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Back to Basics in a Cutting-Edge World: How do we Overcome Manufacturing Challenges for Efficient Gene-Enabled Cell Therapy Programmes?

Anna Osborne
18 January 2022
Anna Osborne evaluates how innovators and regulators can together navigate the changing manufacturing landscape of advanced therapies as discussed in the recent webinar, ‘Overcoming Manufacturing Challenges for Gene-Enabled Cell Therapies’.

The advanced therapies industry has seen a dramatic period of growth over the last few years, with more and more cutting-edge therapeutics moving through late-stage clinical phases. This unprecedented growth has created a need to evolve the manufacturing and regulatory landscape, with considerations given to the specialised needs of cell and gene therapies.

Hosted in partnership with Catalent, a recent webinar provided insight into what the specific challenges are and how tackling them effectively can enable efficient gene-enabled cell therapeutic programs to evolve to commercial scale and achieve success.

The panel of experts included Kelly Davis-Claeys, Director of Global Regulatory Affairs at Catalent, Tim Farries, Chief Scientific Officer at ERA Consulting and Knut Niss, Chief Technology Officer at Mustang Bio, as they discussed key issues arising as cell therapies mature to commercialisation.

1. “The forefront of product development is always ahead of the guidelines” – Tim Farries

The manufacturing and product development innovation within the advanced therapies industry is accelerating programs from preclinical to commercial readiness at a rapid pace. This expediential growth, coupled with unprecedented specialised needs of cell therapies, created a situation where the regulatory agencies had a limited understanding of the advanced therapies environment, and consequently the regulatory guidelines provided by the agencies could be described as fairly generic, if guidance existed at all.

Over recent years’ regulatory agencies have learnt more about the cell and gene therapy space and their guidelines have evolved to manage industry demand. In-depth, specific documentation appropriate for advanced therapies are critical for the innovators. GMP processes need to meet these guidelines for a subsequent speedy submission approval.

Although regulatory agencies continue to impose more guidelines in this field, Knut comments that still many of these guidelines are “in desperate need of updating and need to develop going forward”. Many gaps remain in this area of regulation that need to be addressed, for further potential advanced therapies pipelines to progress to commercialisation.

While innovators may be ahead in their advancements of gene and cell therapies, it is crucial that innovators and regulators partner to navigate this changing landscape. Regulatory agencies rely on innovators, consultants and biotechs to educate them on both general and more intricate principles of gene-enabled cell therapy programs. This allows the agencies to understand the specific processes which will need regulating, as well as the capabilities of the company. In exchange agencies will offer advice from a commercial standpoint, essential for GMP scale up and product approval.

2. “Don’t forget the basics of regulatory” –  Kelly Davies-Claeys

Clear communication between regulators and developers can smooth transitions from preclinical-phases to the manufacturing stages.

As our panel discussed, lack of in-depth regulatory guidelines can present a challenge at the manufacturing stage of gene-enabled cell therapy programs. However, ignore such guidelines in initial stages and companies could run into trouble down the line. What appears to be a common mistake is the use of processes in preclinical-phases which fail to scale-up in the manufacturing transition.

To overcome this potential pitfall, bringing regulators on board in the initial stages can be extremely beneficial. Kelly comments that, “I strongly encourage companies to get a strong regulatory group and consulting team together”. This sets up important conversations between both parties – for the agency to better understand the product and for the developers to better understand regulations for manufacturing, potentially saving time and costs down the line.

For the commercialisation of a product to be a success, the product and manufacturing methods must be validated and qualified. Regulatory agencies can provide useful knowledge on commercialisation, including: the scale up of GMP process and protocols for post-approval changes. This advice can contribute towards the manufacturing of a consistent, reproducible product with good specifications and acceptable purity levels.

The submission for approval of a product which demonstrates these traits will appeal to the agency if it is shown to be safe, effective and can be manufactured efficiently.

Another thing to note is the specific challenges in dealing with regulatory differences across the US and Europe. The FDA are arguably leading the way in advanced therapies expertise – these regulations are often more severe in European jurisdiction, especially when considering regulations for donor requirements. This can present a huge challenge for companies producing therapeutics to reach patients across the world. Thought needs to be put into making sure the product meets regulatory demands in all the necessary geographical areas.

However, Knut comments we are starting to see a “global network of CDMOs”, for example, with partnering occurring between Europe and the US. This progress will allow for cutting-edge products to reach the patients who desperately require them.

3. “Design the process right from the start with a commercial eye” – Knut Niss

In the same way our panel agree upon implementing a regulatory plan in conjunction with agencies from the offset of development, they also concur on the importance of designing a product with the end goal of commercialisation in mind.

During the course of development some manufacturing alterations are inevitable. However, it is essential the product demonstrates good comparability. This isn’t always easy due to the complex nature of advanced therapies, with therapeutics sensitive to even small manufacturing process changes. Noting the complexities of the product and pre-empting potential areas of alteration ensures that the products analytics remain verifiable to satisfy regulatory bodies.

The materials and processes required to scale-up the development of a product can differ significantly to those needed to produce it at a localised scale. Taking time to understand the product and consider what is critical to its manufacturing processes and parameters from the start of the program can reduce the risk of needing to make substantial changes at the GMP stage, which is often very difficult.

Tim notes that it is essential to have a “robust” supply chain, and Kelly adds “it is critical to anticipate hurdles”, from the start. This should allow for the transition from the preclinical phases to GMP manufacturing with limited unforeseen issues. The panel jointly advise in ensuring the ability to produce a consistent product on a commercial scale before initial development begins, to save time, money and effort.

In order to address this, looking at the supply chain from the beginning is vital. It is key to choose processes and materials which are viable on a commercial scale. Quality of material is very important for GMP, and the highest level of safety should be maintained. However, materials also need to be easily sourced in the quantities required when considering development for thousands of patients for large disease areas, the materials should not be a limiting factor in production.

While everything can be done to design a successful commercial product, its development can be limited by manufacturing capacity constraints and supply chain limitations the industry is currently facing. As the gene-enabled cell therapy space continues to thrive and investor money is poured into it we are seeing these issues being addressed. CDMOs, such as Catalent Cell and Gene Therapy, are building more manufacturing space and integrating the manufacturing supply chain from raw material to clinical supply. Innovators themselves are also acting proactively to overcome this by building their own in-house manufacturing capacity, as demonstrated by Mustang Bio.

4. “Expertise is a big problem as the field exploded around us”- Knut Niss

Mirroring the facility capacity and material supply chain constraints, our panel acknowledge how the lack of regulatory expertise in conjunction with the technical, scientific knowledge in this field can also impact getting gene-enabled cell products to market.

As the advanced therapies industry exploded, a skills shortage has become apparent. As capacity expands in this area, the talent pool is fairly limited and unable to meet the demand. Tim explains that, “agencies don’t have the capacity and it is challenging to find the expertise outside of the agencies”.

To overcome this Kelly suggests to gain regulatory expertise from consulting companies or partners. For example, Catalent provides a “wide breadth of regulatory knowledge” and “complements our manufacturing expertise with regulatory guidance”. Every year they contribute to the launch of over 150 new products. Developers can capitalise on such services to optimise their product commercialisation and ensure the product reaches the patients who need it.

Other steps to reduce the impact the lack of regulatory expertise may have on product programs include:

  • Agencies committing to training people with scientific backgrounds and/or an understanding of manufacturing and safety issues to build-up the regulatory workforce.
  • Companies investing in a strong development team with expert GMP insight from the initial stage of development- they should think creatively to overcome the difficulties in preclinical to commercial transition.
  • Companies are taking advantage of CDMO offerings; listening to their manufacturing recommendations, leveraging expertise built up across variety of customer programs, and using them as strong liaisons.


The success of a gene-enabled cell therapy product on a commercial scale appears to come down largely to what is done in the initial stages of the product design.

With all the cutting-edge technology and processes involved in these transformative products, this webinar indicated that a focus on two basic areas are key to making it to market. These two priorities are: paying close attention to regulatory guidance and designing a product with the manufacturing finish line in mind.

It was clearly stressed in the discussion how neglecting regulatory relationships can negatively affect product programs. Investing time into following regulatory guidance and communicating with these agencies is vital.

Acknowledging and having knowledge of GMP requirements when starting the product development process is crucial to avoiding manufacturing issues when it progresses from the clinical stage to a commercialisation scale-up.

In order to be successful in both these aspects, innovators and regulators need to work closely with CDMOs. Listening to CDMO expertise on GMP from the beginning means a product suitable for large scale manufacturing can be produced. Considering CDMO requirements when making regulator guidelines is also key. Communicating these to developers then ensures they work towards producing a product that will be satisfactory not only to the agency but also the CDMO. Capitalising on CDMO knowledge is extremely beneficial and keeps the end goal of successful commercialisation in mind at all stages of the project.

A focus on developing detailed regulatory guidance, forming strong relationships with regulators, ensuring access to expertise and designing a product with good scale-up potential, contributes to overcoming the manufacturing challenges as more gene-enabled cell therapies make it to this stage.

As Tim concluded:

 “Make sure the process is robust before you go too far.”

Want to find out more? You can watch the full panel discussion on demand, here >> 

This feature was produced in partnership with Catalent