2016 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.1 Of the 45 new drugs approved in 2015, 31% (15) were biologics, and the numbers are expected to grow significantly over the next few years.2
According to the 2016 Nice Insight CDMO Outsourcing Survey,3 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.
Industry 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.2
With 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.
As 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.
Preferring 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.
Improvements in Technology and Processes
Many 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.4
Changing 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.5
To 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.6
MS-based methods and next-generation sequencing (NGS) technologies address the need for greater sensitivity in less time.4 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.
Advanced 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.4 As the industry introduces more complex and increasingly potent molecular formats with novel highly potent product-related impurities, ongoing advances will be necessary.
Other 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.6 In response to the increasing need for parallelization and miniaturization of controlled and monitored bioreactors, microbioreactors with working volume below 1L have been developed.
What’s the Outlook for Biosimilars?
Very 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 2015.9 Others are expected to launch in the near future, including biosimilars of mega blockbuster drugs such as Johnson & Johnson’s Remicade and AbbVie’s Humira.
The 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.7
Although 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.
References
- “Biotechnology: Healing, Fueling, and Feeding the World.” Biotechnology Industry Organization (BIO). http://www3.bio.org/about_biotech/.
- Welch, A., “What Biosimilar Makers Need to Know About 2016.” Pharm. Tech. Jan 08, 2016. http://www.bioprocessonline.com/doc/2016-what-biosimilar-makersneed-to-know-0001.
- The 2016 Nice Insight Contract Development & Manufacturing Survey.
- Challener, C.A., “Fine Tuning the Focus on Biopharma Analytical Studies.” BioPharm International. Feb 01, 2016. http://www.biopharminternational.com/finetuning-focus-biopharma-analytical-studies.
- Xu, S., “Rapid Early Process Development Enabled by Commercial Chemically Defined Media and Microbioreactors.” BioPharm International. Feb 01, 2015. http://www.biopharminternational.com/rapid-early-process-development-enabledcommercial-chemically-defined-media-and-microbioreactors.
- BioPharm International ebook, Jun 2015. http://www.biopharminternational.com/ biopharm-international-ebooks-06-15-2015.
- Dhanasekhran, K., et al., “Rapid Development and Scale-Up of Biosimilar Trastuzumab: A Case Study of Integrated Cell Line and Process Development.” BioProcess International. Apr 14, 2015. http://www.bioprocessintl.com/ manufacturing/biosimilars/rapid-development-and-scale-up-of-biosimilartrastuzumab-a-case-study-of-integrated-cell-line-and-process-development/.
- “What Are ‘Biologics’” Questions and Answers, U.S. Food and Drug Administration. http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CBER/ucm133077.htm.
- GaBi Online, “US$67 billion worth of biosimilar patents expiring before 2020.” Jan, 2014. http://www.gabionline.net/Biosimilars/General/US-67-billion-worth-ofbiosimilar-patents-expiring-before-2020.