Gene therapy is an emerging field and industry is yet to work out how best to manufacture these life-saving products says expert. Interest in gene therapy is growing, says Andrew Powaleny, public affairs director at the Pharmaceutical Research and Manufacturers of America (PhRMA).

“As of December 2018, the last time we did our analysis, there were 289 cell and gene therapies in development either in clinical trials or awaiting FDA approval,” he adds.

And the interest is understandable. Gene therapies let doctors treat the root causes of disease, potentially curing patients. Also judging by products like Zynteglo and Zolgensma, which cost $1.7m and $2.1m, respectively, gene therapies will generate significant revenue for firms able to commercialize them successfully.

Manufacturing issues

But manufacturing a gene therapy remains a complex technical challenge. Just ask Zynteglo developer, Bluebird Bio.

Zynteglo is designed to treat patients with transfusion-dependent β-thalassemia (TDT). Development has not always been smooth. For example, in 2017 Bluebird announced it had made “manufacturing process improvements” for Zynteglo after the product disappointed in an earlier trial. However, in June this year  it appeared Bluebird had turned things around when the EMA granted Zynteglo conditional clearance. But, in the approval presentation Bluebird announced it would not be able to launch the product until 2020.

Bluebird explained the delay was to allow it to work with the “EMA to finalize commercial drug product specifications and manufacturing parameters.” The situation changed again last month. The EMA accepted “refined commercial drug product manufacturing specifications” for Zynteglo. And Bluebird now expects the therapy to launch this year.

Similarly, Novartis, owner of the spinal muscular atrophy therapy Zolgensma, has encountered manufacturing issues.  In October the firm said the EMA and Japan’s PMDA had extended their assessments of Zolgensma and asked for more CMC information.

Emerging sector

Bluebird and Novartis’ travails are the high-profile examples, but the wider gene therapy sector faces manufacturing challenges according to Ashleigh Wake, laboratory director, Intertek Pharma Services Manchester.

“Given the newness of medicines of this type there is limited historic information available on which to build strategy and as such adds extra uncertainty to any regulatory submission,” says Wake. “When considering how to build an effective CMC for a gene therapy IND, selection of critical assays will depend on the specific product but may include assays for concentration, purity such as determination of residual cellular DNA or empty viral particles, identity, activity, potency and stability.”

Understanding which tests are critical to determining product quality is a key part of winning approval, continues Wake. “From a regulatory perspective, an understanding of the critical quality attributes (CQAs) which impact product safety, purity, and potency are required. For gene therapy products this means developing and validating analytical assays to assess, vector productivity, vector purity, biological activity and safety.”

With this in mind Intertek recently announced plans to expand its service center in Manchester in the UK.

“Our expansion in laboratory footprint and recruitment of specialists in gene therapy analytics coupled with our integrated approach to analytical method lifecycle… will mean we can develop methods which are best suited for the intended use at the various clinical stages on the way to commercialization,” he points out.

Viral gene therapies

The challenges will keep coming, according to Wake. She says therapies that use viral vectors will increase demand for quality control expertise and analytical technology.“The inherent complexity of viral vector-based products makes physical and biological characterization highly challenging,” she explains, citing the ability to differentiate between full capsids and empty ones as an example. “In order to provide a complete quality control package, a range of analytical methods and technology are required, which incorporate instrumentation such as cryo–electron microscopy, qPCR or DDPCR which are not commonly associated with pharmaceutical quality control, in addition to techniques such as HPLC or analytical ultracentrifugation.”

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