Manufacturing Issues Playing an Important Role in Biosimilar Strategies
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Biosimilar developers have to consider evolving manufacturing technologies and capacity issues in their commercialization strategies.

Biosimilars represent a niche but important opportunity in the global biopharmaceutical market. Although the United States still has not yet have worked out the regulatory details to obtain approval for biosimilars, Europe and other countries, particularly emerging markets, offer market potential. DCAT’s 2014 BioPharmaceutical Forum: Biosimilars—Development, Regulatory, and Marketing Experiences, held March 13, 2014 during DCAT Week ’14, examined both the opportunities and challenges in biosimilar development and commercialization.

Assessing the opportunity

Biosimilars are a small, but growing portion of the global biopharmaceutical market. Biosimilars and non-original biologics (defined as biologics that are neither original nor have followed a dedicated biosimilar pathway) accounted for 0.4% of the $137-billion biologics market in the so-called “mature eight” markets of the United States, EU5 (France, Germany, Italy, Spain, and United Kingdom), Canada, and Japan in 2012, according to IMS (1). In pharmerging markets, the term used by IMS to describe emerging pharmaceutical markets, biosimilars accounted for 10.7% of a $15-billion biologics market in 2012. By 2017, biosimilars are expected to account for 3–5% of an estimated global biologics market of between $205 billion and $235 billion (1).

Patricia Seymour
Senior Consultant
BioProcess Technology
Consultants, Inc.

An important change already underway is the entry of monoclonal antibodies into the biosimilar market. “Biosimilar versions of first-generation biopharmaceuticals are already approved in many markets,” explained Patricia Seymour, senior consultant of BioProcess Technology Consultants, Inc. (BPTC), who spoke at DCAT’s BioPharmaceutical Forum during DCAT Week ’14. “Many monoclonal antibodies will be off patent in the next few years,” she said. “Biosimilar monoclonal antibodies are already available in India and China, and Europe approved its first biosimilar monoclonal antibodies in 2013.”

Manufacturing technologies

For biosimilars in general and particularly with the entry of more complex molecules, such as monoclonal antibodies, biosimilar developers face the challenge of developing a manufacturing process that can achieve comparability to the reference product. Unlike the manufacturing processes of small-molecule drugs that can be chemically synthesized and easily replicated, a biologic is produced from living organisms and has more complexity and heterogeneity. Development activities, beginning with the choice of a cell line, to upstream processing, and final purification center on replicating the host cell line and process conditions of the reference product to drive the process toward producing a “highly similar product.” Because innovators do not typically detail manufacturing processes publicly, biosimilar developers have to ascertain the process conditions to achieve comparability. But an added complication facing biosimilar developers is whether to take advantage of advances in upstream processing to develop more efficient manufacturing processes to produce a biosimilar. Seymour explained that the industry has seen increased yields from titers of less than 1 g/L in 2000 to titers of 10 g/L and above in 2014. A fundamental question for a biosimilar developer in evaluating the cost and time for biosimilar development is deciding whether to use improved manufacturing processes that may result in better yields and more efficient manufacturing processes, but may constitute process changes that result in variation of the biosimilar product and would require additional clinical testing to demonstrate comparability to the referenced product.

Biosimilar developers also face questions in cell-line development. Seymour cited data that outlined the expression systems most widely used based on a review of FDA product approvals from January 2006 to June 2010 (2). In terms of conventional expression systems, mammalian cell-culture systems (primarily Chinese hamster ovary (CHO) cells) account for the majority of expression systems or 56% of the systems used and E. coli 29%. Yeast-based systems account for 7%, transgenic systems 3%, and other systems 5% (2). “For biosimilar developers,” said Seymour, “these cell lines provide less opportunity for innovation, fewer intellectual property advantages, and minimal patent protection. An important issue in biosimilar development is whether alternative expression systems can be used for biosimilar development and commercialization.”

Biomanufacturing capacity

 Table I: Global Distribution of Cell-Culture Capacity
 (Volume in ‘000s Liters)
   2012  2018
 North America 1,821  1,963
 UK/Ireland 196  241
 Europe  744  954
 Korea  60  270
 Japan  115  115
 China  < 1  125
 India  14  35
 Singapore/Malaysia  176  264
 Australia  < 1  3
 Russia  0  7
 South America  0  4
 *Perfusion capacity adjusted to equivalent fed-batch capacity
 where appropriate.

 Source: BioProcess Technology Consultants (BPTC).

 

Biosimilar developers will also have to consider available biomanufacturing capacity. North America will remain the largest source of cell-culture capacity through 2018, (see Table I), noted Seymour. Europe and Asia are the fastest growing markets, and there will continued to be minimal capacity in Latin America. “Overall, biomanufacturing capacity is adequate but tightening,” she says. “Current and anticipated supply of capacity is sufficient to meet the market needs for the foreseeable future,” she says. BPTC estimates that overall, an increase in the number of biopharmaceutical products and expanding markets will increase demand for biopharmaceutical manufacturing capacity by approximately 1 million liters by 2016. Although overall capacity should be sufficient to meet this increase in demand, Seymour had some qualifications. “Existing capacity may not be available at the time needed or under the appropriate conditions,” she said. One reason is that product companies control more than 70% of total biopharmaceutical manufacturing capacity, so contract manufacturers account for about 30% of total biopharmaceutical manufacturing capacity. Utilization rates for the majority of the industry will reach almost 75% by 2015, further tightening available capacity for a given project. “Companies without capacity or ability to secure manufacturing contracts may experience difficulties in accessing capacity in the coming years,” said Seymour.

One issue that biopharmaceutical manufacturers are dealing with is a mismatch between installed capacity and the productivity gains made in upstream processing. Seymour explained that most facilities today were built for low titers (< 1 g/L) processes and consist of multiple 20,000-L bioreactors each with inoculum bioreactors up to 4,000 L. Also, with improved upstream yields, “current facilities struggle to match downstream capacity with bioreactor output due to large process volumes,” she said. “Technologies that enable higher bioreactor titers will exasperate the downstream processing bottleneck,” she said.

To address these issues, Seymour explained that biopharmaceutical manufacturing facilities will evolve to reflect the improvements in upstream yields and address the bottleneck in downstream processing. “New biopharmaceutical manufacturing facilities will consist of smaller bioreactors that will be able to produce quantities similar to today’s larger, so-called ‘six-pack’ facilities and will increasingly use new technologies, including disposables, to reduce capital investment, increase flexibility, and compress timelines and reflect production of producing cell-culture titers of more than 5 g/L.” The smaller facility and improved productivity will reduce capital requirements and “may enable smaller companies to construct their own facilities rather than outsource,” she said. She pointed to other key trends that the improved manufacturing methods will create. “The lower capital cost and increased flexibility would enable biopharmaceutical manufacturing facilities to be built in emerging markets,” said Seymour. “Moreover, more sophisticated manufacturing technologies employing continuous processing, process analytical technology (PAT), and other manufacturing methods will be incorporated into bioprocessing and improvements to downstream processing capabilities.”

Biosimilar alliances
Another facet to the biosimilar landscape are the partnerships and alliances (see Table II) that have emerged in biosimilar development, noted Seymour. Some alliances include: Biogen Idec/Samsung; Biocon/Mylan; Merck/Parexel; Baxter/Momenta Pharmaceuticals; and Amgen/Actavis (formerly Watson); and a terminated agreement between Teva and Lonza.

 Table II: Types of Biosimilar Partnerships and Alliances
 Focus  Capabilities
 Development and regulatory  State-of-the-art analytical and clinical capabilities
 to speed up development and ensure regulatory
 compliance
 Market Access  Optimize time to market and ensure key
 stakeholders (key opinion leaders, payers) are
 onboard and supportive to drive advocacy and
 acceptance
 Manufacturing  Scale and know-how to manufacture at reasonable
 cost of goods
 Sales and marketing  In-house capabilities and understanding of local
 dynamics
 
 Source: BioProcess Technology Consultants; Derived from IMS

 

In late 2011/early 2012, Samsung Biologics and Biogen Idec formed a $300-million joint venture, Samsung Bioepis, to develop, manufacture, and market biosimilars. Samsung holds an 85% stake and Biogen Idec 15%, with Biogen Idec contributing its expertise in protein engineering and biologics manufacturing. Samsung Biologics is a Samsung business formed in April 2011 to specialize in biopharmaceutical manufacturing. The joint venture is not developing biosimilars of Biogen Idec’s proprietary products. The companies announced the formation of the joint venture in late 2011 and completed the formation of the joint venture in February 2012. In December 2013, Biogen Idec and Samsung Bioepis announced an agreement to commercialize anti-TNF biosimilar product candidates in Europe, including biosimilars therapies, to treat conditions such as rheumatoid arthritis and Crohn’s disease.

In February 2013, Merck & Co. and Samsung Bioepis formed an agreement to develop and commercialize multiple undisclosed biosimilar candidates. Under the agreement, Samsung Bioepis is responsible for preclinical and clinical development, process development and manufacturing, clinical trials, and registration. Merck is responsible for commercialization. Samsung Bioepis received an upfront payment from Merck, product supply income, and is eligible for additional payments associated with clinical and regulatory milestones. In February 2014, the companies expanded their collaboration with an agreement to develop, manufacture, and commercialize MK-1293, an insulin glargine candidate for the treatment of patients with Type 1 and Type 2 diabetes. Phase III clinical studies in Type 1 and Type 2 diabetes will begin soon. Under the terms of the agreement, the companies will collaborate on clinical development, regulatory filings, and manufacturing. If approved, Merck will commercialize this candidate. In January 2011, Merck formed an alliance with the contract research organization Parexel, under which Parexel provides access to global clinical development services for designated biosimilar candidates. 

In February 2013, Mylan formed a strategic collaboration with the Indian biopharmaceutical company Biocon Limited for the development and commercialization of generic versions of three insulin analog products. Under the terms of this collaboration, Mylan will have the rights to develop and market Biocon’s Glargine (the generic version of Sanofi’s Lantus®), Lispro (the generic version of Eli Lilly and Company’s Humalog®), and Aspart (the generic version of Novo Nordisk’s NovoLog®). Mylan and Biocon are sharing development, capital, and certain other costs to bring the products to market. Mylan has exclusive commercialization rights in the United States, Canada, Australia, New Zealand, the European Union, and the European Free Trade Association countries through a profit-share arrangement with Biocon and co-exclusive commercialization rights with Biocon in certain other markets around the world.

Baxter International and Momenta Pharmaceuticals Inc. formed a collaboration in early 2012 to develop and commercialize up to six biosimilars. Baxter is providing expertise in clinical development, biologic manufacturing, sterile injectables, and global commercial capabilities, and Momenta is providing expertise in high-resolution analytics, characterization, and product and process development. Based on its 2013 annual financial filing, Momenta provided an update of the collaboration. The companies are advancing two biosimilar candidates. M923, a biosimilar for a branded biologic indicated for certain autoimmune and inflammatory diseases, is the most advanced biosimilar and for which the companies have  a goal of progressing this program to the clinic in Europe, targeted for the second half of 2014. The second candidate, M834, is a biosimilar for a branded biologic indicated for certain autoimmune and inflammatory diseases, according to Momenta’s annual filing, and Momenta is looking to achieve a predefined “minimum development criteria” license payment in 2014. In July 2012, Baxter selected a third product for inclusion in the collaboration, a monoclonal antibody for oncology designated as M511.Baxter later terminated its option to license the product in December 2013 although Momenta said it will continue to develop M511. According to the filing, Baxter has the right, until February 2015, to select up to three additional biosimilars to be included in the collaboration, and Momenta may also consent, at its option, to allow Baxter to name a replacement product for M511, if Baxter requests such replacement .

In December 2011, Amgen and Watson Pharmaceuticals Inc. (now named Actavis following Watson’s 2012 acquisition of Actavis and subsequent decision in early 2013 to use the Actavis name) formed an agreement under which Amgen assumed primary responsibility for developing, manufacturing and initially commercializing oncology antibody products as biosimilars. Actavis is contributing up to $400 million in co-development costs over the course of development, including the provision of development support, and will share product development risks as well as provide expertise in commercialization and marketing for generic/biosimilar products. Based on Actavis’s 2013 annual filling, it will seek to develop biosimilar versions of Herceptin (trastuzumab), Avastin (bevacizumab), Rituxan/Mab Thera (rituximab), and Erbitux (cetuximab).

In September 2013, Hospira Inc received European Commission (EC) approval of Inflectra (infliximab), a biosimilar monoclonal antibody, for the treatment of inflammatory conditions, including rheumatoid arthritis ,ankylosing spondylitis, Crohn’s disease, ulcerative colitis , psoriatic arthritis, and psoriasis. In 2009, Hospira entered into an agreement with South Korean biopharmaceutical company, Celltrion, which is developing monoclonal antibody biosimilars. Hospira obtained the rights to Inflectra in Europe and certain CIS (Commonwealth of Independent States) countries, the United States, Canada, Australia, and New Zealand. Separately, Hospira received approvals for other biosimilars on the European market, including Retacritâ„¢ (epoetin zeta) which was launched in Europe in early 2008 and Nivestim (filgrastim), which entered the European market in 2010 and Australian market in 2011.

One alliance that did not work out was between Teva Pharmaceutical Industries and Lonza. In July 2013, Teva Pharmaceutical Industries and Lonza Group announced their decision to end their joint venture, formed in 2009, for the development, manufacturing, and marketing of biosimilars.

References
1. G. Lewis, “Pharma Transformation in Turbulent Times,” presented at DCAT Week ’14 (New York, 2014).
2. T. Fritz, C. Lightcap, and K. Shah, “Manufacturing Strategies for Biosimilars,” Pharma Manufacturing, June 12, 2012.

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