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Keeping up with the developing regulatory requirements for gene and cell therapies

By Clive Glover

Since the approval of the first five gene or gene-modified cell therapies in the US – Luxturna, Yescarta, Tecartus, Kymriah and Zolgensma – this new technology has been evolving rapidly and more recent approval applications have faced challenges.

The FDA’s requirement on Biomarin to provide an additional two years of clinical data of Valrox before approval signals an increase in regulatory scrutiny for the regenerative medicine industry.

Other safety and manufacturing events such as three patient deaths in the high-dose arm of the Audentes’ ASPIRO trial and an FDA refusal to review the biologics licence application for Bristol Myers Squibb and bluebird bio’s idecabtagene vicleucel CAR-T therapy further emphasise this point.

A crucial challenge faced by cell and gene therapy developers is the necessity to balance clinical considerations with logistical ones such as manufacturing.

Naturally, clinical considerations will always surpass logistical ones, but it is not so simple. That’s why manufacturers must guarantee the development of drug manufacturing processes that are vigorously in compliance with all relevant FDA guidance.

An example issue that the industry is facing is that drug developers are adopting different approaches to produce recombinant AAVs (rAAVs). The majority of AAV gene therapies in clinical trials are produced using transient transfection.

However, there is a challenge in scaling up such procedures, as it is not easy to maintain transient transfection consistency from batch to batch, especially at scales over 500 litres.

That’s why developers have started exploring other techniques, for example using a baculovirus with an insect producer cell, as done by BioMarin to produce its gene therapy for haemophilia.

While this provided greater scalability, using different platforms to produce AAVs could have clinical implications.When comparing rAAVs produced using transiently transfected human cells with baculovirus infected insect cells, alterations in several functionally relevant AAV characteristics are exposed, including post-translational modifications, such as glycosylation, acetylation, phosphorylation and methylation.

It is vital that any baculoviruses used to produce the AAVs are entirely removed from the final product, as any such contamination would have very adverse effects in patients. Therefore, while one may achieve higher production, the incorporation of other manufacturing steps can add complication, and therapeutic dose may also need to increase.

At the same time, any adventitious viruses that could infect the producer cells must also be removed from the final product. Although no patient has contracted a viral infection from a monoclonal antibody or recombinant protein drug to date, this is because of the vigorous procedures in place to remove the unwelcome viruses.

At the same time, cell and gene therapies that utilise AAVs and lentiviruses could face difficulty employing these processes, as it would destroy the viral vector that is either the final drug product or crucial to producing it.

Drug developers are therefore turning to other methods of adventitious virus control such as pass all incoming process liquids through virus filters. These kinds of processes will only become more important in a climate of increasing regulatory examination.

These virus filters use a membrane barrier to remove virus particles. It’s a size-based removal technique using a specially designed polymeric membrane to keep virus particles on the surface and within the pores of the membrane. The addition of viral filters to incoming media streams could help deliver a virus-control strategy that is suitable for these kinds of therapeutics.

The first cell and gene therapies were developed to treat rare and fatal diseases, which is why patients were possibly more likely to accept higher-risk treatment options.

But today’s cell and gene therapies are being produced for more common diseases, to act as therapies that go beyond the traditional approach to disease treatment.For that reason, we must create manufacturing processes for cell and gene therapies that aren’t just rapidly scalable but also guarantee maximum patient safety.

Pall is a global supplier of filtration, separations and purification products for drug developers.

Clive Glover is Director, Strategy at Pall Corporation

29th January 2021

From: Regulatory


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