use. Institute of the National Institutes of Health medical kits for use on the Apollo command Although Germany’s nerve agents were never (NIH) in Bethesda, Maryland. and lunar modules.5 deployed, the unused munitions were While attending a conference on military The medical kits were necessary to ensure discovered by Allied forces after the War, and medicine in the 1950s, Dr. Sarnoff heard delivery of life support, first aid and this sparked development of the German discussions among military personnel about ambulatory medical care for astronauts far compounds and antidotes by British and US their difficulties in training soldiers to use the removed from medical care.5 They included scientists.4 syrette. Concern that combat troops might Rodana’sACE auto-injectors loaded with Atropine became the standard antidote for forego life-saving antidote because of a fear of atropine, marezine, and meperidine; on later nerve agents because it blocked the excessive needles prompted Dr. Sarnoff to develop a flights, the kits also included a new auto- activity of smooth muscle and glands caused better option. In 1958, while still at the NIH, he injector loaded with lidocaine.6 by the nerve agent poisoning and helped to formed Rodana Research Corporation. The Examples of these early kits along with control convulsions.3 Even today, atropine sole purpose of Rodana in its early days was to the Rodana auto-injectors are on display at the continues to be the primary antidote treatment develop a drug delivery device that met National Air and Space Museum in for organophosphorous nerve agent poisoning, military specifications, was easy to use, and Washington, DC. Similar medical kits due to its ability to attach to muscarinic would help overcome the user’s natural fear of containing injectable drugs, emergency items, receptors and competitively block access to hypodermic needles. diagnostic tools, oral drugs, bandages, and these sites by acetycholine.4 Rodana developed the first auto-injector, a topical medications continue to be stowed on The post-WWII discovery of the German pressure-activated device that consisted mainly space shuttles today.7 nerve agents highlighted the need for a new of a tube filled with drug and a needle. To use

Vol 9 No 3 form of military syrette that was lightweight, the auto-injector, a soldier had to remove a NEWUSES&DESIGNS rugged, and easily carried and administered by safety feature and then push the face of the individual soldiers or medics. As a injector firmly against his thigh. By applying Following the adoption of the auto- consequence, a new drug delivery system that moderate pressure, a spring-driven plunger was injector by the military and NASA, Dr. Sarnoff March 2009 resembled a tube was developed. triggered, and this action pushed the needle and his colleagues continued to refine the The US military replaced the WWI-era outward into the thigh to deliver the original design and develop new uses for it. At glass atropine syrette in 1950 with a metal medication.3 Most importantly, the dose was the same time, Rodana became a public version, in which atropine was prefilled and delivered accurately and consistently through a company operating as Survival Technology Inc. sealed into a small collapsible metal tube with rugged, yet simple-to-use system that required (STI). Throughout the years, the company has a hypodermic needle attached at one end.3 To only two steps to deliver the life-saving drug. produced four basic delivery platforms that Drug Delivery Technology deliver the drug, the medic or soldier removed Moreover, the needle was completely hidden evolved from the ACE auto-injector design. 44 the cover and ran a small wire down the needle until after the drug was administered. 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 45

AUTO-INJECTOR EVOLUTION

1. The Original Auto-Injector platform to field a TAB replacement drug platform.10 With the lidocaine HCl atuo- Platform called pralidoxime chloride. This drug and the injector, emergency medical services (EMS) In 1973, the US FDA approved an auto- ComboPen platform are still in use today. personnel could deliver intramuscular lidocaine injector filled with atropine, a modified version Beginning in 1982, the two original platforms for the treatment of cardiac arrhythmias. of the original ACE auto-injector. Like the ACE were packaged together by the Department of Moreover, individuals who had suffered a heart auto-injector, the atropine auto-injector is Defense in the Mark I Nerve Agent Antidote attack and were at risk for arrhythmia could aimed at delivering small volumes in a single Kit (atropine injection and pralidoxime carry the lidocaine HCl auto-injector if they chamber, less than 1 mL of drug, in battlefield- chloride injection). The new kit provided a two- participated in a telephone-based monitoring like situations. The original atropine auto- drug nerve agent antidote consisting of and intervention program.11 (Note, this product injector, which has been in constant use over atropine and the oxime pralidoxime chloride. is no longer available.) Use of the ComboPen the past 35 years, delivered a 2-mg dose of The antidote combination counteracts the auto-injector platform by civilian patients atropine in a 0.7-mL solution. Today, atropine effects of excess build-up of acetylcholine expanded further the following year, with the doses are available for use in homeland defense caused by nerve agent exposure.8,9 Atropine, FDA approval of an auto-injector loaded with settings in 2-, 1-, 0.5-, and 0.25-mg auto- the primary antidote for nerve agent poisoning, epinephrine. The epinephrine auto-injector injectors. The same style of auto-injector also works by competing with excess acetylcholine enabled adults and children to self-administer is used to deliver morphine to treat pain in (ACh) - a neurotransmitter that stimulates drug to quickly treat a critical allergic reaction wounded soldiers. breathing, intestinal function, vascular function, to insect stings or bites, foods, drugs, and other and muscle movement - blocking the effects allergens, as well as idiopathic or exercise- 2. The ComboPen Platform until normal function can return.8 Pralidoxime induced anaphylaxis.12 With increasing The need for a new style of military auto- chloride helps reactivate the enzyme prevalence of reported peanut and tree nut injector arose in the 1970s. The military acetylcholinesterase, which is inactivated allergies, availability of the device quickly discovered that an antidote cocktail of atropine, during exposure to most organophosphorous grew.13 Today, the epinephrine auto-injectors benactyzine, and the oxime N,N’- nerve agents, thereby halting the continued (0.3/0.15 mg) remain mainstays of the trimethylenebis-[pyridine-4-aldoxime bromide] build-up of ACh at receptors and restoring Meridian product line and are marketed - referred to as TAB - was more effective than normal function to nerves, muscles, and worldwide. In 2003, Meridian was acquired by atropine alone in reducing lethality of the nerve glands.9 To administer the antidote using the King Pharmaceuticals, Inc. Today, King agent sarin.4 However, use of the TAB meant Mark I Kit, individuals followed the numbered continues to develop new products aimed at the the US military needed an auto-injector that directions on the auto-injectors, first injecting 2 civilian market. For example, King currently is could accommodate the three-drug cocktail, mg of atropine, followed by 600 mg of conducting a pivotal Phase III clinical study which required a glass container and capacity pralidoxime chloride. evaluating the efficacy of diazepam when for 2-mL drug volume. delivered in the ComboPen auto-injector At the time, STI was developing an auto- NEW BATTLEFIELD OPTIONS: In the 1990s, STI platform for the treatment of acute repetitive injector capable of delivering up to 3 mL of merged with a medical device company and epileptic seizures.14 solution. STI modified the new auto-injector, became Meridian Medical Technologies, Inc. which was originally aimed at delivering At about the same time, Meridian began 3. The BinaJect Platform lidocaine for the treatment of cardiac supplying the US Armed Forces an auto- Further evolution of the auto-injector arrhythmias, to deliver the new TAB antidote. injector filled with diazepam based on the occurred through collaboration between The auto-injector was dubbed the ComboPen ComboPen platform. Because the diazepam Meridian and the US military, which wanted to because the new antidote was a combination of auto-injector was and still is used as an adjunct lighten the load carried by its soldiers and

drugs in a single chamber. The US Department treatment of seizures caused by nerve agent reduce the number of injections that were Vol 9 No 3 of Defense fielded the ComboPen filled with poisoning, soldiers now had three Meridian required to administer the nerve agent antidotes TAB for several years in the 1970s. However, products to counteract the effects of nerve contained in the Mark I Kit. agent poisoning.4 Over the years, the Beginning in the 1980s, the US military

the antidote cocktail reportedly caused March 2009 anticholinergic effects in the absence of nerve ComboPen platform also has been used to worked with Meridian to develop an auto- agents and was associated with adverse events successfully field a number of other nerve injection system that would store and deliver inappropriate for the battlefield. Therefore, the agent antidotes and treatments for allied both atropine and pralidoxime from a single Department of Defense eventually discontinued governments. device. The two drugs would need to be its use.4 delivered in a single continuous intra-muscular USE IN CIVILIAN MEDICINE: In 1986, the FDA injection using a single needle, while THE MARK INERVE AGENT ANTIDOTE KIT: STI approved an auto-injector filled with lidocaine maintaining separation of the two drugs in the Drug Delivery Technology and the military ultimately used the ComboPen HCl based on the original ComboPen auto-injector and at the human injection site. 45 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 46

AUTO-INJECTOR EVOLUTION

Separation of the drugs was required because medicine, but also impacted the utility and Meridian Medical Technologies, Inc.;2005. 9. Pralidoxime Chloride Auto-Injector (pralidoxime chloride injection) [package pralidoxime changes the osmolarity of atropine safety of auto-injectors in multiple settings. insert]. Columbia, MD: Meridian Medical Technologies, Inc.;2003. 10. Lidocaine: new injection device saves lives. American Pharmacy. 1986;NS26:38. and slows its absorption into the blood Before auto-injectors were issued to 11. Visco JP, Capone RJ, Wagner G, Follick M. A telephone based monitoring and 15,16 intervention program for post-MI patients following hospital discharge. Paper stream. combat troops, the devices were evaluated for presented at 33rd Annual Scientific Session of the American College of By 2002, Meridian had accomplished this their reliability in delivering the correct dosage, Cardiology in Dallas, Texas;1984. 12. Drugs@FDA. Website: goal, and the US Army had received FDA the ease with which the drug was dispensed, www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm?fuseaction=Search. DrugDetails. Accessed September 29, 2008. approval to dispense the atropine/pralidoxime the length of the needle after activation, the 13. Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut antidote combination in a single device, called speed required to deliver the medication, and allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. the Antidote Treatment Nerve Agent Auto- the force with which it took to activate the 2003;112(6):1203-1207. 14. A study on the effectiveness and safety of diazepam injection (VanquixTM) for injector (ATNAA). In 2006, DuoDote (atropine auto-injector. Military officials also required patients with epilepsy that receive antiepileptic drugs, but still experience acute repetitive seizures (bouts or clusters of seizures) that require treatment. Website: and pralidoxime chloride injection), a version that auto-injectors be durable enough to http://clinicaltrials.gov/ct2/show/NCT00319501. Accessed November 14, 2008. of the ATNAA product, also was approved by withstand significant changes in temperature 15. Sidell FR, Magness JS, Bollen TE. Modification of the effects of atropine on human heart rate by pralidoxime. Clin Pharmacol Ther. 1970;11(Jan):68. the FDA for use by EMS and homeland and the rugged conditions of a war zone. 16. Sidell FR. Modification by diluents of effects of intramuscular atropine on heart security personnel.12 Use of the auto-injector in the consumer rate in man. Clin Pharmacol Ther.1974;16(4):711-715. market, particularly for acute medical care, led 4. The SoluJect Platform to similar stress-testing; in this case, for the Although the auto-injector has been durability of the devices when carried and used available for nearly half a century, the device’s by adults, teenagers, or children. Where and design continues to evolve in order to address how the auto-injector is stowed was a particular the needs of multiple potential therapeutic uses. concern, so sturdiness when tucked into One such design modification is meant to pockets or pushed into tightly packed address the need for a device that can backpacks had to be considered. accommodate drugs with very short shelf lives As auto-injectors continue to evolve, their when in a liquid form. safety, reliability, durability, and ease of use BIOGRAPHY King currently is in advanced will remain critical considerations for development of a dual-chambered auto-injector researchers. Existing products should be Mike Mesa is that contains a lyophilized drug product and a continuously evaluated to ensure they are Director of Applied Product liquid solvent in separate chambers. Upon appropriate, rugged, and reliable in a variety of Development at activation, the device reconstitutes lyophilized end-user settings. Meridian Medical drug product during the injection sequence. For effective self-administration, auto- TechnologiesTM, Although this auto-injector is being developed injectors must dispense medication easily and Inc., a wholly under contract with an allied government, reliably, regardless of whether the device is owned subsidiary variations of this new device may have engaged by a soldier confronting chemical of King important applications in civilian medicine as weapons, EMS personnel saving lives, or a Pharmaceuticals®, well. teenager battling severe allergies. Inc., a position he has held since 2006. In Meanwhile, use of auto-injectors in the this capacity, Mr. Mesa is responsible for the management of acute and chronic conditions management of multi-year, multi-million dollar continues to be evaluated. Researchers also are REFERENCES projects involving pharmaceuticals and drug delivery development activities from exploring new auto-injector technology and 1. Miller MG. Materia Medica. September 14, 2008. Website: conception through product launch. His duties

Vol 9 No 3 refining existing products. www.vlib.us/medical/pharmacy/matmed.htm. Accessed October 23, 2008. include management of clinical programs, 2. Miller MG. WWI: The Medical Front. The Medical Aspects of WWI Gas Warfare. September 14, 2008. Website: www.vlib.us/medical/gaswar/chlorine.htm. manufacturing scale-up, regulatory activities, Accessed October 23, 2008. and marketing support activities. Mr. Mesa 3. Smart JK. History of chemical and biological warfare: an American perspective. IMPACT OF MILITARY USE ON In: Sidell FR, Takafuji ET, Franz DR, eds. Textbook of Military Medicine: began his career with Meridian in 1969 (then March 2009 Medical Aspects of Chemical and Biological Warfare. Washington, DC: Office of DEVICEFORCIVILIANS The Surgeon General at TMM Publications Borden Institute;1997:9-86. Rodana Research Corporation) and has since 4. Sidell FR. Nerve agents. In: Sidell FR, Takafuji ET, Franz DR, eds. Textbook of held various technical positions from Military Medicine: Medical Aspects of Chemical and Biological Warfare. To be effective in acute medical care, an Washington, DC: Office of The Surgeon General at TMM Publications Borden Laboratory Technician to Technical Services Institute;1997:129-181. Coordinator to Senior Development Engineer. auto-injector device must engage intuitively, 5. Encyclopedia Astronautica: CSM Cockpit. Website: and it must be reliable and sturdy enough to www.astronautix.com/craft/csmckpit.htm. Accessed October 23, 2008. He holds six United States patents relating to 6. Hawkins WR, Zieglschmid JF. Clinical aspects of crew health. In: Parker JF, ed. auto-injector technology and novel ways of survive daily transport in pockets or backpacks. Biomedical Results of Apollo. Houston: Lyndon B. Johnson Space Center;1975. 7. Williams D. Space medicine. In: Tintinalli JE, Kelen GD, Stapczynski JS, Ma OJ, improving drug stability in an auto-injector. Drug Delivery Technology In this regard, military experience with the Cline DM, eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, He can be reached at (443) 259-7800. devices not only prompted their use in civilian 6th Edition. Chapel Hill, NC: McGraw Hill Companies;2004. 46 8. AtroPen Auto-Injector (atropine injection) [package insert]. Columbia, MD: 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 47 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 48 42-49 DDT Mar 2009-Auto-Injector Evolution:Layout 1 2/26/09 11:42 AM Page 49 50-55- DDT Mar 2009-Extractables Leachables:Layout 1 2/26/09 11:44 AM Page 50

EXTRACTABLES & LEACHABLES

A New Approach to Threshold Evaluation & Quantitation of Unknown Extractables & Leachables Using HPLC/CAD By: Xiaochun Yu, PhD, Steve Zdravkovic, Derek Wood, Chunyu Li, Yufei Cheng, PhD, and Xiaoya Ding, PhD

INTRODUCTION concern from carcinogenic and Charged Aerosol Detection (CAD) is noncarcinogenic toxic effects.2 An explored as a suitable alternative for Extractables are compounds that immense challenge in applying this extractables and leachables can be extracted from the threshold is quantitating the quantitation. Because the typical components of a container/closure extractables and leachables prior to CAD response is relatively constant system in the presence of appropriate identification. A typical approach is over a broad range of compounds, solvents and conditions. Leachables to use a surrogate standard for this approach obviates the need for are compounds that leach into the quantitating the unidentified identification, synthesis, or drug product from containers/closure extractables and leachables.3 purification of unknowns. The system components under normal HPLC/UV and LC/MS are commonly relative response factors (RRF), storage conditions. The evaluation of used for detection, but because UV sensitivity, and linearity of this extractables and leachables is and MS response factors can vary approach were evaluated with a series required by various regulatory significantly between compounds, of extractables and leachables agencies because of safety concerns.1 using a surrogate standard for commonly observed in There are many potential extractable quantitation can give highly uncertain container/closure systems. and leachable compounds in a results. Additionally, a case study involving container/closure system or A new approach using corona the evaluation of the extractables of manufacturing process and, as the detection limit of a method is F I G U R E 1 lowered, the number of extractable and leachable compounds that are detected rises. The question then becomes one of practicality and risk/benefit as to detection levels. The Product Quality Research Institute (PQRI) in 2006 submitted a

Vol 9 No 3 recommendation to the US FDA on “Safety Thresholds and Best Practices For Extractables and

March 2009 Leachables in Orally Inhaled and Nasal Drug Products”, which proposed a Safety Concern Threshold (SCT) of 0.15 micrograms/day (Total Daily Intake), below which a

Drug Delivery Technology leachable would have a dose so low CAD Chromatogram (stack plot)

50 as to present a negligible safety 50-55- DDT Mar 2009-Extractables Leachables:Layout 1 2/26/09 11:44 AM Page 51 50-55- DDT Mar 2009-Extractables Leachables:Layout 1 2/26/09 11:44 AM Page 52

an elastomeric packaging component is T A B L E 1 presented to demonstrate one of the many applications of this new technique. Mobile Phase A Purified Water Mobile Phase B Acetonitrile Flow Rate 1 mL/minute Column Synergi Hydro RP 105 4.6 mm, 4 m EXPERIMENTAL CONDITIONS Column Temp 45°C Autosampler Temp Ambient Injector Volume 50 microliters All compounds were purchased from UV Detector Wavelength 254 nm Sigma-Aldrich except cyclic oligomers CAD N2: 35 psi; range: 100 pA of polybutylphthalate (cBT oligomers), Time (Min) %A %B Gradient or isocratic condition 0.0 75 25 Irganox 245, and Ultranox 626. cBT as specified in the text. 5 75 25 oligomers were provided by Cyclics 35 0 100 Corporation, Irganox 245 was provided 60 0 100 by Ciba Specialty Chemicals HPLC Conditions Corporation, and Ultranox 626 was provided by Chemtura Corporation. All final test solutions were prepared in T A B L E 2 acetonitrile at 10 ppm with 10 ppm Gradient 5:95 H2O:ACN 100% ACN Irganox 1010 as an internal standard. The Compounds CAD UV CAD UV CAD UV Irganox 245 0.42 1.04 0.73 0.93 0.68 0.96 Irgafos 168 stock solution was prepared DEHP* NA NA 0.68 3.24 0.64 3.25 in acetone because of its low solubility in cBT** NA NA 0.70 33.45 0.85 32.31 Palmitic acid 0.74 0.00 0.82 0.00 0.72 0.00 acetonitrile, and was then diluted to the Irgafos 168 NA NA 1.27 1.31 1.07 1.43 Irganox 1076 NA NA 1.22 0.54 1.25 0.58 final test concentration with acetonitrile. Ultranox 626 0.79 0.95 0.81 0.97 0.82 0.97 Stock solutions for all other compounds Stearic acid 0.92 0.00 1.11 0.00 0.98 0.00 Bisphenol A 0.40 3.06 0.76 2.68 0.68 2.63 were prepared in acetonitrile. Erucamide 1.17 0.00 0.96 0.00 0.77 0.00 The elastomeric components were Irganox 1010 1.00 1.00 1.00 1.00 1.00 1.00 Average RRF 0.78 0.86 0.91 4.01 0.86 3.92 cut into small pieces, extracted with %RSD 37 126 23 245 22 242 *DEHP is diethylhexylphthalate, also called dioctylphthlate. isopropanol for 24 hours with refluxing, **cBT consists of cyclic oligomers of polybutylphthalate. The reported response is the combined response of the dimer, trimer, and tetramer. and then diluted to a suitable NA, not evaluated at the specified condition concentration with isopropanol prior to Comparison of Relative Response Factors analysis. An ESA Corona Plus CAD detector and an Agilent 1100 HPLC system were T A B L E 3 used for analysis. See Table 1 for the HPLC and CAD conditions. QL Compounds CAD UV at 254 nm RESULTS & DISCUSSION Bisphenol A 0.05 ppm 0.1 ppm Dioctyl phthalate 0.1 ppm 0.2 ppm Relative Response Factor Ultranox 0.1 ppm 0.2 ppm Erucamide 0.2 ppm Not detected Vol 9 No 3 Extractables and leachables cover a Irgafos 168 0.15 ppm 0.2 ppm wide range of compounds with different Irganox 245 0.05 ppm 0.5 ppm structures, including but not limited to, Palmitic acid 0.2 ppm* Not detected March 2009 anti-oxidants and their degradants, Irganox 1076 0.15 ppm 0.5 ppm molding agents (such as lubricants), Irganox 1010 0.1 ppm 0.4 ppm Stearic acid 0.2 ppm* Not detected monomers and oligomers, plasticizers, curing agent for elastomers, residual * With 0.1% formic acid in mobile phase polymerization initiators and catalysts,

Drug Delivery Technology and reaction products formed during HPLC/CAD Versus HPLC/UV Sensitivity 52 harsh processing conditions, such as the 50-55- DDT Mar 2009-Extractables Leachables:Layout 1 2/26/09 11:44 AM Page 53

F I G U R E 2 elastomer curing process. The most critical aspect of using a known surrogate standard to quantitate unknown extractables and leachables is that they have similar response factors. Representative compounds from different extractables and leachables categories, such as antioxidants (BHT, Irganox 1010, Irganox 1076, Irganox 245, Irgafos 168, Ultranox 626), platicizers (dioctylphthalate, diethyl phthalate), fatty acids and related compounds (stearic acid, palmitic acid, erucamide), monomers and oligomers (Bisphenol A, caprolactam, cBT oligomers) were evaluated for their peak area response relative to Irganox 1010 at 10 ppm. The evaluation includes three different elution conditions: (1) A Response Curve of Irganox 1010 CAD Response gradient from 25% ACN to 100% ACN; F I G U R E 3 (2) Isocratic with 5% water and 95% acetonitrile; and (3) Isocratic with 100% acetonitrile. Table 2 compares the CAD relative response factor (RRF) with the UV RRF for each compound. Figure 1 presents a representative chromatogram. Some of the relatively volatile compounds, such as caprolactam, BHT, and diethyl phthalate, were not detected with CAD. The reason for this is when the eluent enters the detector, it is nebulized with nitrogen, and the resulting droplets are dried to remove mobile phase and produce analyte particles. During this process, relatively volatile compounds are also evaporated. Although this is a limitation of CAD, relatively volatile Response Curve of Bisphenol A CAD Response compounds can be detected and quantitated with complementary T A B L E 4 techniques, such as GC/FID or GC/MS.

The RRFs of all the detected Vol 9 No 3 Compounds Equation of Quadratic (Second Order) Fit R2 Bisphenol A y = -508x2 + 56,596x + 6,739 0.9998 compounds are within a narrow range, Dioctyl phthalate y = -323x2 + 42,735x - 13,423 0.9989 especially for the isocratic conditions 2 Ultranox y = -357x + 51,339x + 17,665 0.9985 with RRF %RSD of all compounds at March 2009 Erucamide y = -291x2 + 77,057x + 4,818 0.9996 Irgafos 168 y = -312x2 + 80,592x + 9,717 0.9980 about 22% and 23%. The variation in 2 Irganox 245 y = -322x + 50,284x + 27,365 0.9973 RRF for the gradient condition is greater Palmitic acid y = -619x2 + 39,712x - 117,255 0.9999 2 than with the isocratic conditions because Irganox 1076 y = -457x + 83,398x + 22,715 0.9989 Irganox 1010 y = -315x2 + 62,534x + 28,621 0.9981 of the desolvation differences of the 2

Stearic acid y = -307x + 68,241x - 144,756 0.9998 mobile phase in the detector. Compounds Drug Delivery Technology

Summary of Response Curves that elute earlier (when the mobile phase 53 50-55- DDT Mar 2009-Extractables Leachables:Layout 1 2/26/09 11:44 AM Page 54

F I G U R E 4

Isopropanol Extract of an Elastomer Component

has a lower organic and higher aqueous their QL is about 2 ppm because of peak shoulder at 1.7 minutes. Additionally, content), such as Bisphenol A and tailing. there are a few small peaks at 5.27, 6.34, Irganox 245, exhibit relatively lower It is recognized that with 7.54, 8.33, 8.95, and 9.51 minutes. To RRFs. However, even with gradient optimization of detection wavelength, determine if these small peaks were elution, the overall %RSD of the RRF for HPLC/UV could provide improved greater than the SCT, they were all compounds is still only 37%. The sensitivity over what is presented in Table quantitated with the surrogate standard LC/UV data demonstrates significantly 3. The data, however, suggest that the Irganox 1010, and the amounts are listed greater variation for all mobile phases. sensitivity of HPLC/CAD is comparable in Table 5. The analytical evaluation The LC/UV variability could cause to HPLC/UV. threshold was calculated based on the significant differences in the results for following assumptions. A single piece of the unknown quantitation. Dynamic Range the component in the container/closure The CAD has a wide dynamic range system and the content of the drug in one Sensitivity for detection. The response is not linear container is for 20 days doses, so the AET Adequate sensitivity is critical for but does fit a quadratic or higher order = 0.15 × 20 = 3.0 micrograms/component. the extractables and leachables study. The (cubic or fourth) curve. The quadratic With the worst case RRF 0.68, the final SCT of 0.15 micrograms/day corresponds plots of some of the typical extractables AET=3.0×0.68=2.04micrograms/component. to an analytical evaluation threshold and leachables are shown in Figures 2 Therefore, the small peaks at 5.27, 6.34, (AET) based on the dosing regimen, and and 3. The equations used to fit the 7.54, 8.33, 8.95, and 9.51 minutes will all this threshold is typically very low. A curves are summarized in Table 4. be below the final AET. As a result, these sufficiently high sensitivity is usually peaks do not need further structure required to achieve the necessary AET. Case Study evaluation. The two unknowns at 1.43 Table 3 compares the sensitivity of To demonstrate the applicability of and 1.69 minutes are above the AET and Vol 9 No 3 HPLC/CAD to that of HPLC/UV for HPLC/CAD for extractable studies, a would need further structure evaluation typical extractables. representative elastomer component was by LC/MS or other technique. The sensitivities for the different extracted with isopropanol, and the March 2009 compounds with HPLC/CAD are close extracts were analyzed with HPLC/CAD due to their similar response factors. The (ACN:water, 95:5). A chromatogram of CONCLUSION variation in sensitivity is largely the extract is shown in Figure 4. determined by peak shape and peak The peaks at 7.7 and 11.4 minutes HPLC/CAD can efficiently and width. The fatty acids have a QL of about are identified as palmitic acid and stearic effectively quantitate extractable or Drug Delivery Technology 0.2 ppm when the mobile phase contains acid, respectively. There are also large, leachable unknowns with greater 54 0.1% formic acid; without formic acid, unknown peaks at 1.4 minutes and a accuracy than traditional HPLC/UV, 05-DTMr20-xrcalsLeachables:Layout 12/26/0911:44AMPage55 2009-Extractables Mar DDT 50-55- rdtoa prah h liaebenefit ultimate The approach. more traditional a of requirements time and cost the without development drug of stage early the during efficiently information providing by (QbD) Design by Quality facilitate to process development drug a into incorporated be can approach this Consequently, validation. and development method analytical during studies degradation forced for mass-balance better achieve to utilized quantitation. extractable non-volatile for analysis) residue volatile (non- analysis gravimetric and (HPLC) chromatographic between the correlation balance to used be also can technology This RRF. appropriate an of application for identification second-pass a requires which extractables, for analysis HPLC/UV standard to in comparison cost and time saves This systems. closure container in used materials various for AET the against extractables of evaluation first-pass a for HPLC/CAD allows phase. study E/L early the in decision-making cost-effective facilitate to unknowns for information accurate provides and compounds different for factors response of variations large the and compounds sensitive non-UV for detection UV of limitation the overcomes technique This structure. chemical actual the of regardless xrcalsFo nEatmrComponent Elastomer an From Extractables diinly hstcnlg a be can technology this Additionally, Peak RT (min) RT Peak 11.4 11.4 9.51 8. 8.33 7.74 7.54 6.34 5.27 1 1.43 .69 .69 95 Palmitic acid Palmitic Compound Stearic acid Stearic Unknown 5 Unknown 4 Unknown 3 Unknown U 1 Unknown Unknown 8 Unknown 7 Unknown 6 Unknown nknown 2 nknown 5 E L B A T .Y ,Wo ,Dn .Etatbe n leachables and Extractables X. Ding D, Wood X, Yu 3. Extractables for Practices Best and Thresholds Safety 2. inhalation and spray Nasal Industry: for Guidance 1. Rosanske. Tom and Pentecost, Ann Sue Mejillano, Magdalena Jantzi, Darren Galang, Joel Don DeCou, of input productive the particular, and in Inc., PPD, employer, their of support packaging. product final for systems container/closure and manufacture the in used processes and materials appropriate choosing to regard in development timeline drug the of shortening the is ipoesn.Bohr n.20;21(2):42-51. 2008; Int. BioPharm in bioprocessing. used materials disposable for approach study rdcs 06 PQRI. Drug 2006, Nasal Products, and Inhaled Orally in Leachables and 2002. July CDER FDA documentation. controls and - manufacturing, chemistry, products drug spray and suspension, solution, h uhr iht cnweg the acknowledge to wish authors The ACKNOWLEDGEMENTS M icrograms REFERENCES 126.14 34.66 75.81 1.65 0.86 1.25 0.63 1.48 0.80 8 .15 /C omponent aiu methodologies. using various methods leachable and validation extractable and of development on is focus main etn.D.Xay igcnb otce at: contacted be [email protected]. can Ding Xiaoya Dr. testing. extractables/leachables and characterization; product troubleshooting; formulation and preformulation, stability; transfer; validation, development, including led efforts or publication published has She Services. Specialty and Testing Biopharmaceutical Department, utmrsrieadefficiency. and on service focus customer a with projects large-scale of management and implementation, and design study extractables/leachables validation, and extensive development method has analytical He in PPD. experience at years 7 than more aiain n tutr identification. structure and validation, S E I H P A R G O I B tde.Hscurrent His studies. extractables/leachables and biopharmaceutical various on working PPD at experience years 4 than more has Zdravkovic Mr. lab. cGMP PPD’s at Scientist Senior tv Zdravkovic Steve development, method analytical on experience extensive has also He studies. extractables/leachables on leading scientist a is Yu Dr. lab. cGMP PPD’s at Scientist Research Senior r iohnYu Xiaochun Dr. fteAnalytical the of Director as served and positions leadership scientific key held has Ding Dr. 1996, in PPD joining Since lab. cGMP PPD’s at Affairs Technical and Scientific of Director the r ioaDing Xiaoya Dr. nuty including industry, pharmaceutical the in experience years 17 than more has Wood Mr. division. Services Analytical Development Product lab, cGMP PPD’s at Manager Laboratory ee Wood Derek sa is is sa is sa is

55 Drug Delivery Technology March 2009 Vol 9 No 3 56-58 DDT Mar 09 - DDE Depomed:Layout 1 2/26/09 11:45 AM Page 56

DEPOMED:LEADER IN GASTRIC RETENTION TECHNOLOGY

epomed, Inc., (NASDAQ: DEPO) is a specialty pharmaceutical company with a proven, proprietary AcuFormTM gastric retentive drug DDdelivery technology to improve existing oral medications, allowing for Carl A. Pelzel extended, controlled release of medications to absorption sites in the upper President & CEO gastrointestinal tract. Benefits of AcuForm-enhanced pharmaceuticals include the Depomed, Inc. convenience of once-daily administration, improved treatment tolerability, and enhanced compliance and efficacy. Depomed has two approved products on the “As line extensions market. GLUMETZA® (metformin hydrochloride extended release tablets) is with little approved for use in adults with type 2 diabetes and promoted by Santarus, Inc. in differentiation are the US. Proquin® XR (ciprofloxacin hydrochloride) is approved in the US for the called into question, Big Pharma’s once-daily treatment of uncomplicated urinary tract infections and is marketed by enormous Watson Pharmaceuticals. Depomed’s late-stage pipeline includes product investments in new candidate DM-1796 in Phase III clinical development for the treatment of chemical entity development neuropathic pain and has been licensed to Solvay Pharmaceuticals. Product programs are candidate DM-5689 is in Phase III clinical development for menopausal hot becoming more flashes. Drug Delivery Technology recently interviewed Carl A. Pelzel, President risky. In contrast, Depomed’s model of and Chief Executive Officer of Depomed, to discuss the company’s technology, its leveraging our business model, and strategic goals. AcuForm technology to develop known route to success, as managed care, physicians, chemical entities Q: What do you believe are the has proven to be far current major challenges of the and payers insist on meaningful product less costly and less pharmaceutical industry, and how differentiation. As line extensions with little risky.” can drug delivery technologies add differentiation are called into question, Big Vol 9 No 3 value today? Pharma’s enormous investments in new chemical entity development programs are becoming more risky. In contrast, Depomed’s March 2009 A: Two significant challenges facing Big Pharma are R&D productivity and the need to model of leveraging our AcuForm technology fill the pipeline amid a number of patent to develop known chemical entities has proven expirations of blockbuster products. The to be far less costly and less risky. The reason is receptivity of new products is changing as well. simple. We identify a target product profile in

Drug Delivery Technology New chemical entities are not an automatic advance using a compound with a long-

56 65 D a 9-DEDpmdLyu 2/26/0911:45AMPage57 1 Depomed:Layout DDE - 09 Mar DDT 56-58 rfrnilyasre nteupper the in absorbed preferentially drugs of delivery efficient more a include benefits Clinical XR. Proquin and GLUMETZA drugs marketed two our with successfully it used have who patients of thousands of hundreds the by evidenced as technology proven a also is technology AcuForm lining. gastric the to adhere that tablets or accordions as such unsuccessfully, tried been have approaches Different products. marketed to applied successfully technologies retentive gastric few very been have actually there simple, sounds it While stool. the with removed is and disintegrates fully tablet the are after residuals retained No hours. 8 to 6 stomach over the in retained is of and factor 3X a by size in increases tablet the fluids, gastric with contact Upon polymers. swellable of consists that tablet oral retentive gastric unique A: AcuForm? with delivered products of benefits clinical the are What technologies? other from different technology AcuForm Depomed’s is How Q: profile. the meet to ability our in confidence of degree higher a with forward programs our move then and record, safety established u cFr ehooyi a is technology AcuForm Our eni u rvosciia trials. clinical previous our in have seen we as effects side reduce thus and dose, once-daily a as slowly gabapentin deliver and of absorption site the above stomach the in retained are however, formulations, Our formulations. with immediate-release seen effects side high the of because levels dose target achieving trouble have patients because success optimal without day, typically a times 4 to 3 gabapentin immediate-release of doses large taking by pumps saturable the overcome and absorption of window the maximize to trying are Patients flashes. hot menopausal for 5689 DM- and pain neuropathic for 1796 DM- formulations extended-release gabapentin our are examples best Our compliance. and tolerability, improved convenience, dosing resulting and tract, gastrointestinal fwmnshat rdcs owe So products. health women’s of portfolio a of centerpiece a as rights) full retained we which to and flashes hot for (indicated DM-5689 use to is goal long-term our but pipeline, clinical late-stage our with stage A: products? proprietary own its developing or companies other with technology its Partnering technology? AcuForm its utilizing in strategy Depomed’s is What Q: eaesili h development the in still are We field. OB/GYN the in rights promotion plus sales, on royalty milestones, development in million $64 to up up-front, million $4 receiving while products four of development the for technology our licensed we which in Covidien with deal recent our is example best The cash. additional generating while efforts development internal our minimize to us allows structure This franchise. health women’s our for retained rights and payments, royalty and milestone, up-front, an for exchange in partner a by developed be to compounds for technology our license we which in deals consummate to looking are we Nonetheless, companies. partner for studies feasibility doing avoid and model fee-for-service the exit to decision strategic a made We assets. the for overpaying risk constantly and products new in-licensing on dependent are you which in trap” “licensing the avoid to want do We products. new generate to engine development efficient and cost-effective most the is technology internal an that believe we because base technology our broaden to looking actively and to open are we However, technology. AcuForm our on based are products pipeline and marketed our all fact, In products. proprietary develop to technology our leverage do

57 Drug Delivery Technology March 2009 Vol 9 No 3 65 D a 9-DEDpmdLyu 2/26/0911:45AMPage58 1 Depomed:Layout DDE - 09 Mar DDT 56-58

58 Drug Delivery Technology March 2009 Vol 9 No 3 mrc n ulrgt oDM-5689. to rights full and America ex-North DM-1796 to rights full retained We America. North covering sales, product on 20% to 14% of royalty a and milestones, sales in million $300 to up milestones, precommercial in million $70 to up million, $25 of payment up-front an for Solvay with deal a consummated we end, the In Depomed. for deal best the negotiating in patient also were but auction, competitive a ran and outreach our in broad quite were We products. both license to wanted partners prospective of number a gabapentin, extended-release of formulations similar are DM-5689 and 1796 DM- both Because franchise. health women’s our for indication flash hot our to rights full retain could we so trials III Phase DM-5689 our specifically operations, our finance to us enable would payments license whose and product the of success commercial the to committed who is partner strong a to pain for 1796 A: overcome? to had you were challenges the what and process, the managed you how achieve, to wanted you objectives strategic your through us walk you Can technology. AcuForm your on based is which DM-1796, for Solvay with deal partnership sizable a closed recently also Q:You u olwst ies DM- license to was goal Our odvlpD-76i fibromyalgia. in DM-1796 develop to elects Solvay if field OB/GYN the in rights co-promotional for negotiation first of right a retained we franchise, health women’s a build to objective strategic our with Consistent te oiinlk el nwhich in deals Covidien-like Other markets. capital the from financing external on reliance our reduce and cash additional generate to technology AcuForm our leveraging are we meantime, the In products. other potentially and OB/GYNs, by prescribed are that products Covidien four GLUMETZA, 5689, DM- with products of health women’s basket our create to track on well are we believe We published. were Initiative Health Women’s the of results the after the market in exists that treatments flash hot non-hormonal alternative for need unmet high the given significant is potential market 5689’s DM- field. health women’s the be would choice of field specialty our approval, regulatory achieves program DM-5689 our Provided products. proprietary of basket a with company profitable a become A: steps? next your are What goals? those achieving in role a playing technology AcuForm your see you do How Depomed? of goals long-term the are What Q: u ogtr oli to is goal long-term Our future. the in profitability achieve and crisis economic current the navigate successfully can we confident are we payments, milestone additional anticipated the with Combined 2008. of quarter third end the the of at cash in million $85.5 position with financial strong a in are We programs. DM-5689 and our DM-1796 in trials III Phase large three with Depomed for year execution point. inflection next the reaching after cash generate to them partner to we intend us, to strategic not are programs Levodopa and GERD our both Because fluctuations. level blood reduce and sites absorption the to delivered efficiently more be could Levodopa stomach, the in retained form dosage our With effects. side and efficacy inconsistent to leads tract gastrointestinal upper the in Levodopa of absorption of window narrow the that known been long has It benefits. clinical significant deliver could technology gastric retentive our how for showcase a is latter The Parkinson’s. for program Levodopa or GERD our as such technology, AcuForm our on based compounds of pipeline stage an have early also We there. us get can compounds partner of development the for technology our license we epa n20 en an being 2009 on plan We N 96-DTMrh0-ehSocs:aot12/26/0911:46AMPage59 1 Showcase:Layout 09-Tech March DDT 59-61- I NHALATION aiiepoutlf yls vv rgDlvr ytm soeof one is Systems Delivery Drug Aveva cycles. life and pipelines product maximize R&D fortify produce that to systems capabilities delivery R&D drug of transdermal compliment full a development with its along pipeline from license for products numerous has Aveva Po uiesDvlpet t(5)6417 rvisit or 624-1374 www.avevadds.com (954) at Development, Business of Bloder, VP Robert contact information, more For Nicotine. and Fentanyl,Clonidine, Sufentanil, include licensing for Products needs. market unmet fulfill that products fully transdermal controlled-release with integrated, partners pharmaceutical providing transdermal of systems in delivery pioneer drug a and of manufacturers largest world’s the eieySsesa 80 4-06o visit or 643-8086 (800) at Drug Systems Delivery 3M contact information, more For AAPS. attending No. while Booth 1725 by stop please technologies newest and developments latest our about more the learn To process. of commercialization step and development each for available are support, product marketed and operations, assurance, resources, quality expertise, In-house market. regulatory toxicology, including to product your get help to guidance regulatory with combined feasibility, capabilities manufacturing of and development, range full a offers transdermal 3M technology. delivery or inhalation drug our with molecules your team to biotechcompanies and pharmaceutical with partners Systems Delivery Drug 3M L ICENSING . T & RANSDERMAL O PPORTUNITIES www.3m.com/dds D ELIVERY . t(0)4564 rvisit or 445-6240 (800) at information, technologies.platform more contact Adhesives Research For delivery customized drug dissolvable for films, laminatesadhesive and manufactures innovative and develops pharmaceutical products, including drug-containing active systems. innovative of delivery ARx for need global growing Adhesives Research) addresses the subsidiary of owned wholly (a applications. pulmonary delivery LLC and systems ARx, delivery transdermal passive and active for laminate adhesivesfriendly and specifications. company’s Pharmaceutical The skin- provides division 94 3-40o visit or 433-7480 (954) at Azopharma contact information, more For Organization. Research Clinical Acromon and Services, Preclinical AvivoClin Services, Bioanalytical ADMEQuant Laboratories, Analytical Cyanta Services, Preclinical AniClin IQsynthesis, Technologies, Delivery Drug ApiCross Services, Pharmaceutical Contract Azopharma of include Group companies Our Development. Device Medical Full and ANDA Development, Full Development, NCE Full Development, IND includeFull capabilities Our services. development of spectrum complete the provides Azopharma commercialization, to and studies manufacturing preclinical early and discovery From industries. medicaldevice and biotech, pharmaceutical, the for services stand-alone eeomn Company Development Product Total The Group, Development Product Azopharma D I NNOVATIVE EVELOPMENT TM www.azopdogroup.com www.adhesivesresearch.com rvdsfl rdc eeomn and development product full provides , P rdcst etcustomers’ meet to products manufacture uniqueformulate and capabilitiesintegrates these to analytical capabilities. company The design, supported by liner release mixing, compounding, coating, and synthesis, polymer include adhesive developmentcustom capabilities industry. Adhesives Research’s pharmaceutical the for systems pressure-sensitive adhesive experience manufacturing of years 20 over Adhesives has Research LATFORMS S ERVICES . .

59 Drug Delivery Technology March 2009 Vol 9 No 3 59-61- DDT March 09-Tech Showcase:Layout 1 2/26/09 11:46 AM Page 60

PREFILLABLE DELIVERY SYSTEMS CAPSULE FILLING &SEALING

BD Medical - Pharmaceutical Designed to allow formulation Systems is dedicated to scientists the ability to better developing prefillable drug exploit the potential of lipid-based delivery systems designed to formulations for poorly soluble fit the needs of the compounds, the CFS 1200 helps pharmaceutical industry. accelerate the development Whether a glass or plastic timeframe and achieve Faster prefillable syringe, a nasal Time to First in Man. A fully spray system, a dry drug automatic cGMP-compliant reconstitution system, an machine, it fills and seals up to 1,200 capsules per hour with liquid or injection or self-injection device, BD Medical - Pharmaceutical Systems semi-solid formulations without banding. It is designed for ease-of-use provides the expertise and experience required by the pharmaceutical and high reliability, with the ability to quickly clean and change capsule industry in a packaging partner.We deliver cost-effective alternatives to sizes with available change parts. Product integrity is ensured with gentle conventional drug delivery methods, which differentiate pharmaceutical handling of capsules before sealing and during the drying cycle. Other products and contribute to the optimization of drug therapy. All of its features include a robust filling pump with highly accurate temperature prefillable devices are designed to meet healthcare professionals' control, improved capsule manipulation before sealing and during drying demands for safety and convenience and to fulfill patients' needs for using new “Cap-edge” handling system, and improved design of filling comfort. BD’s worldwide presence, market awareness, and and sealing process that ensures better control and cleanability. Fore more pharmaceutical packaging know-how allow it to propose suitable information, contact Capsugel at (888) 783-6361 or visit solutions for all regional markets and parenteral drug delivery needs. For www.capsugel.com. more information, contact BD Medical - Pharmaceutical Systems at (201) 847-4017 or visit www.bdpharma.com.

UPPER GI DELIVERY DEVELOPMENT &MANUFACTURING

AcuForm is Depomed’s unique, patented, polymer-based technology designed to optimize drug delivery. AcuForm allows for targeted, controlled delivery of pharmaceutical ingredients to the upper GI tract, the preferential absorption site for many DPT is a contract development and manufacturing organization oral drugs. Unlike immediate- and (CDMO) specializing in semi-solid and liquid dosage forms. DPT some extended-release formulations provides fully integrated development, manufacturing, and packaging that pass through the upper GI tract solutions for biopharmaceutical and pharmaceutical products. DPT is within approximately 3 hours the industry source for semi-solid and — from concept to following ingestion, AcuForm’s unique swelling polymers allow the tablet commercialization and beyond. Drug development services range Vol 9 No 3 to be retained in the stomach (gastric retention) for approximately 8 to 9 from preformulation, formulation and biopharmaceutical hours. During this time, the tablet’s active ingredient is steadily delivered development, analytical development, and validation through process to the upper GI tract at the desired rate and time, without the potentially development. Production capabilities include four cGMP facilities, irritating burst of drug that often occurs with other formulations. For clinical trial materials, full-scale commercial production, controlled March 2009 more information, visit Depomed, Inc. at www.depomedinc.com. substance registration Class II-V, and complete supply chain management. Packaging services encompass engineering and procurement resources necessary for conventional and specialized packaging. For more information, contact DPT at (866) CALL-DPT or visit www.dptlabs.com. Drug Delivery Technology

60 59-61- DDT March 09-Tech Showcase:Layout 1 2/26/09 11:46 AM Page 61

BIOAVAILABILITY ENHANCEMENT CONTRACT SERVICE PROVIDER

PharmaForm doesn’t just provide its clients with creative solutions; it creates successful partnerships. As a pharmaceutical contract service provider, it offers a wide range of formulation, drug product development, manufacturing, analytical testing and stability services, patent litigation support services, and product platform Biorise® increases the “intrinsic dissolution rate” of poorly water-soluble licensing opportunities. Its formulation drugs, thereby enhancing their bioavailability and/or onset of action. scientists have core expertise and Eurand’s proprietary Biorise and Diffucaps® technologies can be applied to experience in improving solubility of enable formulation of insoluble drugs and to improve the rate and extent poorly soluble compounds. One such of absorption of drugs from oral dosage forms. Diffucaps is a available technique to clients is multiparticulate system that provides flexible dosage strength, required PK Evaporative Precipitation into Aqueous profile, and optimal release profiles for single drugs and drug Solutions (EPAS), a process that causes the formation of nano-sized combinations. The Diffucaps drug- release system can also be used in particles that can help enhance bioavailability of a poorly soluble combination with other Eurand technologies to enhance drug solubility in compound. PharmaForm’s state-of-the-art facility is registered with the the GI tract. For more information, visit Eurand at www.eurand.com or FDA and the DEA and is cGMP/GLP Compliant. For more information, email us at [email protected]. contact PharmaForm at (512) 834-0449 or visit www.pharmaform.com.

GLOBAL CENTRAL LABS PACKAGING MATERIAL

PPD’s global central ZEONEX Cyclo Olefin labs fully support your Polymer (COP) offers drug development advanced, break-resistant programs with packaging for protein- extensive global reach; based, peptide-based logistical expertise; biopharmaceuticals and highly customized and high-viscosity drugs, as flexible services; strong well as contrast media. Its and consistent science “glass-like” transparency and therapeutic allows for easy inspection expertise; high-quality performance (98.5% data acceptance rate); of the drug prior to and during injection without the concern of efficient, accurate, and rapid sample collection; and state-of-the art breakage. Because of its low water absorption and high purity, drugs laboratories with all relevant accreditations and certifications. Through can be stored for longer periods of time compared to other medical plastics. ZEONEX is optimal for protein- and peptide-based drugs strategically located facilities in North America and Europe, and with the Vol 9 No 3 use of sophisticated logistics and courier services, PPD provides clinical because, unlike glass, it overcomes protein adsorption and pH shift of laboratory services to investigator sites in virtually every country of the a diluents’ concerns. The COP has superior moldability and can be world. PPD recently announced it has expanded its global central lab molded for prefilled , pen injector cartridges, and vials

services into China through an exclusive agreement with Peking Union ranging from < 10 ml to > 250 ml in size. For more information, March 2009 Lawke Biomedical Development Limited. For more information, contact contactZeon Chemicals at (877) 275-9366 or visit Rob Danziger at (859) 442-1300 or visit www.ppdi.com. www.zeonchemicals.com/breakthroughCOP. Drug Delivery Technology

61 62-67-DDT Mar 09 - SP Feat Analytical Labs:Layout 1 2/26/09 11:48 AM Page 62

Analytical Lab Outlook Analytical Testing Labs in the Pharma Industry: Where Do They Stand?

By: Cindy H. Dubin, Contributor Vol 7 No 3 Vol 9 No 3

MARCH 2007 Josef K. Ludwig Robin L. Ciupidro, PhD MARCH 2009 Director of Pharmaceutical Analysis, Manager, Pharmaceutical BASi Development Services Xcelience, LLC

Ruth Moore, PhD SPECIALTY PHARMA SPECIALTY PHARMA Dr. Richard Grant Vice President of Director of Laboratory Services, Analytical Services, SNBL USA UPM Pharmaceuticals, Inc.

62 62-67-DDT Mar 09 - SP Feat Analytical Labs:Layout 1 2/26/09 11:48 AM Page 63

study design. Quick movement in these areas helps meet our In the past few years, stringent control on spending by the sponsors’ deadlines. The ability to start a project quickly is pharmaceutical industry has affected the growth of the analytical directly linked to the quality of the communication between laboratory services market, according to a recent Frost & Sullivan the testing lab and the sponsor. Once an understanding of the research report, North American Analytical Laboratory Services project’s scope and requirements, including time lines, can be Market. Yet, the analytical lab testing market is bound to recover. Major reached, a project can be scheduled and begin very rapidly. cost reduction by pharmaceutical companies has affected laboratories in This brings us back to the price and value topic. With a clear a positive way. Such cost-cutting measures have resulted in the understanding of the project objectives, the price can be outsourcing of laboratory services to contract research organizations quickly negotiated and the value determined. and small analytical laboratories, explains the Frost & Sullivan report. There has been an upswing in the number of samples received by Dr. Moore: There are many more formulations that analytical laboratories, and pharma companies' need to discover that involve low doses of highly potent drugs that present next blockbuster will mean more work for the contract lab. challenges for the development of sensitive and specific One source of competition for the analytical testing lab is the analytical methods to support the testing in complex contract manufacturer. According to a new report by Visiongain, formulation matrices, for attributes such as content uniformity, Contract Pharma 2008-2023, CMOs are increasingly undertaking potency, quantification of degradants, and determination of analytical testing and other value-added services alongside traditional drug-release profile through dissolution testing. contract manufacturing of APIs to generate more revenue. Specialty Pharma magazine gathered some of the leaders in the Dr. Grant: For all of last year and continuing into 2009, analytical testing lab market to find out how the relationship between the analytical biology department of SNBL USA has been the lab and pharma client is shaping drug development. Participants in busier than any other operational area, which is reflective for this discussion include Robin L. Ciupidro, PhD, Manager, the general increase in biologics entering into preclinical Pharmaceutical Development Services, Xcelience, LLC; Dr. Richard development. Our laboratories have validated five new Grant, Director of Laboratory Services, SNBL USA; Josef K. Ludwig, computerized systems and accompanying methods to support Director of Pharmaceutical Analysis, BASi; and Ruth Moore, PhD, rapid multi-target analysis. Luminex, electrochemiluminescent Vice President of Analytical Services, UPM Pharmaceuticals, Inc. (ECL), fluorescent, PCR, and flow cytometry based equipment and methods are the hot new technologies for rapid analysis of multiple analytes. The scientific expertise in many CROs is not Q: What is the hot issue(s) right now in yet matured to support these new technologies, yet the needs for analytical testing are immediate. At SNBL USA, we were drug development from the fortunate to invest early in these new technologies and hired perspective of an analytical testing the scientific staff necessary to support performance of high- lab? quality bioanalytical assays in accordance with GLP standards. Vol 9 No 3

Mr. Ludwig: The hot issues from our sponsors are still timing and price. The changes in the economy impact both us Q: Please discuss the interaction and our sponsors. Money is tight and everybody is a little

between the analytical lab and the MARCH 2009 more concerned with both price and the value of services. Our sponsors are more in tune with pricing factors, including the contracting pharma company quality of their projects, as well as project initiation and throughout the drug development completion. Timeliness is also a key issue. Most sponsors’ study(ies). initial question is: How soon can you start? We have worked on our internal procedures to reduce the time necessary to

Dr. Moore: Successful project outcome is directly related SPECIALTY PHARMA initiate new programs, such as approval of confidentiality to the maintenance of open communications and close agreements and cost proposals, plus having a scientist interaction between the analytical lab and the contracting available to review the technology transfer information and pharma company. The analytical lab must understand the quickly provide follow-up questions to assist in the overall 63 62-67-DDT Mar 09 - SP Feat Analytical Labs:Layout 1 2/26/09 11:48 AM Page 64

project timelines, what analytical tasks are on the critical path, to manage capacity overflow. In this case, Xcelience and the and their impact on other project deliverables. The sharing of contracting pharma company may work together to devise a technical information previously acquired by the contracting full time equivalent (FTE) program, enabling the contracting pharma can contribute significantly to increasing the company to rely on a core group of personnel as an outsourced efficiency of methods development in the analytical lab. In our resource, with the option and flexibility to increase headcount business, the analyst is an active and involved participant at during peak project periods. Once the program is initiated, project team meetings with the client so they can grasp a contracting companies rely on a dedicated project manager as thorough understanding of the entire project objectives, a single user interface for analytical methods transfer, access timelines, and activities that they impact, or those that impact to scientific personnel, status updates, and final reports. For the deliverable items for which they are directly responsible. pharma companies seeking access to drug development expertise, or with limited knowledge of API, or those seeking Dr. Grant: Pharma should begin discussions with their an alternate service provider to help restore a project when a CRO immediately upon determining that outsourcing will be timetable has slipped, partnership takes on quite a different required. Early discussions at the level of analytical scientists, meaning. The ideal interaction balances expertise and several months before the expected date of study initiation, is flexibility. Where prior analytical method development efforts the best way to assure your chosen lab will perform to have stalled, or contracting pharma companies have expectations when it comes time for sample analysis. To encountered timing issues or double-booked capacity, minimize risk, scheduling goals for study planning should Xcelience will work with contracting companies to develop a include that the validation activities are completed before step-by-step plan and quickly mobilize a project team. Our animals or subjects begin treatment. At SNBL USA, scientists experienced staff will perform an evaluation of analytical are assigned to analytical projects based upon their relevant methods to determine whether they are suitable for expertise. To foster and support a partnering relationship, qualification and validation according to the intended use. regular and frequent communication is maintained between the Keeping end-goals in mind, we will optimize run time, attempt sponsoring laboratory personnel and CRO scientists to combine methods where possible, and evaluate linearity, throughout the development and validation processes. This specificity, selectivity, accuracy, and precision. Having an two-way communication from early development or method experienced staff and dedicated project management function transfer through preparation of reports ensures seamless are two key elements that contribute to our ability to back up bioanalysis of client samples with minimal surprises. these commitments.

Dr. Ciupidro: Outsourcing experience and product Mr. Ludwig: The easy answer is…as much as possible, and knowledge are two significant factors determining the amount more communication is always better. We recognize that not of interaction required between a contracting pharma company only do sponsors want constant updates, but they want to be Vol 9 No 3 and an outsourced analytical service provider for a successful immediately involved in any changes or potential issues. We drug development project. At Xcelience, we understand that have found the best way to start a program is with a kick-off the parameters for an ideal partnership will differ based on a meeting, either face to face or via teleconference. This allows number of factors, including company size, company type, the project scope, requirements, direction, and timelines to be MARCH 2009 project goals, knowledge of API, and therapeutic area known and agreed upon by all parties. A complete technology expertise. Overall, the ability to remain flexible to different transfer is also important. This usually includes follow-up client needs is critical as we work with contracting companies questions and possible in-lab familiarization. Routine project to create tailored solutions that enable them to accelerate reviews with sponsor contacts are also helpful to maintain development, meet critical milestones, or manage capacity. timelines and discuss any technical issues. We recognize that

SPECIALTY PHARMA For contracting pharma companies with defined project goals even with the best technology transfer, the contracting lab and core areas of expertise, the ideal outsourcing relationship experts have additional information that may help resolve may require a mode of interaction that optimizes their ability issues quickly and efficiently. Interactions with the sponsors

64 62-67-DDT Mar 09 - SP Feat Analytical Labs:Layout 1 2/26/09 11:48 AM Page 65 62-67-DDT Mar 09 - SP Feat Analytical Labs:Layout 1 2/26/09 11:48 AM Page 66

are also helpful after completion of the project. A wrap-up documentation and procedures in place to allow for full study meeting can answer the questions: Did we meet your quality reconstruction and data integrity. Review the Master Schedule and timeliness requirements? Are there any areas where we to ensure there is an adequate level of staff to support all the could improve? Is there any additional follow up-work that may activities being performed at the analytical laboratory. The be necessary? Quality Assurance unit must be independent of the laboratory and should conduct critical phase audits in addition to review of all data and final reports. Q: What factors should come into play for a pharma company when deciding Mr. Ludwig: When outsourcing non-clinical studies, whether to have analyses performed sponsors should look for an analytical lab with a proven GLP compliance record and a strong knowledge of GLP and OECD in-house or by a contracted lab? requirements. Sponsors should ascertain the willingness and ability of the analytical lab to be transparent, open to audits, Dr. Grant: Considerations for the pharma company should and inspection. It is fundamental for the analytical lab to have include whether their in-house laboratory has the appropriate established SOPs and validated key software and equipment; infrastructure to comply with the regulatory requirements for sufficient number of educated, trained personnel and defined bioanalysis. The costs associated with building and maintaining roles for key personnel; Study Director and Quality Assurance. this infrastructure are relatively high, especially for smaller It is also essential for the analytical lab to have the appropriate companies, which may require only a few assays validated to resources for record retention and characterization of test and GXP standards. CROs are well positioned to conduct these control articles. assays in a compliant and cost efficient manner.

Dr. Moore: The pharma company should review the overall Dr. Moore: The quality systems and experience of the quality system to ensure that SOPs are in place to meet GLP personnel at the contracted lab should be a critical factor in requirements, that the facilities and equipment meet required such a decision, as well as availability of resources relative to standards with respect to maintenance and validation programs, the desired turn-around time at the respective labs. and that adequately qualified and trained personnel are in place to conduct the work and provide quality assurance and regulatory oversight. Q: What GLP requirements should pharma look for in an analytical lab Q: that will be involved in drug What procedures should pharma have Vol 9 No 3 development? in place to ensure the contracted lab complies with GLP regulations? Dr. Grant: Before placing samples with an analytical lab,

MARCH 2009 pharma should review laboratory SOPs and perform a site visit, Dr. Grant: With so many types of testing that can occur in if possible, and ensure there are adequate facilities and a laboratory, it is vital that analytical staff understand and procedures to perform the assay. Of critical importance is practice a systematic approach toward method validation and determining if the analytical staff has the necessary experience sample analysis. An analytical lab must have well-defined to perform the analysis, and that their training has been SOPs that describe their processes. Some key SOPs include appropriately documented. The facility must have the SOPs to method validation, instrument operation and maintenance,

SPECIALTY PHARMA perform the assay embracing the May 2001 Bioanalytical sample handling, staff training, lab investigations, repeat Guidance and subsequent AAPS white papers. Walk through analysis, incurred sample reanalysis, and Quality Assurance the facility and check for instrument maintenance logs, procedures. Pharma should take an active role in reviewing the including computerized validation. There must be 66 method validations and ensuring “fit-for-use” in their study, 62-67-DDT Mar 09 - SP Feat Analytical Labs:Layout 1 2/26/09 11:57 AM Page 67

such as, is there demonstrated long-term stability to encompass Dr. Grant: SNBL USA offers UV-Vis and HPLC (including the anticipated study duration? Method validations and sample SEC) formulation analysis, LC-MS/MS and HPLC bioanalysis analysis plans or protocols must describe unambiguous and of plasma, urine and tissue samples, ligand binding assays predefined acceptance criteria. An adequate chain-of-custody (custom and off-the shelf), multi-analyte profiling (Luminex and sample storage procedures to maintain sample and MesoScale), qPCR, and flow cytometry services as part of accountability should also be ensured. our analytical program. Rapid incorporation of new analytical Dr. Moore: systems and validation of methods to support analysis for a Pharma should have a vigilant and experienced large library of endogenous proteins enable us to stay ahead-of- audit team that would perform a thorough audit of the the-curve and competitive within the drug development contracting lab. QA personnel should exercise due diligence in industry. reviewing the data and reports produced by the testing lab on an on-going basis. Q: What value do customers place on Mr. Ludwig: When outsourcing any study along the drug quality and cost when it comes to discovery chain, it is important for sponsors to recognize that analytical testing in drug development? working with a contract lab should be a partnership. This partnership must have open lines of communication and clear Dr. Moore: Quality of the results is of greatest importance agreed-upon deadlines and expectations. On the part of to our customers. They do expect reasonable costs, but this is in sponsors, it is vital to have an established procedure in place for many cases not the key determinant, and in fact, several clients verifying the contract lab’s compliance with GLP regulations are willing to pay higher prices to labs they are confident will and the company’s relationship with the FDA. This can be provide work of the highest quality. Results from analytical accomplished through on-site audits with the facility to testing are relied upon for making key strategic decisions at all determine compliance with each critical area of the GLPs. This stages of the iterative formulation development process so the is further complicated in many GLP studies where there are quality of the data is critical. three or more parties contributing to the same study - for instance, a preclinical/toxicology contractor, and multiple Dr. Grant: Reliable and high-quality analytical results, analytical testing facilities. These groups are required to work combined with on-time reporting are the most important factors through the study director, and maintaining communication for our customers. Cost considerations are also important to with the sponsor is also imperative. give overall value for their investment.

Mr. Ludwig: I believe that all sponsors and all contract labs Q: What analytical services do you offer are different when it comes to valuing quality against the other Vol 9 No 3 as part of a client's drug development project criteria. We prefer to work with sponsors who program? How have these services understand the increased value they are receiving in the quality of our work. The overall quality, as we see it, not only includes evolved to keep up with the actual data generated, but also the supporting data, MARCH 2009 biopharmaceutical development? processes, and procedures. The strength of these items makes Dr. Moore: actual data generated easily defensible in any audit. We Our analytical services include method encourage our clients to audit our sites, data, and procedures. development and validation for assay of drug substance and drug We believe constant audits (different sponsors) continually product, including the development of stability-indicating improve the quality of our product, and we have a great history assays; content uniformity and dissolution testing; with our FDA inspections to prove it. N SPECIALTY PHARMA preformulation studies such as pH-solubility, Log D, Log P and excipient compatibility tests; and release testing and stability testing of clinical trial materials and commercial drug products. 67 68-73-DDT MAr 2009 -SP-Therapeutic Focus:Layout 1 2/26/09 11:48 AM Page 68

Therapeutic Focus

Cardiology & Oncology Drug Development & Regulation

By: Stuart L. Cantor, PhD, Senior Scientist, and Kadriye Ciftci, PhD, Senior Director Drug Delivery, ICON Development Solutions

reach $80 billion by 2012, according to the development of highly potent, Introduction IMS Health. hydrophobic compounds, and difficulty Heart disease and cancer are still the There are several reasons for this in ensuring their solubility as well as two leading causes of mortality in the increased sales growth, which include specificity to target the tumor site. world. Recent data show that in the US, extended lifespan, increases in obesity Because oncology drugs are cytotoxic, the total direct and indirect costs and hypertension in the US population, maintaining containment facilities during associated with treating cardiovascular an increasing number of patients on the developmental phase for these actives diseases and stroke are estimated to be chemotherapy in major markets, longer can become expensive. Furthermore, $449 billion, by comparison, the treatment periods for a growing number with both of these drug classes, estimated costs for all types of cancer of patients, and the was $219 billion.1 Sales of drugs treating greater availability cardiovascular disorders, hypertension, of more expensive and cancer accounted for roughly 31% of and modern the $287 billion prescription targeted therapies pharmaceutical market in 2007; these to treat these drugs continue to be the largest therapy diseases. However, 2

Vol 9 No 3 classes in the US (Figure 1). In the hotly debated cardiology sector, Pfizer’s Lipitor® issues have risen amassed sales revenues of $12.7 billion over the long-term in 2007, making it the best selling drug safety of coronary in pharmaceutical history. Not to be drug-eluting stents MARCH 2009 outdone, the biotech industry has (DES), efficacy of likewise developed a number of beta-blockers in successful blockbuster cancer therapies treating as intravenous solutions or vaccines, hypertension, and including Herceptin® and Avastin®, the long-term monoclonal antibody-based therapies to safety of statins. In SPECIALTY PHARMA treat breast and colon cancer, the oncology respectively, and Gardasil®, a vaccine sector, there has Figure 1. against cervical cancer.3 Sales of cancer been an increase in drugs are projected to double and could 68 68-73-DDT MAr 2009 -SP-Therapeutic Focus:Layout 1 2/26/09 11:48 AM Page 69

difficulties proving efficacy or organization unexpected safety concerns, particularly (CRO) can assist a during later-stage development amid company with Phase III trials, can be particularly developing a challenging. game plan for the The increased number of extent of both blockbuster drugs that are scheduled to preclinical animal lose patent protection in the coming testing and future years (Figure 2), coupled with the FDA’s clinical trials; Amendments Act of 2007 granting such services can sweeping new powers to the agency for be outsourced by such tasks as requiring drug makers to start-up or virtual do post-marketing clinical trials, are companies with making the regulatory climate more limited in-house expensive and time-consuming for the drug development pharmaceutical industry. Furthermore, resources. The because drug safety issues are CRO can also paramount due to highly publicized help the company cases like Vioxx®, the FDA is closely in its scrutinizing safety data while improving correspondence Table 2. its management of safety signals. with the FDA and offer guidance during the critical pre-IND meeting. physicochemical stability and potential Drug Development Under current regulations, a sponsor is immunologic issues need to be closely Oncology drugs in development are permitted to start their clinical trials 30 monitored and controlled to ensure a generally highly potent as well as days after filing its IND with the FDA drug product’s beneficial effects. cytotoxic; some may even have narrow unless notified earlier that there are “In contrast to most drugs that are therapeutic windows. It is important to issues with the application. chemically synthesized and with a assess the safety of these compounds Recent reports from the known structure, most biologics are early on to determine that they are Pharmaceutical Research and complex mixtures that are not easily effective in treating the disease process Manufacturers of America (PhRMA) identified or characterized. Biological while not damaging healthy tissue. noted that 750 new medicines are being products, including those manufactured According to the M3 Guidance for tested in the fight against cancer, and by biotechnology, tend to be heat Industry, single-dose acute toxicity 256 new medicines are in development sensitive and susceptible to microbial studies are required to be performed for to treat cardiovascular diseases.5,6 While contamination,” says Paul Richards, pharmaceuticals and should be Vol 9 No 3 there have been a number of successful FDA Spokesperson at CBER. evaluated in two small mammalian anti-neoplastic small molecules “Therefore, it is necessary to use aseptic model species before the first human launched over the years, such as 5- principles from initial manufacturing exposure.4 fluorouracil, paclitaxel, and steps in order to ensure sterility of the The ratio of time for animal to finished products, which is also in

doxorubicin, the focus has shifted away MARCH 2009 human testing is 1:1, meaning that the from broad-acting cytotoxic drugs contrast to most conventional drugs.” FDA will allow a company to conduct toward the development of new Furthermore, vaccine clinical human clinical trials for only the same therapies directed against specific development follows the same general time period in which animal data has molecular targets. Although biologics pathway as for drugs and other been supplied. Sometimes, the agency and vaccines derived from larger protein biologics. However, due to the complex can also request that safety and/or nature of many vaccines, each lot must molecules offer promise in these SPECIALTY PHARMA toxicity data in a non-human primate therapeutic areas due to their high be thoroughly tested for safety, sterility, also be supplied before an disease specificity and activity at and potency by the manufacturer. These Investigational New Drug (IND) can be relatively low concentrations as tests, as well as many others that approved. A contract research compared with small molecules, manufacturers must perform, are 69 68-73-DDT MAr 2009 -SP-Therapeutic Focus:Layout 1 2/26/09 11:48 AM Page 70

specified in their biologic license NDAs (ANDAs) from the US and approved drug product, and such filings applications (BLAs). If the product is required for European and Japanese can be used to support new and subject to official release by the FDA’s submissions. Canadian INDs must also innovative drug delivery forms. Data Center for Biologics Evaluation and be in CTD format; however, these are from published studies can even be Research (CBER), the manufacturer referred to as CTAs or Clinical Trial submitted to the FDA. However, the must submit samples of each production Applications for Phases I-III. The CTD company would need to provide lot to the Agency together with a release contains several modules with Modules 2 additional clinical data necessary to protocol showing a summary of the lot and 3 containing critical Chemistry, demonstrate any safety and efficacy manufacturing history and the results of Manufacturing, and Control (CMC) differences between the original drug all the manufacturer’s tests performed on information. and the 505(b)(2) drug. Some of the that lot, says Mr. Richards. While Module 2 deals with both different types of applications covered by “The most challenging aspects to non-clinical and clinical overviews and the section 505(b)(2) are: developing these biologic drugs is the summaries, the quality section or design of efficient and robust Module 3 deals only with CMC issues • change in an active ingredient (ie, fermentation and purification processes and provides information on the different salt, ester, complex, and the production of a stable physicochemical properties and control chelate, clathrate, racemate, or formulation,” says Peter Ihnat, PhD, Sr. of the drug substance as well as the enantiomer) for a listed drug Principal Scientist, Protein Therapeutics, development, manufacture, and control containing the same active Bristol-Myers Squibb. of the finished drug product. Modules 4 moiety; Protein formulations can be and 5 address non-clinical and clinical developed using either lyophilized study reports, respectively. Updates to • change in , strength, powders or liquid parenterals; however, the IND data following Phase I-II trials formulation, dosing regimen, or freeze-drying is not as popular an option can be provided in information ; and/or nowadays due to the increased cost and amendments and annual reports; • change from a prescription longer development time required to however, the emphasis should be on indication to an over-the-counter produce a successful formulation. reporting significant changes that can indication. “Typically, the target level for have a safety-related impact. CMC protein impurities for liquid formulations development will continue in parallel is < 5%, and these are usually due to with the clinical development during The important benefits of using the oligomers or aggregates; however, due to Phase III studies.9,10 505(b)(2) filing route are a faster the immunogenic potential of these If the CMC section will be written pathway toward regulatory approval compounds, impurity levels are for an already approved drug but a new without giving the sponsor the burden of evaluated on a case-by-case basis. dosage form, the Drug Master File supplying duplicate safety and efficacy Moreover, long-term protein stability is (DMF) number, if available, can be data on an already existing compound. monitored using at least two to three referenced for some of the pertinent However, the FDA does still require that

Vol 9 Noorthogonal 3 methods in addition to an in manufacturing information for the drug a sponsor provide additional clinical vitro bioassay to assess biological substance. For all scientific data, the data, termed bridging studies, which are activity,” says Mr. Ihnat. FDA is particularly concerned that the necessary to support any changes or experimental study design and statistical modifications from the listed drug(s) to analysis be sound and free from flaws, the 505(b)(2) drug(s), and these studies MARCH 2009 Regulatory and requires a rationale and justification will allow extrapolation of the efficacy Submissions used for final specifications selected as and safety data. Furthermore, a The CTD or Common Technical well as the use of novel excipients and 505(b)(2) applicant may qualify for 3 or Document was developed to be used for any unusual tests performed. 5 years of Hatch-Waxman marketing 11 regulatory submissions and finalized as Two other regulatory submission exclusivity. the M4 Guidance for Industry in 2004.7,8 pathways available are the 505(b)(2) and The other non-traditional route for SPECIALTY PHARMA This table of contents format is highly combination product options. The regulatory approval deals with recommended for INDs, New Drug 505(b)(2) route offers companies the combination products, such as coronary Applications (NDAs), and Abbreviated advantage of not having to supply the DES, which are considered a drug- device combination product under the 70 safety and efficacy data on an already 68-73-DDT MAr 2009 -SP-Therapeutic Focus:Layout 1 2/26/09 11:48 AM Page 71

Code of Federal Regulations (CFR) 21 such as near-infrared (NIR) or Raman clinical endpoint such as survival or CFR 3.2(e)(1). The Office of spectroscopy, to provide real-time process morbidity, and which is reasonably likely Combination Products (OCP) at the FDA data. PAT finds wide applicability in the to predict clinical benefit. Examples of assigns such products to a lead agency pharmaceutical industry and can be used tumor assessment endpoints are response center, based upon the product’s primary to assess blend and content uniformity, rate to drug therapy or time to tumor mode of action. OCP ensures timely, prediction of dissolution time, and can progression, measured using anatomic consistent pre-market review and determine the end-point of a coating or imaging techniques. Once accelerated appropriate post-market regulation of drying operation. Not only can end- approval has been granted, continued combination products by facilitating the product testing be reduced, which can marketing of the product will be review process involving more than one save a company money, but the FDA can contingent on the sponsor’s providing agency center. In this case, the also provide some regulatory flexibility timely and conclusive evidence from investigational device exemption (IDE) for any process changes that could occur validation trials that establishes that the application would be sent to the FDA’s in the future, provided that they are experimental drug is safe and provides Center for Devices and Radiological accompanied by scientific justification.13 tangible clinical benefit. The product Health (CDRH) with significant “The Agency considers PAT to be a approval can be withdrawn if consultation by the Office of New Drug tool for designing, analyzing, and confirmatory studies fail to show clinical Quality Assessment (ONDQA)/Division controlling manufacturing through timely benefits, or if the drug sponsor fails to of Cardiovascular and Renal Products. measurements (ie, during processing) of conduct the confirmatory studies. Many scientific and regulatory issues critical quality and performance attributes A fast-track status is granted by the will arise due to the complex nature of a of raw and in-process materials and Agency for those drugs also developed to coronary DES. Some important concerns processes, with the goal of ensuring final treat life-threatening diseases and that that would need to be evaluated and product quality. The goal of PAT is to demonstrate the potential to address an discussed in a submission include acute enhance understanding and control of the unmet medical need. In this instance, a and chronic stent biocompatibility, manufacturing process and to facilitate rolling NDA can be approved that allows polymeric coating characterization (ie, innovation in development, for completed sections of the NDA to be thickness, uniformity, integrity, adhesion manufacturing, and quality assurance by submitted to the FDA on an ongoing to stent), and drug release profile. The focusing on process understanding. These basis. The FDA strongly recommends predominant percentage composition of a concepts are applicable to all several meetings, including a pre-IND combination product does not dictate the manufacturing situations,” says Jon E. consultation, meetings following Phases Agency center(s) where it is regulated, Clark, MS, Associate Director for the I-II, and a pre-NDA meeting to expedite rather, it is the primary mode of action or Office of Pharmaceutical Science (OPS) the approval process. The other the “most important therapeutic action of Policy Development at the FDA CDER. designation, priority review, is for drugs a combination product” that determines Due to the serious nature of the showing a significant therapeutic benefit where a combination product will be diseases they treat, both cardiology and compared to the standard of care. In this regulated. For example, DES submissions oncology drugs qualify under the fast- case, the FDA would review a NDA

are assigned to CDRH because the track drug development program within 6 months as opposed to the Vol 9 No 3 device’s role in physically maintaining classification. The three designations standard review completion timeline of vessel lumen patency provides the most given by the FDA are accelerated 10 months. important therapeutic action of the approval, fast-track, and priority combination product. The drug plays only review.14,15 In 1992, accelerated approval a secondary role in reducing restenosis or for oncology drugs was codified into law Outsourcing Key MARCH 2009 re-narrowing of the coronary arteries, a under Subpart H (21 CFR part 314.530) Capabilities phenomenon which is caused by the and added to the new drug application In addition to hearing the term CRO body’s formation of scar tissue in regulations. Accelerated approvals are as a common buzzword these days, the response to stent implantation.12 granted for the treatment of serious or fact is that both small and large While the agency currently does not life-threatening conditions and a benefit pharmaceutical companies can benefit SPECIALTY PHARMA require the use of Process Analytical over available therapy exists. from utilizing the added services and Technologies (PAT) for their submissions, This designation requires using a expertise of a global CRO while focusing the use of PAT for CMC documentation surrogate endpoint for efficacy, ie, an on their core competencies. The CRO is looked upon favorably. PAT uses tools, evaluation intended to substitute for a 71 68-73-DDT MAr 2009 -SP-Therapeutic Focus:Layout 1 2/26/09 11:48 AM Page 72

market size is currently estimated at about $15 billion in revenue per year and is growing at a healthy annual rate of 14.8%. By 2010, the market is forecast to be in Stuart Cantor, the vicinity of $22.9 billion, according to Frost & Sullivan. A CRO should be chosen PhD carefully at the outset of a project after considering the budget, timelines, the range Senior Scientist of services provided, and the resources offered. A CRO can assist with the review and ICON Development Solutions editing of the regulatory submissions and can either represent the company as their sole agent or accompany their client in meetings with the FDA. For smaller companies with limited resources, limited regulatory expertise, and tight timelines, meetings with the FDA early in the development process can alert the company if they are going down the wrong pathway.

Meetings with the FDA can be arranged at both the pre-IND stage, where the Dr. Stuart Cantor graduated from the University of company can ask questions to see if they have done enough work to prove a drug’s Maryland Pharmacy School and is a Senior Scientist safety, and also before going through the time and expense for Phase III clinical trials for ICON. Dr. Cantor currently assists global clients (an after Phase II meeting). These meetings are invaluable in identifying additional with their CMC sections of regulatory documents for safety, toxicity, or efficacy issues pertinent to cardiology and oncology IND/NDA solid dosage forms and biologics, and also handles filings. More frequent interaction with the FDA would be recommended (ie, end of clinical supply chain management issues. He has 7 Phase I meeting) if the drug would be marketed to a small patient population with a pharmaceutical publications online/in-process, and rare disease or condition, ie, orphan drug classification for a disease affecting less has published a book chapter on wet granulation. than 200,000 people in the US. Orphan drugs would also be granted accelerated He interned at Wyeth and Bristol Myers Squibb approval status, and NDAs are given a priority review timeline of 6 months. (BMS) and studied different granulation processes A CRO can act as a regulatory resource for a company to guide them as to what and their mechanical properties. His research covered preformulation, formulation, analytical the minimum agency requirements are to prove safety and efficacy and which tests method validation, blend segregation, and chemical would be superfluous. Another key advantage of using a CRO is that they have the imaging. His expertise is in extrusion- capability to offer their clients a strategic viewpoint on risk assessment and spheronization, wet granulation, and NIR management, and can additionally shoulder some of that risk in interactions with the spectroscopy. Dr. Cantor previously developed the FDA. The Agency will take a global view of the scientific data to assess the risk- sugarless fiber chews for diabetics launched by benefit ratio, ie, the benefits of the drug substance and final drug product must far BMS under the Choice® DM brand. outweigh any complications or potential risks to human health. The Agency also examines what therapeutic advantages the new product has over therapies currently in Kadriye Ciftci, the market. Sometimes there is no information available on comparator products as PhD the regulatory submission is for a first-in-class therapy. In such instances, a CRO can Senior Director Drug provide key information as it can draw from a wide knowledge base from past client Delivery experiences with a variety of dosage forms. ICON Development N Solutions

Vol 9 No 3 References

1. Rosamond W, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. [Available at: http://circ.ahajournals.org/cgi/content/full/117/4/e25 (DOI: 10.1161/circulationaha.107.187998); Accessed August 6, 2008]. 2. Buono D. IMS study finds decline in prescription drug market growth. Drug Store News. (April 21, 2008) [Available at: http://findarticles.com/p/articles/mi_m3374/is_5_30/ai_n25407255; Accessed July 30, 2008]. Dr. Kadriye Çiftci is Senior Director of Drug 3. Lawrence S. Billion dollar babies-biotech drugs as blockbusters. Nature Biotechnol. 2007;25(4):380-382. [Available at: http://www.nature.com/naturebiotechnology ; Accessed August 6, 2008]. Delivery/Formulations at ICON Development

MARCH 2009 4. FDA Guidance for Industry M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER), (July 1997). Solutions. She has more than 15 years of 5. 2008 Report: Medicines in Development for Cancer. [Available at: http://www.phrma.org/files/meds_in_dev/Cancer2008.pdf; Accessed July 27, 2008]. experience in academia and pharmaceutical R&D. 6. 2007 Report: Medicines in Development for Heart Disease and Stroke. [Available at: http://www.phrma.org/files/Heart2007.pdf; Accessed July 27, 2008] 7. FDA Guidance for Industry M4: The CTD- Quality Questions and Answers/Location Issues. CDER & CBER, (June 2004). Dr. Ciftci completed her training at the University of 8. FDA Guidance for Industry M4: The CTD- General Questions and Answers. CDER & CBER, (December 2004). 9. FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Illinois at Chicago and the University of Michigan Therapeutic, Biotechnology-derived Products. CDER & CBER, (November 1995). Medical School. She previously worked as a Tenure- 10. FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies. Chemistry, Manufacturing, and Controls Information. CDER, (May 2003). 11. FDA Guidance for Industry: Applications covered by Section 505(b)(2). CDER (October 1999). track Assistant Professor at Temple University and a 12. FDA Guidance for Industry: Coronary Drug-eluting stents- Nonclinical and clinical studies. Center for Devices and Radiological Health (CDRH) and CDER (March SPECIALTY PHARMA 2008). Research Fellow at the Schering Plough Research 13. FDA Guidance for Industry: Q8 Pharmaceutical Development. CDER & CBER (May 2006). Institute. Her special interests include cancer 14. FDA Guidance for Industry: Fast Track Development Programs- Designation, Development, and Application Review. CDER & CBER (January 2006). 15. Dagher R, Johnson J, Williams G, Keegan P, Pazdur R. Accelerated Approval of Oncology Products: A Decade of Experience. J Natl Cancer Inst. 2004;96(20):1500- research, gene therapy, and the development of 1509. novel drug delivery systems, particularly biotech 72 products and vaccines. 68-73-DDT MAr 2009 -SP-Therapeutic Focus:Layout 1 2/27/09 3:18 PM Page 73

Company Pg Phone Web Site

3M 5 800-643-8086 www.3m.com/dds

AAPS National Biotech Conference 43 www.aapspharmaceutica.com/nationalbiotech

Aveva DDS 7 954-624-1374 www.avevaDDS.com

Azopharma Cover, 4 954-433-7480 www.azopharma.com

BD 13 800-225-3310 www.bdpharma.com

BIO 27 www.bio.org

Bioject 15 800-683-7221 www.bioject.com

Capsugel 17 888-783-6361 www.capsugel.com

Depomed 9 650-462-5900 www.depomed.com

DPT 75 1-866-CALL-DPT www.dptlabs.com

Eurand 76 937-898-9669 www.eurand.com

ExcipientFest 51 800-640-3228 www.excipientfest.com

Freedonia Group 65 440-684-9600 www.freedoniagroup.com

Innercap Technologies 2 813-837-0796 www.innercap.com

Meridian Medical Technologies 47-48 www.meridianmeds.com

NeoMPS SA 41 www.neomps.com

Partnerships with CROs 49 www.cropartnerships.com Vol 9 No 3

PharmaCircle 25 847-729-2960 www.pharmacircle.com MArch 2009 PharmaForm 11 512-834-0449 Ext. 264 www.pharmaform.com

PPD 3 910-815-3476 www.ppdi.com

RDD (Respiratory Drug Delivery) 31 www.rddonline.com Drug Delivery Technology 877-275-9366 www.zeonex.com/parenterals2 Zeon 14 73 74-75- DDT March 09- External Delivery :Layout 1 2/26/09 11:49 AM Page 74

The Fear Factor of Phailure By: John A. Bermingham

learned a long time ago that people who use profanity as a course could be devastating. What I am concerned about are those normal part of their language are people who generally have a companies with outmoded business models and complacent and/or IIpoor vocabulary, so they insert profanity in place of proper incompetent CEOs who will have billions of government dollars language. I have heard one particular word used as a noun, (meaning our tax dollars) at their disposal. I can assure you that in pronoun, verb, adjective, adverb, dangling participle, conjunction, business, any bailout company will first look at the senior and preposition, sometimes all in the same sentence. management and its recovery plan before dollar one is invested. Not wanting to offend anyone by using the F-word, I am Almost always, the bailout company will bring in at least a new steering clear by changing the way I spell a certain word. Why? CEO they have experience with or whose competency is Because the F-word, Failure, no longer exists. It has been replaced unquestioned. I mean, who led the company into the position by the B-word…Bailout. where it needs a bail out in the first place? Is it the same person Phailure is something all of us have had to deal with because who is getting access to the billions? of an error or misjudgment that caused it in the first place. This Phinally, I mean finally, what is the repayment schedule for phailure then resulted in the development of a recovery plan to our investment? If there isn’t one, I highly recommend that the deal with said phailure, and then ultimately learning from it. government take a $500,000,000 reserve against bad debt, the Phailure is one of the best teachers a person can have. same as any business would do. And don’t forget the government Think about whether you have learned more throughout your oversight committee will be composed of career politicians, most life from your successes or your phailures. I have learned from of whom are lawyers, who have never run a business but will be experience that while I have learned from successes, there is aided by outside experts. Maybe I should have titled this article nothing like a phailure. A phailure really grabs your attention. the Fear Factor of a Bailout! N Man, if you are like most people, you agonize for a period of time over the phailure and try to think through the reasons for that phailure. Whether you are running a race or running a business, B IOGRAPHY one of the success factors that drive a person to succeed is the Fear Factor of Phailure. No one likes to lose. John A. Bermingham is the President & CEO of Cord Crafts, LLC, a leading manufacturer and Now for the B-word. I am not against President Obama’s marketer of permanent botanicals. Prior to Cord trillion dollar plus economic stimulus bill per se. Something has to Crafts, he was President & CEO of Alco Consumer be done to help our country recover from the economic problems Products, Inc., an importer of house ware, home Americans and the globe are facing. What I am concerned about is goods, pet, and safety products under the Alco the fiddling with the genetic DNA of our capitalist society or free brand name and through licenses from the enterprise system. ASPCA and Red Cross. He successfully turned around the company in 60 days and sold Alco to a strategic buyer. Mr. Bermingham In business, a bailout is when one company gets into trouble was previously the President & CEO of Lang Holdings, Inc. (an and another company steps in and bails it out with liquid assets to innovative leader in the social sentiment and home décor avoid a bankruptcy. The company that injects the liquid assets industries) and President, Chairman, and CEO of Ampad (a leading

Vol 9 No 3 often ends up with the controlling interest of the company it bailed manufacturer and distributor of office products). With more than out. This is what the government plans to do. They are concerned 20 years of turnaround experience, he also held the positions of that too many large companies phailing would be devastating to Chairman, President, and CEO of Centis, Inc., Smith Corona the US economy as well as the global economy. Thus, the Corporation, and Rolodex Corporation. He turned around several March 2009 business units of AT&T Consumer Products Group and served as the government is rejecting the F-word and replacing it with the B- EVP of the Electronics Group and President of the Magnetic word. Products Group, Sony Corporation of America. Mr. Bermingham So that means companies that made huge mistakes over the served 3 years in the U.S. Army Signal Corps with responsibility past several years, instead of going into a Chapter 11 bankruptcy for Top Secret Cryptographic Codes and Top Secret Nuclear Release reorganization as is typical, are instead going to be bailed out by Codes, earned his BA in Business Administration from Saint Leo the US government with taxpayer dollars. I am still alright with University, and completed the Harvard University Graduate School Drug Delivery Technology of Business Advanced Management Program. this because the alternate option of letting things take their own 74 74-75- DDT March 09- External Delivery :Layout 1 2/26/09 11:49 AM Page 75 * DDT March 2009 Covers:DDT Cover/Back April 2006.qx 2/26/09 11:31 AM Page 1