What are the driving factors behind the investments in new and expanded manufacturing capabilities in the cell and gene therapy sector?  Firstly, there is an acute shortage in existing manufacturing capacity in the cell and gene therapy development process with access for new programs at times exceeding eight months.  The current shortage has companies appreciating that manufacturing readiness needs to be at the forefront of the clinical and commercialization strategy.  We’ve already seen some companies delay commercial launches because of the lack of manufacturing capacity. Manufacturing capacity to support Phase I trials with small patient populations typically isn’t an issue.  However, as hundreds of companies move their cell and gene therapies through the development process, supporting larger patient populations in Phase III trials and commercial launches will be a challenge. 

The US FDA predicts it will receive more than 200 regenerative INDs per year by 2020. The FDA also predicts that they will be approving 10 to 20 cell and gene therapies a year by 2025, based on an assessment of the current pipeline and the clinical success rates of these products. To cope with this demand, the FDA is hiring an additional 50 clinical reviewers dedicated to these revolutionary products.¹ “The activity reflects a turning point in the development of these technologies and their application to human health,” former FDA Commissioner Gottlieb’s statement read. “It’s similar to the period marking an acceleration in the development of antibody drugs in the late 1990s, and the mainstreaming of monoclonal antibodies as the backbone of modern treatment regimens.”

There have been two predominant themes at this years’ trade shows, workshops, and at the CEO roundtables. The first theme can be summed up in this quote from Joanne Beck, Celgene Executive Vice President for Global Pharmaceutical Development: “It came as a surprise that manufacturing could play such an important role in a therapy.” In addition, many of these executives are seeing the opposite of traditional drug development, where the regulatory body spends 80% of the review focused on the clinical data and 20% on manufacturing. In the cell and gene therapy space these numbers are often inverted with 80% of the review focused on manufacturing.  The regulatory review for regenerative therapies is largely going to be focused on manufacturing and operational capabilities.

Former FDA Commissioner Scott Gottlieb noted: “One example is how we’re considering innovative trial designs whereby individual academic investigators would follow the same manufacturing protocols and share combined clinical trial data in support of approval from the FDA. This is an innovative way of making sure that small investigators who are working with cells that are being manufactured in ways that render them subject to our current laws and regulations—because the cells are, for example, more than ‘minimally manipulated’—can nonetheless seek the FDA’s approval through a less burdensome process.”   In fact, bringing manufacturing capabilities in house for later stage development is seen as a competitive advantage to some.  All too often, we’ve seen companies that have great success in an academic setting try and bring therapies to market, only to realize that they don’t have the capacity to keep up with larger demand.  In addition to pharma and biotech companies expanding their own capabilities, it’s no surprise that contract manufacturing companies, like Lonza, have made a substantial investment in their cell and gene therapy manufacturing capabilities.  In fact, last year Lonza committed to build a 300,000-square-foot location in Houston, which will be the largest dedicated cell and gene therapy manufacturing facility in the world.

The second theme revolves around the fact that the “process is the product”.  The process of manufacturing Autologous or Allogeneic therapies is complex and expensive.  For starters, the manufacturing facility must maintain GMP accreditation, which in and of itself is not easy.  Secondly, there is great variability between patients; lots; and, raw materials.  We constantly hear CEO’s talking about the need to scale out (adding new resources), not scale up (increasing capacity of existing resources).  The products companies are dealing with are living and change with each patient.  Moving apheresis products from the clinic to the manufacturing facility must be done quickly, efficiently, and with minimal risk.  Companies must understand the impact of moving these products at different temperature bands to ensure they arrive at their destination in the desired and required condition. 

The process for autologous therapies is incredibly complex due to the variability of the individual patient.  Trying to scale (leukapheresis; selection and activation; gene transfer; cell expansion; and, infusion) is difficult.  In many cases, the patient is extremely ill and the manufacturer has a limited number of chances to get it right.  They can’t afford to have a breakdown in the supply chain.  There is no room for failure.  The supply chain stake holders need to lead, or at least have a strong voice, regarding process design and standardization of the space.  We also know regulatory bodies and industry organizations are framing new guidelines governing the distribution of temperature-sensitive materials. Guidelines relating specifically to the cold chain are in place in Argentina, Australia, Austria, Bahrain, Brazil, Canada, China, The Czech Republic, Egypt, the EU, India, Ireland, Italy, Jordan, Mexico, Romania, Singapore, Saudi Arabia, South Africa, South Korea, the United Arab Emirates, the United States, Syria and Venezuela.  The Food & Drug Administration, the Parental Drug Association, the U.S. Pharmacopeia, the International Air Transportation Association and other organizations also have established guidelines for the transportation of temperature sensitive products. 

Today there are more than 800 active IND’s on file with the FDA and we’re just starting to see development of therapies targeting solid tumors.  Will today’s manufacturing capacity be able to keep up with the speed at which these products are being driven through the development process?  Today the answer is no.  However, the industry has started to adjust by making significant investments in brand new facilities or large expansions of existing locations.

There are several examples of manufacturing expansion, among them are: 
Pfizer recently announced that they will be investing an additional $500 million and adding 300 more jobs to increase manufacturing capability at their newly completed gene therapy plant on a 230-acre campus in Sanford, NC. The expansion comes only two years after the pharmaceutical company started a separate $100 million expansion of a gene therapy manufacturing facility that added 40 jobs to what is now a 650-person workforce.²

Additionally, Precision BioSciences opened their first in-house cGMP manufacturing facility dedicated to genome-edited allogeneic CAR T-cell therapies in the United States.  They believe that the facility also has the potential to be a commercial launch facility with the capacity to generate up to 10,000 doses of CAR T-cell therapies and 4,000 doses of gene therapies per year.³

Precigen, Inc., a wholly owned subsidiary of Intrexon Corp. and a clinical stage biopharmaceutical company, announced the official opening of their new manufacturing facility recently. Precigen started the build-out of the nearly 5,000-square-foot manufacturing facility in 2018.  The new facility adds to Precigen’s existing facility in Germantown, MD.⁴   

Another example of manufacturing expansion is from Iovance Biotherapeutics, a late-stage biotechnology company developing cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology. They announced the plan to build an approximately 136,000-square-foot commercial-scale production facility in Philadelphia for production of their leading therapy lifileucel.⁵

Kite, a Gilead Company, announced plans for a new facility in Frederick County, MD, which will produce innovative cell therapies for people with cancer. The 20-acre site will significantly expand Kite’s ability to manufacture a variety of chimeric antigen receptor T (CAR T) therapies, including Yescarta^®(axicabtagene ciloleucel), Kite’s first commercially available CAR T cancer therapy, and investigational T cell receptor (TCR) cell therapies being evaluated in solid tumors.⁶

Finally, bluebird bio opened their first wholly owned manufacturing facility to produce lentiviral vectors for their investigational gene and cell therapies.  The 125,000-square-foot facility currently employees 50 scientists, engineers, manufacturing and operations personal but is estimated to grow to 70 employees by the end of 2019.⁷

Additionally, contract manufacturing companies also have been expanding their footprints.  Some examples are:
 
In 2017 Brammer Bio announced the completion of renovations and the launch of their late-stage clinical capacity and commercial-ready cGMP manufacturing site in Cambridge, MA for gene therapy products.⁸
 
In Europe, MaSTherCell S.A., signed a lease for a 61,000-square-foot plant in Belgium that will be built into a manufacturing site for late-stage and commercially approved cell and gene therapy products.⁹
 
PTC Therapeutics signed a long-term lease agreement with Bristol-Myers Squibb (BMS) to gain access to approximately 185,000 square feet of space, including an existing state-of-the-art biologics production facility and supporting research and operations buildings on the BMS Hopewell, NJ campus. PTC plans to further develop the biologics facility to support future gene therapy production.¹⁰
 
The biggest takeaway from all of the above manufacturing expansion?  That the daily drum beat of companies expanding or creating their own manufacturing capabilities is growing louder and will continue for the foreseeable future as the number of clinical trials keeps increasing and as new therapies are commercially approved.  Companies that have the capacity to meet demand and are able to mitigate manufacturing risk will not only have a competitive edge, they’ll be delivering lifesaving therapies in predictable and consistent manner to meet the needs of patients.
 
 
References:
1.     https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics. 
2.     https://businessfacilities.com/2019/08/pfizer-investing-additional-500m-sanford-north-carolina/
3.     https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-opens-first-house-cgmp-manufacturing
4.     https://finance.yahoo.com/news/precigen-opens-gene-cell-therapy-200500012.html
5.     https://www.globenewswire.com/news-release/2019/05/29/1856278/0/en/Iovance-Biotherapeutics-Announces-New-Facility-to-Support-U-S-Production-of-Tumor-Infiltrating-Lymphocyte-Cell-Therapy-Products.html
6.     https://www.businesswire.com/news/home/20190424005257/en/
7.     https://www.biopharma-reporter.com/Article/2019/04/10/Bluebird-ramps-up-lentiviral-vector-production-with-Durham-Facility
8.     https://www.prnewswire.com/news-releases/brammer-bio-launches-gene-therapy-product-manufacturing-operations-in-massachusetts-300561571.html
9.     https://www.biopharmadive.com/news/masthercell-to-build-cell-and-gene-therapy-plant-in-belgium/551322/
10.  https://www.contractpharma.com/contents/view_breaking-news/2019-08-05/ptc-therapeutics-expands-in-new-jersey-by-securing-state-of-the-art-biologics-facility/