Cell source, reagents and validation key to FDA; Novocell, Lonza outline their methods.(Stem Cells)

ATLANTA -- Manufacturers seeking to market therapeutics from stem cells should focus their efforts on building quality into the product through the consistent control of cell source, reagents, facility, personnel and equipment, and the validation of manufacturing process, aseptic processing, and test methods, a top Center for Biologics official told BIO May 19.

And, Kimberly Benton, Ph.D., deputy director, Division of Cellular and Gene Therapies Office of Cellular, Tissue, and Gene Therapies, also said that abiding by general biologics standards will go a long way.

In her presentation, Benton admitted that "flexibility is needed for diverse and novel products in evolving fields," and noted that "cell therapy and gene therapy products--and therefore stem cell products do not lend themselves to a one-size-fits-all concept of product development and regulation."

She directed manufacturers to focus their efforts on building quality into the product through the consistent control of cell source, reagents, facility, personnel and equipment, and the validation of manufacturing process, aseptic processing, and test methods.

When asked about FDA's guidance on checking the stability of cells Benton said: "We don't have a guidance for stem cells, but we do have guidance for biologics ... we don't have any specific criteria, but we're looking at it." She also offered that, unlike health agencies in other countries, FDA doesn't put guidance out until they have specific experience in that area.

She said FDA recommends adherence to general biologics standards (21 CFR 610) and Benton noted that stem cell products currently fit regulatory definitions of:

* Human cells, tissues, or cellular and tissue based products (HCT/P) (21 CFR 1271.3(d))

* Biologics (PHS Act)

* Drugs (FDC Act)

* Cell therapy

* Gene therapy, when genetic material is transferred to cells ex vivo

A common thread in the stem cell discussion was the regulatory and manufacturing challenges presented by attempts to scale up. According to Benton: "Cell manufacturers should strive to develop a manufacturing process that will consistently yield a safe, pure, potent product and at the scale you anticipate for commercialization."

Allan Robins, Ph.D., chief technical officer at Novocell, said the first challenge to scalability is "to scale up while maintaining the comparability of living cell products." He also said that increasing scale up capabilities is an area of focus for Novocell because "current technology yields small batches of cells appropriate only to treat a limited number of patients." Novocell's goal is to establish scalable manufacturing systems to support "hundreds of thousands of doses per year by 2012-14."

In further discussion on the scale up process and accompanying testing, Jon A. Rowley, Ph.D., director of cell therapy research and development for Lonza, compared allogenic and autologous cell sourcing and commented: "Efficiencies of scale can be applied to allogenic cell sourcing," but both methods are very expensive and require testing. From FDA's perspective, donor testing and screening is recommended for autologous donors, and for allogenic donors Benton referred to 21CFR Part 1271 Subpart C for guidelines on donor screening, which involves medical history interview, physical assessment and medical record review.

Establishing methods to account for and control individual donor variability is also a concern for manufacturers and regulators. "We can't expect there won't be any karyotypic variability, but at what level we can tolerate it is something we're still grappling with," admitted Benton while Robins offered that when Novocell makes large cell banks very early in the life of a cell line, the karyotype will remain stable in 20 or 30 passages. He then commented that "epigenetic stability is something we're starting to look at. [We have] very little info about epigenetic stability."

Expounding on current challenges, Robins said, "For us, working out what are pre-clinical studies that need to be done and for FDA, working out whether that shows safety, is an issue we need to work through ... One of the biggest issues is the fact that we can't do classic PK and PD studies on cells like we do on little white pills. There are not very many good animal models to do transplant models; we're limited with human cells to put in rats to test efficacy and long-term safety." PK stands for pharmacokinetics and PD is pharmacodynamics.

Testing also becomes an issue, from FDA's perspective, when a phase of manufacturing is outsourced. A manufacturer stated intentions to conduct phases one and two in-house, but move phase three to a contract manufacturer, to which Benton cautioned: "Normally FDA is comfortable with a manufacturing site change between phases, but do it before phase three so clinical trial data will correlate with final manufacturing." She explained that it was an issue of comparability. "Our level of comfort when making a site or manufacturing change needs to be supported by testing... will have to do more data gathering in animal studies or clinical studies."

To resolve challenges of stem cell manufacturing, FDA will continue working with stakeholders to exchange information via advisory committees, regulations, guidance documents, public workshops, liaison meetings, and international harmonization activities.

By Tara Y. Coyt

Atlanta Correspondent

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