Have We Got Novel Drug Production And Compliance Timelines All Wrong?

By Antony Hitchcock, principal and owner, AGH Bioconsulting

Over recent years we have seen a rapid growth in the development of new clinical products and whole new modalities of drugs, many targeting unmet clinical areas and offering hope to patients who previously had none. In response, regulatory authorities in the U.S. and EU have developed schemes where new treatments are prioritized for regulatory assessment, including many cell and gene therapy products.

The Hard Reality Of Developing Novel Drugs

While writing a previous article on the United States Pharmacopeia’s (USP) new guidelines for plasmid DNA production, I was surprised by the USP’s Rebecca Potts, who said that one of the drivers for updating the guidelines was the concern that many of the products given Fast Track designations were not coming to the market as rapidly as expected, if at all, due to manufacturing issues.

Alongside this, I was recently fortunate to be invited to a meeting in London looking at future manufacturing challenges, and it was apparent that clinical developers are frustrated with the slow development of products and the hurdles they face in trying to get products into the clinical and commercial supply.

Having spent 40 years in the industry and 35 in developing manufacturing processes to provide materials for early clinical to late-phase studies and commercial supply chains, I have observed one important and endemic behavior that leads products and development programs to fail.

This article will consider the time and broad-based steps it takes to bring novel drugs to market and offer a new way of thinking about manufacturing development and timelines, which, for some, may fly in the face of established ways of doing things.

Setting The Stage: Scalability And Regulations Lag Behind

First, the drug development process itself, historically, has been slow and expensive. Recent years have seen a revolution in the approaches taken to identify new clinical entities, such as the ever-increasing use of AI-driven approaches to design new molecules, including proteins and viral vectors. We also have seen a rapid increase in the adoption of new modalities, not least in the cell and gene therapy space and including approaches to improve the targeting of new therapies. An example of this is the targeting elements in the nanoparticles used to deliver mRNA therapies.

Unlike some products such as mAbs with well-established production processes, many new clinical entities lack historical process knowledge.

When faced with the challenge of producing new clinical entities, we must address two issues.

• First, we need to identify ways of producing the product at the scales required, whether it be for safety studies, clinical development, and, if successful, commercial scale.
• Second, we must address the regulatory requirements around the manufacturing processes, process consistency, and the analytical requirements related to product testing, including identity, purity, safety, strength, and potency. Both elements are critical and cannot be taken in isolation.

Additionally, we need to recognize that, for more novel therapies, regulatory guidelines may not exist and, where they do, they may change during the clinical development of a novel modality as regulators gain experience with new product types. This also applies to manufacturing technologies, which are continually evolving, especially for new therapeutic modalities where new approaches are explored and developed.

For many highly novel therapies, there are limited road maps to guide and de-risk the development process and limited, if any, experience or knowledge around large-scale clinical production to fall back on. Therefore, we need alternative approaches to de-risk development and address the issues around manufacturing failures.

The Cost Of Neglecting The End Game

Novel products are frequently developed within academic spinouts with short-term funding that want to sell off the clinical entity or company. Consequently, these companies are inevitably focused on achieving short-term goals around a proof of concept, rather than the long-term clinical development and commercialization. An inevitable consequence of this short-term focus is that the decisions made to achieve these goals often have long-term effects from a manufacturing and regulatory perspective. In some cases, this is because of a lack of understanding of the long-term implications. It also stems from the assumption that future product owners will resolve the problem.

These short-term decisions not only delay and add cost, but they also can affect the viability of the product, not least with regard to the robustness and scalability of processes.

The Solution: Start Compliance And Production Planning During Development

To address these issues, I suggest that product developers should establish longer-term approaches to meeting manufacturing and regulatory requirements.

While inevitably there are a significant number of unknowns in manufacturing development plans, it should be possible to extend road maps for new clinical entities from preclinical to commercial supply, including key product milestones. Such plans must take a multidimensional view of the production process, which looks at all aspects, including:

• raw and starting materials supply chain,
• in-process controls,
• testing and release of products, and
• regulatory requirements.

From a manufacturing perspective, the key issues are to identify potential development work and process changes that are required to meet the initial requirements for clinical production and then to map out the requirements for the development of the process and material supply through to commercial production.

For example, an increasing number of processes and products, including multiple approaches to plasmid DNA products, are now being developed around cell-free production routes using enzymic synthesis processes.

These products may be available for lab processes, but are they available in GMP grades? Can suppliers produce sufficient material for commercial supply? Are there alternative suppliers or must you depend on a single supplier?

With any plan, there is also a need to recognize emerging technologies that could be used within a manufacturing process at some point in the future. For example, in viral vector manufacturing, the switch from transient production to stable cell lines could have significant effects on production costs and scales. The challenge here is deciding when and how to adopt a new approach during clinical development.

Three Activities To Support Early Process And Compliance Development

Onboard the right expertise, and do it early

Therefore, there is a need to bring manufacturing and regulatory expertise from industry and academia into companies as early as possible to help guide and support their manufacturing, with regard to both short-term and long-terms plans, essentially establishing manufacturing advisory boards alongside scientific ones to support these activities. Additionally, there is a clear need to establish the required manufacturing skill bases, through training and potentially establishing partnerships with CDMOs to support development activities.

Let the plan lead

Having established a plan, use it. The first point is that it is a “living document” that needs to be reviewed and updated on an ongoing basis, based on new knowledge and experience gained within development programs and from outside of the organization. One of the key uses of a development plan is to identify and understand criticalities within the plan and prioritize development work and potential process changes. It is important to identify when process changes can and need to be introduced and their potential impact on product safety and product function. This includes changes that could potentially invalidate preclinical and clinical data, requiring studies to be repeated, which introduces significant risk into development programs.

Plan for change

Third, there is a need for acceptance of process change. Currently, there is a strong temptation for product developers to try to de-risk production processes for complex products by introducing early process lockdowns — in other words, avoiding process changes to retain critical process characteristics. However, experience shows that this can create significant problems as processes scale to meet the demands for late-stage clinical and commercial supply.

Regulators understand the need for process change, expect it, and provide guidance, not least with regard to the International Council for Harmonisation guidelines in the form of quality by design approaches.

The ability to plan and manage change is a critical element within a development plan. This includes establishing reference materials and developing the analytical procedures to be able measure them. This is especially important with regard to product function and potency assays, but historically, developers have not invested in the development of potency assays until late in clinical development programs. With more complex products such as gene therapy, it is apparent that these assays need to be developed as early as possible within development programs.

Establishing Value For Long-term Strategies

Why should companies – especially early-stage companies – invest in long-term strategies? What is the value for them, especially when their business strategy is to exist only to reach the early-phase clinical trials and then divest?

In my experience working within the CDMO environment and as a consultant, product developers often underestimate material requirements for clinical studies through oversimplified calculations of demands, especially when it comes to process losses and regulatory requirements. These misjudgements frequently result in failed batches and additional costs and delays, which outweigh any savings achieved by skipping late-phase considerations.

The second impact is on potential value of the company to potential buyers. Companies buying into new clinical projects are clearly aware of and understand the risk of failure within clinical development programs. Likewise, highly novel modalities with no established manufacturing approaches may deter potential investors who know how much additional investment in manufacturing development, delays, and a greater risk of failure can deter potential buyers or decrease the value of a company. However, companies that can show how they have mitigated risks in the past and have clear strategies for addressing late-phase clinical and commercial supply add substantial leverage to their pitch.

Conclusion

We are amid a revolution in medicines with the potential to address an increasing number of unmet clinical needs. However, while recognizing the need to meet short-term goals, there is a clear need for product developers to address manufacturing challenges earlier and, critically, to recognize the value of manufacturing solutions not just to meet short-term clinical needs but long-term solutions to deliver much-needed medicines to patients waiting for them.

About The Author:

Tony Hitchcock is the principal and owner of AGH Bioconsulting. He has spent his decades-long career in the in the biotechnology field, with over 30 years in the production of complex biologic for clinical trials in the European Union and U.S. He has worked in areas of process development and manufacturing with experience in engineering and process systems. He has worked on the development of more than 30 products for clinical trials including plasmid DNA, viral and bacteriophage products, and recombinant proteins from microbial, mammalian, and insect cell sources. Contact him at tony@aghbioconsulting.com.