4 BioProcess International 14(6) June 2016

Volume 14 Number 6 JuNe 2016

Issue Highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6From the Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Editorial Advisory Board . . . . . . . . . . . . . . . . . . . . . . 8Spotlight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

Focus on . . . Product Development . Bacteriophages, an Alternative to Antibiotics: Challenges and Possible Solutions for Bringing These Products to the Market . . . . . . . . . . . . . . . . . . . 14 Bruno Speder

Disposables . Bridging Polymer Science and Biotechnology Applications with Single-Use Technologies . . . . . . . . . . . . . . . .14 Ekta Mahajan and Gary Lye

Compliance . Quality By Design for Monoclonal Antibodies, Part 1: Establishing the Foundations for Process Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Brendan Cooney, Susan Dana Jones, and Howard Levine

Technical arTiclesOsmolality Measurements for High-Concentration Protein–Polymer Solutions: Variation Based on Working Principles of Osmometers . . . . . . . . . . . . . . . . . . . . .20 Erinc Sahin, Aastha Puri, Vishal Nashine, Mehrnaz Khossravi, and Rajesh Gandhi

Enhanced Biosimilar Product Characterization: A Case Study Using Raman Spectroscopy Combined with Dynamic Light Scattering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28 Wei Qi, Stacy Kenyon, Maria Taddei, Jessica Cheung, and Hiten Gutka

A Single-Use, Clinical-Scale Filling System: From Design to Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34 Doug Camposano, Alexander Mills, and Catherine Piton

supplier sideSingle-Use Technology Enables Flexible Factories . . . . . .52 Jennifer Campbell and Sebastien Ribault

ask The experTLiposome and Viral Vector Characterization: Use of Electron Microscopy and Image Analysis . . . . . . . . . . . . . . .60 with Josefina Nilsson

elucidaTionDeciding on an Integrated Continuous Processing Approach: A Conference Report . . . . . . . . . . . . . . . . . . . . . . .60 Miriam Monge

Ask the Expert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58Index of Advertisers . . . . . . . . . . . . . . . . . . . . . . . . . .58

Read more about the articles in this issue on page 6. Find us online at www.bioprocessintl.com.

oN the CoVerIllustrating this month’s theme, a quality assurance technician checks vials at AstraZeneca’s facility in Maccleston, UK . (WWW.ASTRAZENECA.COM)

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©2016 BioProcess International (USPS 0022-044, ISSN 1542-6319) is published eleven times a year by Informa Life Sciences Group at 52 Vanderbilt Ave ., New York, NY 10017, Phone: 1-212-520-2777, fax 1-212-661-5052, www .bioprocessintl .com . Periodicals postage is paid in Westborough, MA and additional mailing offices . POSTMASTER: Send address changes to BioProcess International, PO Box 1170, Skokie, IL 60076 . Canadian publication agreement No . 41067503 . Canadian return address DPGM 7496 Bath Road Unit 2, Mississauga, ON L4T 1L2 . Electronic subscriptions are available online . Articles are abstracted by the Chemical Abstracts database at www .cas .org .

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6 BioProcess International 14(6) June 2016

iN this issueFocus on Product DevelopmentBacteriophages are viruses that can infect and kill bacterial cells . Emergence of bacterial resistance to most currently available antibiotics has brought interest in the use of phages as alternative therapeutics . Their clinical development won’t be straightforward, though, with regulatory questions arising around novel aspects of these products . On page ##, Bruno Speder describes problems and potential solutions for bringing these products to the market .

Focus on DisposablesAs single-use applications increasingly span operations from cell banking to drug product development, interest in understanding the interaction of extractables with proteins and cells is increasing . On page ##, cochairs Ekta Mahajan and Gary Lye report on a recent conference where users, academia, and suppliers delved into the science of plastics as it applies to bioprocessing .

Focus on ComplianceThe FDA’s 2002 GMP update changed how biopharaceutical companies interact with regulators, focusing their efforts on a science- and risk-based approach . On page ##, authors from Bio Process Technology Consultants begin a two-part analysis of that shift, which led to use of iterative risk assessments along with quality-by-design methodologies to gain product and process understanding . Such approaches support innovative solutions to manage risk associated with the variability inherent in pharmaceutical manufacturing .

Differing Osmolality MeasurementsOsmometers measure osmolality based on freezing point (FP) or vapor pressure (VP) of solutions . On page ##, authors from Bristol-Myers Squibb compare instruments with those working principles for their accuracy . The team found VP osmometers to be more reliable than FP osmometers for high-concentration formulations and those with high concentrations of ingredients that can decrease water activity . An antifreeze effect manifested at different concentrations for different products and formulations . With low concentrations of polymers, proteins, and sugars, both instrument types provided satisfactory results .

Raman + Dynamic Light ScatteringBiophysical characterization of drug products is important to the biopharmaceutical industry, especially to companies developing biosimilars . Most available technologies cannot be used for head-to-head biophysical comparison of optimized biosimilar formulations with innovator products . On page ##, authors from Malvern Instruments and Oncobiologics describe such a comparison for a monoclonal antibody

formulation using an instrument that combines Raman spectroscopy with dynamic light-scattering analysis .

A Single-Use Filling ApplicationA major challenge in replacing cleanable filling lines based on stainless steel filling needles is to ensure that an alternative single-use system can satisfy all critical performance parameters established for the existing process . On page ##, authors from Merck and Pall report on such a project at a Pennsylvania facility that fills clinical, finished drug products . The final system design incorporated a Bausch+Ströbel filling machine with a Pall single-use wetted path . To test the system, Merck filled about 7,500 syringes at a dosing accuracy meeting specification with no visible particulates .

Flexible Factories Need DisposablesFacing drug-price discounts, biosimilar drug developers must achieve manufacturing cost reductions . As authors from Millipore SAS explain on page ##, single-use technology can help by replacing expensive stainless steel systems with more flexible systems . The flexible factory concept enables fast set up of new facilities and facilitates technology transfer . Flexibility is especially important for biosimilars .

Manufacturing

8 BioProcess International 14(6) June 2016

A udience: the key element behind all style and content decisions in any spoken or written material . When publications existed only in print, audience-related

criteria were easier to maintain than they are these days . Bound periodicals lived in libraries sequestered by subject . Unless you knew where “your” material lived, you were unlikely to stumble upon it — but information could get lost . Manual crossreferencing wasn’t easy, and I would not want to return to the days before powerful Internet search engines! But now, readers often are directed to materials for which they themselves are not the primary audience .

Audience considerations can drive editors nuts: Will academic readers be upset by the promotional appearance of trademark symbols? Will supplier authors be upset when we (by policy) leave registration marks out? Will engineers recognize the meanings of acronyms from microbiologists? Will the passive voice favored in laboratory notebooks be appropriate for readers from different disciplines?

The need to learn everything we can about our audience is a major incentive for us to attend industry events covering a range of subject matter . We attend single-use conferences, advanced-therapy events, and supplier-organized seminars; sit in on business-focused plenaries and highly technical presentations; sample the smorgasbord of tracks at large

multitopic events and tour supplier and end-user facilities, large and small . All this is so we can incorporate how people work, what equipment they use, and what they hope for the future into our editorial plans from month to month and year to year .

One special event gave BPI publisher Brian Caine, associate publisher Chris Johnson, and me the opportunity to network with a diverse audience of key industry players at the April BPI European Summit in Vienna, Austria . High above the city, with sweeping views of the Danube and surrounding countryside, we enjoyed lively conversations at a VIP dinner hosting about 30 presenters and advisors — some thought leaders we’ve worked with for years along with enthusiastic newcomers to our segment(s) of the industry .

I learn as much from such conversations about what people do not know as what they do . So many are new to a position, learning different regulatory directions and how to place their new roles into context . This reinforces what I often tell authors and reviewers: We serve an audience of both knowledgeable readers and those who are new to the subject matter .

That underscores the importance of sharing expertise, asking questions, seeking out resources, and simply establishing a comfortable basis of communication . We are grateful to our Informa colleagues for recognizing the value of these relationships and organizing an event that gave us much food for thought and ideas for topics to pursue . There are many vehicles these days for sharing information and formats that offer something for everyone — and multigenerational perspectives about which vehicles are most preferred . Frequent communication with our authors, advisors, advertisers, and readers helps us best serve the informational needs of them all .

from the editor

Siddharth Advant, Kemwell BioPharma, USA and IndiaHazel Aranha, Field Marketing Manager, Purification Technologies, Sartorius Stedim North America, Bohemia, NY, USAR. Lee Buckler, VP Business and Corporate Development, RepliCel Life Sciences Inc ., Vancouver, BC, CanadaPeter Calcott, President, Calcott Consulting LLC, Berkeley CA, USAJohn J. Dougherty, Regulatory Scientist, Eli Lilly & Company, Indianapolis, IN, USAJim Faulkner, Head of Manufacturing, Autolus Ltd ., London, UKPete Gagnon, Vice President of Process Sciences, Peregrine Pharmaceuticals, Inc ., Tustin, CATimothy K. Hayes, Vice President and Strategic Regulatory Advisor, ProMetic BioTherapeutics Inc ., League City, TX, USAKenneth Hughes, President, Roker Biotechnologies, Inc ., Toronto, ON, CanadaSusan Dana Jones, Principal Consultant, BioProcess Technology Consultants, Acton, MA, USAAlois Jungbauer, Professor, University of Natural Resources and Life Sciences, Vienna, AustriaDennis M. Kraichely, Associate Director and CMC Team Leader, Johnson & Johnson Pharmaceutical R&D, Malvern, PA, USA Blanca Lain, Protein Purification Process Development Consultant, Boston, MA, USAAdriana E. Manzi, Managing Director, Atheln, Inc ., San Diego, CA, USAMiriam Monge, Director of Marketing for Integrated Solutions, Sartorius Stedim Biotech, Göttingen, GermanyBryan D. Monroe, founder and primary consultant, Primus Consulting, Kingston, WA

Thomas J. Pritchett, Senior Consultant, Quality Services Consulting, Palm Desert, CA, USAT. Shantha Raju, Scientific Director, Janssen Research and Development, Spring House, PA, USANadine M. Ritter, President and Analytical Advisor, Global Biotech Experts LLC, Alexandria, VA, USA Sally Seaver, President, Seaver Associates LLC, Concord, MA, USARobert P. Shaw, Program Director, EMD Millipore, Billerica, MA, USA Abhinav Shukla, Vice President of Process Development, KBI Biopharma, Raleigh-Durham, NC, USANanda Subbarao, Senior Consultant, Biologics Consulting Group, Plainsboro, NJ, USAMichiel Ultee, Principal Consultant, Ulteemit BioConsulting, LLC, Hillsborough, NJ, USAScott M. Wheelwright, Principal Consultant, Complya Asia Co . Ltd ., Suzhou, ChinaWilliam G. Whitford, BioProcess Strategic Solutions Leader, GE Healthcare Life Sciences, Logan UT, USAShuichi Yamamoto, Professor, Process Design and Engineering Laboratory, Yamaguchi University Graduate School of Medicine, Tokiwadai, JapanJianguo Yang, Chief Executive Officer, Abpro-China; Vice President, Abpro-US, Woburn, MAJerry X. Yang, President, DZM Biotech Ltd ., Daqing, China

Members of the BioProcess International Editorial Advisory board volunteer their time to advise the editors about industry trends, technologies, potential authors, and topics of interest. They review all technical manuscripts, and their recommendations help the editors make final publication decisions. Members of the advisory board are not expected to endorse any products, technologies, or companies mentioned; the editors refrain from soliciting reviews from any advisor for whom such a conflict of interest may be involved.

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