Advancing Biologics Development and Manufacturing

The vigorous growth of the biopharmaceutical market has boosted the demand for biopharmaceutical contract manufacturing services.¹ Today, pharmaceutical and biotechnology companies outsource a broad spectrum of services from early stage drug development (e.g., cell line, process, analytical, and formulation development) all the way to commercial-scale manufacturing.

The outsourcing decision is often made by the need to expedite research and development, shorten the time to market, gain access to novel technologies and regulatory expertise, and minimize risks, at competitive cost.

Complexity in biologics development and production, an obligation to better understand the product, and implementation of quality by design (QbD) have driven drug innovators to engage with their contract manufacturers much earlier than prior conventional practice. This shift in buyers’ behavior has given rise to the contract development and manufacturing organization (CDMO). Generally, a full-service CDMO offers a comprehensive set of services that connect all the aspects of the development stage of drug production through to commercial manufacturing in an integrated process, whereas traditional contract manufacturing organizations (CMOs) focus mainly on large-scale manufacturing. To some degree, an experienced CDMO can serve as a one-stop-shop for drug innovator development and manufacturing needs.

Biologics Market Expansion

The debut of the first recombinant protein, human insulin, in 1982 marked a new era of modern medicine: therapeutic biologics. Biologics have profound clinical performance and a better regulatory approval rate than small-molecule drugs. They can generally offer better efficacy and thereby command a high premium price. Together these major boons have pushed therapeutic biologics into the center of drug discovery and development. The development pipeline for biologics looks strong: the U.S. alone hosts over 900 clinical-stage biologic molecules targeting more than 100 diseases.² In the last two years, FDA’s Center of Drug Evaluation and Research (CDER) has approved record-high numbers of novel medicines since 1996 with 41 in 2014 and 45 in 2015. The number of new biological approvals is also steadily increasing: 13 new therapeutic biologics were approved in 2015, up by 2 from 2014. Additionally, nine of them were recognized as “First-In-Class,” an indicator for the innovative nature of a drug.^{3, 4} The innovation in biologic therapeutics is unlikely to slow down any time soon.

The fervor in searching for new biological entities (NBEs) is undoubtedly linked to the revenues already realized in the market. The biopharmaceutical market has experienced robust growth in recent years and the momentum continues to build. Being the fastest-growing sector of the pharmaceutical industry, the global biopharmaceutical sales generated a revenue of nearly $162 billion in 2014, accounting for about 20% of the entire pharmaceutical market.⁵ In the same year, 7 of the 10 best-selling prescription drugs in the world were biologics earning a combined revenue of more than $60 billion.6 By 2020, this market is expected to reach approximately $278 billion at a current compound annual growth rate (CAGR) of 9.4%, twice of the overall pharma market growth rate.^{1, 5}

To date, most development-stage and marketed biopharmaceuticals are proteinbased products with monoclonal antibodies (mAbs) leading the market growth, followed by recombinant proteins. Niche specialty areas, such as antibody-drug conjugates (ADCs) and bispecific antibodies are also gaining attention. Of the top 10 best-selling biological drugs of 2014, five were mAbs (Humira — No. 1, Remicade — No. 2, Rituxan — No. 3, Avastin, and Herceptin). Four recombinant proteins (Lantus, Enbrel, Avonex, and Neulasta) and one vaccine (Prevnar) made up the remaining five.⁷ The majority of these top-selling biopharmaceuticals are used in two therapeutic areas: five for autoimmune diseases (Humira, Remicade, Rituxan, Enbrel, and Avonex) and three for cancer and cancer-related diseases (Avastin, Herceptin, and Neulasta). In the next few years, breakthroughs in immunotherapy, gene, and cell therapy will bring more novel, diversified biologics into the market.

In addition, the biosimilar market is expected to gain significant growth in the next five years, especially in the U.S. By 2020, most of the top-selling biologics will fall off patent, which opens up tremendous opportunities for the biosimilar market. As a result, innovative pharma and biotech companies have entered competition with generic manufacturers to develop biosimilars. The United States is slower in adopting biosimilars than other developed countries. 2015 was a turning point for the U.S. biosimilar market: the FDA approved its first biosimilar drug, Zarxio, which was developed by Sandoz, the generic branch of Novartis. It was launched six months later at a 15% discount to its reference drug, Amgen’s Neupogen.8 With a regulatory framework in place and 29 biosimilars currently in clinical trials, more biosimilars will launch in the U.S. market in the coming years.9 Overall, the global biosimilars market is expected to grow rapidly in the next five years at a CAGR of 22.1% and reach $6.22 billion by 2020.¹⁰

Developing Biologics Requires State-of-the-Art Facilities and an Array of Technical and Operational Expertise

Unlike small-molecule drugs, which contain active pharmaceutical ingredients (APIs) with well-defined chemical structures, biopharmaceutical APIs do not always have well-defined or even static structures. These molecules are hundreds to a thousand times larger than small molecules with inherent structural instability, which poses a constant challenge to the production process. In addition, the biopharmaceutical manufacturing process is more complex and costly to develop, operate, and maintain than the chemical process for small molecules. Successfully developing biologics requires a combination of state-of-the-art facilities and a broad array of technological and operational expertise.

With more biological products and biosimilars entering the market, the competition within the biopharmaceutical sector will continue to be fierce. Biopharmaceutical makers strive to reduce manufacturing cost, improve process efficiency, deliver high quality and efficacy, and accelerate speed to market. The latter is more critical for biosimilar developers. As for biopharmaceutical CMOs/CDMOs, they have to be agile in adopting technological advances in order to lead process innovation and operational efficiency. As the industry is gradually shifting away from large scale production (10,000 – 20,000 Liters) to smaller scales for more niche and targeted therapies (e.g., personalized medicine), flexibility in operational capabilites, production scales, and multiple-product operations can be a great advantage for CMOs/CDMOs.

Perfusion Manufacturing

Another trend in biomanufacturing is the increasing adoption of continuous bioprocessing with perfusion being the leading technology. The advantage of continuous bioprocessing is evident. First, in a perfusion system, cell culture lives in consistent optimal conditions with a constant flow of media and removal of waste. High cell density (i.e., 100 million/mL) can be achieved and operated for extended periods, resulting in higher volumetric productivity than traditional fed-batch manufacturing. The product is harvested continuously, enabling continuous downstream purification at a small scale. Second, continuous bioprocessing is more capital-equipment efficient. Perfusion bioreactors are smaller in size, requiring less space, infrastructure, utilities, and labor. Third, perfusion technology is quite flexible and can be adapted to various cell types and applications, including vaccine, mAb, and cell therapies (e.g., stem cells).^{12, 13}

There are two major factors in adopting perfusion manufacturing. First, perfusion processes require more process knowledge, equipment, and technology. Second, as a result of the increased need for highly specialized technical equipment, perfusion-based manufacturing is more complex from a development, manufacturing, and regulatory perspective than fed-batch bioprocessing.¹³ Assisted by CMC Biologics’ expertise, these challenges can be managed with good science, experience, advanced analytics, and technical expertise. The biopharmaceutical industry is going to see more advances in perfusion technology, as well as wider adoption of continuous bioprocessing in the future. CMC will be at the forefront of these advances as it continues to develop innovative perfusion processes for its clients.

References

1. Persistence Market Research. Global Biopharmaceuticals Market Will Reach US$ 278 Bn by 2020, Press Release, July 27, 2015. Accessed at: http://www.persistencemarketresearch.com/ mediarelease/biopharmaceutical-market.asp
2. Medicines In Development: Biologics 2013 Report, America’s Biopharmaceutical Research Companies. Accessed at: http://www.digdeepsolutions.com/wp-content/uploads/2015/04/ biologicsoverview2013.pdf
3. FDA Center for Drug Evaluation and Research, “Novel Drugs 2015 Summary”, January 2016. Accessed at:http://www.fda.gov/ downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/ UCM481709.pdf
4. FDA Center for Drug Evaluation and Research, “Novel New Drugs 2014 Summary”, January 2015. Accessed at: http:// www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ DrugInnovation/UCM430299.pdf
5. Otto R., Santagostino A., Schrader U., “Rapid growth in biopharma: Challenges and opportunities”, December 2014. Accessed at: http://www.mckinsey.com/insights/health_ systems_and_services/rapid_growth_in_biopharma
6. Nisen M., The best selling prescription drugs in the world last year, 2015. Accessed at: http://qz.com/349929/best-selling-drugsin-the-world
7. Morad R., “Top 10 Best-Selling Biotech Drugs”, BioSpace, September 30, 2015. Accessed at: http://www.biospace.com/ News/top-10-best-selling-biotech-drugs/393360
8. Hirschler B., Shields M., “Novartis launches first U.S. ‘biosimilar’ drug at 15 percent discount”. Accessed at: http://www.reuters.com/article/us-novartis-drugidUSKCN0R30C220150903
9. HealthCare Recruiters International, “Biosimilars Market in the US – 2015”, September 31, 2015. 
10. Markets and Markets, “Biosimilars Market by Product (Recombinant Non-Glycosylated Proteins (Insulin, Filgrastim, Interferons, rHGH), Glycosylated (Monoclonal Antibodies, EPO), Peptides (Glucagon, Calcitonin)) & Application (Oncology, Blood Disorders) – Global Forecast to 2020”, Press Release, July 2015. Accessed at: http://www.marketsandmarkets.com/ Market-Reports/biosimilars-40.html?gclid=CMyzr7NhMoCFdEYHwodB_sH7Q
11. Hernandez R., “Contract Biomanufacturing Firms Become More Specialized,” BioPharm International 28 (9) 2015. Accessed at: http://www.biopharminternational.com/ print/299076?page=full
12. Langer E.S., Rader R.A., “Continuous Bioprocessing and Perfusion: Wider Adoption Coming as Bioprocessing Matures”, BioProcessing Journal, 2014 www.bioinfo.com/Continuous_Bioprocessing.pdf
13. Carstens J.N., Ph.D., Clarke H.R.G., Ph.D., Jensen J.P., “Perfusion! Jeopardy or the Ultimate Advantage?” CMC Biologics, September, 2009. http://www.cmcbio.com/ Portals/0/CMC/docs/perfusion.pdf