CMOs Invest in Biologics Manufacturing


From DCAT Value Chain Insights (VCI)

By Patricia Van Arnum posted 09-13-2016 15:21

  

Editor's Note: This article was updated to reflect further developments from September 2016 to end of November 2016.

Driven by new product development for biopharmaceuticals, contract manufacturing organizations (CMOs) are expanding. So what are the key projects?

In 2015, biologics accounted for 24% of global pharmaceutical sales and for six of the top 10 selling products. In 2010, small molecules accounted for 80% of the global pharmaceutical market and biologics 20%. Market estimates place biologics at near parity with small molecules in early-stage development. So what is the impact on biomanufacturing?

A look inside the biologics market
Biologics' share of the overall global pharmaceutical market has increased steadily over the past several years. The global biologic medicines market is projected to exceed $390 billion by 2020 and account for 28% by value of the total global pharmaceutical market, according to a recent report by the IMS Institute for Healthcare Informatics.In 2015, biologics accounted for 24% of global pharmaceutical sales and for six of the top 10 selling products, according to IMS. In 2010, small molecules accounted for 80% of the global pharmaceutical market and biologics 20%. By 2015, biologics had increased their share by four percentage points to 24%. In looking at the industry’s pipeline, biologics are almost at parity with small molecules in preclinical development, but small molecules continue to dominate in later-stage development (Phase II to registration) (see Table I ).

Table I: Industry Pipeline: Small Molecules Versus Biologics
Preclinical Small molecules:  689 (52%) Biologics: 645 (48%)
Phase I Small molecules: 525 (55%) Biologics: 426 (45%)
Phase II Small molecules:  731 (56%) Biologics: 584 (44%)
Phase III Small molecules: 300 (61%) Biologics: 192 (39%)
Pre-registration/registration Small molecules: 134 (65%) Biologics: 72 (35%)
Source: IMS Lifecycle R&D Focus (December 2015)

A roundup of recent activity
Led by increased product development in biologics, several contract biologics manufacturers have announced expansions for biomanufacturing, including for vaccines and other niche products. Below is a roundup of announced projects in 2015 and 2016 to date.

Avid Bioservices. Earlier this year, Avid Bioservices, a contract biologics manufacturer and part of the pharmaceutical company, Peregrine Pharmaceuticals, commissioned a second biomanufacturing facility in Tustin, California. The 40,000-square-foot biomanufacturing facility uses single-use equipment for manufacturing of late Phase III clinical and commercial production of biologics. The company is designing a third manufacturing facility dedicated to clinical manufacturing. The new clinical suite is expected to be complete and ready for clinical manufacturing activities by mid- 2017.

Boehringer Ingelheim. Boehringer Ingelheim, both a pharmaceutical company and contract biologics manufacturer, announced in December 2015 plans to invest approximately EUR 500 million ($561 million) in biopharmaceutical production at its site in Vienna, Austria, through the addition of a new large-scale biopharmaceutical production facility for active ingredients manufactured using cell cultures.The biopharmaceutical production plant will go into operation by 2021.

In Vienna, Boehringer Ingelheim has up to now produced pharmaceutical active ingredients using microorganisms; over the next few years, cell culture technology will also be transferred there. At its site in Biberach, Germany, the company has two large-scale facilities for the market launch and cell-culture-based manufacture of biopharmaceuticals. Biberach will remain Boehringer Ingelheim’s largest European cell culture and global launch site for biopharmaceutical products.

Brammer Bio. Brammer Bio, a cell and gene therapy contract development and manufacturing organization (CDMO), is investing in a build-out a 50,000-square-foot facility dedicated to late-phase development, including Phase III and commercial production of viral vector-based and cell-based advanced therapies. The facility, which will be in Lexington, Massachusetts, is scheduled to be qualified and operational by the second quarter of 2017.

Brammer Bio was founded early in 2015 following a merger with Florida Biologix to create a cell and gene therapy CDMO. The company operates process development and Phase I/II clinical manufacturing in Alachua, Florida and is building out the Lexington facility to meet Phase III development and manufacturing needs. Brammer Bio is focused on providing clinical and commercial supply of autologous and allogeneic cell therapies and viral vector products for in vivo and ex vivo therapeutic applications, along with process and analytical development, and regulatory support. Brammer Bio occupies 45,000 square feet of process development and Phase I/II clinical manufacturing space in Alachua, Florida, and is developing the 50,000-square-foot facility in Lexington with plans to build-out large-scale, Phase III/commercial ready viral vector manufacturing suites, segregated cell and gene therapy suites, and quality control and analytical laboratories for clinical and commercial launch services.

Catalent Pharma Solutions. In October 2016, Catalent broke ground for a new $34-million extension to its Madison, Wisconsin biologics manufacturing facility. When completed, the additional 22,000 square feet of space will accommodate a new 2 x 2,000-liter single-use bioreactor system, allowing the company to support late-phase clinical and commercial production of up to 4,000-liter batches. The new footprint will also support expansion of analytical and process development laboratories as well as additional office space.

Opened in April 2013, Catalent’s Madison facility houses the company’s proprietary GPEx cell-line technology used to create mammalian cell lines. Catalent provides development, manufacturing, and analytical services for new biological entities and biosimilars from the Madison facility. It was designed for flexible cGMP production, from 10-liter up to 1,000-liter scale, and non-GMP production up to 250-liter scale. It also features single-use technologies and unidirectional flow.Work to extend its integrated analytical capabilities was completed in January 2016, and Catalent has also completed investments to expand process development capability at the site, including integration of an Ambr 15 microbioreactor system into its cell line and upstream development process.

CMC Biologics. In June 2016, as part of its ongoing global manufacturing capacity expansion, CMC Biologics, a contract biologics manufacturer, completed the first stage of the expansion for its manufacturing facility in Copenhagen, Denmark with the addition of a single-use Bioreactor 3PACK facility. The Bioreactor 3PACK configuration consists of three 2,000-liter single-use production bioreactors, and associated seed train for scale-up, allowing for flexible production with scales from 2,000 liters to 6,000 liters in a single production suite. The bioreactors can be run singly, simultaneously, sequentially or in staggered fashion to achieve desired production needs. The 3PACK line was ready for production runs in June 2016.

With the combination of multiple 2,000 liters single-use bioreactors, CMC Biologics is using single-use technologies to achieve large-scale manufacturing of biologics. Three additional 2,000-liters single-use production bioreactors will be added in 2017 to complete the fit-out of a Bioreactor 6PACK line, thereby establishing identical Bioreactor 6PACK facilities in its US and European manufacturing facilities. CMC has three facilities in: Seattle, Washington; Berkeley, California; and Copenhagen, Denmark.

In July 2015, CMC Biologics completed the expansion of manufacturing facility in Bothell, Washington with the addition of a single-use Bioreactor 6Pack facility. The Bioreactor 6Pack configuration consists of six 2000-L production bioreactors and a 2000-L seed train, allowing for flexible production with scales from 2000 L to 12000 L in a single production suite. 

Earlier in 2016, CMC Biologics, and IDT Biologika GmbH formed a strategic collaboration to for the manufacture of antibody drug conjugates (ADCs). Under the pact, CMC Biologics performs process development and manufacture of the bulk monoclonal antibody, and IDT Biologika performs services from conjugation of the cytotoxic drug to the antibody substance through to the aseptic fill, finish, and packaging of the ADC final drug product. 

Fujifilm Diosynth Biotechnologies. Fujifilm Diosynth Biotechnologies, a contract biologics manufacturer, is in the process of establishing a long-term collaboration with MSD, the name for Merck & Co. outside the US and Canada, to invest in and operate a large-scale microbial biologics facility for the supply of active pharmaceutical ingredients (API) to its customers. The collaboration involves a $60-million investment by MSD at its Brinny manufacturing plant in Innishannon, County Cork, Ireland. MSD in Brinny has been in operation for more than 30 years and is an integrated site for the development, testing, and manufacturing of biologics. It is intended that the large-scale biologics operations at MSD in Brinny will be operational in early 2018 for biotech and pharma customers of Fujifilm Diosynth.

Fujifilm Diosynth Biotechnologies operates manufacturing sites in Billingham, the UK and Research Triangle Park, North Carolina. The collaboration with Merck addresses a market need for large-scale microbial biologics manufacturing and complements the company's existing microbial capacity that ranges from 100 L up to 5000 L both in the US and UK.

Fujifilm Diosynth Biotechnologies also recently completed the construction of a new three-story, 62,000-square-foot facility in Research Triangle Park, North Carolina. The new building, called BioProcess Innovation Center, houses the company’s Process and Analytical Research and Development, Process Sciences and Stability Groups. These will concentrate on delivering process development and product characterization services. In addition to its North Carolina facilities, Fujifilm Diosynth Biotechnologies has facilities in Billingham, UK and College Station, Texas.

In January 2015, Fujifilm completed its acquisition of a 49% stake in Kalon Biotherapeutics LLC, a biopharmaceutical contract manufacturing organization based in College Station, Texas with expertise in vaccine manufacturing. In addition to Fujifilm, Kalon is owned by State of Texas, acting by and through the Office of the Governor, and The Texas A&M University System (TAMUS). Kalon was founded in 2011 by TAMUS. It is a subcontractor to one of the three Centers for Innovation in Advanced Development and Manufacturing awarded by the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority to develop and manufacture medical countermeasures to protect public health in emergencies, including incidents of bioterrorism or an outbreak of pandemic influenza. Kalon’s focus is in manufacturing vaccines using mammalian cell cultures. It has the capacity to use up to 20 mobile cleanrooms (MCRs), which can be installed at the National Center for Therapeutics Manufacturing facility. The MCRs enable concurrent manufacturing of several types of vaccines.

iBio. Earlier this year, iBio was launched as a contract manufacturing organization for the development, scale-up, and large-scale manufacturing of biologicals. The company was launched as a joint venture of Bio Inc., a biotechnology company specializing in developing and manufacturing plant-based biological products, and affiliates of Eastern Capital. iBio entered into a 35-year operating lease with the Eastern Affiliates to control a 139,000-square-foot Class A life sciences building located on approximately 21 acres in Bryan, Texas. The facility, previously owned by Caliber Biotherapeutics LLC and its affiliates, and now owned by the Eastern Affiliates, is located on a technology corridor abutting the campus of Texas A & M University, home of the National Center for Therapeutics Manufacturing, a center for research in the production of vaccines and protein therapeutics.

In November 2016, iBio reported that it had completed the product development capacity expansion of its subsidiary, iBio CMO, for production of pharmaceutical proteins in hydroponically-grown green plants. iBio is currently developing several vaccine and therapeutic candidates and is expanding to the monoclonal antibody product category. The expansion enables iBio to conduct concurrent product development work ffrom laboratory-level feasibility and testing through cGMP production of active pharmaceutical ingredients for toxicology studies and Phase 1 human clinical trials.

IDT Biologika. In September 2015, IDT Biologika, a contract vaccine manufacturer and provider of fill/finish services, opened a vaccine manufacturing unit facility in Rockville, Maryland. This is the first US vaccine manufacturing facility for IDT Biologika, which is headquartered in Dessau-Rosslau, Germany.

The new facility is BSL-2 compliant and meets all US Food and Drug Administration and European Medicines Agency standards. IDT Biologika shares the 75,000-square foot building with Aeras, a nonprofit, global biotech organization developing new tuberculosis vaccines and is partnering with the nonprofit organization on process development and manufacturing of candidate tuberculosis vaccines candidates. The goal is to provide contract services to US companies for Phase I and Phase II clinical vaccine projects.<\p>

JHL Biotech. In May 2016, JHL Biotech, a contract biologics manufacturer, opened a biopharmaceutical manufacturing facility with single-use bioprocessing technology in Wuhan, China. The facility uses the KUBio manufacturing solution delivered by GE Healthcare to manufacture biosimilars and monoclonal antibodies for late–stage clinical trials and commercial supply. KUBio is a prefabricated cGMP-compliant facility and process solution designed for scalable manufacturing. The facility will also provide process development and manufacturing services for JHL’s global customer base.

JHL’s new facility in Wuhan has the same standardized GE FlexFactory technology as its existing site in Taiwan, which allows it to scale up to a capacity of 2,000 liters. The JHL Center of Excellence in Taiwan does biosimilar pre-clinical and early-clinical phase R&D work. JHL’s facility in Wuhan, China will do commercial-scale manufacturing of biologic therapies. JHL Biotech provides cell line cloning, process development, and manufacturing capabilities and services.

Lonza. In January 2016, Lonza announced an expansion of its mammalian production capacity at its facility in Slough, UK. Two 1000-L single-use bioreactors will be installed at the site. This expansion will increase the existing single-use manufacturing capacity in Slough while allowing current operations to continue without interruption. The additional mammalian manufacturing capacity is now available. Lonza’s cGMP facility in Slough is the center of excellence for development and clinical supply. The site provides cell-line construction, process development, and clinical manufacturing services for mammalian-derived biotherapeutics.

In July 2015, Lonza announced plans to construct a new 100,000-square-foot facility for viral and immunotherapy development and manufacturing in the Houston, Texas area, complete with a segregated fill/finish suite. This new facility will more than double Lonza’s capacity for the production of viral gene and virally modified therapeutics. The multipurpose facility is expected to come on line in the first half of 2017 and will include eight independent cGMP modular cleanrooms for 2,000 L-scale production in single-use bioreactors. Grade-B cleanrooms will also be constructed to continue the manufacture of European Medicines Agency-regulated cell therapy products. The site master plan includes expanded process development and quality-control areas, shell space for future additional cleanrooms, and land for further potential expansions.

MilliporeSigma. In May 2016, MilliporeSigma announced an expansion of its Carlsbad, California facility for viral and gene therapy products. Scheduled for completion in 2016, the Carlsbad campus will increase from 44,000 square feet to 65,000 square feet, with 16 modular viral bulk manufacturing cleanroom suites, two fill/finish suites and twice the warehouse capacity. The expansion will incorporate single-use equipment in a flexible, scalable format for clinical and commercial bulk drug production.

The Carlsbad facility, MilliporeSigma’s flagship site for SAFC's viral and gene therapies offering, will remain fully operational throughout the expansion. MilliporeSigma gained the facility through its $17 billion acquisition of Sigma-Aldrich in 2015, which included Sigma-Aldrich's SAFC business. The company’s new capacity at Carlsbad positions MilliporeSigma to offer services at the clinical to commercial scales and is complemented by cell-banking services in Rockville, Maryland, viral and gene therapy manufacturing capacity in Glasgow, Scotland, and global biosafety testing by BioReliance.

In a separate expansion for its life-sciences business, MilliporeSigma plans to build a new campus in Burlington, Massachusetts that will serve as a major hub for the North American life science business of Merck KGaA, Darmstadt, Germany. The 280,000-square-foot facility will include a customer collaboration laboratory and training center as well as office space.

The campus will house both a customer service and call center and an M Lab Collaboration Center, a shared exploratory environment where the company’s scientists and engineers work together with customers. The M Lab Collaboration Center will be one of nine centers worldwide created specifically for collaboration, where hands-on training, customer experiments, and application troubleshooting take place in a non-GMP environment. Other locations will include Brazil, China, France, India, Singapore, and South Korea. This new enhanced M Lab Collaboration Center in Burlington will replace the flagship M Lab at the company’s facility in Billerica, Massachusetts. MilliporeSigma’s 850 full-time Billerica-based employees will relocate to the new campus when construction is complete in the second half of 2017.

The five-story, single-tenant building in Burlington includes an opportunity to expand an additional 70,000 square feet. Merck KGaA, whose life science business operates as MilliporeSigma in the United States and Canada, leases the property. MilliporeSigma will maintain its other North American life science hub in St. Louis, Missouri.

Samsung BioLogics.  Samsung BioLogics is investing a total of KRW 850 billion ($776 million) in building its third biopharmaceutical manufacturing plant in the Incheon Free Economic Zone in Songdo, Korea. The plant is expected to be completed in 2017, with operations scheduled to begin in the fourth quarter of 2018 after validation. The plant will have a capacity of 180,000 liters. Once this third plant is in operation in 2018, Samsung BioLogics is expected to have a total production capacity of 360,000 liters.

Rentschler Biotechnologie. Rentschler Biotechnologie, a Laupheim, Germany-based contract development and manufacturing organization for biopharmaceuticals, reported in November 2016 that it opened a new single-use bioreactor at the company’s site in Laupheim with a capacity of 2,000 liters. This expansion follows an expansion of cGMP manufacturing capacity recently, which put into operation a twin system of two 3,000-liter stainless-steel bioreactors.In combination with its first 2,000-liter single-use bioreactor put into operation in 2015, Rentschler now has two 1,000-liter and two 2,000-liter single-use manufacturing systems.

Samsung BioLogics is also planning an initial public offering (IPO) on the Korea Composite Stock Price Index (KOSPI) this year, following a resolution at its board of directors. The company will select lead managers for the IPO in September 2016 to decide on the timing of the listing and the volume of shares to be offered.

WuXi AppTec. In January 2016, WuXi AppTec Co. Ltd., a contract service provider and technology platform company, started construction of an integrated biologics solution center at the company’s headquarters in Shanghai, China. The company plans to invest a total of $120 million in this dedicated, 250,000-square-foot facility, which will be operational in 2017 and accommodate 800 scientists. The biologics development center of the project will use WuXi’s proprietary Chinese hamster ovary (CHO) cell line platform to develop fed-batch and perfusion processes. The co-located cGMP clinical manufacturing facilities will support four concurrent campaigns using 3 x 2000-L fed-batch and 2 x 500-L perfusion bioreactors.

In May 2015, WuXi Biologics, a wholly owned subsidiary of WuXi PharmaTech (Cayman) Inc., began construction on a new $150-million biologics manufacturing facility in Wuxi, China.The new mammalian cell-culture manufacturing facility will use disposable bioreactors. The new facility is to be completed by January 2017 and will house fourteen 2000-L disposable bioreactors for fed-batch cell culture and two 1000-L bioreactors for perfusion runs. The facility will also be built to run advanced continuous or semi-continuous manufacturing processes in addition to traditional fed-batch and perfusion modes.

The facility further expands WuXi's biologics manufacturing capabilities. In August 2012, WuXi completed a biologics clinical drug substance and drug product manufacturing facilities in Wuxi. Since then, the facilities have ramped up to produce clinical supplies for the US, European Union, China, and other markets.

In October 2016, WuXi AppTec, opened a new 150,000-square-foot biomanufacturing facility for cell and gene therapies in Philadelphia. The facility is designed for cell-therapy products that use viral vectors such as chimeric antigen receptor T cell (CAR T cell) therapies. The facility will also permit expansion of viral-vector manufacturing to support gene therapy clinical and commercial programs and will permit large-scale production in 2,000-liter single-use bioreactors. When fully configured, the new facility could employ an additional 200 manufacturing and support staff. The facility supplements WuXi's existing 20,000-square-foot cGMP cell therapy manufacturing facility as well as a 50,000-square-foot facility for the commercial manufacturing of allogeneic and autologous cell-based therapeutics.

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