Cell and Gene Therapies: Challenges in Scale-up to Commercial Manufacturing

The cellular therapy and gene therapy fields are undergoing very rapid growth. This includes a large and growing number of products in the development pipeline, and new products with significant sales, including blockbusters, now entering world markets. Billions are being invested in research and commercial development with markets in $10s of billions expected in the next 5-10 years. However, various major challenges, most associated with commercial manufacturing, need to be addressed for cellular and gene therapies to fully attain their potential. These findings have been confirmed by BioPlan Associates’ annual global survey of bioprocessing professionals ⁽¹⁾. Note, gene therapy is often included with cellular therapies, since a large percentage of cellular therapies in development include genetic modification and also involve gene therapy, usually requiring separate manufacture of viral vectors.

AREAS WHERE CELLULAR THERAPY MANUFACTURING FACES CHALLENGES:

Basic Approach: Most cellular therapies in active development are autologous, using the patient’s own cells. Manufacture of these products is done on a one-patient-product-at-a-time basis. This is obviously inefficient and costly; often with one patient’s product taking up a full cleanroom or biosafety cabinet for 1 or several weeks. Many products will remain such individually targeted and manufactured. But most innovators indicate they currently would seek to shift to allogeneic manufacturing, with cells cultured to produce multiple patient treatments. Most cellular therapies will seek an allogenic direction at some point.
Technology: Most cellular therapy manufacturing involves cell culture technology that has changed little in decades, requiring manual handling of cells at many stages, with negligible automation. Most cellular processing is performed in ‘open systems’ at much lower levels of sterility and aseptic fluid transfer compared to conventional ‘closed system’ bioprocessing using connected and sealed process lines. Gene therapies, particularly their core viral vector technologies, are in a much better position, with allogeneic viral vector-infected cell culture in bioreactors much the same as with conventional recombinant protein manufacture.
Scales: Even allogeneic cellular therapy manufacturing has its own limitations. Relatively large amounts of cells are generally needed for cellular therapies, with even allogeneic manufacturing having severe limits, such as at most 10s of patient treatments being cultured at a time even in if scaled-up to larger bioreactors. Similarly, large amounts of viral vectors are needed for gene therapies, with even their manufacture in >100 or 1000 L bioreactors often only producing enough for dozens of patients. Without major advances in technology, commercial cellular therapies manufacturing will generally involve scaling-out, running multiple process lines in parallel, rather than scaling-up with larger bioreactors and associated equipment.
Facilities: There already is a shortage of cellular and gene therapies manufacturing capacity, with needed process lines and facilities simply not existing ^(2,3). There is currently a significant shortage of relevant capacity, with 5x additional capacity needed (would be used if available), and this expected to worsen as more products advance in development and enter the market. The 17th annual BioPlan survey reported that 44% of respondents expect to increase their cellular/gene therapies manufacturing capacity by ≥100% over the next 5 years (see Fig. 1)

OURCE: 17TH ANNUAL REPORT AND SURVEY OF BIOPHARMACEUTICAL MANUFACTURING, BIOPLAN ASSOCIATES, INC. ROCKVILLE, MD APRIL 2020

Staffing: Cellular therapies manufacturing is very labor-intensive, generally requiring highly trained and experienced staff. But there are dire shortages and problems hiring bioprocessing professionals, with those with cellular therapies experience even further limited. Our study shows hiring is already creating a serious set of bottlenecks, and this challenge will only increase in coming years, in nearly all areas of bioprocessing.
Competition: Cellular therapies must now deal with new competition for facilities, staff, etc., including $billions rather suddenly being invested in manufacturing of pandemic vaccine and therapeutics ⁽⁴⁾.
Despite its potential to dramatically improved healthcare, cellular therapies face a number of challenges in actually being manufactured and, related to this, being available and affordable. Over one-half (52.9%) of BioPlan survey respondents expect that in 5 years cellular/gene therapy manufacturing will have significant shortages of manufacturing capacity and bottlenecks.

By guest blogger
Ronald A. Rader
Senior director, Technical Research
BioPlan Associates, Inc. Rockville, MD USA
+1 301-921-5979

^{REFERENCES CITED:}

1. _{LANGER, E.S.., ET AL., BIOPLAN ASSOCIATES, 17TH ANNUAL REPORT AND SURVEY OF BIOPHARMACEUTICAL CAPACITY AND MANUFACTURING, BIOPLAN ASSOCIATES, APRIL 2020, 528 PAGES (CLICK HERE OR SEE WWW.BIOPLANASSOCIATES.COM/17TH).}
2. _{RADER, R.A., ET AL., TOP 1000 GLOBAL BIOPHARMACEUTICAL FACILITIES INDEX, WWW.TOP1000BIO.COM.}
3. _{RADER, R.A., CELLULAR AND GENE THERAPIES FACE A MANUFACTURING CAPACITY CRUNCH,” BIOPHARM INTL., SEPT. 1 2020, P. 46-50}
4. _{RADER, R.A., LANGER, E.S. AND JHAMB, K., COVID-19 IMPACT ON BIOPROCESSING: ACCELERATING TRENDS AND LONG-TERM IMPACT OF NOVEL CORONAVIRUS-19 ON BIOMANUFACTURING AND BIOPROCESS SUPPLY CHAINS, WHITE PAPER, BIOPLAN ASSOCIATES, 16 PAGES, JULY 2020 (HTTPS://BIOPLANASSOCIATES.COM/WP-CONTENT/UPLOADS/2020/07/COVID-19-IMPACT-ON-BIOPROCESSING-WHITE-PAPER-BIOPLAN-20200605.PDF).}