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13th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and ProductionA Study of Biotherapeutic Developers and Contract Manufacturing Organizations

April 2016

BioPlan Associates, Inc.2275 Research Blvd., Suite 500Rockville, MD 20850 USA301.921.5979www.bioplanassociates.com

Copyright ©2016 by BioPlan Associates, Inc.

All rights reserved. Unauthorized reproduction strictly prohibited.

associates, inc.

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Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

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13th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and ProductionA Study of Biotherapeutic Developers and Contract

Manufacturing Organizations

April 2016

BioPlan Associates, Inc.

2275 Research Blvd, Suite 500

Rockville MD 20850

301-921-5979

www.bioplanassociates.com

Copyright © 2016 by BioPlan Associates, Inc.

All rights reserved, including the right of reproduction in whole or in part in any form. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the written permission of the publisher.

For information on special discounts or permissions contact

BioPlan Associates, Inc. at 301-921-5979, or [email protected]

Managing Editor: Eric S. Langer

Project Director: Donnie E. Gillespie

Assistant Editor: Ronald A. Rader

Layout and Cover Design: ES Design

IS BN 978-1934-106-28-0

COVER1: Automated Allegro systems for single use downstream operations.

© Pall Corporation, used with permission.

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AC K N O W L E D G M E N TWe wish to recognize our sponsoring institutions, and our media sponsors. Their efforts in assuring the cooperation and participation in the survey of their respective memberships helped guarantee the large group of survey participants to ensure data accuracy.

Our Institution Partners, all of whom contributed their time and effort to ensure the broad, international coverage of this project, include:

■ AusBiotech (Malvern, Victoria, Australia)

■ ABO China (Beijing, China)

■ Beijing Pharma and Biotech Center (Beijing, China)

■ BIO (Biotechnology Industry Organization, Washington, D.C.)

■ Bio-Process Systems Alliances/SOCMA (BPSA) (Washington, D.C.)

■ BioMaryland (Rockville, MD)

■ California Life Sciences Association (CLSA) (San Francisco, CA)

■ Colorado BioScience Association (Denver, CO)

■ KTN (Knowledge Transfer Network) (London, United Kingdom)

■ D2L Pharma (Bangalore, India)

■ EuropaBio (Brussels, Belgium)

■ Massachusetts Biotechnology Council (Cambridge, MA)

■ Ma ssachusetts Life Sciences Center (Waltham, MA)

■ MichBio (Ann Arbor, MI)

■ North Carolina BioSciences Organization (Research Triangle Park, NC)

■ North Carolina Biotechnology Center (Research Triangle Park, NC)

■ Pharma & Biopharma Outsourcing Association (PBOA) (Ringwood, NJ)

■ Washington Biotechnology & Biomedical Association (WBBA) (Seattle, WA)

To ensure global coverage for this project, we again invited major Media Sponsors to support our outreach to biopharmaceutical decision-makers. Our media sponsors, who helped ensure broad and representative coverage of industry participation, include:

■ American Pharmaceutical Review (Fishers, IN)

■ BioPharm International (Iselin, NJ)

■ BioProcess International, (Westborough, MA)

■ BioProcessing Journal (Winthrop, MA)

■ Contract Pharma, (Ramsey, NJ)

■ Genetic Engineering and Biotechnology News (New Rochelle, NY)

■ Life Science Leader (Sewickley, PA)

■ Pharma IQ (London, United Kingdom)

■ Pharmaceutical Manufacturing (Schaumburg, IL)

■ Pharmaceutical Outsourcing (Fishers, IN)

■ Pharmaceutical Processing (Rockaway, NJ)

■ Pharmaceutical Technology (Iselin, NJ)

■ Pharmaceutical Technology Europe (Iselin, NJ)

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The early participation of our authors and sponsors in evaluating the areas and trends to be surveyed this year ensured the project was designed to cover the most relevant issues in biopharmaceutical manufacturing today. As always, their continued support was critical to the success of the project.

Eric S. LangerEditor

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A B O U T B I O P L A N A S S O C I AT E S , I N C . BioPlan Associates, Inc. is a biotechnology and life sciences market analysis, research, and publishing organization. We have managed biotechnology, biopharmaceutical, diagnostic, and life sciences research projects for companies of all sizes for almost 30 years. Our extensive market analysis, research and management project experience covers biotechnology and biopharmaceutical manufacturing, vaccine and therapeutic development, contract research services, diagnostics, devices, biotechnology supply, physician offi ce labs and hospital laboratory environments.

We prepare custom studies, and provide public information our clients require to make informed strategic decisions, defi ne objectives, and identify customer needs. With market information, our clients are better able to make informed, market-based decisions because they understand the trends and needs in high technology industries.

BioPlan Associates, Inc. 2275 Research Blvd., Suite 500Rockville, MD 20850 USAwww.bioplanassociates.com Tel: 301-921-5979

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E D I T O REric S. Langer, MS, President, BioPlan Associates, Inc.Eric S. Langer, MS, President, BioPlan Associates, Inc.

Mr. Langer is President and Managing Partner and President of BioPlan Associates, Inc., a biotechnology and life sciences consulting company that has been providing management and market strategy services, and technology analysis to biopharmaceutical and healthcare organizations since 1989. He has over 25 years’ experience in biotechnology and life sciences management and market assessment. He is an experienced medical and biotechnology industry practitioner, strategist, researcher, and science writer. He has held senior management and marketing positions at biopharmaceutical supply companies. He teaches Biotechnology Marketing, Marketing Management, Services Marketing, Advertising Strategy, and Bioscience Communication at Johns Hopkins University, American University, and lectures extensively on pricing and channel management topics. Mr. Langer has a degree in Chemistry and a Masters in International Business. He has written and consulted extensively for companies involved in: large scale biopharmaceutical manufacturing, global biotechnology in China, Asia, and the Middle East; he has expertise in cell culture markets, media, sera, tissue engineering, stem cells, diagnostic products, blood products, genetics, DNA/PCR purifi cation, blood components, and many other areas.

Ronald A. Rader, Senior Research DirectorMr. Ronald A. Rader has written and edited dozens of books and studies on biotechnology topics. He created the fi rst biosimilars pipeline database, and is qualifi ed with a B.S. (Microbiology), M.L.S. (Library Science). He has nearly 30 years’ experience as a biotechnology, pharmaceutical and chemical information specialist and publisher. From 1988, he was Editor/Publisher of the Antiviral Agents Bulletin, the only periodical specializing in antiviral/HIV drug and vaccine development. In 1994, he published the Federal Bio-Technology Transfer Directory, abstracting and indexing all federal laboratory, e.g., NIH, inventions and technology transfers in biotech/biomedical areas, further marketed as an online database until 2000. Mr. Rader published Biopharmaceutical Products in the U.S. Market fi rst in April 2001. Mr. Rader has been Manager of Information Services, Porton International plc, Prior to that he served as a biomedical/chemical information specialist/manager/analyst with companies including Gillette Medical Evaluation Labs., Gillette Co.; MITRE Corp.; Biospherics; Computer Sciences Corp. (CSC); Technical Resources Inc.; and Bio-Conversion Labs.

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13th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production • April 2016A Study of Biotherapeutic Developers and Contract Manufacturing Organizations

CONTENTSMethodology .............................................................................................................. xxiii

CHAPTER 0: Demographics ............................................................................................ 1

0-1 Respondents’ Area of Involvement ...........................................................................1

0-2 Respondents Qualifi cations ......................................................................................3

0-3 Facility Locations .......................................................................................................5

0-4 Areas of Biopharmaceutical Manufacturing Operations ........................................7

0-5 Production Operations, Phase of Development ......................................................9Employees at Facility ................................................................................................. 12Batches Run at Facility per Year ................................................................................ 13

CHAPTER 1: INTRODUCTION AND DISCUSSION ................................................................ 15

1-1 INTRODUCTION: THE BIOPHARMACEUTICAL INDUSTRY ...................................15

1-2 Some Biopharmaceutical Market Trends ................................................................17

1-3 Market Potential ........................................................................................................19

1-4 Biopharmaceutical R&D Pipelines ..........................................................................20

1-5 Biosimilars in the Pipeline .......................................................................................23

1-6 Biopharmaceutical Approvals Generic...................................................................26

1-7 Global Biopharmaceutical and Recombinant Protein/MAb Markets ..................29Overall Health of the Biopharmaceutical Sector ........................................................ 30U.S. Industry Leadership Continues .......................................................................... 32Biopharmaceuticals in the Rest-of-the-World ............................................................. 32

1-8 Biopharmaceutical Markets by Product Class ......................................................35mAbs are the Leading Product Classes .................................................................... 35

1-9 Biopharmaceutical Blockbusters ............................................................................37

1-10 Commercial Product Expression Systems ............................................................38

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1-11 Animal Derived Products and Biopharmaceuticals ..............................................39

1-12 Cost-containment and Price Controls ....................................................................40

1-13 Future Trends in the Biopharmaceutical Industry .................................................40

1-14 Overview of Biopharmaceutical Market Trends .....................................................41

CHAPTER 2: Overview of Critical Issues in Bioprocessing ............................................ 45

2-1 Protein A Resins Continue to Serve Monoclonal Antibodies Manufacture Well, While Incremental Improvements Continue ...........................46

2-2 Biosimilars: Cost Effective Manufacturing Creating Pressures for Mainstream Biologics ..............................................................................................51

2-3 Training: From Startup to Market Production – A GxP Training Philosophy for Success .........................................................................................54

2-4 Facility Planning, Design and Engineering - The Changing Environment – Flexibility is a Key Attribute ..........................................................60

2-5 Alternatives to Protein A ..........................................................................................66

2-6 The Use of Membrane Chromatography throughout a Product’s Life Cycle ......75

2-7 Continuous Bioprocessing and Perfusion: Single-use Technology Aiding to Increase Adoption ...................................................................................80

2-8 Mergers and Acquisitions in the Pharmaceutical Industry, 2015 ...............................................................................84

2-9 The Bioprocessing Equipment Supply Chain: Materials in Single-use Products are the Weakest Link ...............................................................................89

2-10 Trends in Aseptic Bioprocessing Capacity for the Fill and Finish of Recombinant Biologics: An Analysis of US and European In-house Capacity and Capacity Utilization ..........................................................................94

CHAPTER 3: Emerging Issues in Biopharmaceutical Manufacturing ............................. 89

3-1 Industry Trends in 2015 ..........................................................................................101Productivity and Innovation ......................................................................................102

3-2 Budget Issues in 2016 ............................................................................................104Budget Change Comparisons .................................................................................107

3-3 Operational Changes .............................................................................................110

3-4 New Bioprocessing Products Development Opportunities in 2016 ..................111Innovations in Single-use/Disposable Equipment .................................................... 113Discussion of Needed Single-use Innovations ......................................................... 113Other Areas for Innovation ....................................................................................... 115New Product Development Focus, From 2010 to 2016 ........................................... 115New Product Development Areas: Biotherapeutic Developers vs. CMOs .............. 117New Product Development Areas: U.S. vs. Western Europe vs. ROW .................. 119

3-5 Factors in Biomanufacturing Creating Improvements ........................................121Factors Improving Biomanufacturing Performance, 2010 - 2015 ............................ 121

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TABLE OF CONTENTS / FIGURES AND TABLES

Factors Improving Biomanufacturing Performance, Biotherapeutic Developers vs. CMOs (2015 Data) .......................................................................... 123Factors Improving Biomanufacturing Performance, U.S. vs. Western Europe vs. ROW (2015 Data) .................................................................... 125

3-6 Cost-Cutting Actions & Development Timelines .................................................127Cost-Cutting Changes: Specifi c to Outsourcing ....................................................... 129

3-7 Assay Development ...............................................................................................131

3-8 Continuous Bioprocessing Operations Issues ...................................................133

3-9 Discussion ..............................................................................................................137

3-10 Perfusion Operations and Continuous Bioprocessing Trends ..........................137Continuous Bioprocessing: Trends and Opportunities ............................................. 138

3-11 Selecting Bioreactors in New Facilities ................................................................140

3-12 Discussion: Industry Trends and Issues ...........................................................144Industry Growth and Adaptation ............................................................................... 144Cost Cutting Trends ................................................................................................ 144Trends in Assay Development ................................................................................. 145Trends in Speeding Development and Approval Timelines ...................................... 145Trends in Bioprocessing Industry Desires for Improved Products and Services ..... 146

CHAPTER 4: Capacity Utilization ................................................................................. 135

4-1 Capacity Utilization Trends ....................................................................................147Capacity Utilization Defi nitions ................................................................................. 147Relevance of Capacity Utilization ............................................................................ 148Capacity Utilization in Biomanufacturing, 2016 ........................................................ 149Capacity Utilization Changes Since 2004 ............................................................... 150Average Growth Rate in Capacity Utilization, 2006-2016 ........................................ 152

4-2 Capacity Utilization: CMOS vs. Biotherapeutic Developers................................153

4-3 Capacity Utilization: U.S. vs. Western European Manufacturers ........................156

4-4 Respondents’ Current Total Production Capacity ...............................................158Mammalian Cell Culture ........................................................................................... 158Estimated Bioreactor Capacity Distribution, Biotherapeutic Developers and CMOs ............................................................................................ 161Biopharmaceutical Developers/Manufacturers as CMOs ........................................ 163Microbial Fermentation Capacity ............................................................................. 164Yeast Production Capacity ....................................................................................... 165Insect cells Production Capacity .............................................................................. 166

4-5 Current State of Capacity Utilization ....................................................................167Future Capacity Issues ............................................................................................ 168

4-6 Range of Titers for MAb Production .....................................................................169Annual Mab Titer Change, 2008-2016 ..................................................................... 171

4-7 Discussion: Capacity and Industry Trends ..........................................................172Capacity Utilization .................................................................................................. 172

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CHAPTER 5: Current and Future Capacity Constraints ................................................ 165

5-1 Current Capacity Constraints................................................................................179Respondents Experiencing No Capacity Constraints .............................................. 181Respondents’ Perception of Capacity Constraints, 2004-2016 ................................ 181Perception of Capacity Constraints: Biotherapeutic Developers vs. CMOs ............................................................................................. 184Capacity Constraints: U.S. vs. Western European BiotherapeuticDevelopers & CMOs .............................................................................................. 186

5-2 Expected Capacity Constraints.............................................................................188Respondents’ Expectations of Capacity Constraints by 2021 .................................. 188Expected Capacity Constraints by 2021: Comparing 2004 to 2016 Data ................ 190Expected Capacity Constraints by 2021: CMOs vs. Biotherapeutic Developers ... 193Expected Capacity Constraints by 2021: U.S. vs. Western Europe........................ 194

5-3 Factors Impacting Future Production Capacity...................................................195Factors Creating Future Capacity Constraints ......................................................... 195Factors Creating Future Capacity Constraints, 2008 vs. 2016 ................................ 197Factors Creating Future Capacity Constraints: BiotherapeuticDevelopers vs. CMOs .............................................................................................. 199CMOs’ Capacity Bottleneck Projections, in Retrospect ........................................... 201Biotherapeutic Developers’ Capacity Bottleneck Projections, in Retrospect ........... 202Factors Creating Capacity Constraints: U.S. vs. Western European Respondents 203

5-4 Key Areas to Address to Avoid Future Capacity Constraints ............................205Analysis of Areas to Avoid Capacity Constraints: ChangingPerspectives, 2006-2016 ......................................................................................... 207Key areas to Address to Avoid Capacity Constraints; Biotherapeutic Developers vs. CMOs: 2016 vs. Recent Years ........................................................ 209Key Areas to Address to Avoid Capacity Constraints: U.S. vs. Western Europe ..... 211

5-5 Discussion ..............................................................................................................213Overall Capacity Constraints ................................................................................... 214

CHAPTER 6: Future Capacity Expansions .................................................................... 207

6-1 Planned Future Capacity Expansions ..................................................................219Planned Future Capacity Expansions, 2009-2021 ................................................... 220Planned Future Capacity Expansions by 2021; CMOs vs. BiotherapeuticDevelopers ............................................................................................................... 222Planned Five-Year Capacity Expansions; U.S. vs. Western European Manufacturers .......................................................................................................... 224Planned Future Capacity Expansions of >100% ...................................................... 226

CHAPTER 7: Outsourcing Trends in Biopharmaceutical Manufacturing ..................... 217Why Outsource? ...................................................................................................... 229Critical Outsourcing Operations ............................................................................... 229Relating Outsourcing to Workforce Reduction ......................................................... 230

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Strategic Manufacturing Planning ............................................................................ 230Future Projections .................................................................................................... 231

7-1 Current Outsourcing by Production System .......................................................232Summary of Findings: ............................................................................................. 233Facilities Currently Outsourcing No Production (All Production“In-house”), 2006-2016 ............................................................................................ 235

7-2 Future Outsourcing ................................................................................................237Biotherapeutic Developers’ Outsourcing, 2021 Projections, by System .................. 237Biotherapeutic Developers Outsourcing Some Production in 2021 ......................... 239

7-3 Outsourced Activities in Biopharmaceutical Manufacturing .............................241Comparison of Biomanufacturers’ Outsourcing, (2010-2016) .................................. 243Increased Outsourced Activities, 24-month Projections .......................................... 245Outsourcing Activities Projected at ‘Signifi cantly Higher Levels’, Comparison of 2010-2016 Trends ........................................................................... 247Average Percentage of Activities Outsourced Today ............................................... 249Comparison of Outsourcing Activities, 2010-2016 ................................................... 251Change in Spending on Outsourcing Activities ........................................................ 253

7-4 Critical Outsourcing Issues ...................................................................................254Selecting a CMO: 2016 ........................................................................................... 254Selecting a CMO, 2006-2016 ................................................................................... 256Changes in Critical Issues when Considering a CMO, 2008-2016 .......................... 258

7-5 CMOs’ Problems with Their Clients ......................................................................260

7-6 Country Selections for International Outsourcing (Off-shoring) of Biomanufacturing ..................................................................................................262U.S. vs. Western European Respondents’ Outsourcing Destinations ..................... 264Western European Respondents’ Outsourcing Destinations ................................... 2695-Year Projection for Biomanufacturing International Outsourcing/Off-shoring ....... 272

7-7 Offshoring Trends ...................................................................................................2745-Year Projection for Percentages of Biomanufacturing International Outsourcing/Off-shoring ........................................................................................... 276

7-8 Discussion of Outsourcing and Offshoring: .......................................................279Selecting a CMO ...................................................................................................... 282

CHAPTER 8: Disposables and Single-Use Systems in Biopharmaceutical Manufacturing ............................................................................................................ 271

8-1 Use of Disposables and Single-Use Systems ......................................................285Disposables Applications in Biopharmaceutical Manufacturing ............................... 286Trends in Disposable Applications: 2006-2016 ........................................................ 288Annual Growth Rate for Disposables Market Penetration / Usage .......................... 29010-year Growth in Disposables Applications, Percentage-point Gains .................... 292Disposable Use by Stage of Production/Application ............................................... 294Use of Disposables: CMOs vs. Biotherapeutic Developers .................................... 296

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8-2 Leachables and Extractables ................................................................................298Paying for L&E Testing, 2015 vs. 2016 .................................................................... 298

8-3 Reasons for Increasing Use of Disposables & Single-Use Systems .................300Reasons for Increased Use of Disposables, 2006 through 2015 ............................ 302Reasons for Increased Use of Disposables: Biotherapeutic Developers vs. CMOs (2015 data) ........................................................................... 304Single Most Critical Reason for Increasing the Use of Disposables ........................ 305

8-4 Factors That May Restrict Use of Disposables ...................................................307Factors That May Restrict Use of Disposables: Trends 2006-2015 ......................... 309Factors that May Restrict Use of Disposables: CMO’s vs. Biotherapeutic Developers (2015 data) .............................................................................................. 311Most Critical Reasons for Restricting Use of Disposables ....................................... 312Most Important Reasons for Not Increasing Use of Disposables, 2008-2016 ......... 314Most Important Reasons for Restricting Use of Disposables: Biotherapeutic Developer vs. CMO ................................................................................................. 316Top Reasons for Not Increasing the Use of Disposables: U.S. vs. Western Europe Respondents ............................................................................................... 318

8-5 Standards Setting for Disposable, Single-use Systems .....................................320Standardizing Single-use Designs ........................................................................... 320Standardization Factors, 2013-2015 ........................................................................ 322Suppliers’ Expectations for Standards Setting Bodies ............................................. 323

8-6 Budgets for Disposable Systems .........................................................................325

8-7 Need for Single-use Sensors, and Bioreactor Attributes ...................................326Single-Use Adoption Issues ..................................................................................... 326Single-use Adoption Factors, U.S. vs Western Europe ............................................ 327Single-Use Sensor Technologies ............................................................................. 328

8-8 Recycling and Disposal of Single-use Plastics ...................................................330Waste Disposal of Single-use Devices .................................................................... 330

8-9 Satisfaction with Single-use Device Vendors .....................................................332Single-Use Attribute Importance Analysis ................................................................ 334Single-use Suppliers’ Delivery Problems, 2013-2016 ............................................. 336

8-10 Single Use Operations and Trends .......................................................................338Percentage of Unit Operations that are Single-Use ................................................. 338Distribution of Responses ........................................................................................ 340

8-11 Discussion of Single-use Bioprocessing .............................................................341Single-use Advantages ............................................................................................ 341Growth in the Use of Single-use Systems ............................................................... 342Downstream Single-use Systems Use ..................................................................... 343CMOs’ Use of Single-use Equipment ....................................................................... 343Downstream Bottlenecks Persist ............................................................................. 344Modular: The Next Trend after Single-Use .............................................................. 344Single-use Equipment Sourcing, Quality Issues, and L&E Testing .......................... 345

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CHAPTER 9: Downstream Purification ........................................................................ 335

9-1 Impact of Downstream Processing on Capacity .................................................351Impact of Downstream Processing on Capacity, Biopharmaceutical Developers vs. CMOs .............................................................................................354Impact of Downstream Processing on Capacity, U.S. vs. Western European Biomanufacturers ....................................................................................356

9-2 Specific Purification Step Constraints .................................................................358Changes in Impact on Capacity of Purification Steps, 2008-2016 ...........................360

Specific Purification Step Constraints, U.S. vs. Western European Biomanufacturers .....................................................................................................361

9-3 Downstream Purification Issues ...........................................................................362Protein A and Alternatives ........................................................................................362

Changes in Perception of Protein A and Alternatives ............................................... 363Protein A Downstream Purification Issues, U.S. vs. Western Europe ...................... 364

9-4 mAb Purification Capacity Estimates ..................................................................365Current Upstream Production Titer vs. Max Capacity .............................................. 365

9-5 New Downstream Processing Technologies ........................................................368New Downstream Processing Solutions; 2010 – 2016 ............................................370

New Downstream Processing Technologies; Biotherapeutic Developers vs. CMOs ..............................................................................................372

New Downstream Processing Technologies; U.S. vs. Western Europe .................. 3749-6 Improvements to Downstream Operations ..........................................................376

Comparison of New Downstream Technology Implementation; Biomanufacturers vs. CMOs ....................................................................................378

Comparison of New Downstream Technology Investigations; U.S. vs. W. Europe vs. ROW ...................................................................................380

9-7 Discussion ..............................................................................................................382

CHAPTER 10: Quality Issues, Batch Failures, and PAT in Biopharmaceutical Manufacturing ............................................................................................................ 371

Introduction ..............................................................................................................385

10-1 Hurdles to Implementing Process Analytical Technology .................................386Trends in PAT, 2008-2016 ........................................................................................386

PAT Adoption Will Increase ......................................................................................388

10-2 Batch Failure Frequency in Biopharmaceutical Manufacturing ........................389

10-3 Primary Cause of Batch Failures, Percentages of Failures ...............................3922016 Results included: ............................................................................................392

2015 results included: .............................................................................................392

10-4 Quality Problems in BioManufacturing Attributed to Vendors ..........................397

10-5 Automation Implementation .................................................................................399Comparison of Implementation Plans 2009 - 2013 .................................................. 399



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10-6 Quality Initiative Implementation .........................................................................400Initiating quality initiatives requires substantial organizational resources and commitment. .................................................................................... 400Comparison of Quality Initiative Implementation, 2009 - 2016 ................................ 402

10-7 Global Quality Supply Management .....................................................................404Quality Supply Management-US vs. W. Europe ...................................................... 405

10-8 Discussion ..............................................................................................................406Hurdles Hindering Implementation of PAT ............................................................... 406Batch Failures Due to Single-Use Adoption or Continued Stainless Steel Use? ..... 407Quality Problems Traced to Vendors ....................................................................... 407Process Information Needs and Value Drive Automation ....................................... 408Quality Initiatives Are Becoming Commonplace and the New Industry Norm ......... 408Challenges to Implementing PAT, QbD and other Quality Initiatives ........................ 409Supply Management Issues with Single-Use Systems ............................................ 409

CHAPTER 11: Hiring, Employment Growth, and Training in BiopharmaceuticalManufacturing ............................................................................................................ 395

Introduction .............................................................................................................. 41111-1 Hiring Trends ...........................................................................................................412

Trends in New Hires, by Area; 2008 – 2016 ............................................................ 41311-2 Hiring in 2021: 5-year Trends .................................................................................415

11-3 Hiring Challenges Today .......................................................................................416Hiring Diffi culties; 2010 - 2016 ................................................................................. 418Hiring Diffi culties: U.S. vs. Western Europe ............................................................. 420U.S. vs. Western Europe Hiring Trends ................................................................... 420

11-4 Training in Biopharmaceutical Manufacturing ....................................................422Changes in Training for New Manufacturing Employees, 2009-2016 ...................... 423

11-5 Discussion .............................................................................................................424Options Developing for Bioprocessing Training ....................................................... 424Continued Growth in Biopharmaceutical Manufacturing Jobs ................................. 425

CHAPTER 12: Fill and Finish ........................................................................................ 411Introduction .............................................................................................................. 427

12-1 Demographics ........................................................................................................427Areas of Involvement ............................................................................................... 427Geographic Location, Facilities ................................................................................ 428

12-2 Trends in Fill-Finish and Related Bioprocessing Capacity ...............................429Analysis of US and European In-house Capacity and Capacity Utilization ............ 429Challenges in Estimating Fill-Finish Capacity ......................................................... 430

12-3 Current Fill-Finish Trends ......................................................................................431Recent Industry Trends .......................................................................................... 433Future Fill and Finish Trends ................................................................................... 434

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Suppliers’ Innovation Trends .................................................................................... 434Industry Capacity Data ............................................................................................. 435New Technology Implementation in Fill-Finish ......................................................... 436

12-4 Discussion ..............................................................................................................437Voice of Industry: ..................................................................................................... 437

CHAPTER 13: Suppliers to Biopharmaceutical Manufacturing and Life Sciences ....... 425Introduction .............................................................................................................. 443

13-1 Demographics ........................................................................................................443Areas of Involvement ............................................................................................... 443Location of Vendor Sales ........................................................................................ 446Respondents’ Primary Job ...................................................................................... 448

13-2 Growth Rate of Sales by Suppliers ......................................................................449Average Industry Growth Rate, By Segment ........................................................... 451Vendor Sales Growth Rates, by Industry Segment, 2007 to 2016 ........................... 452Supplier Annual Sales, Distribution .......................................................................... 454

13-3 Discussion of Vendor and Industry Growth ........................................................455

13-4 Budget Issues and Problems Faced by Industry Suppliers ...............................456Budget Challenges in 2016 ...................................................................................... 456Vendor Average Budget Changes for 2009 -2016 ................................................... 458Vendor Pricing Changes .......................................................................................... 460Future Price Changes .............................................................................................. 461Supplier Budget Issues ............................................................................................ 462

13-5 Cost Cutting Actions by Vendors ..........................................................................462Cost Cutting Actions, By Segment ........................................................................... 464

13-6 Problems Clients Have with Their Vendors ..........................................................466

13-7 Vendor Expansion Plans .......................................................................................468Biopharma Vendor Business Trends, 2010 vs 2016 ................................................ 470

13-8 New Technology Areas in Development by Vendors ...........................................472

13-9 Sales Staff Training.................................................................................................478Days of Training Provided ....................................................................................... 478Areas where Training May Help Sales Staff Perform, Trends 2010 - 2016.............. 478Clients’ Demands on Vendors .................................................................................. 480

13-10 Biopharma Vendors’ Financial Outlook for 2016 ...............................................482

13-11 Discussion of Biopharma Suppliers ....................................................................484Bioprocessing Vendors Will See Continued Market Growth .................................... 484Single-use Systems Are Increasingly Driving Sales ................................................ 484Trends Favor Increased Vendor Sales ..................................................................... 485Vendors are Offering More Services, Going for Larger Sales .................................. 485Biopharma Suppliers in Emerging Regions ............................................................. 486

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FIGURESFig 0.1: Area of Primary Involvement in Biopharmaceutical Manufacturing, 2010 to 2016 .......................................................................................2

Fig 0.2: Respondents’ Job Responsibilities, 2011 - 2016 .........................................................4

Fig 0.3: Facility Location ...........................................................................................................5

Fig 0.4: Facility Location, by Region .........................................................................................6

Fig 0.5: Biopharmaceutical Manufacturing Systems, (2007-2016) Trends ...............................8

Fig 0.6: Phase of Development of Surveyed Respondents (2006-2016) Trends ....................10

Fig 0.7: Phase of Development of Surveyed Respondents, (U.S. vs Western Europe) ..........11

Fig 0.8: Distribution of Employees at Facility, and Organization .............................................12

Fig 0.9: Distribution of Total Batches Run at Facility Last Year, by Scale of Production .........14

Fig 1.1: Investigational Drugs: Large Molecule (Protein Therapeutics), Worldwide, 2010 - 2015 .............................................................................................21

Fig 1.2: Worldwide Pipeline & Launched Products, Large Molecules, January 2015 ............22

Fig 1.3: Current Worldwide Pipeline & Launched Products, Large Molecules, January 2015 ..............................................................................................................23

Fig 1.4: Number of Biosimilars in the U.S. Pipeline by Launchable Dates .............................24

Fig 1.5: Biosimilars Launchable Dates by Sum of Current Reference Products Sales ($millions) ..........................................................................................25

Fig 1.6: FDA Approvals of New Biopharmaceutical Products 1982-2015 ..............................26

Fig 2.1: A GxP Training Philosophy for Success ....................................................................56

Fig 2.2: Trends in FDA Key Compliance Themes ...................................................................59

Fig 2.3: Antibody binding capacities on two prototype mixed mode membranes from Natrix Separations. .............................................................................................77

Fig 2.4: Example of chromatographic like separation achieved on a mixed mode membrane from Natrix Separations. (updated for this year’s edition) .......................77

Fig 3.1: SINGLE most important biomanufacturing trend or operational area, 2014-2016 ...............................................................................................................103

Fig 3.2: Biomanufacturers’ Budget Shifts in 2016 .................................................................105

Fig 3.3: Approximate Average Change in Biomanufacturers’ Budgets for 2016 ..................106

Fig 3.4: Average Biomanufacturers’ Budget Change, 2009-2016 ........................................109

Fig 3.5: New Product Development Focus Areas .................................................................112

Fig 3.6: New Product Development Areas of Interest: 2010 - 2016 ......................................116

Fig 3.7: New Product Development Areas of Interest: Biotherapeutic

Developers vs CMOs ...............................................................................................118

Fig 3.8: New Product Development Areas of Interest: U.S. vs. Western Europe vs. ROW ...120

Fig 3.9: Factors in Biomanufacturing Performance Creating “Signifi cant” or “Some” Improvements: 2010 – 2015 (Data from 2015) ............................................122

Fig 3.10: Factors in Biomanufacturing Performance Creating “Signifi cant” or “Some” Improvements: Biomanufacturers vs CMOs (2015 Data) ........................................124

Fig 3.11: Factors in Biomanufacturing Performance Creating “Signifi cant” or “Some” Improvements: U.S. vs. Western Europe vs. Rest of World (2015 Data) .................126

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Fig 3.12: Cost-Cutting Changes: Actions Undertaken During “Past 12 Months” Comparing 2011-2016 .............................................................................................128

Fig 3.13: Cost-Cutting Changes, Outsourced Jobs, by Segment, and Geography (2011-2016) ...........................................................................................130

Fig 3.14: Biomanufacturing Assay ‘Areas’ Urgently Requiring New, Improved Testing Methods, 2011-2015 (2015 Data) ................................................132

Fig 3.15: Perfusion Operations Issues: Perfusion vs. Batch-Fed Processes ..........................135

Fig 3.16: Perfusion Operations Issues: Comparison 2010 - 2016 .........................................136

Fig 3.17: Continuous Bioprocessing Technologies Evaluation, Next 12 Months ....................138

Fig 3.18: Likelihood of Implementing bioreactor, by type ......................................................142

Fig 3.19: Likelihood of Implementing Single-use Bioreactors, Clinical Scale, 2012-2016 .....143

Fig 4.1: Capacity Utilization, By System................................................................................150

Fig 4.2: Capacity Utilization, By System, 2004-2016 ............................................................151

Fig 4.3: Change in Capacity Utilization, CAGR, 2006-2016..................................................152

Fig 4.4: Capacity Utilization, By System, Biotherapeutic Developer vs. CMOs ....................155

Fig 4.5: Capacity Utilization, By System, U.S. vs Western Europe .......................................157

Fig 4.6: Current Production Capacity Distribution, Mammalian Cell Culture ........................159

Fig 4.7: Production Capacity Distribution, Mammalian Cell Culture, 2011-2016 ..................160

Fig 4.8: Current Production Capacity Distribution, Microbial Fermentation ..........................164

Fig 4.9: Current Production Capacity Distribution, Yeast ......................................................165

Fig 4.10: Current Production Capacity Distribution, Insect cells ............................................166

Fig 4.11 Mammalian Cell Culture Capacity Estimates 2003-2015 .........................................167

Fig 4.12 Microbial Fermentation Capacity Estimates 2003-2015...........................................168

Fig 4.13: Range of Titres for Mabs Obtained at Various Production Scales, Distribution .......170

Fig 4.14: Average Mab Titre Trend 2008-2016 ........................................................................171

Fig 5.1: Capacity Constraints, by Stage of Production .........................................................180

Fig 5.2: Capacity Constraints, 2004 through 2016 ................................................................182

Fig 5.3: Capacity Constraints Trends, 2004-2016 .................................................................183

Fig 5.4: Capacity Constraints, Biotherapeutic Developers vs. CMOs ..................................185

Fig 5.5: Capacity Constraints, US vs. Western Europe .........................................................187

Fig 5.6: Expectations of Capacity Constraints; by Stage of Production; Five-year Projections ................................................................................................189

Fig 5.7: Expectations of Capacity Constraints: Five-year Projections Made in 2004-2016 ..191

Fig 5.8: Expectations of Capacity Constraints: Five-year Projections Made in 2004 thru 2021 (Trend Line) ..............................................................................................192

Fig 5.9: Five-year Projections for Capacity Constraints: Biotherapeutic Developers vs. CMOs ..............................................................................................193

Fig 5.10: Five-year Projections for Capacity Constraints: U.S. vs. Western Europe ..............194

Fig 5.11: Factors Creating Future Capacity Constraints .........................................................196

Fig 5.12: Factors Creating Future Capacity Constraints, 2008-2016 ......................................198

Fig 5.13: Factors Creating Future Capacity Constraints: Biotherapeutic Developers vs. CMOs ..............................................................................................200

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Fig 5.14: Factors Creating Future Capacity Constraints, U.S. vs. Western European Biomanufacturers .....................................................................................204

Fig 5.15: Key areas to Address to Avoid Capacity Constraints ..............................................206

Fig 5.16: Key areas to Address to Avoid Capacity Constraints; 2006-2016 ..........................208

Fig 5.17: Key Areas to Address to Avoid Capacity Constraints; Biotherapeutic Developers vs. CMOs ..............................................................................................210

Fig 5.18: Key areas to Address to Avoid Capacity Constraints; U.S. vs. Western Europe .....212

Fig 6.1: Industry Average Planned Production Increase by 2021 ........................................220

Fig 6.2: Planned Future Capacity Expansion: 5-year Estimates, 2009 through 2021 ...........221

Fig 6.3: Planned Future Capacity Expansion: 5-year Estimates; Biotherapeutic Developers vs. CMOs ..............................................................................................223

Fig 6.4: Planned Future Capacity Expansion: 5-year Estimates; U.S. vs. Western Europe ........................................................................................................225

Fig 6.5: Percent of Respondents Projecting Production Increases of over 100% by 2021; 5-year Trend ....................................................................................227

Fig 7.1: Current Percent Production Outsourced; by System ...............................................234

Fig 7.2: Biopharmaceutical Manufacturing Facilities Outsourcing NO Production, 2006-2016 .............................................................................................236

Fig 7.3: Future Outsourcing: Percent Production Outsourced; by System, in 2021 .............238

Fig 7.4: Five-year Projections: % Biotherapeutic Developers Planning to Outsource at Least Some Production; Projections made 2007-2016 ........................................240

Fig 7.5: Percent of Biomanufacturers Outsourcing at Least Some Activity Today ................242

Fig 7.6: Percent of Biomanufacturers Outsourcing at Least Some Activity Today--2010 - 2016 ..................................................................................................244

Fig 7.7: Outsourcing Activities Projected to be Done at ‘Signifi cantly Higher Levels’ in 2 Years ......................................................................................................246

Fig 7.8: Outsourcing Activities Projected to be Done at ‘Signifi cantly Higher Levels’ in 2 Years, 2010 - 2016 Trends .....................................................................................248

Fig 7.9: Current Outsourcing: Average Percentage of Activity Outsourced Today ...............250

Fig 7.10: Estimated Average Percent of Activity Outsourced by Facilities, 2010 thru 2016 ...252

Fig 7.11: Change in Spending on Outsourcing for R&D or Manufacturing, 2012 - 2016 .......253

Fig 7.12: Outsourcing Issues: BioManufacturing by Contract Manufacturing Organizations .255

Fig 7.13: Important Outsourcing Issues: BioManufacturing by Contract Manufacturing Organizations, Trends 2006-2016 ............................................................................257

Fig 7.14: Important Outsourcing Issues: Response Shifts Over Time 2006-2016, Percentage Point Differences ...................................................................................259

Fig 7.15: Most Common Mistakes Biopharmaceutical Sponsors Make with their CMOs, 2010-2013 ................................................................................................................261

Fig 7.16: Country Selections as Destination for International Outsourcing of ............................... BioManufacturing (All Respondents) .......................................................................263

Fig 7.17: Percent U.S. Respondents Considering Country as ‘Possible’ Outsourcing Destination ...............................................................................................................265

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Fig 7.18: Percent U.S. Respondents Considering Country as “Strong Likelihood” or “Likelihood” as Outsourced Capacity Destination ...............................................267

Fig 7.19: Percent Western European Respondents Considering Country as ‘Possible’ Outsourcing Destination ...........................................................................................270

Fig 7.20: Percent European Respondents Considering Country as “Strong Likelihood” or “Likelihood” as Outsourced Capacity Destination ...............................................271

Fig 7.21: Percent of Biomanufacturing Operations Off-shored (International Outsourcing) within 5 Years ...........................................................................................................273

Fig 7.22: Percent Biomanufacturers Performing at Least “Some” International Outsourcing/Off-shoring during Next 5 Years (2011-2016) ......................................275

Fig 7.23: Estimated % Operations Done as International Outsourcing/Off-shoring during Next 5 Years (2011-2016) .............................................................................277

Fig 8.1: Usage of Disposables in Biopharmaceutical manufacturing, any Stage of R&D or Manufacture .............................................................................................287

Fig 8.2: Usage of Disposables in Biopharmaceutical manufacturing, any Stage of R&D or Manufacture; 2006-2016 ..............................................................................289

Fig 8.3: Average Annual Growth Rate, Disposables, 2006-2016 ..........................................291

Fig 8.4: 10-Year Percentage-Point Change in First-Usage of Disposables, 2006-2016 .......293

Fig 8.5: Usage of Disposables in Biomanufacturing, by Stage of Manufacture (R&D - Commercial) .................................................................................................295

Fig 8.6: Usage of Disposables in Biopharmaceutical Manufacturing; Biotherapeutic Developer vs. CMO..........................................................................297

Fig 8.7: Value of Useable Leachables and Extractables Data ..............................................299

Fig 8.8: Reasons for Increasing Use of Disposable System Components in 2015 (data from 2015) .......................................................................................................301

Fig 8.9: Reasons for Increasing Use of Disposable System Components, 2006-2015 ........303

Fig 8.10: Single Most Critical Reason for Increasing Use of Disposables, 2009 - 2016 .........306

Fig 8.11: Reasons for Restricting Use of Disposables (2015 Data) ........................................308

Fig 8.12: Factors Restricting Use of Disposables, 2006-2015 (2015 Data) ............................310

Fig 8.13: Top Reasons for Not Increasing Use of Disposables, 2016 .....................................313

Fig 8.14: Top Reasons for Not Increasing Use of Disposables, 2008-2016 ...........................315

Fig 8.15: Top Reasons for Not Increasing Use of Disposables, Biotherapeutic Developer vs. CMO ..................................................................................................317

Fig 8.16: Top Reasons for Not Increasing Use of Disposables, U.S. vs. Western Europe .....319

Fig 8.17: Single-use/Disposables Standardization Factors (2015 Data) ................................321

Fig 8.18: Single-use/Disposables Standardization Factors, 2013-2015 (2015 data) ..............322

Fig 8.19: Suppliers’ Perception of Organizations Responsible for Establishing Standards for Single-use Devices ............................................................................324

Fig 8.20: Single-use / Disposable Device Adoption Factors...................................................326

Fig 8.21: Single-use / Disposable Device Adoption Factors; U.S. vs Western Europe ..........327

Fig 8.22: Need for Improved Single-Use Sensors, 2012-2016 ...............................................329

Fig 8.23: Single-use Recycling; Respondents’ Desires for Disposal vs. Actual Disposal Process ......................................................................................................330

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Fig 8.24: Single-use Product Vendor Satisfaction Factors, 2008 - 2016 .................................333

Fig 8.25: Importance of Single-use Product Attributes vs. Level of Vendor Satisfaction ........335

Fig 8.26: Percentage Point Gap between Importance of SUS Product Attributes and Level of Satisfaction, 2013-2016 ..............................................................................337

Fig 8.27: Estimated Percentage of Facilities’ Unit Operations that are “Single-use” (2014-2016) ..............................................................................................................339

Fig 8.28: Distribution of Responses, % Single-use Devices in Biomanufacturing ..................340

Fig 9.1: Impact of Downstream Processing on Overall Capacity, 2008-2016 .......................353

Fig 9.2: Impact of Downstream Processing on Overall Capacity; Biotherapeutic Developers vs. CMOs ..............................................................................................355

Fig 9.3: Impact of Downstream Processing on Overall Capacity; U.S. vs. Western Europe 357

Fig 9.4: Impact on Capacity of Depth, Chromatography and UF Purifi cation Steps ............359

Fig 9.5: Impact on Capacity of Purifi cation Steps: Experiencing at “Signifi cant” or “Severe” Constraints, 2008 - 2016 ...........................................................................360

Fig 9.6: Impact on Capacity of Purifi cation Steps, U.S. vs. Western Europe ........................361

Fig 9.7: Issues Regarding Protein A Usage ..........................................................................362

Fig 9.8: Issues Regarding Protein A Usage, 2009 - 2016 .....................................................363

Fig 9.9: Issues Regarding Protein A Usage; U.S. Vs. Western Europe.................................364

Fig 9.10: mAb Operations: Current Upstream Production Titer (Distribution of Responses) ......................................................................................366

Fig 9.11: Bioreactor Yield at which DOWNSTREAM Purifi cation Train Becomes Bottlenecked ............................................................................................367

Fig 9.12: New Downstream Processing Solutions ...................................................................369

Fig 9.13: New Downstream Processing Solutions Comparison 2010-2016 ............................371

Fig 9.14: New Downstream Processing Solutions; Biotherapeutic Dev. vs. CMO ..................373

Fig 9.15: New Downstream Processing Solutions; U.S. vs. Western Europe..........................375

Fig 9.16: Improving Downstream Operations, 2011 - 2016 ....................................................377

Fig 9.17: Improving Downstream Operations; Biomanufacturers vs. CMOs ..........................379

Fig 9.18: Improving Downstream Operations (U.S. vs. Western Europe vs. ROW) ................381

Fig 10.1: Hurdles Hindering Implementation of PAT (2008 - 2016) ........................................387

Fig 10.2: Batch Failure Frequency Distribution, 2009 - 2016 ..................................................391

Fig 10.3: Average Rates of Failure, by Primary Cause, and Phase of Manufacture ...............393

Fig 10.4: Average Rates of Failure, by Primary Cause, and Phase of Manufacturing 2009 - 2016 (Commercial Manufacture) ..................................................................394

Fig 10.5: Average Rates Failure, by Primary Cause, and Phase of Manufacturing 2009 - 2016 (“Clinical” Scale) ..................................................................................396

Fig 10.6: Quality Problems Traced to Vendors; 2008 – 2016 ..................................................398

Fig 10.7: Quality Initiative Implemented Currently, or within Next 12 Months .........................401

Fig 10.8: Quality Initiative to be Implemented in “Next 12 Months,” Comparing 2009 - 2016 ..............................................................................................................403

Fig 11.1: New Hires in Biopharmaceutical Manufacturing (2016) ..........................................412

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Fig 11.2: Estimated Hiring, by Area, 2008-2016 .....................................................................414

Fig 11.3: New Hires in Biopharmaceutical Manufacturing (2021) ..........................................415

Fig 11.4: Areas Where Hiring Diffi culties Exist in Biopharmaceutical Operations ..................417

Fig 11.5: Areas Where Hiring Diffi culties Exist in Biopharmaceutical Operations; 2010 - 2016 ..............................................................................................................419

Fig 11.6: Areas Where Hiring Diffi culties Exist in Biopharmaceutical Operations, U.S. vs. Western Europe ..........................................................................................421

Fig 11.7: Training for New Operations/Manufacturing Employees ..........................................422

Fig 11.8: Average Annual Changes in Training for New Operations/Manufacturing Employees, 2009 – 2016 ..........................................................................................423

Fig 12.1: Fill-Finish Operation Type ........................................................................................427

Fig 12.2: Fill-Finish Operation Location ...................................................................................428

Fig 12.3: Fill-Finish Capacity Utilization Averages, 2015-2016 ...............................................430

Fig 12.4: Most Important Trends in Fill-Finish, 2015-2016 ......................................................432

Fig 12.5: Novel Fill-Finish Technology Implementation Plans within 24 Months, 2015 vs 2016 ............................................................................................................436

Fig 13.1: Area of Biopharmaceutical Involvement, Vendor .....................................................444

Fig 13.2: Area of Biopharmaceutical Involvement, Vendor Comparison 2010 to 2016 ..........445

Fig 13.3: Geographic Locations in which Vendors Currently Actively Sell Products or Services, 2008 - 2016 .........................................................................................447

Fig 13.4: Respondents’ Primary Job Function ........................................................................448

Fig 13.5: Average Annual Vendor Sales Growth Rate, 2007 - 2016 .......................................449

Fig 13.6: Biopharmaceutical Supply Market Segment Sales Growth Distribution ..................450

Fig 13.7: Average Annual Vendor Segment Sales Growth Rates, 2016 .................................451

Fig 13.8: Average Annual Vendor Sales Growth Rate, 2007 - 2016, by Segment ..................453

Fig 13.9: Vendors’ Approx. Annual Sales to Biopharmaceutical Segment %, 2012-2016 ......454

Fig 13.10: Vendors’ Average Budget Change for 2016 ............................................................457

Fig 13.11: Vendors’ Average Budget Change for 2009 - 2016, Summary ................................459

Fig 13.12: Vendors’ Average Pricing Changes (2015 responses) ............................................460

Fig 13.13: Vendors’ Average Pricing Changes, 2009-2015 Actual and 2016 projected ..........462

Fig 13.14: Actions undertaken to reduce overall costs, prior 12 months, 2011 – 2016 ............463

Fig 13.15: Actions undertaken to reduce overall costs in past 12 months, By Segment..........465

Fig 13.16 (See Fig 10.6; recap): Quality Problems Traced to Vendors ....................................467

Fig 13.17: Biopharma Business and Marketing Plans, 2016 ....................................................469

Fig 13.18: Biopharma Business and Marketing Plans, 2010-2016 ...........................................471

Fig 13.19A: Top New Technologies or New Product Development Areas ..................................473

Fig 13.19B: Top New Technologies or New Product Development Areas ..................................474

Fig 13.20: Areas Where Training May Help Sales Staff Perform Better; 2010 – 2016 ...............479

Fig 13.21: Client Demands of Vendors, Service and Support, 2012 - 2016 .............................481

Fig 13.22: Vendors’ Optimism; Financial Performance 2011-2014, and Projected Performance in 2016 ...............................................................................483

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TABLESTable 1.1 Biopharmaceutical Approvals Generic, 2015 ............................................................27

Table 1.2 Number of Products in U.S. and European Markets* .................................................29

Table 1.3 Summary of Worldwide Biopharmaceutical Revenue Growth by Product Class, 2007 and 2015 .................................................................................35

Table 1.4 Blockbuster Biopharmaceutical Products* ................................................................37

Table 1.5 Expression Systems/Host Cells for U.S./EU-Marketed Cultured Biopharmaceuticals ...................................................................................................39

Table 2.1 Factors involved in facility decision-making...............................................................63

Table 3.1 Areas of Signifi cant Projected Budget Percentage Increases for Biomanufacturing, Past Years: .................................................................................108

Table 4.1 Western European Biomanufacturers’ Average Capacity Utilization .......................156

Table 4.2 U.S. Biomanufacturers’ Average Capacity Utilization ..............................................156

Table 4.3 Distribution of Mammalian Cell Culture Capacity, Product Manufacturers .............162

Table 4.4 Compound Annual Change in Mab Titre, 2008-2016 ..............................................172

Table 5.1 “Severe” or “Signifi cant” Capacity Constraints, by Stage of Production, 2009-2016 ...............................................................................................................180

Table 5.2 “Severe” or “Signifi cant” Capacity Constraints today, W. Europe vs. U.S., 2010-2016 ......................................................................................................186

Table 7.1 Mammalian and Microbial Cell Systems, No outsourced production (i.e., all in-house manufacturing) .............................................................................233

Table 7.2 Mammalian and Microbial Cell Systems, outsourced up to half of production ........233

Table 7.3 Mammalian and Microbial Cell Systems, outsourced more than half of production .....................................................................................................233

Table 7.4 Percent of U.S.-based Respondents Indicating Country as a “Strong Likelihood”or “Likelihood” as Outsourcing Destination, 2009-2016 ..........................................268

Table 7.5 Percent of European-based Respondents Indicating Country as a “Strong Likelihood” or “Likelihood” as Outsourcing Destination, 2011-2016 ..........272

Table 9.1 Percent experiencing “Serious” or “Some” capacity problems due to downstream processing 2008-2016 ........................................................................354

Table 9.2 Percent U.S. vs. Western Europe facilities experiencing “Serious” capacity problems due to downstream processing, 2009-2016 ............................................356

Table 9.3 Percent U.S. vs. Western Europe facilities not expecting to see bottlenecks due to downstream processing, 2008-2016 ............................................................356

Table 9.4 Current Upstream Production Titer vs. Max Capacity ..............................................365

Table 10.1 Batch Failures, Average Weeks per Failure, per Facility, 2008-2016 .......................389

Table 13.1 Selected “Other” Responses, New Technology Areas in Development ..................475

Table 13.2 Average Vendor Sales and Technical Training Days, 2011 - 2013 ..........................478

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M E T H O D O LO G YThis report is the thirteenth in our annual evaluations of the state of the biopharmaceutical manufacturing industry. The strength of this study’s methodology remains in its breadth of coverage, which yields a composite view from the respondents closest to the industry. This year, BioPlan Associates, Inc. surveyed 222 qualifi ed and responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations in 27 countries; plus 191 industry vendors and direct suppliers of materials, services and equipment to this industry segment. Using a web-based survey tool, we obtained and evaluated information regarding respondents’ current capacity, production, novel technology adoption, human resources, quality, and outsourcing issues. We assessed respondents’ projected reasons for bottlenecks, and their perception of how these bottlenecks might be resolved.

We continue to provide additional in-depth analysis of specifi c issues affecting the industry in Chapter 2. These Monographs cover the events shaping the past year, and evaluate how they will affect, or create trends that will shape biopharmaceutical manufacturing over the next fi ve years. We also have included this year a chapter on Fill-and Finish operations. Over the past few years, advances in technologies, drug delivery, and single-use applications have increasingly made this segment an area of interest for innovation.

To ensure comprehensive global coverage, we partnered with world-wide organizations to ensure the most accurate overview of the worldwide biopharmaceutical industry. Our industry partners are included in our acknowledgment section. In addition, to support this coverage, we also include acknowledgment of our media partners, whose assistance enabled us to reach the high quality of respondents required in this quantitative analysis.

Further information on methodology, breakouts on specifi c segments, and data from earlier surveys may be obtained by contacting us at the address below.

Eric S. LangerPresidentBioPlan Associates, Inc.2275 Research Blvd., Suite 500Rockville, MD 20850301-921-5979 [email protected]

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CHAPTER 0: DEMOGRAPHICS

C H A P T E R 0:D E M O G R A P H I C S

Survey respondents included a diverse group of biopharmaceutical senior managers and executives covering a spectrum of global biopharmaceutical and CMO fi rms. In addition, in Chapter 13, we include responses from global suppliers and vendors in this industry.

As in previous years, we included fi rms of all sizes. While we specifi cally sought input from larger manufacturers with substantial current capacity, we also obtained data from mid-tier and smaller companies with clinical scale production, and also from companies using CMOs for product manufacture and from CMOs. Respondents had a broad range of responsibilities, though all were directly involved with manufacturing in some way. Most were senior staff within their organizations.

This was an international effort, and we received responses from individuals at organizations around the world, including input from facilities in 27 countries.

The diversity of respondents provides a comprehensive view of the industry from those closest to the present state of their organizations; those with a good understanding of the current and future business drivers, and their company’s manufacturing plans and needs. This offers a means for understanding the industry and its future course. The breakdown of organizations into CMOs and biotherapeutic manufacturers provides insights into two major segments of the industry. These two types of organizations have different business drivers, risk profi les, and costs of capital.

0-1 RESPONDENTS’ AREA OF INVOLVEMENTOf the 222 biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) staff responding to this year’s survey, 23.0% were primarily involved in La rge-scale cell culture production for therapeutics, slight decrease down from 23.6% last year, and continued decline from 27.7% in 2014. 27.0% were involved primarily in Process Development for biopharmaceutical manufacturing, an almost 6% percentage point increase from 21.9% last year, and back up to levels seen in 2013; 12.6% were involved in sc ale-up (or clinical-scale) production for biopharmaceuticals only, a small increase from 11.0% last year.

Respondents involved with Large-scale Microbial Fermentation for therapeutics accounted for 5.9%, an increase in 1.7% percentage points and a change from last year’s decline of 4.2%, and 8.1% of respondents indicated they were primarily involved in Vaccine production, down from 9.3% reported last year. ‘Other’ large-scale biopharmaceutical manufacturing respondents accounted for 6.3% of the total this year, a decline from 9.7% in 2015, and ‘Other’ contract manufacturing (CMO) for biopharmaceuticals accounted for 2.3% of respondents, down from 3.8% last year. Lastly, 9.5% were employed in Large-scale contract manufacturing (CMO) for biopharmaceuticals, the slightest decrease from most prior years. This year, 5.4% of



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respondents accounted for Fill/Finish operations, a slight decline from 6.8% last year. Overall, the makeup of respondents remains overall consistent with prior years’ studies, with the most signifi cant changes seen in Process Development for biopharmaceutical manufacturing and ‘Other’ large-scale biopharmaceutical manufacturing. Despite variations, including decreases, in reporting involvement in aspects of biopharmaceutical manufacturing, this year’s data continues to fall within the range defi ned by prior years’ data reporting, with the relative rankings remaining largely unaffected.

Fig 0.1: Area of Primary Involvement in Biopharmaceutical Manufacturing, 2010 to 2016

"In which area of biopharmaceutical manufacturing is your organization currently involved?"

Comparison 2010 to 2016

27.0%

23.0%

12.6%

9.5%

8.1%

6.3%

5.9%

2.3%

21.9%

23.6%

11.0%

9.7%

9.3%

9.7%

4.2%

6.8%

3.8%

27.7%

16.8%

10.1%

5.9%

10.1%

5.0%

2.1%

26.1%

25.6%

8.0%

5.9%

13.4%

6.7%

8.8%

5.5%

21.5%

28.5%

11.3%

6.6%

9.9%

7.3%

7.9%

7.0%

23.9%

25.0%

12.5%

8.0%

11.1%

7.1%

7.7%

4.8%

19.0%

26.3%

14.4%

9.2%

8.0%

7.0%

10.1%

6.4%

5.4%

22.3%Process Development for

biopharmaceutical manufacturing

Large-scale cell culture production for therapeutics

Scale-up (or clinical-scale) production for biopharmaceuticals only

Large-scale contract manufacturing (CMO) for biopharmaceuticals

Vaccine production

Other large-scale biopharmaceutical manufacturing

Large-scale microbial fermentation for therapeutics

Fill/Finish operations, primarily

Other contract manufacturing (CMO) for biopharmaceuticals

Year 2016Year 2015Year 2014Year 2013Year 2012Year 2011Year 2010




0-2 RESPONDENTS QUALIFIC ATIONSRespondents were asked about their areas of responsibility, as indicated by job titles. Over 92% had titles of VP, Director or President/CEO, consistent with last year’s 91.7% and nearly 88% in 2014. VPs, Directors or Managers of Manufacturing, Production, and Operations comprised 27.1% of respondents, a sharp decline from 34.2% last year. Combining VPs with Process Development Directors and Managers, the percentage comes to 63.6%, a 3.3%-point decrease from last year’s 66.9%, and closer to 62.7% reported in 2014.

Biopharmaceutical Scientist or Engineer respondents lacking VP/Director/Manager responsibilities in Process Development, R&D or Production made up 7.9%, another persistent decline from prior year respondents (8.3% in 2015 and 12.1% in 2014.) This year, 15.8% of respondents indicated they were VPs, Directors or Managers of QA, QC, Validation, or RA, the largest number of respondents in this area since data collection started in 2011. Presidents/CEOs represented 7.4% of respondents, a reversal from the decline seen in prior years; and VPs or Directors of R&D accounted for 5.4% of respondents, still averaging similar totals seen in past years. The largest percentage change this year continues for those reporting VP or Director: Operations responsibilities, with a 6.8%-point decrease from last year.




Fig 0.2: Respondents’ Job Responsibilities, 2011 - 2016

Which best describes your primary job responsibilities?

36.5%

21.2%

15.8%

7.9%

7.4%

5.9%

5.4%

32.7%

21.5%

11.7%

8.3%

6.8%

12.7%

6.3%

35.9%

19.0%

10.4%

12.1%

7.4%

7.8%

7.4%

28.2%

16.3%

11.9%

15.0%

11.5%

8.4%

5.3%

22.8%

20.9%

13.9%

16.9%

9.6%

9.3%

5.0%

24.1%

18.8%

11.4%

12.5%

7.7%

6.3%

6.3%

VP, Director, Mgr: Process Development

VP, Director, Mgr: Manufacturing,Production

VP or Director, Manager: QA, QC, Validation, RA

Engineer or Scientist: PD, R&D, Production

President / CEO

VP or Director: Operations

VP or Director: R&D

2016

2015

2014

2013

2012

2011




0-3 FACILIT Y LOC ATIONSThis year we surveyed respondents based in 27 countries. Almost 62% of the respondents were from the United States, with the Northeastern U.S. continuing to make up the largest group of respondents in the U.S., at 33.3%, no change from last year’s total. Respondents from Western Europe made up 21.4% of the total, a continued increase from last year’s 19.7%. Other countries in the survey (“Rest of World”) made up 17.5% of the respondents.

Further information about biopharmaceutical manufacturing facilities worldwide is available at the Top 1000 Global Biopharmaceutical Facilities Index Web site from BioPlan Associates (www.Top1000Bio.com).

Fig 0.3: Facility Location

Other Countries include: Austria, Bulgaria, Chile, Hungary, Iran, Japan, Korea, Lithuania, Puerto Rico, South Africa, Sweden, Taiwan

Where is your facility located?

33.5%

8.3%

6.8%

6.8%

6.3%

5.8%

4.4%

3.9%

2.9%

2.4%

1.9%

1.9%

1.5%

1.5%

1.5%

1.0%

1.0%

1.0%

1.0%

6.3%

0% 5% 10% 15% 20% 25% 30% 35%

US-Northeast

US-Southwest

US-Southeast

US-Central

India

Germany

US-Northwest

Belgium

United Kingdom

Canada

France

Israel

Austria

Italy

Korea

Iran

Ireland

Mexico

Sweden

Other Countries

Other Countries include: Brazil, China, Holland, Iceland, Japan, Netherlands, Puerto Rico, Singapore, South Africa, Switzerland, Turkey




We note that U.S. respondents continued its steady rate at 61.2%, down 1.7%-points from 62.9% last year, 65.8% in 2014, and nearly consistent with the 61.7% U.S. respondents in 2011. Western European responses remain relatively constant near 20% since 2011, with the slightest increase to 21.4% this year.

This year ROW responses only rose 0.1 point from last year’s 17.4%, although still off the peak of 22.0% in 2013. This year we see a slight uptick in Western European respondents and U.S. bioprocessing professionals remain to be more motivated to participate in this and other industry surveys.

Fig 0.4: Facility Location, by Region

Western Europe respondents include: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, Switzerland, and the United Kingdom.

“Rest of World” respondents include: Australia, Canada, Chile, India, China, Iran, Singapore, Egypt, Japan, Russia, Estonia, Israel, Argentina, Brazil, Bulgaria, Cuba, Korea, Lithuania, New Zealand, Poland, Slovenia, South Africa, and Taiwan.

Respondents' Facility Location by Region (Biotherapeutic Developers and CMOs)

Rest of World

WesternEurope

U.S.61.2%

17.5%

21.4%




0-4 AREAS OF BIOPHARMACEUTIC AL MANUFAC TURING OPERATIONSMammalian Cell Culture systems continue to dominate product development and manufacture. Further, a large percentage of products in the pipeline entering the market are mammalian-expressed, including various recombinant monoclonal antibody products. With the recent and on-going increases in mammalian system titers and yields, many facilities are standardizing using mammalian vs. microbial systems; in some cases, even products that could be manufactured in microbial systems are now being considered for manufacture in mammalian systems, if these will get the job done, such as to produce pre-clinical or early clinical supplies.

This year, we see a decrease in Mammalian Cell Culture and Microbial Fermentation; small upticks in the overall percentage of respondents for Yeast and Insect cells.

Respondents involved in Mammalian Cell Culture decreased from last year’s study (79.3% vs. 85.9%). Although respondents were permitted to select multiple platform systems, the modest drop in mammalian systems is possibly due to more facilities standardizing on one or another platform.

We saw a similar decrease for Microbial Fermentation systems where 37.5% of respondents noted involvement in this area, a 7.4%-point decrease from the previous year (44.9%), and continuing the decrease seen in prior years.

On the other hand, less common systems including yeast, plant saw modest increases. For this year, 17.4% said that their facility had production operations in Yeast, a reversal from the decline seen in recent years. The percentage of those involved with microbial manufacture, including Plant Cells, saw a slow rise over the past couple of years, which still continues in this year’s study (9.2%). Insect cells declined to 2.7% this year, going back to levels seen in 2014.




Fig 0.5: Biopharmaceutical Manufacturing Systems, (2007-2016) Trends

In which of the following does your facility currently have production operations for biopharmaceutical products?

2007- 2016 (Trends)

85.9%85.9%

75.5%

79.1%

73.1%70.4%

66.4%

76.8%

44.9%42.9%

46.9%

51.7%

47.4%50.4%

52.7%

63.4%

15.7%18.7%

20.8%21.4%

16.7%

29.9%

7.6%5.6%

7.3%10.8%10.3%

8.8%10.6%

7.0%

14.1%

3.0%

79.3%

79.2%

37.5%

48.0%

17.4%

20.8%20.9%19.8%

9.2%

2.7%3.5%2.5%2.1%3.2%

3.8%2.6%4.3%

2.0% 0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Year

2016

Year

2015

Year

2014

Year

2013

Year

2012

Year

2011

Year

2010

Year

2009

Year

2008

Year

2007

Mammalian Cell

Culture

Microbial

Fermentation

Yeast

Insect Cells

Plant Cells




0-5 PRODUC TION OPERATIONS, PHASE OF DEVELOPMENTWe identifi ed the phases of pipeline development in which respondents’ organizations (companies) had products. This year, over half (52.5%) of respondent companies had R&D biopharmaceutical operations, a reversal from last year’s decline of 47.8%, and readjusted with levels seen in prior years. 57.6% indicated their company having Preclinical operations, a continued small decline from last year’s 59.2% and 63.8% in 2014. Respondent organizations involved with R&D have shifted back to their relative 50% level seen in almost all prior years, but still remain much lower than the 73.3% in 2006. Preclinical started at 75.4% in 2006, remained declining each year after, and has remained consistently near the 60% mark, as seen in this year’s 57.6%.

The percentage of respondents whose companies have biopharmaceutical products on the market has slightly increased to 54.2%, up from 53.2% last year. The percentage involved with products in Phase III development decreased to 55.9% this year, down from its marked increase last year (60.7%), and relative to prior years.

This area continues to see small fl uctuations as the industry continues its overall maturation, with most respondents now employed by companies with revenue streams from marketed biologics. In fact, 2009 has been widely noted as the year the biopharmaceutical industry fi nally, as a whole, turned a profi t. Overall, the employers of the biopharmaceutical manufacturing professionals interviewed are rather evenly distributed over the pipelines from pre-clinical though commercial manufacturing, with each phase being worked on by 50+% of survey respondent organizations.




Fig 0.6: Phase of Development of Surveyed Respondents (2006-2016) Trends

In which phases of development does your organization currently have biopharmaceutical products?

2006-2016

57.6%

52.5%

56.5%

55.9%

54.2%

47.8%

59.2%

64.7%

61.2%

60.7%

53.2%

57.5%

63.8%

69.1%

64.3%

56.5%

55.6%

53.4%

56.8%

53.9%

50.0%

46.1%

56.3%

50.9%

58.0%

58.0%

52.8%

50.2%

53.5%

50.7%

59.1%

50.3%

50.7%

48.3%

50.3%

49.5%

63.3%

62.1%

58.0%

54.9%

56.7%

50.1%

57.3%

50.8%

50.8%

47.1%

49.9%

53.5%

57.9%

56.0%

53.3%

51.8%

56.0%

60.1%

69.0%

62.3%

57.6%

51.3%

44.9%

73.3%

75.4%

62.6%

63.6%

46.5%

42.8%

52.5%

0% 10% 20% 30% 40% 50% 60% 70% 80%

R&D

Preclinical

Phase I

Phase II

Phase III

Marketed

biopharmaceuticals

2016

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006




This year, we see Western Europe respondents indicating a higher response of involvement by their companies with Preclinical products at 71.1% vs. 57.7% for the U.S., a major shift from last year in which W.E. respondents indicated only 59.0% vs. 61.4%, respectively.

European respondents involved in commercial products declined signifi cantly to 52.6%, (from 61.5% last year), while increasing for the U.S. to 56.7% (from 50.4% last year).

The U.S. continued to report lower percentages in Phase I clinical trials this year vs. Western Europe (57.7% vs. 65.8%), both global areas down from 67.7% and 69.2%, respectively, last year. Another major shift seen this year is signifi cantly lower percentage in Phase III clinical trials for Western Europe vs. U.S., (57.9% and 60.6%), a big decrease from last year (71.8%) for Western Europe.

Fig 0.7: Phase of Development of Surveyed Respondents, (U.S. vs Western Europe)

In which phases of development does your organization currently have biopharmaceutical products?

U.S. vs Western Europe

57.7%

57.7%

61.5%

60.6%

56.7%

47.4%

71.1%

65.8%

63.2%

57.9%

52.6%

51.9%

0% 10% 20% 30% 40% 50% 60% 70% 80%

R&D

Preclinical

Phase I

Phase II

Phase III

Marketed

biopharmaceuticals

U.S.

Western Europe




Employees at FacilityTo evaluate issues such as capacity, disposables usage and other factors, we asked respondents for the number of staff within their own facility, and within their total organization. The largest percentages of respondents remained to be at facilities with 100-499 employees. Continuing the trend, the largest share of respondents, 41.6%, tend to be from organizations with greater than 5,000 employees. This distribution refl ects the distribution of bioprocessing and other professionals’ employment in the (bio)pharmaceutical industry. This includes the increasing involvement and even dominance of larger companies in biopharmaceutical R&D and products marketing. And with most Big Pharma type companies continuing to move into biopharmaceuticals, the dominance of large companies as employers of biopharmaceutical manufacturing professionals will continue.

Fig 0.8: Distribution of Employees at Facility, and Organization

About how many employees currently work at your facility & organization? (n=178)

9.0%

6.2%

10.1%

11.2%

28.7%

20.2%

11.2%

3.4%

4.5%

3.9%

5.1%

6.2%

16.3%

8.4%

14.0%

41.6%

1-9

10-24

25-49

50-99

100-499

500-999

1000-4999

5000+

# Employees at MY FACILITY

# Employees at ENTIRE ORGANIZATION




Batches Run at Facility per YearTo continue our evaluation of issues such as batch failure rates, and to ensure we are capturing organizations involved in signifi cant manufacturing processes at various scales of manufacture, we asked again this year for the number of batches or production runs the respondent’s facility (not the organization) ran over the past 12 months.

We found that for ‘Clinical Scale’ manufacturing, the largest number of facilities reported producing between 1 and 20 batches per year (71.4%), a continual increase from 63.5% last year and 60.9% in 2014. At the ‘Commercial Scale’, only 10% reported producing over 150 batches per year, down from 14.9% last year; most (among those manufacturing) reported running between 0-70 batches per year (74.2%), up from 71.5% last year.

To compare consistency of respondents’ operations, year-by-year, we evaluated the number of batches run/year. This year (asking about 2015), we found between “0-10” batches were run by 55.4% (Clinical Scale) and 42.5% (Commercial Scale) of respondents. So, fewer than half of respondents are operating at with no, or a low number of production runs for Clinical manufacturing, while 35% are at facilities doing ≥100 commercial runs/year.

Looking at prior years’ studies, we have found that companies are running more batches this year. While Commercial Scale “0-10” batches remained consistent with 2009 levels (42.5%), Clinical Scale “0-10” batches have sharply increased to 55.4%, up from 40.5% last year. This increase in clinical manufacturing runs suggests an increase in preclinical studies and candidate products entering development.




Fig 0.9: Distribution of Total Batches Run at Facility Last Year, by Scale of Production

How many total batches did your facility run during the past 12 months?

(Commercial vs Clinical Scale)

10.9%

23.5%

21.0%

16.0%

9.2%

13.4%

2.5%

0.0%

2.5%

0.0%

0.0%

0.8%

27.5%

7.5%

7.5%

10.0%

7.5%

6.7%

7.5%

4.2%

6.7%

0.8%

4.2%

10.0%

0

1-5

6-10

11-20

21-30

31-50

51-70

71-90

91-110

111-120

121-150

>150

Distribution of Batches Run, Clinical ScaleDistribution of Batches Run, Commercial Scale

Tota

l Bat

ches

Run

, Ran

ge



CHAPTER 1: I N T R O D U C T I O N A N D D I S C U S S I O N

C H A P T E R 1: I N T R O D U C T I O N A N D D I S C U S S I O N

1-1 INTRODUC TION: THE BIOPHARMACEUTIC AL INDUSTRYThe pharmaceutical and biopharmaceutical industries remain active, profi table and growing economic activities, despite not all that long ago having recovered from worldwide economic problems. There are estimated to be over well over 10,000 therapeutics in R&D, both drugs (chemical substance pharmaceuticals) and biopharmaceuticals (biotechnology-derived pharmaceuticals), with nearly 40,000 ongoing (or recently reported) clinical trials. Among these, an estimated 40% or likely over 4,000-5,000 candidate products in R&D are biopharmaceuticals. A signifi cant portion, about 1,400 products in the development pipeline, is follow-on biopharmaceuticals, mostly biosimilars but also a large number of biobetters. This industry activity represents a considerable increase from as short as fi ve or more years ago and also refl ects a basic shift in the pharmaceutical industry from small molecule drugs to biopharmaceuticals for new, innovative and profi table products. The large number of biosimilars and biobetters in development indicate the maturation of the biopharmaceutical industry, as its current major products start to go off-patent.

However, as companies of all sizes, particularly Big Pharma-type companies that now do most biopharmaceutical R&D, continue to cut back on expenses as much as possible and consolidate R&D, some may be concentrating more on fewer products, so this may tend to shrink the pipeline somewhat. But in terms of biopharmaceuticals, any such decrease in overall large pharmaceutical company R&D is likely currently being counter-balanced by established, including Big Pharma companies, companies increasingly moving into biopharmaceuticals. But even if the pipeline is shrinking (which will only be evident in hindsight), this is not necessarily an indicator of problems. Any pipeline shrinkage may simply refl ect the industry doing a good or better job in eliminating less promising candidates before they enter in early-stage clinical trials. Thus, a somewhat shrinking clinical pipeline could indicate better selection of products for development with a higher percentage ultimately being successful. This ‘failing faster,’ i.e., earlier in development, is much less costly and disruptive than products failing later in development. If industry is doing a better job of weeding out poor candidate products earlier, industry may actually be on track for increased future success and increased productivity and profi ts, with fewer costly late-stage failures and a higher percentage of pipeline products making it to the market.

The pharmaceutical R&D pipeline and industry are becoming increasingly dependent on biopharmaceuticals. These products are being developed by an ever-increasing cross-section of the pharmaceutical industry, including Big Pharma and even generic drug companies, with many of these active in developing biosimilars. These sources, along with




smaller biopharmaceutical developers, which have been the traditional original source for most innovative biopharmaceuticals, before licensing by larger companies, are continuing to expand the global biologics pipeline. Biosimilars are bringing in many new biopharmaceutical players. And new entrants based in China, India and other developing countries are also increasingly entering biopharmaceutical R&D. Thus, an increasing number and percentage of new pharmaceuticals entering the market will be biopharmaceuticals vs. small molecule drugs; and these will likely originate from more diverse sources. Combine this with biopharmaceuticals generally costing much more and providing higher profi t margins, and the pharmaceutical industry will increasingly be dependent on biopharmaceuticals for profi ts, innovation and its basic survival.

As biopharmaceuticals become an even more important part of the pharmaceutical industry, many new players are entering the fi eld and most current manufacturers are expanding their bioprocessing capacity. Not only must bioprocessing output (if not liter capacity) expand to handle manufacture of an increasing number of approved products and higher volumes as markets for many products further expand, e.g., with approvals for new indications and growth in international markets, the industry must also be capable of handling a large number of pipeline products. Most recent large capacity expansions generally have involved building large fi xed stainless steel bioreactor-based bioprocessing systems for commercial product manufacture, while production of supplies for R&D and clinical testing are now essentially dominated by use of single-use/disposable bioreactor-based systems, with this requiring much less facilities and infrastructure investment and construction. However, recently there has been signifi cant increase in new single-use commercial-scale manufacturing facilities under construction and coming online. This now includes modular facilities. The strategic importance of biopharmaceutical manufacturing and manufacturing capacity are increasing, and understanding the markets for biopharmaceuticals and bioprocessing technologies and services is becoming ever more important to those in the industry.

Planning and decision-making concerning the manufacture of biopharmaceuticals are becoming more complex as companies continue to implement cost-saving efforts, often including cutting back on the number of products in their development pipelines, and outsourcing even more support and even critical tasks. In addition, manufacturers must choose from an ever-increasing number and diversity of bioprocessing options. This includes new and improved cell lines and genetic engineering/expression systems technologies; bioprocessing equipment, including new and improved single-use and stainless steel equipment; and outsourcing manufacturing to CMOs which are expanding their capacity, technologies, and service offerings. Increasingly, companies must make diffi cult and costly strategic decisions about commercial manufacture earlier in product development.

A number of questions need to be answered by biopharmaceutical developer even before a product is shown effective in clinical trials. These include aspects such as:

■ Should we use an older, off-patent expression system or a new, much higher yield, but more likely royalty-bearing system?

■ Should we use single-use/disposable or fi xed stainless steel bioprocessing equipment for clinical supplies manufacture?

■ If we use single-use bioprocessing systems to support development, do we want to be among the pioneers to use single-use equipment for commercial manufacture or should we stick with familiar, trusted, but more expensive and labor-intensive, fi xed stainless steel equipment for commercial manufacture?




Effective planning within the biopharmaceutical and bioprocessing markets is required to avoid problems later on. This demands a high level of leadership, partnership, information sharing and communication between manufacturers, CMOs and bioprocessing technology and equipment suppliers as they develop new manufacturing technologies, devices and capacity to keep pace with industry needs. Strategic production decisions must be based on solid bioprocessing and sales projection data, combined with a broad understanding of trends and effective benchmarking of capacity and production issues.

This study provides an on-going evaluation of the vital manufacturing trends shaping this industry, and is designed to help keep those in the industry aware of the external trends and issues affecting biopharmaceutical manufacture decision-making.

1-2 SOME BIOPHARMACEUTIC AL MARKET TRENDSThe biopharmaceutical industry survived the relatively recent worldwide economic downturn. In fact, the industry has done rather well for itself during what for most other industries was a recovery period – not contracting or losing much at all in recent years – and has been showing consistent clear signs of full recovery and renewed growth. In fact, the biopharmaceutical industry continues to remain dynamic and growing. This year, as in 2015 and prior years, survey results show that companies are spending and investing more in their R&D, new technologies, bioprocessing capacity, staff and other infrastructure. Companies, particularly larger and more established ones, are continuing to aggressively look for opportunities to cut costs and increase effi ciency, with this continuing to benefi t contract manufacturing and research organizations (CMOs and CROs). Prior rather common severe arbitrary cuts in staff and divestment of facilities have largely ended, but this may simply refl ect reaching the limits of eliminating in-house expertise and facilities. Some specifi c trends are discussed below.

The industry is healthy and its status is improving: The world market for biopharmaceuticals is now over $200 billion; growing at a healthy rate. New products and new markets, particularly internationally, continue to support market growth. The world market for recombinant protein therapeutics is now ≥$150 billion, with non-recombinant vaccines and blood/plasma products comprising the remainder. The continued high growth rate in biopharmaceutical markets (revenue) will continue to drive investment in the industry, including at the expense of traditional small molecule drug development. Biopharmaceuticals vs. drugs have simply proven themselves to be profi table investments, e.g., with much higher profi ts per sale and likelihood of attaining commercial success, including capturing market share, with this often simpler or more straightforward with innovative biopharmaceuticals. Also, biopharmaceuticals vs. drugs tend to be developed for diseases and indications generally lacking current good options for treatment, assuring them of eager markets upon launch. A large portion of biopharmaceuticals coming to market still involve treatment of ignored or currently untreatable indications, making them particularly welcome and needed. Many new entrant companies of all sizes and types, including generic drug and foreign companies, are developing biosimilars and plan to use these to establish them in the industry. This is resulting in a signifi cant increase in the number of players in the biopharmaceutical industry.

Overall, 2016, like 2015, is fully expected to be a good year for the biotechnology and biopharmaceutical industries, with these remaining viable, relatively insulated from the worst of any major economic problems, growing and well-positioned for solid future growth.




Cost-containment and Controls: The past year was noisier than recent prior years in the U.S. in terms of protests over exceedingly high pharmaceutical prices. Most attention was directed not to biopharmaceutical products, rather to a few expensive hepatitis C drugs and marketed drug products where prices were drastically increased. The arrival of biosimilars in the U.S. and other major markets may take some pressure off of calls for increased government cost-containment and price controls in the U.S. and other major markets. In the U.S. and many other markets worldwide, drugs for chronic hepatitis C that are actually curative but set records for related costs are resulting in increased attention to pharmaceutical pricing practices. In some other countries, cost containment and government-directed cost controls continue to adversely affect biopharmaceuticals. This includes the U.K. National Institute for Health and Clinical Excellence (NICE) issuing more product reviews rejecting some biopharmaceuticals as too expensive and not cost-effective for use by the country’s National Health Service (NHS), effectively making these products non-marketable in the U.K. In the U.S., insurance providers continue to increasingly effectively take control of prescriptions away from physicians and consumers, forcing use of products for which they have secured preferential prices and often simply just refusing to pay for expensive biopharmaceuticals that they (not the prescribing physician and his patient) do not consider the most appropriate. As biosimilars become available, much as with generic drugs, U.S. insurers will surely force physicians, pharmacists and consumers to use these rather than more expensive innovator products.

Manufacture in Developing Countries is Increasing: Biopharmaceutical manufacture outside of the usual major market countries is increasing, as indicated by BioPlan’s Top 1000 Global Biopharmaceutical Facilities Index (www.top1000bio.com), which ranks facilities worldwide in terms of known or estimated capacity, employment, and production. Much new and increased capacity is being added internationally, with biopharmaceutical markets in many developing countries rapidly growing and domestic/regional companies increasingly serving these markets, often with biogeneric or other outright copies of innovator products that are simply marketed as substitutable for the innovator product (without much, if any, real testing, and without real GMP-quality manufacturing). Developed country-based companies seeking to expand in internationals markets will increasingly have to deal with such local/regional competition. Another factor that will result in increasing manufacture in lesser-developed countries is that these countries’ governments are increasingly seeking to assure domestic manufacture of biopharmaceuticals being sold in their markets. Already, many countries are starting to tell vaccine manufacturers that they want products for their markets manufactured in-country, preferably or requiring this be done by locally-owned or joint venture companies. And as single-use equipment and manufacturing technologies continue to improve and, particularly, as modular bioprocessing facilities enter the market, foreign countries (or their proxy/subsidized companies) will increasingly undertake manufacture of needed products, such as commonly-used vaccines, with or without the assistance and participation of original product developers and current manufacturers. This can be seen in countries such as Brazil, and Cuba has long domestically manufactured diverse biopharmaceuticals for itself and international commerce.

Worldwide Standardization of Manufacturing: Particularly with larger companies, as more biopharmaceutical manufacturing is performed worldwide, companies are working to standardize their products and manufacturing processes on a worldwide basis. For many, this includes having 2nd- or even 3rd-source geographically-spread facilities either actively manufacturing or serving as backups, having received approvals for manufacture for the U.S. and other major markets. Adoption of single-use and modular bioprocessing systems for commercial manufacturing will accelerate this trend.




1-3 MARKET POTENTIALThe biopharmaceutical market will continue to expand. There are currently 1,000s of therapeutics in R&D, including >40% now being biopharmaceuticals. This shift towards biopharmaceuticals refl ects a fundamental shift within the pharmaceutical industry, with the largest traditionally small molecule drug-oriented Big Pharma companies moving heavily and rapidly into biopharmaceuticals. These companies are increasingly developing their own, licensing in or otherwise acquiring more biopharmaceutical products. For these companies and others, biopharmaceuticals provide higher revenue (cost more) and profi ts per sale, and with biopharmaceuticals often requiring more complex detailing and other sales support, increasingly fi t well with the resources and marketing-intensive business models of large international pharmaceutical companies. Overall, there is a major shift towards biopharmaceutical R&D, manufacturing and marketing, often at the expense of traditional small molecule drug candidates.

However, due to economic concerns, all pharmaceuticals, particularly biopharmaceuticals which tend to be the most expensive, face increasing cost containment and control efforts worldwide. The U.S. remains the world’s main pharmaceutical market, including in terms of sales and profi ts. Government-based cost-containment and control efforts remain limited in the U.S. Despite political demands for lowering pharmaceutical expenses for government programs, such as Medicare for older patients, the major U.S. health care overhaul legislation (“Obamacare’) enacted in late 2010 is having minimal, apparently no, negative impact on biopharmaceutical usage. If anything, this health care overhaul actually provides continued long-term support for use of innovative (bio)pharmaceuticals, particularly if the alternatives are no treatment (none being available) are involve use of less effective therapeutics. Cost-containment and control efforts can be expected to increase in most other countries, particularly, those already having implemented cost controls, with expensive biopharmaceuticals being an easy target for elimination or reduction. Along these lines, India has substantially boosted its price controls and generics-favoring policies, including not allowing pharmaceuticals to be marketed by trade name (only by generic name).

However, since most biopharmaceuticals are used for indications for which there are few, if any, alternatives; the overall market is rather protected from widespread cost-containment and controls. Those countries that have imposed cost controls, so far, generally each represent small markets. Improved manufacturing methods and cost management for biopharmaceutical production will continue to slowly advance, which will tend to reduce the cost of goods, which may result in lower consumer prices. With continued reductions in manufacturing costs, including better process monitoring, higher-yield expression systems, and increased use of more cost-effective single-use/ disposable bioprocessing systems, biopharmaceuticals appear to be positioned to further increase their role in world pharmaceutical markets.

The world biopharmaceutical market is currently likely now over $200 billion/year. This continues to grow worldwide at ≤15%/year, making biopharmaceuticals a fairly recession-proof, growing and profi table industry. The market for recombinant proteins now is about $150 billion. Much of this growth in biopharmaceutical revenue is due to an increasing number and sales of recombinant monoclonal antibodies, now a >$50 billion market. These products have been shown to be rather reliable in terms of development and reaching the market, with antibodies generally being very specifi c, targeted, not causing severe adverse effects and by now familiar and well-received in the marketplace. Recombinant monoclonal antibody sales will further rapidly increase in coming years as new products enter the market and approved indications are expanded for existing products, while new biosimilars may reduce overall prices slightly, but these lower price may well result in higher sales.




But despite the industry being healthy and growing, broader economic issues, the broader pharmaceutical industry’s long-term problems with innovation and profi ts, investors now coming to expect constant cut-backs, layoffs, increased outsourcing, etc. will continue to force biopharmaceutical companies of all size to cut costs wherever possible. This is shown in this year’s survey data showing that the industry continues to recognize the need for continual improvements in performance and optimization of R&D, manufacturing and marketing. Financing, particularly for new smaller companies, although reported to have increased in 2015, will tend to remain restricted in 2016. Many companies of all sizes are having to seek alternative funding methods, increase their collaborations and licensing (vs. conducting in-house R&D), decrease the number of candidates in development, and are otherwise taking steps to make themselves more effi cient and productive.

The use of contract manufacturing organizations and the use of single-use bioprocessing equipment are making product manufacture, particularly for R&D and clinical trials, more effi cient and often less costly. Especially for smaller and under-funded companies, going with CMOs for production or using single-use equipment for in-house candidate product manufacture are the only viable options. These approaches reduce up-front capital and fi nancing needs, because companies can avoid $50-$150 million or more facilities costs for construction of fi xed, dedicated stainless steel bioreactor-based bioprocessing systems, while a typical fully single-use facility for commercial manufacture can still easily cost $25-$40 million.

Despite the biopharma industry’s bright future, successful companies in this complex worldwide industry will continue to require complete and accurate knowledge of the market and competing technologies, along with adequate lead-times, large capital expenditures, and careful planning. Biopharmaceutical development and manufacture are very costly, the industry is very competitive, investors increasingly demand higher stock prices and profi ts, and weak companies and products tend to die, so no company can afford to make tactical or strategic mistakes. This makes accurate market and manufacturing planning all the more essential. The industry needs to keep on top of the current situation and future trends.

This report summarizes survey data and information obtained from biopharmaceutical manufacturers worldwide in late 2015 and early 2016. Its intent is to provide a quantitative-based overview and assessment of industry capacity, production trends, and benchmarks, along with presenting industry views on these and other subjects. As an on-going benchmarking effort, this study offers a view into current and future potential global industry problems and opportunities.

1-4 BIOPHARMACEUTIC AL R&D PIPELINESFigure 1.1 shows survey respondent responses concerning the indications of the biopharmaceutical products their companies are working on. Cancer and infectious diseases continue to dominate the biopharmaceutical development pipeline. Trials have increased with most indications. Cancer treatment remains by far the most active area, with over 4,000 products now in development.




Fig 1.1: Investigational Drugs: Large Molecule (Protein Therapeutics), Worldwide, 2010 - 2015

Source: BioPharm Insight, www.infi nata .com/biopharma-solution/by-product/biopharm-insight.html, February 2015

Note: Biopharm Insight includes multiple counts for the same therapeutic, when in multiple phases and locations of clinical trials. Therefore, the total counts will be higher than the actual number of drugs and relevant trials.

3,155

1,298

1,144

975

847

788

706

563

405

383

351

349

282

248

173

122

4,341

4,346

2,518

1,118

1,052

666

712

703

630

174

355

322

309

255

273

222

144

112

536

4,021

2,198

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617

602

644

547

159

296

317

269

217

291

224

124

90

476

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2,195

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638

479

287

313

294

330

268

424

214

170

107

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734

860

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199

603

255

309

420

299

409

372

172

224

101

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2,194

764

732

956

701

543

337

473

313

359

239

190

537

194

128

190

962

5,562

Cancer

Infectious Diseases

Immune System

Hormonal Systems

Central Nervous System

Cardiovascular

Musculoskeletal

Hematological

Diagnostic / ImagingAgents / Delivery

Respiratory

Gastrointestinal

Dermatology

Eye and Ear

HIV Infections

Pain

Genitourinary

Nephrology

Miscellaneous

201520142013201220112010




A trend in recent years has been a major increase in the number and percentage of monoclonal antibodies in clinical trials. This can be expected to further increase, as the key ‘Cabilly’ patents broadly covering most conventional recombinant monoclonal antibody manufacture, held by Genentech/Roche, expire in the U.S. in 2018; as blockbuster and other monoclonal antibody-related patents expire and; related to this, as a large number of biosimilar antibodies enter the market. An increasing portion of cancer therapeutics involve recombinant monoclonal antibodies or antibody fragments, further indicating that the number and percentage of marketed monoclonal antibodies will increase in coming years. And we may fi nally see antibody fragments and other microbially-manufactured antibody-like agents start to substantially supplement or even displace traditional mammalian antibody manufacture.

Figure 1.2 shows the breakout of the cumulative pipeline for large molecule biologics in various stages of development and launched (on the market). Typically, less than 10% of the total numbers of products that enter clinical development actually make it to the marketplace.

Fig 1.2: Worldwide Pipeline & Launched Products, Large Molecules, January 2015

(Note: Cumulative Worldwide Pipeline, Large Molecules, Having Attained Various Stages of Development)

Source: BioPharm Insight, www.infi nata.com/biopharma-solution/by-product/biopharm-insight.html January 2015

10,114

2,541 2,716

1,161

199

4,961

0

2,000

4,000

6,000

8,000

10,000

12,000

Pre-Clinical/Discovery

Phase I / INDFiled

Phase II Phase III NDA / BLAFiled

ProductLaunched




Fig 1.3: Current Worldwide Pipeline & Launched Products, Large Molecules, January 2015

Source: BioPharm Insight, www.infi nata.com/biopharma-solution/by-product/biopharm-insight.html, January 2015

1-5 BIOSIMILARS IN THE PIPELINEThere is a very healthy pipeline of follow-on (biosimilar and biobetter) products in development targeted for the U.S., EU and other major markets (see www.biosimilarspipeline.com). Biosimilars are further discussed in more detail in another section below. This pipeline includes nearly 800 biosimilars, about ≥600 of these presumed targeted to major markets, and about 500 biobetters in development, a total of about 1,400 follow-on biopharmaceutical products in the development pipeline for over 100 currently-marketed biopharmaceuticals (see www.biosimilarspipeline.com). While biosimilars are fi nally starting to substantially penetrate the market in the European Union, in the U.S., despite approval of 2 biosimilars, including an antibody, in 2015, FDA is still moving at a glacial pace – only approving its fi rst product about 5 full years after passage of BPCIA legislation enable FDA approval of biosimilars. FDA still has not yet issued many needed guidelines. Basic issues affecting biosimilars future markets, such as product names (nomenclature) and interchangeability, have yet to be resolved, with these among many issues making planning biosimilar development and marketing very diffi cult. At least the initial guidance and approvals from FDA are reassuring, in the sense that they contain few surprises and are unlikely to disrupt ongoing development activities.

Most biosimilars/biobetters are being manufactured using current vs. the generally decades-old legacy technology and equipment being used for most reference product manufacture. Biosimilars will include products pioneering new expression systems and other bioprocessing technologies. Ultimately, many of these products could well be signifi cantly better in some or many respects, including safety and effi cacy, such has having higher purity, than their usually several decades-old legacy reference products. If too different, including two better, this

Not Classified0.2%

Pre-Clinical/ Discovery

46.5%

Phase I / IND Filed11.7%

Phase II12.5%

Phase III5.3%

NDA / BLA Filed

Product Launched22.8%




would negate biosimilar approval (with full approval required). Many biosimilar developers are using CMOs for development and manufacturing services. Major CMOs report recent revenue increases of 15% attributable to biosimilar contracts.Fig 1.4 below shows the number of U.S.-marketed reference products by the years of their biosimilar versions’ launchability in the U.S. Ability to launch requires both relevant patents and regulatory-granted market exclusivities, essentially orphan status and 12-year new exclusivity granted to all new full BLAs, be expired upon product launch. Note, in the U.S., there are large numbers of biosimilars likely to enter the market in the next few years, with another large group, including many blockbuster monoclonal antibodies, likely entering the market late in the decade.

Fig 1.4: Number of Reference Products by U.S. Biosimilars Launchable Dates

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The projected economic impact of biosimilars/ biobetters, from a U.S.-centric perspective is portrayed in Fig 1.5. This shows the magnitude of cumulative current reference product sales by the year of likely biosimilars for these products first entering the U.S. market (i.e., expiration of all patent and market exclusivities.) With patents expiring on the majority of currently marketed biopharmaceuticals, including most recombinant proteins and mAbs, these products with current cumulative annual revenue of about $100 billion will encounter much new competition in the U.S. (and other major markets) from biosimilars (and biobetters) starting in just a few years.

Fig 1.5: Biosimilars Launchable Dates by Sum of Current Reference Products Sales ($millions)




1-6 BIOPHARMACEUTIC AL APPROVALS GENERICFDA approvals of biopharmaceutical products by year are shown in Figure 1.6.

Fig 1.6: FDA Approvals of New Biopharmaceutical Products 1982-2015

2015 was a record year for FDA biopharmaceutical approvals, including a record number of recombinant protein/mAb approvals. The spike of approvals is, likely, reflecting the increased number and percentage of biopharmaceuticals in the development pipeline. It remains to be seen in coming years whether this is part of trend for increasing FDA biopharmaceutical approvals.

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Table 1.1 lists biopharmaceutical products approved (in rev. chron. order) by FDA in 2015.

Table 1.1: Biopharmaceutical Approvals Generic, 2015

insulin glargine rDNA [Basaglar; Abasria; LY2963016]

granted on 12/16/2015 to Boehringer Ingelheim for treatment of diabetes; Note, a 505(b)(2) drug approval, which many would now call a biosimilar

Faxtor X blood-derived [Coagadex; Coagulation Factor X (Human)]

granted on 12/16/2015 to Bio Products Laboratory Ltd. for treatment of for hereditary Factor X defi ciency

von Willebrand factor rDNA [Vonvendi] granted on 12/9/2015 to Baxalta U.S. (formerly Baxter) for treatment of von Willebrand’s disease (VWD)

lyosomal acid lipase [Kanuma; sebelipase alfa]

chicken egg-expressed granted on 12/8/2015 to Alexion (from acquisition of Synageva) for treatment of lyosomal acid lipase (LAL) defi ciency [2nd product from genetically engineered animals]

Infl uenza vaccine quadravelent [Fluad; infl uenza vaccine, inactivated, egg-cultured, quadravelent with MF59/squalene adjuvant]

granted on 12/3/2015 to Novartis (with product and its approval to be transferred to Seqirus, part of CSL Group) for prevention of infl uenza; fi rst U.S. non-aluminum-based adjuvanted infl uenza vaccine

SLAMF7 mAb DNA [Empliciti; elotuzumab; Signaling Lymphocyte Activation Molecule Family member 7 monoclonal antibody, recombinant]

granted on 11/30/2015 to Bristol Myers Squibb (BMS; with Abbvie) for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1-3 prior therapies

EGFr mAb rDNA [Portrazza - necitumumab; epidermal growth factor receptor monoclonal antibody]

granted on 11/24/2015 to Janssen Biotech for treatment of metastatic squamous non-small cell lung cancer(VWD) in combination with gemcitabine and cisplatin

CD38 mAb rDNA [Darzalex - daratumumab] granted on 11/16/2015 to Eli Lilly for treatment of multiple myeloma

Factor VIII rDNA, pegylated [Adynovate - BAX 111]

granted on 11/11/2015 to Baxalta (formerly Baxter) for treatment of hemophilia A

IL-5 mAb rDNA [Nucala; mepolizumab] granted on 11/4/2015 to GlaxoSmithKline (GSK) for treatment of asthma

HSV-1/GM-CSF rDNA [Imlygic - alimogene laherparepvec; a live herpes simplex virus type 1 (HSV-1) oncolytic virus resulting in expression of GM-CSF]

granted on 10/27/2015 to Alexion Pharmaceuticals for treatment of unresectable recurrent cutaneous melanoma

alkaline phosphatase rDNA [Strensiq; asfotase alfa; an alkaline phosphatase catalytic domain fusion protein]

granted on 10/23/2015 to Alexion Pharmaceuticals for treatment of perinatal, infantile and juvenile-onset hypophosphatasia (HPP)

dabigatran mAb rDNA [Praxbind - idarucizumab]

granted on 10/16/2015 to Boehringer Ingelheim to reverse the blood-thinning effects of Pradaxa (dabigatran)

insulin degludec rDNA [Tresiba - insulin degludec]

granted on 10/16/2015 to Novo Nordisk for treatment of diabetes mellitus

insulin degludec/aspart rDNA [Ryzodeg 70/30 - a 70/30 mixture of insulin degludec (approved the same day) and insulin aspart]

granted on 10/16/2015 to Novo Nordisk for treatment of diabetes mellitus

Factor VIII [Nuwiq] granted on 10/16/2015 to Octapharma USA for treatment of hemophilia A


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