By Clive Glover, PhD

Clive Glover
Clive Glover, PhD
General Manager, Gene Therapy
Pall Life Sciences

Gene therapy is a fast-growing sector in the life sciences industry, and there are countless reasons to be enthusiastic about it. The fact that we can use specific gene-modifying technology to amend genetic disorders and provide patients with such impactful treatment is amazing. However, we’re still a long way from seeing gene therapy products being manufactured in quantities needed to meet patient demand. One of the greatest challenges is how to scale up the manufacture of gene therapy products to industrial levels and do so in a way that remains efficient and cost effective. For gene therapies to meet their potential, we need to solve this manufacturing challenge.

Manufacturing for commercialization

Many of the gene therapy applications under development utilize viral vectors to carry the therapeutic gene into the target cells. Current viral vector manufacturing techniques are often characterized by low yields and inefficient processes. This is not a problem for disease states that require low doses and have small patient populations. However, for other, more prevalent diseases, such as hemophilia or Duchenne muscular dystrophy, there are more patients, and they require significantly larger doses.

Drug developers could create larger doses of virus by increasing the amount produced upstream. However, this process is more labor intensive, increases the risk of batch failure, and increases batch cost—often making commercialized large-scale batch production cost prohibitive.

If you build it, you can manufacture it

There are many decisions that must be made when planning the commercialization of a gene therapy. An important one is whether to invest in in-house capabilities or to work with a contract development and manufacturing organization (CDMO).

Creating in-house manufacturing capabilities allows companies to maintain complete control of their operations. However, it requires a large capital investment prior to regulatory approval. Companies often need to be able to forecast demand by up to five years because of the length of time needed to build and qualify a new facility.

Working with a CDMO is often an excellent choice because it can help the drug developer avoid huge capital outlays on manufacturing facilities before a therapeutic is approved, thereby reducing the overall company risk. Furthermore, CDMOs often have substantial process knowledge, having built up their expertise by working on a wide variety of different therapies. This means that there can often be a shorter process development time, thus reducing time to market. However, operational costs can be higher, and there can be CDMO capacity limitations, which can cause significant delays.

Integrated solutions and their benefits

Many gene therapy products are manufactured using individual steps that are both manual and involve open operations. Manufacturing efficiency is reduced, and the risk of product contamination increases.

Scalable, automated, and closed platforms can reduce these risks. These integrated manufacturing solutions create efficient, cost-effective manufacturing, irrespective of the in-house or CDMO setting.

Time, risks, and overall costs can be further reduced by adding single-use technologies to the closed systems. Anywhere from a couple of days to a couple of weeks can be saved through reduced cleaning, validation, and set-up times, fewer in-process hold steps, and less involvement from an operator to oversee equipment.

Closed systems are also more amenable to automation, which can further reduce timelines and costs and, perhaps most importantly, yield products of consistent quality. Automation can help bring a degree of process control, improve reproducibility, and reduce the risk of batch failure.

For these quality reasons alone, it is incredibly important that manufacturers move toward—and as close as possible to—an integrated solution for viral vector manufacturing.

Implementing an integrated solution

A key goal of process development should be establishing a cost-effective manufacturing process that has manageable risk. It is important not only to optimize each unit operation, but also to consider how all unit operations fit together with a reduction in process steps.

A completely integrated system means that all unit operations work together in a continuous manner and that all consumables are compatible. It will also ensure that the process runs the same way each time and that there is a high likelihood the process will routinely run with optimal productivity.

Another key challenge in employing an integrated solution is choosing the right skill set to implement the best solution. Some companies hire a person to manage this process, whereas others hire engineering firms.

An alternative solution is to work with an end-to-end solutions provider. This is a very efficient approach because the provider selects the equipment based on the process needs. The provider will then check if the required equipment fits into the clean room design and will recommend compatible automation concepts. This approach ensures that the equipment is selected based on process needs rather than fitting the process to the selected equipment. Because consumables will also come from the equipment provider, there is a high likelihood that the process will work more efficiently.

One of the key benefits of working with an integrated solutions provider is being able to postpone the capital purchase decision until 18 months prior to product launch. This significantly reduces overall company risk because within this time frame clinical data and information about product demand can accrue.

Integrated solutions are also available in a modular, or POD, format. POD systems (prefabricated containment clean room systems) can be built quickly and can delay capital investment even further. These can be a good option because they allow more time for clinical data evaluation and for determining whether the product should be commercialized.

Summary

Gene therapies have the potential to revolutionize global healthcare treatments for diseases. For those living with diseases where other treatments have failed, gene therapies provide hope for a better life.

Despite their potential, we must remember that manufacturing and providing these therapies in an economically feasible way is still challenging. Companies must understand all manufacturing options available to them and select the one that best fits their product’s process, scale, and manufacturing timelines. It is also important to consider whether manufacturing expertise will come from in-house employees or a supplier partnership, be outsourced, or involve a combination of these options. Fully understanding and optimizing manufacturing will enable more efficient and cost-effective production and ultimately will help advance patient access to the final product.

 

Clive Glover, PhD, is General Manager, Gene Therapy, Pall Life Sciences.