How Do You Define Manufacturing?
By Louis Garguilo, Chief Editor, Outsourced Pharma
“When an executive at a cell-therapy company talks about ‘manufacturing,’ is it the same animal as when an executive of a small-molecule company uses the word?”
As I’ve learned, it’s worth the risk of what sounds like an uneducated question.
In fact, Bone Therapeutics CEO, Miguel Forte, who we met in part one, provides a compelling reply:
“Manufacturing always needs to mean the same thing.”
“It’s always the same concept – reliably achieving a GMP-quality product.”
He adds: “And I think this is an important, fundamental point.”
Insert Meaning
Adherence to meaning, and achieving that meaning, is where variances enter, and must be carefully considered.
Forte explains differences in these terms: small molecule products are ‘unidirectional,’ biologics ‘bi-directional’ (or two dimensional), and cell therapy ‘three dimensional,’ because characterization is more complex in a living entity.
“If you have a statue,” says Forte, “the characteristics won't change. If you have a living being the characteristics do. Nonetheless, you should always be able to recognize and identify that being.
Of course readers understand this as “characterization” of the key common attributes that define your product, and the ability to reproducibly and consistently achieve them.
“In terms of quality and GMP,” says Forte, “this is manufacturing.”
“I agree complexity is different, but the principle remains. I believe it is important to educate, and demystify the differences while acknowledging the complexity."
But what of the materials sourcing component?
With small molecules, it's raw materials, starting materials, APIs – these often procured and produced for you by your CDMO. Isn’t this a key differentiator from cell (or gene) products?
Again, the risk of the question spurs serious analysis.
“An interesting point as well. Part of that added complexity is the sourcing of material,” says Forte. “Obviously, in the case of autologous, cells – materials – derive from the patients you identify, and those go through a manufacturing process. Yes, there is batch-to-batch variability because each individual batch goes back to a specific patient."
That's important, he adds, because the process and the characterization should be applied to each batch understanding you have that additional element of variability.
With allogeneic, says Forte and as readers know, sourcing starts with healthy donors and offers more opportunity to “standardize your donor elements.” You begin with a reduced variability – although you still have the aforementioned variability of working with living organisms.
“However,” Forte finishes here, “acknowledge the variability within that reduced variability,” and manufacture with the same meaning and goals.
A Nod To The Future
Like others, Forte foresees the industry moving beyond one-batch / one-donor (allogeneic), to one-cell-source (namely, induced pluripotent stem cells [iPS cells]) / multiple (if not nearly indefinite) numbers of batches.
“That's where the field is moving. There's a lot of interest in iPS cells, because you address this ability to go from autologous to allogeneic, and now to a sourcing that enables you virtually an infinite level of production.
“And to your original point,” he remarks, “we are progressively reducing the variability of the sourcing material, making it easier to achieve the definition of manufacturing. Probably 70% of the regulatory discussions today are about CMC, manufacturing, and characterization.”
He adds: “Clearly, some cell therapies are challenged with satisfying the FDA and others you have control of your product, source material, characterization and manufacturing reproducibility.”
Despite those challenges, Forte is fully committed to the harnessing of this industrial proposition, and understands it is essential to defining manufacturing forever forward.
“We should not be complacent and say, ‘Well, cell therapy is different.’
“Yes, there are elements of variability impacting our ability to reach that traditional meaning. So we have to intentionally build that into our efforts; fit our industrial propositioning of cell and gene therapy in the traditional perspective of identifying the characteristics of your product, controlling your manufacturing process, establishing the quality, and delivering a consistent product.”
Final Words
Any final thoughts before closing? is my final question.
“I’d like to express for your readers some experiences, and the witnessing of how until the present time the advantages of MSCs have been amateurishly utilized,” he replies.
Mesenchymal stem cells (MSCs) are derived from various sources; researchers are increasingly aware of potential uses. According to PubMed Central, MSCs can self-regenerate, differentiate into several cell lineages, and participate in immunomodulation: “MSCs have become a promising tool in developing modern and efficient future treatment strategies.”
Forte continues: “In the first iterations, these cell therapies have shown value, but not sufficient value. I think MSCs have an opportunity to be more professionalized.”
“We need to prepare future workers at university, instead of learning about MSCs on the job. For example, we want to improve MSCs ability to control inflammation. If you talk about COVID and lung inflammation, MSCs have been used, and shown activity, but again, that activity has not been optimized.
“In terms of professionalizing MSCs, Bone Therapeutics is focusing on not only bone marrow sourcing, but also from [the above-mentioned] iPS cells. These provide us manufacturing advantages – higher consistency, easier processing, and an opportunity to gene-modify at the earliest stage. This is in our DNA, no pun intended. The industry should be looking to do this for immunomodulation and other indications.”
And when Forte says “the industry,” as we clearly learned in part one, he by necessity includes CDMOs and other service providers. These partnering organizations need to join the discussions and help implement – and can in fact lead in many cases – the innovations taking place within today’s drug industry.
Because the industry stalls when manufacturing meaning cannot be applied across all our models of drug and therapy outsourcing.