From the Editor: Advanced Therapies

PHOTO COURTESY OF THE CELL AND GENE THERAPY CATAPULT (HTTPS://CT.CATAPULT.ORG.UK)

This special summer issue serves as an “expression platform” for as many different industry voices as we could squeeze in between our front and back covers. To get even more points of view than our authors could provide, we used a reader survey. With a focus on cell and gene therapies (CGTs), the results elucidated in this section continue to outline broadly the current working environment of some 200 BPI readers.

Herein, consultants from Latham BioPharm Group and Apprentice.io present a vision for the future of smart technologies in good manufacturing practice (GMP) production of advanced therapies. Also, Matthew Durdy describes the important role that innovation organizations such as the Cell and Gene Therapy Catapult can play in building just such a future. And we welcome our section sponsor, Sartorius, to share this space with us.

But first, we summarize some answers from respondents to our reader survey who are involved in advanced-therapy work — and, as elsewhere, thank them for their participation in this “expression platform.” Note again that percentages are rounded to the nearest whole number, and some questions allowed for “check all that apply.”

Your Voice Here

Demographics: About 39% of our survey respondents said that their companies have at least some programs for CGTs, and 20 of those were CGT “specialist” companies (with no programs for antibodies/proteins, but some of them have programs for vaccines and oligos/mRNA). Another 10 respondents work for companies that address CGT facilities, engineering, and technology concerns. And 18 respondents represented companies with programs for regenerative and tissue therapies.

Because our survey had no dedicated CGT section, the responses described below are drawn from across the upstream, downstream, analytical, and business sections. Although we can’t be certain that the responses come from people who work directly with CGTs, we can be confident that their organizations do and that they are likely to have more than basic familiarity with CGT workflows. Most of them are managers, executives, and scientists/engineers in chemistry, manufacturing, and controls (CMC). A few work in quality functions, analytical/formulation, drug discovery, marketing, information technology (IT), and other areas. And in general, the larger trends that we observed in the other parts of our survey for each area were paralleled within this smaller subgroup.

Supply-chain concerns continue to persist, at least “somewhat” (the most commonly chosen answer) — particularly for culture media/supplements and single-use supplies (especially connectors), as would be expected for people working on advanced therapies. Timely delivery of ordered materials came across as a key problem. As expected, CGT respondents were the only ones in our survey who reported using serum-containing culture media, but most showed the same preference for serum-free, xeno-free media, animal-origin–free, and chemically defined media as respondents working with other biologics. Supply-chain concerns also were raised for formulation excipients/adjuvants and drug-product containers, which did not figure highly overall — suggesting that they may be more of a concern for advanced-therapy operations.

“For cell-culture media and supplements,” one reader said, “lot-to-lot variation and cost increases are the main concerns for CGT developers. Single-use components are often customized and [single-vendor] sourced. End users rely on vendors for continuous supply.”

Next-Generation Technologies: Most CGT respondents saw potential in artificial intelligence (AI) even if current adoption is relatively low. Automation seems to be more widely implemented, having advanced enough to provide improvements in process efficiency for some companies. That said, some CGT respondents noted difficulties with implementing automation. So far, it’s more likely to help streamline operations without affecting head count than to enable companies to get the same amount of work done with fewer people.

According to our CGT respondents, process intensification usually is taken into consideration but may not be a key goal for all operations. It also is more likely to be built into new processes than reverse-engineered into legacy ones — and most CGT processes are new. And environmental sustainability was somewhat of a priority for most CGT companies represented in our survey.

Regulatory concerns seem to be the biggest barrier to adoption of industry 4.0 principles and technologies. Most CGT respondents also noted the importance of management buy-in and addressing fears of the steep learning curve associated with requisite software. Identifying and training sufficiently qualified staff to work in a manufacturing 4.0 environment seems to be standing in the way, as well.

Analytics and Product Development: Among CGT analytics, immunoassays reigned supreme in our survey. Spectroscopic and PCR methods tied for second place — outpacing the chromatography–mass-spectrometry combination that’s making itself so useful in the protein world. Unsurprisingly, one respondent highlighted flow cytometry as an important analytical method for CGT-related workflows. All respondents highlighted challenges relating to the lack of available control/reference standards, and limited sample availability also figured strongly. Compared with companies developing protein drugs, advanced-therapy developers seem to be facing more problems with assay validation and qualification, which present unique challenges for their products. Robustness and reproducibility of CGT-specific assays were of some concern.

Advanced-therapy developers may be more likely than classical biopharmaceutical sponsors to explore potential combination-product options. But they share similar concerns over stability studies — perhaps even more so, considering the delicate nature of CGT and regenerative-medicine products. CGT respondents report encountering more difficulties finding CDMOs with the necessary expertise (and timeslots) to work on their projects.

Working Together: Few CGT respondents said that their companies perform all analytical activities in house. Clinical and preclinical laboratory testing seem to be most outsourced, but much process development work is as well. Most companies have forged licensing/partnering agreements with others. Those tendencies suggest that many of our CGT respondents hail from smaller companies that rely more on outsourcing. Companion diagnostics are a popular type of collaborative project.

The most frequent regulatory concern among our CGT representatives related to the lack of harmonization among guidance documents across jurisdictions. Respondents also highlighted high costs and required documentation associated with requisite testing, which have been perennial complaints throughout the biopharmaceutical industry. But the differences between US and European approaches to advanced therapies — beginning with their choice of regulatory monikers for such things — are widely recognized. And the rest of the world only complicates matters. Clearly, ambiguity and inconsistency at least somewhat characterize the current regulatory landscape for cell, gene, and tissue therapy developers.

Editors’ Perspective

Our August eBook will focus on autologous cell-therapy manufacturing, and our October featured report will address gene therapies. Look for more advanced-therapy themes early in 2025 — and we welcome your input on best analytical practices and how to negotiate the regulatory and technological hurdles encountered in developing these products.