Cell and gene therapy makers have suffered manufacturing setbacks, but experts working in the supply chain say ensuring high quality raw material is the key to success.

Manufacturing issues have plagued the few advanced therapies to have made it to the market. Dendreon’s Provenge (sipuleucel-T) suffered from high complexity of manufacturing and administration, Novartis’ Kymriah (tisagenlecleucel) saw some variability in its product specifications, and – most recently – Bluebird Bio has been accused of lacking manufacturing readiness for its recently approved gene therapy Zynteglo (autologous CD34+ cells encoding βA-T87Q-globin gene).

To overcome these sorts of issues in cell and gene therapies, industry needs to ensure a high quality of raw material, according to Dominik Clark, global head of Cell Therapy at HemaCare.

Image: iStock/Canan turan

Speaking with Bioprocess Insider at the Phacilitate conference earlier this year, he said that what you start with ultimately impacts the manufacturing process for that therapy, and therefore the final product.

“The starting material is perhaps the most important, most critical part of the cell and gene therapy process,” he continued, adding that when it comes to cell and gene therapies, “garbage in equals garbage out.”

10 to 140 billion cells

At the same industry event in Miami, Thomas Heathman, business leader at Hitachi Chemical Advanced Therapeutics Solutions (HCATS) agreed with Clark’s point, adding that quality and consistency needs to begin at the collection point as this is when production can be best controlled.

He said that his firm, a cell therapy contract development and manufacturing organization (CDMO), can handle any starting material but the lower the quality, the less consistent the product becomes. This inevitably leads to higher manufacturing complexities and higher costs for the end-user.

Over a three month period, Heathman said his firm received starting materials with total nucleated cell counts (TNCs) varying from 10 billion to 140 billion cells/unit.

“At the top end, this is not such an issue [though sometimes this needs to be reduced to save viral vector wastage further on in the manufacturing process] but at the bottom end this creates a big risk of not being able to manufacture the product appropriately.”

Any variation of the incoming product will become compounded over time, especially if preservation methods are not utilized, which leads to a “huge knock-on effect” along the whole process, increasing the number of manufacturing deficiencies, he continued. And from an operational standpoint, this can also lead to the “nightmare” of scheduling resources such as personnel and clean room space, especially when juggling numerous products as a CDMO might.

But there is good news, he added, as methods to help maximize the potential of the starting material are being utilized. These include the use of specific collection containers, reagents and environmental controls, though Heathman stressed the importance of good communications between clinical sites, the manufacturer and logistics provider to help ensure product success.