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    BPI October 2016 PDF

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    biok October 2016 | Volume 14 | Number 9| ww ™ "g fea are FeO NTERNATIONAL FOCUS ON Biosimilar MAbs: Can Regulators Develop an Industry Standard? Evaluating Viral Risk of Raw Materials Does Innovation Require Collaboration? TECHNICAL ARTICLES Speeding Up Biologics Development and Manufacturing Improving Efficiencies in Chromatography and Freeze-Thaw Applying Tentacle lon-Exchange for Improved Viral Safety The Finesse solution Anything’s possible Today's bioprocessing challenge: demand smarter solutions. Finesse solutions are built to work with your systems — not the other way around. Finesse offers state-of-the-art equipment, intelligent control software, and ‘custom integration services to optimize your bioprocessing unit operations, » universal control and automation platform compatible with all leading suppliers » Service, automation, and integration expertise ‘to harmonize old and new equipment » Addition of new sensors and peripherals without software modifications » Configurations fom prelinical through praduction scale www.Finesse.com @Finesse Learn more about Finesse Solutions: SmartFactory” cGMP facilites Universal contollers with “TruBio® software Trufluor* single-use sensors SmartGlass™ and SmartVessel” bioreactors Explore Lonza’s Custom Manufacturing Facilities From Your Mobile Device Save yourself a costly and time consuming fight by touring our modern custom manufacturing sites from any electronic device. Take your first in-depth look at cur state-of the-art biological ane chemical development and production facilites To view Lonza’s online tours, visit www lonzavirtualtours.com 12012189200 = vie Custom Offerings Include: Protein & Vaccine Design and Optimization Cell and Viral Gene Therapies Mammalian Biopharmaceuticals Microbial Biopharmaceuticals BioConjugates Cytotoxies Highly Potent APIs Peptides ‘Small Molecules Drug Product Services www.lonza.com/oursites The 2016 BPI Award Ceremony, Seu cd ‘and honor the people, organizations, and technologies eee blotherapeutic development eee October 5, 2016 at the Sens Oey Seed ser nics Excellence in Leadership Aecognices any single ise leadership has successfaly helped his or her business achieve operational excellence Dr. Marcel Bassil, ociate Director, Biotech —-‘Benta Pharm Industries Dr. Igor Fisch, Chief Executive Officer Selexis Olivier Loeillot General Manager GE Healthcare Emerging Company Recognizes the companies to watch! New science, new technologies that have seen Cell and Gene Therapy Catapult Cell Therapy NuMe Digital Health Quad Technologies Cell Therapy Corporate Citizenship that have made uni munity ueand signfcont contributions to the loco The Baxter International Foundation Biogen Closing the Hemophilia Gap in the Developing World GlaxoSmithKline The PULSE Partnership Excellence in Fact Recognizes fac ity Design or Retrofit tha exerpitis innovation through the us of key technologies andlor designs FUJIFILM Diosynth ——_Re-Purposing a Microbial Facility Biotechnologies for Multi-Product GMP Manufacturing Gibraltar Laboratories cGMP Independent Lab and Sterilization Services JHL Biotech Installation of KUBio Biomanufacturing Solution G-CON/GEA Pharma Systems/Pfizer_ The PCMM Consortium Dreiscienca Pall Life Sciences/FloDesign Disruptive Cadence Acoustic Separator Puridify/Gsk FibroSelect industrial Use @ Glycotope SAM - Perfusion in an Ambr System meses Ds 38 Nova Biomedical BioProfile FLEX2 Fa ame Stratophase Ranger Service cessing te Pall Life Sciences Cadence Acoustic Separator Sore Puridify FibroSelect WIB Sanofi Continuous Disposable Technology KNect Bio-Layer Interferometry 365 Ovizio ‘Line F Sciex High Throughput Glycoslyation Analysis Mark Petrich, Director, Single-Use Systems Engineering Merck BioProcess INTERNATIONAL Mixed mode chromatography media from Avantor (see Deorker and “Thiyagarajn, ight) illustrate this months downstream processing theme, bun WATORUATINA SCOR Issue Highlights. From the Editor. Editorial Advisory Board Spotlight. Focus ON The Regs. Biosimilar Therapeutic Monoclonal Antibodies: Gaps in Science Limit Development of an Industry Standard for Their Regulatory Approval, Part 1 12 Simran J. Kaur, Darryl Sampey, Lester W. Schulthels, Leonard P. Freedman, William E, Bentley Compliance. Viral Risk Evaluation of Raw Materials Used in Biopharmaceutical Production, 2 He TECHNICAL ARTICLES Emerging Technology Trends in Biologics Development: ‘A Contract Development and Manufacturing Perspective. ....... 32 Kumar Dhanasekharan, Kevin Humbard, Benjamin Kester, ‘Shyamal Chaudhari, Yunsong Li, and Vietor Vine Selective and Flexible Chromatography Media: Enabling Improved Biopharmaceutical Operational Efficiencies 38 Nandu Deorkar and 8. Thiyagarajan ‘SUPPLIER SIDE Viral Clearance in Antibody Purification Using Tentacle lon Exchangers Lars H. Peack, Estelle Zelter and Patricia Gr M4 snhalgh Validation of Controlled Freezing and Thawing: A9-L Bottle Study 52 Jerry King ELUCIDATION Collaboration Is Key to Innovation in Biotechnology. ...64 Donald Johnston Ask the Expert: Thermo Fisher Scientific ........ 60 Ask the Expert: Applikon ....+ese+eeeeeeeeee++:61 Index of Advertisers......cssseceseesereees+ 63 Read more about the articles in ths issue on page 6 Find us online at wwwbiopra Yuval Shimoni, Andre Pastor, Robert To, Venkatesh Srinivasan, and Joerg Peters PO Box 70, Dexter, OR 9743 @BioProcessint Eelitorin Ciet S.Anne Montgomery amontgomeryebioprocesint com (@8P Anne Senior Technical Eltor Chery Scott scatt@eloprocessnticorn (G80! TechEcitor Managing Editor Maribel los rviosabioprocessinLeom 281 Maribel Eelitoril Assistant Alison Center" acenterabioprocessintcom Find 8 ctations online in the Chemical ‘Abstracts Database (cas org). ‘One Research Drive, Suite 400A Westborough, MA 01381 Ialesnguines meds eevertsing} Publisher Brian Caine 1-508-616-1443, beainesbioprocessntcor Associate Publisher and Strategic Marketing Consultan (Eastern NA) Christopher Johnson. 1-505-614-1273 «johnsanebioprocessint com Strategic Marketing Consultant (Western NA) Mike Kelly 1-646-957-8074, rmkeliybloprocessnticom Strategic Marketing Consultan (EU/AP) Joanna Taylor #4-0)-20.785-9392 Joanna aylorainforma com Sales and Marketing Coordinator Kim Rafferty 1-503.614-1225, eallery@bioprocessintcom Production and Creative Manager ‘Genevieve McCarthy 1-212520.2752 ‘genevieve mecarthy@informausacom Director of Business Operations and ficience Development Nora Pastenkos.1-2125202733, nora pasterkos@informausa com Marketing and Digital Content Strategist Leah Rosin. 508.614.1167 lresinabioprocessnticom List Rental Amy Miler 508-614-1251" amileraibeusacom Reprints Rhonda Brown ‘rondabatosterpintingcom For subserition Inquiries, call 1-847-504-8165, {oll free 1-877-232-2398, oremall bloprocesse = @BPA Intensify your downstream process Unlock process intensification by accessing our innovative downstream solutions. With a proven track record of modern chromatography resins, purposefully designed bioprocess colurnns and simplified buffer management, our integrated solutions enhance your purification workflow. Connect to Gé’s extensive record of successful delivery of downstream excellence to accelerate your bioprocess journey. gelifesciences.com/bioprocess Focus on The Regs ‘Therapeutic monoclonal antibodies chellenge biosimilar development because variables in posttranslation and higher-order structure can affect safety and efficacy. Proprietary control by innovators over specific ‘manufacturing controls and analytical techniques to assure product quality means that biosimilar ‘manufacturers must still depend on clinical studies to demonstrate biosimilarity. On page 12, authors from the University of Maryland outline regulatory issues for biosimilar approval and highlight the scientific gaps that currently prevent development of minimum industry standards for similarity testing between biosimilar and innovator antibody products Focus on Compliance ‘Applying a risk-based, raw material (RM) control strategy aligns with regulatory expectations and isa recognized means to address potential changes of/at suppliers, their processes, their providers, and RMs throughout a product ifecycie. On page 22, authors from Bayer describe a tool for virus-sk determination pertaining to all Ms used in a drug substance bioprocess. They also discuss a quality risk assessment in which supply chain is only one of the components. Technology Trends Speeding Development Contract development and manufacturing organizations (CDMOs) face tight timelines driven by client expectations. Those are in turn driven by a need for speed to clinical testing. One way to move things along is to establish platform processes for certain classes of molecules. On page 32, authors from Cook Pharmica describe their company’s approach and share data generated with an Ig1 to provide a perspective into some novel process and analytical technologies. Process Chromatography Media Selectivity and Flexibility New approaches to purification are required to address challenges posed by the increased complexity of producing biologics, while improving process efficiency ‘and reducing operating costs. Increasingly, process. developers are exploring mixed-mode and multimode chromatographic media to achieve these separations. Innovative process chromatography media can reduce the number of steps required for purification, leading to improved efficiency and yield, as well as potential cost savings in downstream processing, On page 38, Nandu Deorkar explores the mechanisms by which mixed-mode (hydrophobic and anionic exchange) and multimode (cation and anion exchange) interactions can improve selectivity efficiency, and operational flexibility Tentacle lon Exchangers for Virus Clearance Reliable reduction of the numberof vial particles throughout a downstream purification process must be ensured through different techniques such as chemical treatment, ftration, or chromatography. Tentacle ion exchangers have been successfully shown to remove Viruses in different MAb purification applications On page 44, authors from MiliporeSigma review published applications of diferent types of such media in different modes of operation. Cont ing Freeze and Thaw Freeze-thaw processes affect the quality of biopharmaceuticals and cells, but no consistent method yet has arisen for controlling the rates of freezing and thawing of biological formulations. On page 52, Jerry King refutes that claim by validating rate-controlled freezing and thawing using 9-L bottles, Downstream Processing ONE SOURCE ONE LOCATION SIMPLIFY YOUR CONTRACT MANUFACTURING PARENTERAL @ DEVELOPMENT & RUG BRODUEE BULK DRUG SUBSTANCE Accelerate the delivery of your life-enhancing products to patients, work with one point of contact, and one set of business practices. SECONDARY PACKAGING Contact busdev@cookpharmica.com to learn more OOK MME wy w.cookpharmica.com " + CLINICAL + COMMERCIA takes us into the new year with increasing steepness and submitting graphics for your manuscripts, see the form our velocity, Here come the fll supplements and special reviewers receive with your blinded manuscript, examine our projects! And as the new year approaches, our momentum is copyright forms, and consider relevant themes and submission often halted abruptly by the November and December holiday dates for 2077. have also included some of our key copy- schedules, during which many of our contacts seem to vanish, editing and house-style criteria — an increasingly rare service E very September, we editors step onto a virtual slide that _ teach an old editor new tricks). You can find details about The highlight of ou fall season s always the BioProcess we provide inthis age of open-source publishing you're International Conference and Exposition in Boston, this __looking for more information, please let me know. A critical year occurring the very week that you should be receiving this issue forthe editors is that our submission deadlines are fll issue and supplement. We work closely with our Informa three months earlier than those published for sending in conference colleagues to ensure that conference presentations advertising-elated fies. hope that the description of our {and print offerings together enhance your work experience, _editoral process will help explain why that is necessary providing multipte viewpoints on key themes. We collaborate ‘As we head into BPI's 15th-anniversary year ths January, for on-site interviews and webcasts, preconference white ‘youll see some changes in how we arrange themes and special papers, and other highlights. And we seek to develop reports, All cur key topics remain, and the year begins in manuscripts with those presenters whose especially timely talks earnest with focused sections on single-use technologies generate the greatest "buzz" during our weekin Massachusetts, (January), cell and gene therapies (February), and outsourcing We hope to see you there at our annual celebration of the (March), We are looking for viewpoints, white papers, analyses, industrys accomplishments — which helps us determine what and manuscripts detailing how to address current industry key topics to explore editoraly in the coming year. Many needs. Perhaps you would ike to contact one of us to plan a thanks to the organizers for another excellent program of writing project before the holidays descend upon us timely insights. And our biannual BPI Awards banquet is Opportunities abound, and we will be looking great! Finalists will be announced shortly after write offering a number of new publication this, and | am eager to share the final results with you ‘options in 2017. We hope to talk to ‘As we head into this busy planning season, | want to tell you many af you in Boston and — as about one important project that has been completed:the always — look forward to working latest revision of our online Author Guidelines (www. with you in the new year. bioprocessintcom/about/author-guidelines). Whereas past versions have been rested by printed page izes teonine of Poses Unc version can link toa number of supporting documents (you can Rm eas Errata its 4 mil tayo Parent Principles of Fermentation Processes Rapa Fermenation Process Ussign: From Osvelopmant to Manufacture Short Courses Ee and CPD for the foes Reboot =F Coy oY color SSM aT: (UT Ch MII ony o:en ce spe crn sin BS eso xporenents or Boprces Opnsaion idusral Bltecnology an Boretning hora r iy + Access to cutting edge research methodologies Pe eo Cee etd Updates on latest technical and regulatory developments ‘Anaya! Dts Analysis forthe Boprocesing nssry Flexible professional development and options for qualifications) Bloprocess Desig & Feonamie Evaluation Dee eee eeu ec] BS siorrcessFacity Des ‘Acquire the tools to optimise process performance and economic \acenes Bootes Davtoprert nd Conmersiaaon www.ucl.ac.uk/mbi a se Tecnology Rapid Maulcrng = % EE EW MBI® Modular training, designed for the bioprocess industry, in collaboration with industrial ) UCL experts, to support continued professional development, knowledge transfer & upskilling For further information on course dates and bookings contact: E: mbitraining@ucl ac.uk | T: +44 (0) 207 679 9619 = Side View Siddharth Advant, Kemwell BioPharma, USA and Inia Hazel Arana, Fed Manoger Purlention Technolgies, Sartorius Stes North America, Bohemia, NY, USA. I. Lee Buckler, VP Business and Corporate Development Replicel Life Sciences nc, Vancouver, 5C, Canada Petar Caleot, President, Calcot: Consulting LIC. Berkeley CA, USA. ‘Yuan Chang, Associate Director and CMC Team Leader, Biopharmaceutcal Development Medimmune, Gathersburg, MD, USA ‘Michel Chartraln, Distinguished Seer Invesugator Merck & Co, IN, New York NY USA John J. Dougherty, Regultery Siete, lily & Company, Indianapolis IN USK 4m Faulkner, Hecd of Manufacturing, Autolus td, London, UK Pete Gagnon, Vice President of Process Sciences Avid Bioservices, Tustin, CA, Timothy K. Hayes, Vice President and strategie Regulatory Advisor, broMeti BoTherapeutis Inc, League City TK USA. Kenneth Hughes, President Roker Biotechnologies, Inc, Toronto, ON, Canada Susan Dana Jones, Principal Constant, loProcess Technology Consultants, Acton, MA, USA Alote Junghauer, Profesor University of Natural Resources an Life Sciences Venn, Austria Dennis M. Kraichly, Associate Director and CMC Team Leader Johason & Johnson Pharmaceutical RED, Malvern, PA, USA Blanca Lain, Protein Purcatin Process Development Consultant, Boston, MALUSA ‘Adriana E. Manzi, Managing Decor, Athen Inc, San Diego, CA, USA (Miriam Monge, Decor of Marketing for integrated Solutions Sartorius ‘Sted Biotech, Gotingen, Germany Bryan D. Monroe, founder and primary consultant, Primus Conslting, Kingston, WA. “T. Shantha Raju, Senior Drecrorof Anaya Scences Mesimnue, Mountain View, CA USA Madina M. Ritter, President and Anaiytical Advisor, Global Biotech Experts LIC, Alecanana, VA, USA Sally Seaver, President Scaver Associates LC, Concord MA USA ‘Robert P. Shaw, Program Director EMO Nilipre Bieri, MA USA ‘Abhinav Shukla, Senior Vice President of Development and ‘Manufacturing, Kl Biopharma, Raleigh-Durham, NC USA Manda Subbarae, Senior Consultont. Biologics Corsuting Group, Plainsboro, NI, USA Michiel Ultee, Principal Consultant, Ukeemit BioConsulting, LLC, Hilsborough AU, USA ‘Scott M. Wheelwright, Principal Consultant, Complya Asia Co. ic, Suzhou, hina ‘Wiliam G. Whitford Bioprocess Strategic Solutions Lecder GE Healthcare Life Selences, Logan UT, USA ‘Shuichi Yamamoto, Professor Process Design and Engineering Laboratory, Yamaguchi University Graduate School of Medicine, ‘okiwadal, Japan Hianguo Yang, Chie Executive Oficer,Abpro-Crina; Vice Presiden, ‘AbproUs, Woburn, MA Jerry X. Yang, President, OZM Biotech Lis, Daging, China Member BoProces Internationa to! sry board volunteer tine adie the eto tout ins rend ebroegien potenti author and topes entre Thay view al echnical mara andthe recommendavors ep teers mak ral pba decisions Members ofthe aor board ‘reno’ emecied to endorse any products enol er compas mentored he eats eran om socting reviews am any avr whom such acondetef QOSINA ~ Interest may be nvled Thousands of Stock Components F 2 J ease MpAUE IMP4SUER Compression Fittings Union Elbow Union Ebene Reda : IMP AAUAN MpaweT mpaauar Male Union Male Branch Female Union Side View Top View Too vow Se View : Top view srs ; Ferue j Pan apap wpa Gosina also offors PharmaFluor® Tubing to ft your projoct needs weer "Allrademarks and reltred tama are propery hei spect ownere Visit Qosina.com to see over 5000 stock components, place orders and request a catalog Cee were a mes Me Re ner uml ce eat Cream gene ten Cees el Ue Ree ny Tea Cee Adaptive Pathways Pilot Program Results A final report became available this past summer about the European Medicines Agency's (EMA) pilot project on developing medicines for unmet needs. ‘The project showed that adaptive pathways can bring multiple stakeholders together — including regulators, health-technology assessment (HTA) bodies, healthcare professionals, and patients — to evaluate drug development and data gathering. ‘Adaptive pathways allow for a planned, progressive approach to bringing medicines to patients. The concept makes use of existing approval tools (eg, conditional ‘market authorization) used in the European Union since 2006. It also builds on experience gained with strengthened postmarket monitoring introduced by the European Union's 2012 pharmacovigilance legislation. Under this paradigm, drugs are authorized for small groups of patients who benefit most from them. Then as additional evidence is gathered on each drug's performance, progressive licensing adaptations will extend or restrict their previously authorized indications. Adaptive pathways can support development in dificult indications for generating evidence (eg, infectious diseases, Alzheimer’s and degenerative diseases, and rare cancers). In March 2014, the EMA launched its pilot project to explore practical use of the adaptive pathways concept ‘with drugs already in the works. The agency invited companies to submit ongoing development programs that could meet the following requirements: a staggered approval from very small, restricted patient populations to increasingly wider populations; a binding plan of postlicense evidence gathering; and involvement of key. stakeholders in the process. The same principles and legal tools apply as for any other new medicine. During this project, EMA received 62 applications, 18 of which were selected for consideration. At the end of the pilot, six applications had progressed to receiving formal advice by the EMA and HTA bodies and one received simple scientific advice. Most proposals were considered unsuitable for adaptive pathways, and the companies involved were advised to pursue traditional development routes. This program helped the EMA to identify a number of aspects for further consideration: a need for increased patient involvement in selecting candidates for adaptive pathways, the importance of defining strategies for real- ‘world evidence collection to assess drug efficacy and effectiveness, and the potential for payers to provide Input on pricing strategies. Adaptive pathways is still developing concept that will be refined as more medicines are considered. strong pharmacovigilance system and cooperation ‘among stakeholders will provide for systematic monitoring of the safety and overall performance ofa drug in clinical practice. Those are the two key elements underpinning the adaptive pathways concept Itis particularly important forall involved stakeholders to agree before market authorization on a plan of postlcense knowledge ‘gathering and that the drug developer commits to ‘carrying out that plan. Once authorization i granted, the plan becomes a legally binding regulatory obligation Drug developers who are interested in following the adaptive pathways approach for Europe should submit € proposal to the EMA. An updated guidance document ‘outlines steps to follow. To gather the views and proposals from stakeholders on the adaptive pathways approach, the agency is organizing a workshop on 8 December 2016 ABall Ina 2015 report, Allied Market Research forecasts the global biosimilars market to grow rapidly through 2020 — from an overall revenue of US52.55 billion in 2014 to approximately $26.55 billion by 2020 (a compound annual growth rate, CAGR, of 49.1%). Key driving factors fostering that market growth should be low pricing, ease of development, and reliable and timely regulations with quick biosimilar approvals. ‘The matket for follow-on biologics originated primarily from expiration of patent protection for many blockbuster biopharmaceuticals with high annual revenues, Their high prices, coupled with rising healthcare costs around the ‘world, have led to an increased demand for biosimilars. To gain approval from the European Medicines Agency (EMA), the US Food and Drug Administration (FDA\, and the World Health Organization (WHO), biosimilars must meet one of two criteria Either be interchangeable with reference biologics in terms of efficacy or function, or demonstrate a lack of meaningful clinical difference from the originals. Favorable regulatory environments with pathways for approval across major regions such {as Europe and the United States would persuade more developers and companies to invest in the market, The US market for biosimilars gained momentum after the launch of its fist approval: Sandoz/Novartis' Zarxio {filgrastim, follow-on to Amgen’s Neupogen) in September 2015. Sandoz claims that the biosimilar has gradually eroded the original's US market share by 13% In March 2016, the FDA approved its second biosimilar product: Hospira/Pfizer’s Infiecta (infliximab, follow-on to Janssen Biotech’s Remicade). Already approved in Canada, Mexico, ‘Australia, and much of Europe, itis the first biosimilar monoclonal antibody (MAb) to be approved in the United States. Similar developments would unlock new ‘opportunities for drug developers on the global market. Many European countries have commissioned studies that focus on Celltrion’s biosimilar Remsina (infliximab). That also would foster biosimilar market growth across Europe. Furthermore, the products being sold in many Nordic countries at a huge discount rate (~75%), further boosting its adoption. Erythropoietin and MAbs, both glycosylated proteins, together accounted for about a third of the total global biosimilars market revenue in 2014. Among leading Continued on page 58 oning Global Biosimilars Market P| DLT Moe tanto he tnt co nd'revolutionary Bioprocess Platform Software. www.infors-ht.com/eve oe Focus | > THE REGS Biosimilar Therapeutic Monoclonal Antibodies Gaps in Science Limit Development of an Industry Standard for Their Regulatory Approval, Part 1 iosimilars are biologically derived pharmaceuticals intended to have clinical similarity to a legally marketed innovator product when that product’ patent or market exclusivity has expired. By contrast with generic small-molecule drugs, clinical performance ofa biologie pharmaceutical i @ function of its structural complexity and higher-order structure (IOS). Biomanufacturing controls of such complex products cannot fully ensure chemical similarity between an innovator product and differences in chemical modifications and HOS can significantly ater a product's safety and efficacy. "Therefore, to substantiate claims of clinical funetionality, a demonstration of bioequivalence is inadequate for biosimilar pharmaceuticals. This is different from regulatory approval for generic drugs, in which bioequivalence demonstration is adequate. The overall challenge in approving biosimilar pharmaceuticals is to enable scientific inference of similarity in safety and efficacy for a new biologically derived product compared with an innovator ‘without repeating burdensome clinical studies In Pact 1 of this two-part article, we focus on the stientific gaps that complicate determination of biosimilarity for one subset of biologically manufactured products: 12. BloProcessIntermationel 3) Fab Hinge 5-S bondi therapeutic monoclonal antibodies (TMAbs). Notably, many biosimilar products have been approved around the world, including in the United States: e.g, Sandoz’s Zarxio biosimilar to Amgen's Neupogen (filgrastim) and Cellerion/Pfizer’s Inflectra biosimilar to Janssen/J8Js Remicade (infliximab). First we briefly describe the regulatory landscape for the development of biosimilar TMAbs, Then we identify certain specific structural components of TMAbs — drug substances in Part 1, drug products in Part 2— that warrant particular attention becat alterations to them are likely to aff therapeutic safety and effectiveness Finally, in Part 2 we consider whether studies can further the development of analytical industry standards to ensure comparability of putative biosimilar ‘TMAbs with innovator TMAbs. And wwe suggest that the time is right t te £TMAb reference material ran J, Kaur, Darryl Sampey, Lester W. Schultheis, Leonard P. Freedman, William E. Bentley Dal and to der ight cha evaranle domain varabiedomen 0), binding region complementary determining ons (CDRS, wieteas the Fe region ishighiy conserved aos ‘malecuar soecies, The h bonds and 3) 38) daman age egion contains two nas ed analytical industry standards and ‘manufacturing controls to specific reductions in preclinical and clinieal studies for regulatory approval of certain biosimilar’TMAbs. US Reautation oF Biosimitar TMAss Biosimilars or “follow-on biologics” are potentially cost-effective alternatives to innovator biopharmaceuticals because they can significantly reduce the time it takes for product and process, development with a lowered regulatory burden (1,2). The FDA approved the first TMAB in 1986 (3), and about 30, "MAD products now account for annual sales in excess of US$60 billion (Table 1} @. Pursuing the biosimilar path rather than using the original innovator product could save 15-30% for more in revenues (5-7) ‘Many innovator biologics will reach patent or market exclusivity expiry Is your Tis supply secure and sustainable? Is it always there hen needed? Cen it be relied upon to meet the most, stringent global compliance standards? ANGUS Life Sciences, the word's only fully integrated manufacturer of TRIS AMINO?, never iets customers down, providing quality chemistries and supported by reliable, raceable supply chains. Dedicated regulatory and tech’ ble menufaciuring processes and sound environmental stewards! ents, sus ANGUS Life Scie ties the right way empowering customers to do business the best way SECURE YOUR SUPPLY AT ANGUS.COM WERE HERE TO HELP. VISIT US AT: CPhl Worldwide Stand 6MS5 BioProcess Booth 1135 Angus é LIFE SCIENCES Resronsints Caar “Table 1: Top-seing terapeutic monoclonal antibody (Ma) praduets in 2013 2013 Sales Antibody/Brand Name Target Company USS billions) Indication Adalimumab/viumira TNF-a Abbott Laboratories 11,00 Autoimmune ExanerceptiEnbrel_ TNFa Amgen and Pizer 876 Autoimmune Ra, {fusion protein) psoriasis, Crone’) lnfiimab/Remicade TNF-a Janssen Biotech, Inc 837 Autoimmune Riwximabyfituxan, CD20 ‘Biogen Idecand 79) Nor-Hodgkin Mabthers Genentech lymanema Bevacizumabitvastin VEGF Genertech/Roche «687 Colorectal cancer TrastuzumabMerceptin HER2 Genertech/Roche—«65T_—_—Breast cancer Ranibieumab/Lucent’s VEGF Genentech and 427 Macular Novers, degeneration "IN = tumor necrosifocor Rh» theumtoid anti VEGF = vascular endothe growth factor ‘Hekas humanepsderma growin ator receptor? within the next few years (5,6). In anticipation, US policy has been established to promote biosimilar approvals. Biosimilars are defined by the US law under Section 351(K) of the Public Health and Serviee Act (PHSA) as biologie products that are “highly similar to the reference product notwithstanding minor differences in clinically inactive components,” and without “clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product” (7). Regulatory bodies had to consider evaluation of comparability in pharmaceaticals long before biosimilars were considered as potential low-cost alternatives to innovator products (tt, 12). The advent of biosimilars increases evaluation complexity. During innovator-product reviews such as for MAbs, the issue of clinical comparability naturally arises because subtle manufacturing ns may yield glycosylation alterations or other posttranslational modifications to the TMAb product (13). Subtle molecular variations (microheterogeneities) can affect product potency and/or toxicity Fortunately, industry sponsors and regulatory reviewers already have experience in making scientific determinations from analytical and biological activity data. T? International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICED established guidelines in 2004 that describe a comparability exercise 14 BloProcessinternatonal 4) to ascertain whether a biologically quality despite changes in ‘manufacturing (6,9). The 1999 ICH. Q6B guideline describes how to use analytical procedures to establish acceptance criteria for proteins made ay cell culture expression systems (16) So despite manufacturing changes, an innovator TMAb ean retain its clinical safety and efficacy previously demonstrated in clinical studies (to). Guidelines established by ICH Q6B outline basie underlying principles used to set specifications, including characterization, analysis, and ‘manufacturing controls (11,16). Further, prespecified quantitative parameters eg primary stracture, glycosylation, disulfide structure, charge variants, size variants, biophysical characterization (secondary structure, tertiary structure, and thermal stability) ,and biological characterization — ‘must be identified to determine acceptability of raw materials, excipients, and final products. QB also indicates the usefulness of pharmacopoeial tests for evaluating biologically manufactured pharmaceuticals in such areas as sterility, endotoxin levels, microbial limits, particulates, dose uniformity, and container volume, Release and shelfife limits are established for potency and degradation products from both drug substance and finished drug product. In 2006, the European Medicines Agency (EMA) published the first regulatory guidance for biosimilar approval (12,18). Since then, many biosimilars have been approved in the roduet retained its European Union (14), one of which is the TMAb Inflectra (infliximab) that was also recently approved in the United States (15). The EMA has now published TMAb product-elass specific data for production, quality control, and nonclinical and clinical studies (16,17). Those guidelines in terms of quality, safety, and efficacy —with a reference product authorized in the European Union. Although those products are not exp identical, even minor detected

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