Emily Moran - Vice President, Viral Vector Manufacturing, The Center for Breakthrough Medicines (CBM)
Biotechnology has changed the face of pharmaceutical discovery, research, and development by replacing small molecule drugs with macromolecules produced in cultured cells and microorganisms. Through an equally monumental paradigm shift, Cell- and Gene-Based Therapies (CGTs) represent the next generation of biotherapies in which, rather than serving as expression systems, the cells and genetic constructs themselves become the therapy.
CGTs both involve the transfer of a novel gene or genes into patients. Gene therapy does this directly, by inserting new genes in vivo. Cell-based treatments harvest a patient’s cells (typically immune system cells), genetically modify them ex vivo, then re-introduce them into the patient.
Although the U.S. Food and Drug Administration has only approved 23 cell and gene therapies, more than 1200 such treatments are currently undergoing clinical evaluation (about 10% in phase 3), with thousands more at discovery and preclinical stages. This unprecedented surge in interest in CGTs has created a significant gap between the needs of the industry and the skilled resources available.
The manufacture of CGTs, moreover, tends to occur near patient centers at several (or many) smaller facilities instead of at mega-plants. Production tends to be decentralized, with many smaller teams and operations, thus adding to the already formidable technical and logistical complexity.
To succeed in this marketplace, therefore, developers must attract, cultivate, train, and retain talented, motivated individuals to form high-functioning production teams.
Where Do We Start?
Most individuals enter the biomanufacturing workforce directly from high school or via undergraduate, graduate, and post-graduate academic laboratories.
Most academic training environments focus on bioprocesses involving mammalian or microbial cell cultures as the central upstream unit operation, at “typical” scales of 5-100 liters for development and 100-plus liters for clinical supply and post-approval production. The principal downstream unit ops are chromatography and filtration.
Since production scales for CGTs are typically much lower than for therapeutic proteins, and cells or gene delivery systems are the product, trainees entering emerging biotherapy markets require a different skill set compared with someone applying to a generic “biotechnology company.” Training programs must include preparation in the unit operations involved in CGT production, e.g., cell expansion and harvesting, transfection, viral vectors, cold chaining, cell analysis, process analytics, Quality by Design, etc. It must also go beyond basic technical expertise to include the core aspects of current Good Manufacturing Practices (cGMPs), in particular aspects related to documentation, contamination control, data integrity, automation, and operating protocols.
Essential Skills
As academic skills catch up with current industry needs, degree and certification programs need to stress not just the acquisition of specific scientific skills, but a greater appreciation for regulatory compliance and “good practices” on which trust in our medical system depends. These include:
Good Laboratory Practices (GLPs): FDA defines GLP as “a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.” The objective of GLPs is to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of laboratory results.
Good Manufacturing Practices (GMPs): GMPs are wide-ranging guidelines for manufacturing human and veterinary drugs. The objectives of GMPs include risk minimization, product consistency, process control, and ultimately, Quality by Design. GMPs cover all aspects of production from ingredients, production facility, equipment, and personnel training—anything that may affect the quality of the finished product.
Good documentation practices: Documentation of laboratory or production results, although not an official FDA designation or initiative, is defined as “measures that collectively and individually ensure [that] documentation, whether paper or electronic, is secure, attributable, legible, traceable, permanent, contemporaneously recorded, original and accurate. FDA has published extensively on data compliance particularly, with respect to electronic data, through CFR Part 11.
Automation: Most bio-industry workers first encounter laboratory and process automation on the job, requiring rapid education with a steep learning curve. Automation has long been viewed by companies as a necessity rather than a luxury, but the same has not been true for academic laboratories. If we are to industrialize CGT-related processes to reduce cost of goods and make these therapies available to more patients, this must change. As more companies migrate to a “Biopharma 4.0” environment, process automation and machine learning will become a critical skill, required in facility design and operation.
Data capture and management: Commercial laboratories, including service groups at biotech companies, now routinely employ Electronic Laboratory Notebooks (ELNs), Laboratory Information Management Systems (LIMSs), and data capture/entry and process monitoring via portable, cloud-connected devices. As with automation, these are viewed as luxuries in academic labs. At commercial scale, the incorporation of automation into an overarching Enterprise Resource Planning system will further improve and simplify the supply chain and preserve a favorable bottom line.
Ongoing training: Academic programs tend to be transactional and heavily geared towards acquiring specific credentials: a PhD or B.S. degree, or specific skill sets (e.g., “HPLC”). The problem with this model is, that it is dead-ended by design. Skills rapidly become outdated as laboratory and manufacturing technologies evolve and may even become obsolete in the face of paradigm-shifting events such as CGTs. The key to retaining employees, then, is to make them more valuable within your organization by encouraging (or even requiring) continuing education. Ongoing training imparts essential skills and also tends to improve worker loyalty.
Excellent resources exist for initiating and promoting continuing education through academic-industry partnerships, for example the National Institute for Innovation in Manufacturing Biopharmaceuticals, and the National Institute for Bioprocessing Research & Training.
Conclusion
From the production floors to analytical labs and everything in between, CGTs are changing the face of biotech. Companies hoping to staff CGT programs face shortages related to reduced enrollment across higher academia, plus the inevitable lag in the acquisition of appropriate hands-on skills. To assure their graduates can compete in this fast-changing environment, biotech training programs must prepare its graduates for both operational and regulatory competence—through training experiences that more closely represent their eventual work environments.
Author Biography
Ms. Moran is an experienced leader in cell and gene therapy and biologics manufacturing – with a focus on commercial readiness, industrialization, and manufacturing stabilization. Ms. Moran is experienced in Viral Vector Manufacturing, aseptic processing, upstream and downstream technology, supply chain and demand planning, quality auditing, and facility and organization while employing lean manufacturing standards. Prior to CBM, Ms. Moran was the Head of Viral Vector Manufacturing for Lonza in Houston, Texas, prior to Lonza, Emily worked in multiple areas of operations at Sanofi Pasteur.
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