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There’s no need to answer, because the question is entirely rhetorical; of course there isn’t. The journey that a high-potential large-molecule drug must make to attain blockbuster or biosimilar status is a long and winding one. The ecosystem that nurtures and creates these biologic therapies is as complex as the molecules they are developing.\u003c/h3\u003e\n\u003cp\u003e\u003c!--more--\u003e\u003c/p\u003e\n\u003ch4\u003eIntroduction\u003c/h4\u003e\n\u003cp\u003eAccording to PhRMA, (general) research and development spending by its members grew from $2 billion in 1980 to an estimated $51.6 billion in 2013. The percentage of sales that went to R\u0026amp;D in 2013 reached 23.4% of domestic sales. Clearly a lot of that R\u0026amp;D money will continue to be spent in developing pipelines in the biopharmaceutical sector.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOf the billions of dollars spent on R\u0026amp;D each year for clinical research, roughly 90% is spent on clinical trials of medicines and devices in the U.S. In 2013, PhRMA states that the biopharmaceutical industry sponsored an impressive 6,199 clinical trials involving more than 1.1 million people. Investing in biotech R\u0026amp;D has yielded better returns than the pharma-industry average, note McKinsey \u0026amp; Co. analysts. The current biologics development pipeline supports an outlook of continued healthy growth. According to McKinsey, the number of biotech patents applied for has been growing at 25% annually since 1995 and there are currently more than 1,500 biomolecules undergoing clinical trials.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv class=\"callout\"\u003e\n\u003ch4 class=\"callout-title\"\u003eImmune therapies are quickly becoming the fourth pillar of cancer treatment.\u003c/h4\u003e\n\u003c/div\u003e\n\u003cp\u003eThe success of the clinical pipeline will lead to an unprecedented number of new molecule launches, rising from a handful a few years ago to 10 to 15 annually in the coming years. A further steep increase is to be expected as multiple players begin to receive approvals to produce biosimilars after 2015.\u003c/p\u003e\n\u003cp\u003eOne recently approved biologic is making headlines and offers the industry a case history of biopharmaceutical R\u0026amp;D success. In December 2015, the Washington Post reported that President Jimmy Carter had advanced melanoma and was beginning radiation therapy.\u003csup\u003e3\u003c/sup\u003e\u0026nbsp;The report said Carter would also be receiving an infusion of Keytruda, Merck’s first among a promising new class of immuno-oncology (I/O) drugs aimed at unleashing the human immune system to fight cancer cells. Keytruda was launched in the fourth quarter of 2014, and according to Merck, global sales in 2015 were approximately $566 million.\u003csup\u003e4\u003c/sup\u003e\u0026nbsp;Keytruda, as well as similar I/O therapies, works by allowing the body’s immune system to recognize and attack cancer cells as it would do to any other intruder.\u0026nbsp;\u003cem\u003eImmune therapies are quickly becoming the fourth pillar of cancer treatment, say industry experts.\u003c/em\u003e\u0026nbsp;These types of drugs are expensive — Keytruda is roughly $150,000 per year, but it has shown remarkable results in some patients, including Carter, who announced he was “cured” of his melanoma.\u003c/p\u003e\n\u003ch4\u003ePromise of Immuno-Oncology Therapies\u003c/h4\u003e\n\u003cp\u003eIn early March, the Tufts Center for the Study of Drug Development (CSDD) announced findings of a new report on investments in research and development for new I/O drugs.\u003csup\u003e5\u003c/sup\u003eTufts says dramatic improvements in complete response rates in trials for new I/O therapies are helping to increase the number of alliances between pharmaceutical, biotech companies, universities and cancer centers. Thirteen universities and cancer centers in the U.S. have announced research alliances with pharma and biotech companies, and the number of I/O alliances between pharma/big biotech and small enterprises grew at a torrid pace, accounting for $39 billion in research commitments over three years.\u003c/p\u003e\n\u003cp\u003eCurrently, more than 130 biotech and 20 pharma companies are developing I/O therapies, according to Tufts. That activity reflects — and is fueling — worldwide I/O product sales, explains Tufts, with annual revenues expected to reach $25 billion to $40 billion by 2020, up from $2.5 billion in 2015.\u003c/p\u003e\n\u003cp\u003eThe biopharmaceutical industry’s recent successes have been fueled by massive commitments of private and public capital, as well as billions in corporate operational budgets and other resources. Success breeds success, and it’s clear that oncological therapies are going to attract even more investment. The following offers a review of the complexities of the biopharmaceutical supply chain and trends across a development ecosystem that is, by most accounts, effectively translating research dollars into highly successful treatments that save lives. To a great degree, contract service providers, including CROs and CDMOs, are becoming an integral part of the industry’s success and are fast becoming key contributors in this incredibly dynamic pharma sector.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003eReferences\u003c/h4\u003e\n\u003col\u003e\n\u003cli\u003ePharmaceutical Research and Manufacturers of America (PhRMA),\u0026nbsp;“2015 Biopharmaceutical Research Industry Profile.” Mar 2015. http://www.phrma.org/sites/default/files/pdf/2015_phrma_profile.pdf\u003c/li\u003e\n\u003cli\u003eOtto, R., Santagostino, A., Schrader, U.,\u0026nbsp;“Rapid growth in biopharma: Challenges and opportunities.” Dec, 2014. http://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/rapid-growth-in-biopharma\u003c/li\u003e\n\u003cli\u003e“Good news from Jimmy Carter. He’s cancer-free,” Washington Post. Dec 06, 2015.\u003cbr /\u003ehttps://www.washingtonpost.com/politics/good-news-from-jimmy-carter-hes-cancer-free/2015/12/06/ea56a120-9c65-11e5-a3c5-c77f2cc5a43c_story.html\u003c/li\u003e\n\u003cli\u003eMerck Press Release, “FDA Approves KEYTRUDA® (pembrolizumab) for the treatment of Patients with Metastatic Non-Small Cell Lung Cancer who Express PD-L1 with Disease Progression on or After Platinum-Containing Chemotherapy.” Oct 02, 2015.\u003cbr /\u003ehttp://www.mercknewsroom.com/news-release/prescription-medicine-news/fda-approves-keytruda-pembrolizumab-treatment-patients-metas\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e5.Tufts Center for the Study of Drug Development Press Release, “Promise of Immuno-Oncology Therapies Is Boosting R\u0026amp;D Funding and and Alliances.” Mar 08, 2016.\u0026nbsp;\u003cbr /\u003e\u003ca href=\"http://csdd.tufts.edu/news/complete_story/pr_ir_mar_apr_2016\"\u003ehttp://csdd.tufts.edu/news/complete_story/pr_ir_mar_apr_2016\u003c/a\u003e.\u003c/p\u003e\n\u003chr\u003e\n\u003ch4\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003e\u0026nbsp;Chapter 1\u003c/p\u003e\n\u003ch2\u003ePreclinical Development: The Safety Hurdle Prior to Human Trials\u003c/h2\u003e\n\u003ch3\u003eHere novel molecules find their human potential and begin translating discovery into meaningful therapeutics.\u003c/h3\u003e\n\u003cp\u003eBefore any new biopharmaceutical molecules reach the preclinical stage, they have to pass through a series of selections at the discovery stage: target discovery and validation, hits generation and screen, and lead selection and optimization.\u003c/p\u003e\n\u003cp\u003ePreclinical testing is the final deciding gate prior to clinical studies, and only 12% of the candidates advance to the Phase I clinical trial. From this point, the success rate for the investigational biologics increases at each clinical phase, with 17% at Phase I, 27% at Phase II, 58% at Phase III, and 82% at the registration phase.\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;On average, drug discovery and preclinical development take three to six years and account for 30.8% of costs per approved compound, approximately $788 million.\u003csup\u003e2, 3\u003c/sup\u003e\u003c/p\u003e\n\u003ch4\u003ePreclinical Testing\u003c/h4\u003e\n\u003cp\u003eDuring preclinical development, the critical question biopharmaceutical developers seek to answer is whether the novel molecule is safe to be tested in humans — which is also the primary concern of regulatory agencies. The safety assessment starts early, in the stage of screen preparation when bioassays (used to assess biochemical and functional properties such as binding and efficacy assays) of lead molecules are initially developed.\u003c/p\u003e\n\u003cp\u003eAs the candidates advance to the preclinical stage, more extensive tests have to be performed both in vitro and in vivo to gain better understanding of their pharmacodynamics (PD) and pharmacokinetics (PK) behavior and establish their pharmacologic, safety, and toxicity profile. Concomitantly, biopharmaceutical developers need to assess their manufacturability and plan for GMP clinical-scale production since larger quantities of biopharmaceuticals will be needed for clinical trials.\u003c/p\u003e\n\u003cp\u003eAt the end of the preclinical study, the most promising molecules are selected for human testing. Before initiating clinical trials, the sponsor is required to submit an Investigational New Drug application (IND) for any trials conducted in the U.S., which usually goes into effect 30 days after the FDA receives it. A typical IND must contain three categories of information: preclinical data on animal pharmacology and toxicology studies; chemistry, manufacturing, and control (CMC); and clinical protocols and investigator information.\u003csup\u003e4\u003c/sup\u003e\u0026nbsp;The regulatory landscape is more complex in the EU, where clinical trials are regulated by the National Competent Authorities (NCAs) in each member state (currently 28 member states) instead of one central agency, the European Medicines Agency (EMA). Similar to an IND, a Clinical Trial Authorization (CTA) application must be submitted to the NCAs.\u003csup\u003e5\u003c/sup\u003e\u0026nbsp;Timelines for\u0026nbsp;review and approval of CTA applications vary among NCAs, ranging from less than 14 days to 90 days.\u003csup\u003e6, 7\u003c/sup\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cimg src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P1_Sidebar1.jpg\" alt=\"16Q2_Feature_Biologics_P1_Sidebar1.jpg\" title=\"16Q2_Feature_Biologics_P1_Sidebar1.jpg\" data-constrained=\"true\" style=\"width: 650px\" width=\"650\"\u003e\u003c/h4\u003e\n\u003ch4\u003e\u003ca href=\"http://www.niceinsight.com/Userfiles/Pharma-Almanac/PA_Q2_C1_F1.png\"\u003e\u003c/a\u003ePreclinical testing challenges\u003c/h4\u003e\n\u003cp\u003eOne significant challenge associated with preclinical testing of biopharmaceuticals is the selection of relevant animal species. In general, the regulation requires toxicology studies to be conducted in two relevant species. The animal toxicity data is essential to determine the safe starting dose and dose range for the first-in-human (FIH) study and identify potential adverse effects relevant to humans. However, for many biologics, there are limited choices of relevant species due to their high tissue- and/or species-specific activity. Sometimes, nonhuman primates may be the only relevant species. When relevant animal species are not available, alternate approaches are considered such as using homologous molecules or transgenic animal models.\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P1_Sidebar2.jpg\" alt=\"16Q2_Feature_Biologics_P1_Sidebar2.jpg\" title=\"16Q2_Feature_Biologics_P1_Sidebar2.jpg\" data-constrained=\"true\" style=\"width: 650px\" width=\"650\"\u003e\u003c/p\u003e\n\u003cp\u003eTo date, protein-based biologics (i.e., monoclonal antibodies (mAbs), fusion proteins, and recombinant proteins) account for most development-stage and marketed biopharmaceuticals. One specific challenge with therapeutic proteins is immunogenicity, the generation of antidrug antibodies (ADAs). The undesired immunogenicity may affect biologic’s PK and PD and induce immune reactions. The ICH S6 addendum provides specific instructions on when ADAs level should be measured. On the other hand, ICH S6 recognizes the limitation of nonclinical studies in predicting potential immunogenicity of human or humanized proteins in humans. In other words, immunogenic responses observed in animals are not indicative for humans.\u003csup\u003e10\u003c/sup\u003e\u0026nbsp;Based on the perspective of Dr. Andrew J. McDougal, a FDA/CDER nonclinical reviewer, specific safety concerns for mAbs include cross-reactivity, slow elimination, exaggerated pharmacology, and slow recovery from toxicity. Safety concerns for cytokines and growth factors are species- specificity, interaction with host endogenous cascade, and tumor-promoting potential.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cimg src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P1_Sidebar3.jpg\" alt=\"16Q2_Feature_Biologics_P1_Sidebar3.jpg\" title=\"16Q2_Feature_Biologics_P1_Sidebar3.jpg\" data-constrained=\"true\" style=\"width: 650px\" width=\"650\"\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch4\u003eCollaborations with CROs for preclinical testing\u003c/h4\u003e\n\u003cp\u003eBringing a novel biopharmaceutical from bench to bedside takes a broad range of collaborations across biopharmaceutical industry, academia, patient and disease groups, government, and contract research organizations (CROs). Groundbreaking discovery (i.e. a novel drug target) flourishes in academia. However, it is the industry that leads the efforts in translating the discovery into meaningful therapeutics. To improve the R\u0026amp;D efficiency and accelerate development, engaging with CROs has become a widely adopted strategy by the biopharmaceutical industry. According to the 2016 Nice Insight CRO Outsourcing Survey, 80% of the respondents acquire or plan to acquire preclinical trial services while 53% of them currently engage with cros for preclinical (includes discovery phase) research. Among a cluster of 16 preclinical trial services, bio-analytical testing (53%), research models (animal models) (50%), analytical testing (49%), chemistry and stability testing (48%), and biostatistics, surgical services (for animal models), and general toxicology (45% respectively) are the top 5 most needed services.\u003csup\u003e12\u003c/sup\u003e\u0026nbsp;Midsized pharma/ biotech companies demonstrate a slightly higher than average demand for all of the surveyed preclinical services while the service demand from small pharma/biotech is lower than average.\u003c/p\u003e\n\u003cp\u003eIn selecting CROs for biopharmaceutical preclinical development, a CRO’s development experience weighs heavily in a sponsor’s decision-making process. A CRO’s experience and expertise in bioanalytics, pharmacology, toxicology, and PK and PD is critical in designing appropriate studies so that valuable safety information of the molecule of interest can be collected and evaluated. Vertical integration is another desired feature often sought by biopharmaceutical clients when selecting a CRO. Drug discovery and development is a continuous coordinated process of research, production, and regulation. In the preclinical phase, CROs with expanded expertise in manufacturing, regulation, and clinical studies are more capable of synchronizing preclinical testing, production and regulatory compliance in a holistic manner, and are thus poised for a long-term partnership with biopharmaceutical manufacturers.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003eAuthors\u003c/h4\u003e\n\u003cp\u003eSteve Kuehn, Cynthia Challener, Ph.D., Marilyn Seiger, MA, MBA and Carrie Cao, Ph.D.\u003c/p\u003e\n\u003ch4\u003eReferences\u003c/h4\u003e\n\u003col\u003e\n\u003cli\u003ePhilippidis, A.,“Studies Suggest that When It Comes to Drug Development Success, Size Matters,” GEN Exclusives. Apr 09, 2012. http://www.genengnews.com/insight-and-intelligence/studies-suggest-that-when-it-comes-to-drug-development-success-size-matters/77899586/.\u003c/li\u003e\n\u003cli\u003eGaffney, A., Mezher, M.,“Regulatory Explainer: Everything You Need to Know About FDA’s Priority Review Vouchers,” RAPS. Jul 02, 2015. http://www.raps.org/Regulatory-Focus/News/2015/07/02/21722/Regulatory-Explainer-Everything-You-Need-to-Know-About-FDA%E2%80%99s-Priority-Review-Vouchers/.\u003c/li\u003e\n\u003cli\u003eDiMarsi, J.A.,\u0026nbsp;“Cost of Developing a New Drug Briefing,” Tufts Center for the Study of Drug Development. Nov 18, 2014. http://csdd.tufts.edu/files/uploads/Tufts_CSDD_briefing_on_RD_cost_study_-_Nov_18,_2014..pdf\u003c/li\u003e\n\u003cli\u003eFDA, “Investigational New Drug (IND) Application.” http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm\u003c/li\u003e\n\u003cli\u003eEuropean Medicines Agency, “Clinical trials in human medicines.”\u003ca href=\"http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp\u0026amp;mid=WC0b01ac058060676f\"\u003ehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp\u0026amp;mid=WC0b01ac058060676f\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eCharnas, R.,“EU Perspective on Regulatory Issues for Biologics.” Feb 29, 2008. https://www.sitcancer.org/meetings/am08/primer08_oncology/presentations/16_charnas.pdf\u003c/li\u003e\n\u003cli\u003eNHS Health Research Authority, “MHRA-Clinical Trial Authorisation.”\u003ca href=\"http://www.hra.nhs.uk/research-community/the-review-process/mhra-clinical-trial-authorisation\"\u003ehttp://www.hra.nhs.uk/research-community/the-review-process/mhra-clinical-trial-authorisation\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eICH Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S6(R1).\u003ca href=\"http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/Step4/S6_R1_Guideline.pdf\"\u003ehttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/Step4/S6_R1_Guideline.pdf.\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eMcVean, M.,\u0026nbsp;“Preclinical Development to IND: Drugs, Biologics, Cellular/Gene Therapies and Vaccines,” PreClinical Research Services, Inc. Apr 18, 2014. http://www.cobioscience.com/biobootcamp/McVean_BioBootCamp_Preclinical%20Dev%20to%20IND_2014.pdf.\u003c/li\u003e\n\u003cli\u003eKingham, R., Klasa, G., Carver H.K.,\u0026nbsp;“Key Regulatory Guidelines for the Development of Biologics in the United States and Europe,” John Wiley \u0026amp; Sons, Inc. 2014.\u003ca href=\"https://www.cov.com/-/media/files/corporate/publications/2013/10/chapter4_key_regulatory_guidlines_for_the_development_of_biologics_in_the_united_states_and_europe.pdf\"\u003ehttps://www.cov.com/-/media/files/corporate/publications/2013/10/chapter4_key_regulatory_guidlines_for_the_development_of_biologics_in_the_united_states_and_europe.pdf\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eMcDougal, A.J.,“Preclinical Development [CDER]: Biological Therapeutics for Cancer Treatment,” iSBTc Oncology Biologics Development Primer. Feb 28, 2008.\u003ca href=\"https://www.sitcancer.org/meetings/am08/primer08_oncology/presentations/3_mcdougal.pdf\"\u003ehttps://www.sitcancer.org/meetings/am08/primer08_oncology/presentations/3_mcdougal.pdf\u003c/a\u003e.\u003c/li\u003e\n\u003cp\u003eThe 2016 Nice Insight Contract Research — Preclinical and Clinical Survey.\u003c/ol\u003e\n\u003chr\u003e\n\u003ch4\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eChapter 2\u003c/p\u003e\n\u003ch2\u003e2016 Sees Rapid Advances in Biotechnology Clinical Development\u003c/h2\u003e\n\u003ch3\u003eBringing a promising molecule to commercial, therapeutic reality requires intensive focus on process development and analytical and clinical validation.\u003c/h3\u003e\n\u003cp\u003e2016 looks to be another good year for the biopharmaceutical industry and its outsource service partners, as budgets and pipelines continue to escalate. Pipelines have shifted to a greater focus on biologics compared to small-molecule drugs. Currently, there are more than 250 biotechnology health care products and vaccines available to patients, many for previously untreatable diseases.\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;Of the 45 new drugs approved in 2015, 31%\u003csup\u003e15\u003c/sup\u003e\u0026nbsp;were biologics, and the numbers are expected to grow significantly over\u0026nbsp;the next few years.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the 2016 Nice Insight CDMO Outsourcing Survey,\u003csup\u003e3\u003c/sup\u003e\u0026nbsp;about two-thirds of companies are developing large-molecule products as new biological entities (NBEs), surpassing small-molecule products at 57%, while half focus on biosimilars — another jump from previous years. Most of these companies are developing antibody drug conjugates and vaccines, followed closely by hormones, blood factors and growth factors.\u003cbr /\u003eIndustry analysts predict 2016 will feature the launch of as many as 12 new drugs expected to become blockbusters by 2020, including biosimilars of major blockbuster drugs that will soon be coming off patent. The predictions for top 10 drug sales in 2016 include many current biosimilar prospects.\u003csup\u003e2\u003c/sup\u003e\u003cbr /\u003e\u003cimg loading=\"lazy\" src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P2_Sidebar4.jpg\" alt=\"16Q2_Feature_Biologics_P2_Sidebar4.jpg\" width=\"716\" height=\"302\"\u003e\u003cbr /\u003eWith strong growth in this market, biopharma companies are increasingly relying on outsourcing providers for technical and scientific expertise, regulatory support and operational efficiency. Contract service providers are well positioned for accelerated growth in the years ahead.\u003c/p\u003e\n\u003cp\u003eAs the development of biologics becomes increasingly more complex, big biopharma companies are acquiring smaller and medium-size companies and partnering with high-quality service providers to fuel new product development. The trend of small biotech partnering with large pharma for clinical development has facilitated the development of more novel molecules.\u003c/p\u003e\n\u003cp\u003ePreferring fewer, well-qualified contractors, sponsor companies are choosing outsourcing partners that offer sophisticated technology, advanced methodologies, comprehensive services, and the needed skills and expertise to develop high-quality products with optimal efficiency. The continuing trend of industry consolidation enables drug sponsors to develop their candidates under one roof, and helps ensure a continuum of quality throughout the development process.\u003c/p\u003e\n\u003cp\u003e\u003cimg loading=\"lazy\" src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P2_Sidebar5.jpg\" alt=\"16Q2_Feature_Biologics_P2_Sidebar5.jpg\" width=\"716\" height=\"224\"\u003e\u003c/p\u003e\n\u003ch4\u003eImprovements in Technology and Processes\u003c/h4\u003e\n\u003cp\u003eMany current candidate biologics — antibodies and antibody fragments, highly potent antibody-drug conjugates (ADCs), cell and gene-based therapies — are different from the first simple recombinant proteins. They require more advanced methods for characterization and the identification and removal of contaminants. Drug developers have been continuously challenged to develop analytical methods to accurately determine the chemical, physical and therapeutic properties of different actives, and potential contaminants, from raw material selection to process analysis, formulation development and release testing.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eChanging expectations of biologics characterization have driven improvements in analytical equipment, processes and systems. With the move toward continuous processing and other advances, more rapid and sensitive analytical techniques are required. In addition, rapid early bioprocess development is crucial to timely regulatory filing for biologics, often leaving a narrow space for early process development. It is typical to spend considerable time and resources in late-stage development to achieve a higher titer and improve the manufacturing process. A relatively high titer process in the early stage enables rapid downstream and analytical development.\u003csup\u003e5\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo meet these needs, production and analytical technologies have advanced dramatically over the past two decades. Newer methodologies have emerged, such as ultra-performance liquid chromatography (UPLC) systems, which have improved resolution and sensitivity in shorter run times. 2D high-performance liquid chromatography (HPLC), a new version of a traditional methodology, provides a convenient and accurate method for characterizing single-product peaks, side products, and excipients. High-resolution mass spectrometry (MS) allows for the analysis of samples that are incompatible with traditional MS.\u003csup\u003e6\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMS-based methods and next-generation sequencing (NGS) technologies address the need for greater sensitivity in less time.\u003csup\u003e4\u003c/sup\u003e\u0026nbsp;NGS is also being applied to quality control testing in the lab. It is a highly sensitive, universal test to detect and identify any adventitious virus throughout the product lifecycle in a single, comprehensive analysis that minimizes false negatives without prior specification of their nucleic acid sequences. The process involves the sequencing of all nucleic acid material present and the application of algorithms, filtering steps, and taxonomic assignment to determine the presence and identity of contaminating viruses in biologic compounds.\u003c/p\u003e\n\u003cp\u003eAdvanced MS instruments with significantly increased sensitivity provide greater insights into the impurity profiles of biotherapeutics and allow the identification of previously unknown host-cell contaminants.\u003csup\u003e4\u003c/sup\u003e\u0026nbsp;As the industry introduces more complex and increasingly potent molecular formats with novel highly potent product-related impurities, ongoing advances will be necessary.\u003c/p\u003e\n\u003cp\u003eOther improvements are rapid microbiological screening methods, more automated approaches to complex analytical problems, and improved systems for data analysis. Biopharmaceutical development and process validation have been accelerated by mini bioreactor systems, which can rapidly generate a large amount of development data, significantly reducing process development time.\u003csup\u003e6\u003c/sup\u003e\u0026nbsp;In response to the increasing need for parallelization and miniaturization of controlled and monitored bioreactors, microbioreactors with working volume below 1L have been developed.\u003c/p\u003e\n\u003ch4\u003eWhat’s the Outlook for Biosimilars?\u003c/h4\u003e\n\u003cp\u003eVery healthy indeed, based on broad forecasts of strong market growth. With an estimated $67 billion of patents on biological products expiring by 2020, biosimilars represent a major opportunity for the industry. The FDA approved the first biosimilar, Zarxio from Novartis, in 2015.\u003csup\u003e9\u003c/sup\u003e\u0026nbsp;Others are expected to launch in the near future, including biosimilars of mega blockbuster drugs such as Johnson \u0026amp; Johnson’s Remicade and AbbVie’s Humira.\u003cbr /\u003eThe development of biosimilars, compared to new drugs, faces significantly condensed timelines from cell line to first-in-human trials. A biosimilar development program needs to accelerate quickly toward preclinical and Phase 1 studies. Phase 2 studies typically are not required because dose response and other patient-treatment concepts are already established by the innovator medicine. Phase 3 studies are typically limited to fewer patients, which ultimately shortens timelines and costs.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cimg loading=\"lazy\" src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P2_Sidebar6.jpg\" alt=\"16Q2_Feature_Biologics_P2_Sidebar6.jpg\" width=\"716\" height=\"224\"\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the FDA published guidelines on biosimilar development in 2012, the need for a well-defined development process, beginning with characterization and then comparison with the attributes of the reference product, is crucial. The industry has been eager for further regulatory guidance to determine interchangeability for biosimilars. Because of the complexity of biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the follow-on product is to conduct clinical trials. Critical guidance on how biosimilars should be labeled to ensure regulatory transparency and accurate prescribing has yet to be issued by the FDA.\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003eReferences\u003c/h4\u003e\n\u003col\u003e\n\u003cli\u003e“Biotechnology: Healing, Fueling, and Feeding the World.” Biotechnology Industry Organization (BIO).\u0026nbsp;\u003ca href=\"http://www3.bio.org/about_biotech/\"\u003ehttp://www3.bio.org/about_biotech/\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eWelch, A.,“What Biosimilar Makers Need to Know About 2016.” Pharm. Tech. Jan 08, 2016.\u0026nbsp;\u003ca href=\"http://www.biosimilardevelopment.com/doc/what-biosimilar-makers-need-to-know-about-0001\"\u003ehttp://www.biosimilardevelopment.com/doc/what-biosimilar-makers-need-to-know-about-0001\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eThe 2016 Nice Insight Contract Development \u0026amp; Manufacturing Survey.\u003c/li\u003e\n\u003cli\u003eChallener, C.A.,\u0026nbsp;“Fine Tuning the Focus on Biopharma Analytical Studies.” BioPharm International. Feb 01, 2016.\u0026nbsp;\u003ca href=\"http://www.biopharminternational.com/fine-tuning-focus-biopharma-analytical-studies\"\u003ehttp://www.biopharminternational.com/fine-tuning-focus-biopharma-analytical-studies\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eXu, S.,\u0026nbsp;“Rapid Early Process Development Enabled by Commercial Chemically Defined Media and Microbioreactors.” BioPharm International. Feb 01, 2015.\u003ca href=\"http://www.biopharminternational.com/rapid-early-process-development-enabled-commercial-chemically-defined-media-and-microbioreactors\"\u003ehttp://www.biopharminternational.com/rapid-early-process-development-enabled-commercial-chemically-defined-media-and-microbioreactors\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eBioPharm International ebook, Jun 2015.\u003ca href=\"http://www.biopharminternational.com/biopharm-international-ebooks-06-15-2015\"\u003ehttp://www.biopharminternational.com/biopharm-international-ebooks-06-15-2015\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eDhanasekhran, K., et al.,\u0026nbsp;“Rapid Development and Scale-Up of Biosimilar Trastuzumab: A Case Study of Integrated Cell Line and Process Development.”\u0026nbsp;BioProcess International. Apr 14, 2015.\u0026nbsp;\u003ca href=\"http://www.bioprocessintl.com/manufacturing/biosimilars/rapid-development-and-scale-up-of-biosimilar-trastuzumab-a-case-study-of-integrated-cell-line-and-process-development/\"\u003ehttp://www.bioprocessintl.com/manufacturing/biosimilars/rapid-development-and-scale-up-of-biosimilar-trastuzumab-\u003c/a\u003e\u003ca href=\"http://www.bioprocessintl.com/manufacturing/biosimilars/rapid-development-and-scale-up-of-biosimilar-trastuzumab-a-case-study-of-integrated-cell-line-and-process-development/\"\u003ea-case-study-of-integrated-cell-line-and-process-development\u003c/a\u003e/.\u003c/li\u003e\n\u003cli\u003e“What Are ‘Biologics’” Questions and Answers, U.S. Food and Drug Administration.\u003ca href=\"http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm133077.htm\"\u003ehttp://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm133077.htm\u003c/a\u003e\u003c/li\u003e\n\u003cli\u003eGaBi Online, “US$67 billion worth of biosimilar patents expiring before 2020.” Jan, 2014.\u003ca href=\"http://www.gabionline.net/Biosimilars/General/US-67-billion-worth-of-biosimilar-patents-expiring-before-2020\"\u003ehttp://www.gabionline.net/Biosimilars/General/US-67-billion-worth-of-biosimilar-patents-expiring-before-2020\u003c/a\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003chr\u003e\n\u003ch4\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003eChapter 3\u003c/p\u003e\n\u003ch2\u003eIncreased Investment in R\u0026amp;D Driving Growth of Outsourcing to\u0026nbsp;Biopharmaceutical CDMOs\u003c/h2\u003e\n\u003ch3\u003eBringing a biologic therapy to commercial reality takes an absolute dedication to operational, technical excellence; contract manufacturers are increasingly providing this capability.\u003c/h3\u003e\n\u003cp\u003eIncreased investments at the discovery and early development phases are leading to robust pipelines and creating demand for greater clinical- and commercial-scale manufacturing capacity. While biologic drug manufacturers are expanding their own in-house capabilities, these companies are also increasingly turning to outsourcing partners, particularly for the production of drug substances and products that require specialized expertise.\u003c/p\u003e\n\u003ch4\u003eIncreased outsourcing indicated\u003c/h4\u003e\n\u003cp\u003eEstimates of the biopharmaceutical contract manufacturing market vary somewhat, but there is a consensus that the strong growth witnessed in recent years will continue going forward. HighTech Business Decisions (HBD) valued the market at $3 billion in 2015 with the growth of annually.\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;The company predicts that big bio/pharma companies will increase outsourcing levels from 16% to 34% from 2015 to 2019, leading to a value for the market of $4.1 billion by the end of the period.\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;In addition to the robust biopharma pipeline and greater rates of new drug commercialization, increased funding of biotech companies and a broader array of service offerings by contract manufacturing organizations (CMOs) are considered to be key contributors to this healthy growth.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cimg src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P3_Sidebar7.jpg\" alt=\"16Q2_Feature_Biologics_P3_Sidebar7.jpg\" title=\"16Q2_Feature_Biologics_P3_Sidebar7.jpg\" data-constrained=\"true\" style=\"width: 650px\" width=\"650\"\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eSix biopharma CMO / CDMO executives interviewed by HBD indicated that the number of requests for proposals that they received in 2015 was higher than that in 2014, with one company experiencing an increase of more than 10%.\u003csup\u003e1\u003c/sup\u003e\u0026nbsp;They pointed to varied reasons for the increase, ranging from a greater number of RFPs for smaller, specific projects to growing interest in outsourcing at early stages to CDMOs with a comprehensive suite of services in order to avoid technology transfer issues and speed time to market. Biosimilar projects are also increasing in number.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cimg src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P3_Sidebar8.jpg\" alt=\"16Q2_Feature_Biologics_P3_Sidebar8.jpg\" title=\"16Q2_Feature_Biologics_P3_Sidebar8.jpg\" data-constrained=\"true\" style=\"width: 650px\" width=\"650\"\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWhile outsourcing continues to be seen as an effective means of increasing cost efficiency, cost savings is no longer the primary driver.\u0026nbsp;\u003c/em\u003eBiopharmaceutical companies are also seeking technical expertise (such as for the manufacture of antibody-drug conjugates and bispecific antibodies), operational efficiency, regulatory support and the advantage of focusing on core competencies, according to Roots Analysis\u0026nbsp;\u003csup\u003e3\u003c/sup\u003e: “Spanning multiple operations within wider manufacturing processes, outsourcing is increasingly being viewed as a strategic imperative.”\u003c/p\u003e\n\u003cp\u003eHBD identified over 500 companies that claim to be CMOs / CDMOs, but note that only approximately 90 of them have the actual capabilities needed to manufacture recombinant proteins at large scale. Roots Analysis, meanwhile, says that over 160 biopharmaceutical CMOs offer services ranging from cell line development to biologic API manufacturing to fill/finish operations. These companies include both pure contract service providers such as Lonza and CMC Biologics and large bio/pharma companies that have excess capacity available for contract manufacturing, such as GlaxoSmithKline Biopharmaceuticals and Boehringer Ingelheim BioXcellence.\u003c/p\u003e\n\u003cp\u003eThe extent to which biopharmaceutical CMOs / CDMOs are benefiting from significant increases in spending by bio/pharmaceutical companies of all sizes is revealed in the results of the 2016 Nice Insight CDMO Outsourcing Survey\u0026nbsp;\u003csup\u003e6\u003c/sup\u003e\u0026nbsp;of bio / pharma professionals (n=587). Most notably, 95% of respondents indicated that they currently or intend to use biopharmaceutical manufacturing services. In addition, a similar percentage of survey participants use or plan to use CDMOs / CMOs for clinical- and commercial scale biologic API manufacturing (57% and 30%, respectively) as do for small-molecule API manufacturing (56% and 33%, respectively). With respect to the spending levels for the survey participants using biomanufacturing services, 73% and 26%, respectively, spend over and less than $50 million annually on all outsourcing activities.\u003c/p\u003e\n\u003ch4\u003eHeightened M\u0026amp;A Activity\u003c/h4\u003e\n\u003cp\u003eThe strong growth in the contract biopharmaceutical market has attracted the interest of new entrants. One notable example is Samsung Biologics, whose success, according to CEO Tae Han Kim, is based on the company’s extensive manufacturing and engineering expertise which was gained in the semiconductor industry. This is coupled with Samsung Biologics’ ability to attract highly skilled industry experts with direct experience in biologics plant design and construction, validation and cGMP operations.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eMerger and acquisition (M\u0026amp;A) activity has also been fairly intense in the contract biopharma sector. The market is fairly fragmented with a large number of players (vide infra), so it is not surprising that consolidation is occurring. There are additional drivers, however — the largest perhaps, being the desire of CMOs to transform themselves into international CDMOs. Such service providers can meet client needs for global partners with small- to large-scale capabilities, expanded service offerings and advanced technologies.\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"http://thatsnice-testing3.com/legacy/Q2_%202016/Sidebar%20Images/16Q2_Feature_Biologics_P3_Sidebar9.jpg\" alt=\"16Q2_Feature_Biologics_P3_Sidebar9.jpg\" title=\"16Q2_Feature_Biologics_P3_Sidebar9.jpg\" data-constrained=\"true\" style=\"width: 650px\" width=\"650\"\u003e\u003c/p\u003e\n\u003ch4\u003eCapacity Considerations\u003c/h4\u003e\n\u003cp\u003eResults of two different industry surveys of biopharmaceutical contract manufacturers suggest that CMOs / CDMOs will be expanding capacity in the coming years. Capacities for mammalian cell culture and microbial fermentation in 2015 were reported by BioPlan Associates to be nearly 82% and 68%, respectively, with mammalian capacity utilization in the U.S. (72%) higher than that in Europe (51%), and vice versa for microbial capacity utilization (55% and 66%, respectively).\u003csup\u003e5\u003c/sup\u003e\u0026nbsp;In addition, the surveyed CMOs expected on average 5-year planned increases of 49% and 25% for mammalian and microbial bioreactor capacity, respectively. Companies adding notable capacity include Patheon Biologics, AbbVie (for pipeline support and CMO services), KBI Biopharma and Fujifilm Diosynth Biotechnologies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors: Steve Kuehn, Cynthia Challener, Ph.D., Marilyn Seiger, MA, MBA, Carrie Cao, Ph.D.\u003c/strong\u003e\u003c/p\u003e\n\u003ch4\u003eReferences\u003c/h4\u003e\n\u003col\u003e\n\u003cli\u003eDowney, W.,“Biopharmaceutical Contract Manufacturing Capacity Expansions.” Contract Pharma. Jun 02, 2015. \u003ca href=\"http://www.contractpharma.com/issues/2015-06-01/view_features/biopharmaceutical-contractmanufacturing-capacity-expansions\"\u003ehttp://www.contractpharma.com/issues/2015-06-01/view_features/biopharmaceutical-contractmanufacturing-capacity-expansions\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eStanton, D.,\u0026nbsp;“Bio-CMO sector to grow over 40% on Big Pharma’s burgeoning pipelines.” BioPharma-reporter.com. Apr 25, 2015. \u003ca href=\"http://www.biopharma-reporter.com/Upstream-Processing/Bio-CMO-sector-to-grow-40-on-Big-Biopharma-s-burgeoning-pipelines\"\u003ehttp://www.biopharma-reporter.com/Upstream-Processing/Bio-CMO-sector-to-grow-40-on-Big-Biopharma-s-burgeoning-pipelines\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eRoots Analysis, “Biopharmaceutical Contract Manufacturing Market, 2015 –2025.” Press Release. Sept 16, 2015.\u003c/li\u003e\n\u003cli\u003eGarguilo, L.,“Samsung BioLogics: How To Build A CMO Business.” Outsourced Pharma. Jun 26, 2015. \u003ca href=\"http://www.outsourcedpharma.com/doc/samsung-biologics-how-to-build-a-cmo-business-0001\"\u003ehttp://www.outsourcedpharma.com/doc/samsung-biologics-how-to-build-a-cmo-business-0001\u003c/a\u003e.\u003c/li\u003e\n\u003cli\u003eBioPlan Associates Inc., “Top 15 Trends in BiopharmaceuticalManufacturing.” Contract Pharma. Sep 11, 2015.\u003c/li\u003e\n\u003cli\u003eThe 2016 Nice Insight Contract Development \u0026amp; Manufacturing Survey.\u003cbr /\u003e\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n","date":"2016-04-01T12:00:00","dateGmt":"2016-04-01T16:00:00","roundtable":{"topic":null,"question":null,"roundtable":null},"featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/16Q2_Feature_Biologics1.jpg"}},"articleTags":{"edges":[{"node":{"name":"Biologics","slug":"biologics","id":"dGVybTo4OTc4"}},{"node":{"name":"Biosimilars","slug":"biosimilars","id":"dGVybTo5MTEz"}},{"node":{"name":"CDMO","slug":"cdmo","id":"dGVybTo4OTk0"}},{"node":{"name":"Features","slug":"features","id":"dGVybTo5MTQ1"}},{"node":{"name":"HomePageFeatured","slug":"homepagefeatured","id":"dGVybTo5MDQx"}},{"node":{"name":"New Biological Entities","slug":"new-biological-entities","id":"dGVybTo5MTY2"}},{"node":{"name":"Q2 2016","slug":"q2-2016","id":"dGVybTo5MTQ3"}}]},"mainTopic":{"mainTopic":null},"articleFields":{"articleId":"PAP-Q02-16-FA-001","accentColor":null,"vimeoId":null,"associatedCompanies":null,"authors":[{"author":{"id":"cG9zdDo3OTc3OQ==","title":"Emilie Branch","slug":"emilie-branch","featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/E_Branch_TN.webp"}},"authorFields":{"bio":"\u003cp\u003eEmilie is responsible for strategic content development based on scientific areas of specialty for Nice Insight research articles and for assisting client content development across a range of industry channels. Prior to joining Nice Insight, Emilie worked at a strategy-based consulting firm focused on consumer ethnographic research. She also has experience as a contributing editor, and has worked as a freelance writer for a host of news and trends-related publications\u003c/p\u003e\n","email":"emilie@thatsnice.com","linkedin":"https://www.linkedin.com/in/emiliebranch/","title":"Strategic Content Manager","company":{"id":"cG9zdDo3NzEwNA==","title":"Pharma’s Almanac","slug":"pharmas-almanac"}}}}]}},"vimeoThumb":false},"__N_SSG":true},"page":"/articles/[slug]","query":{"slug":"articles-q2-tn-biopharmas-ascendent-supply-chain-reveals-its-present-potential-future-promise-chapter-2"},"buildId":"3j1kwQFJR4bAVxAE0sM1B","isFallback":false,"gsp":true,"scriptLoader":[]}</script></body></html>