By Tim Kelly, M.B.A., COO, Homology Medicines
While the past decade’s focus on scientific advances has accelerated the advancement of genetic medicines, including gene and cell therapies, manufacturing is vital to product quality, safety, efficacy and clinical trial and commercial supply. In the case of adeno-associated virus (AAV)-based gene therapy and gene editing product development, manufacturing is no simple task. As the industry advances these genetic medicines, manufacturing is also ramping up, and with it optimization and efficiencies of scale. Since the industry is still maturing, and manufacturing know-how is often kept proprietary, companies must learn, adapt, and master novel innovations as well as challenges on their own.
As more companies and academics focus efforts on potential one-time treatments, key learnings will continue to inform manufacturing advances for genetic medicines. In fact, it should be expected that the AAV manufacturing learning curve will be faster than previous learning curves in the biotech industry. However, AAV manufacturing has unique challenges, and some of them were openly discussed during a recent FDA Advisory Committee, highlighting the need for deeper focus on product quality as one critical example. Some of these challenges include:
- Lack of chemistry, manufacturing and controls (CMC) capability leading to insufficient product quality levels;
- Lack of full breadth of analytical method and qualified quality control capability;
- Limited process development and optimization capability at contract development and manufacturing organizations (CDMOs), leading to production of clinical trial material that may not meet regulatory expectations;
- Limited experience and expertise with genetic medicines’ manufacturing platforms and techniques;
- Rapidity of product development, which could outpace time needed to cultivate the appropriate manufacturing expertise; and
- Customized processes and systems to develop one product rapidly, which may not be suitable for future commercialization and/or able to be leveraged across a platform for other treatments.
However, organizations that take a unique and holistic approach to manufacturing, whether internally or through a CDMO, have the best chance of controlling their destinies by developing, learning from, and optimizing methods and processes to build an integrated system that works best for their technologies. The most important factor may be the understanding and persistent willingness to accelerate through the learning curve. It is important to build a flexible system, particularly early on, to facilitate process improvements and rapid continuous learning, as well as to focus on developing comprehensive analytical methods. When taken together, these offer greater efficiencies and ensure product quality at every step in the process. Organizations have to forge a new path forward guided by the ability to learn and integrate rapidly.
At Homology Medicines, we have integrated different capabilities side-by-side in a fresh approach to process development and manufacturing, building a model that meets the needs of our programs. To accomplish this, we have built a uniquely flexible GMP facility, tested and optimized a novel platform, assembled an experienced and expert team, and developed a manufacturing capability that applies to both our gene therapy and nuclease-free gene editing programs. We have realized the value of incorporating learnings from industry and our own internal experience to develop “Homology practices” to avoid potential pitfalls or adoption of bad habits in manufacturing genetic medicines. This has led to a “plug and play” platform capability that can accommodate multiple serotypes and consistently deliver high quality vector scaled up to 2,000-liter bioreactors with specific focus on potency, vector profile, and extremely low levels of residuals.
Some of our key learnings include:
- The earlier the better when it comes to investing in process development, extensive vector characterization, and manufacturing;
- Data-driven decisions are key, and your own data are the most important;
- An integrated experienced core team is paramount; matching experience with novel expertise is a potent mix for accelerating learning; and
- Building for the present is insufficient; building a scalable platform that can be leveraged, improved, and meet future demand is the ultimate goal.
Lesson 1 – The earlier the better when it comes to investing in process development, extensive vector characterization, and capabilities. While it may be expensive, investing early in process development and manufacturing is key to a product’s future success and patient safety. The genetic medicines industry is booming with more than 100 clinical trials ongoing with AAV-based therapies, which has already put a strain on capacity and capabilities for both internal CMC, as well as external CDMOs. As reported in The New York Times, “Other [gene therapy] companies are not always able to afford the manufacturing costs or find a manufacturer. Some have taken to buying slots in virus production queues years in advance — like buying a nonrefundable airline ticket long before your vacation and hoping you can get away when the time comes." Short-term capacity is just the tip of the iceberg as below the surface lies two big challenges - the first are the demands for large-scale supply of pivotal studies and commercial inventory; the second is the ability to develop a process that will deliver the required vector quality and meet the accelerating expectations of regulators. Additionally, the real source of value for a company is the ability to learn, master and leverage vector capabilities internally. It may not always be feasible to build your own facility early on like Homology did, but it is instrumental in maximizing learnings in areas such as process development and analytics, leading to improved efficiencies and accelerated timelines - all while maintaining control over your own preclinical and clinical supply material and, importantly, your development timelines.
Lesson 2 – Data-driven decisions are key, and your own data are the most important. With the advent of gene therapy and gene editing, much has been said to be impossible. In line with developing internal best practices, it is key to evaluate your own vectors in your own hands to determine what will actually work for your technology as it relates to manufacturing processes. Running head-to-head comparisons with different processes in diverse in vitro and in vivo models is worth the early work to make informed decisions. For example, one of the common beliefs that has been perpetuated in our industry is that HEK293 transfection cannot be scaled up. Instead of accepting that as fact, we and others have done the work to establish that it is not only possible, but in our case, it is the preferred platform for our proprietary vectors and offers linear scalability up to the 2,000-liter bioreactor scale.
Lesson 3 – An integrated and experienced core team is paramount; matching experience with novel expertise is a potent mix for accelerating learning. The right technology and science are vital, but it is people that drive all the accomplishments. A large part of our investment in process development and manufacturing is in the team who propel and fortify the culture of rapid learning and integration. In hiring, it is important to seek employees who are innovative thinkers since there is no roadmap and team players who have the unique technical and operational experience. At an AAV company, manufacturing must work in an integrated manner with all departments, and Homology has housed our integrated team under one roof to ensure cross-functional collaboration as the normal way of operating. For example, our internal expertise includes many who worked on the world’s first FDA approval of a single-use bioreactor. We have been leveraged this experience to build our single-use facility in a highly efficient manner, which has allowed us to accelerate timelines.
It is also important to have strong partnerships with CDMOs to balance and stay adaptable as a company and programs grow. Selecting a CDMO that fits the company’s evolving needs and can align culturally is key. The selection process should consist of assessing capabilities with the intention of building a long-term relationship. We still partner with a CDMO because there are several advantages of having a dual source, and we believe this will be increasingly valuable as we and others prepare for potential commercialization.
Lesson 4 – Building for the present is insufficient; building a scalable platform that can be leveraged, improved, and meet future demand is the ultimate goal. Rare disease drug development is like a marathon but running one sprint after another continuously. Time is always of the essence, and it is particularly so in rare diseases. To move gene-based programs forward, companies may begin clinical development using an academic or non-optimized process that will require adjustments down the road. Our leadership team has worked in rare diseases for most of our careers, so we understood the importance of building our own manufacturing process and platform such that it could be used from early development through to commercialization and across both our gene therapy and gene editing programs. Starting with a high-quality process and vector should now be the standard in our industry.
A “plug and play” model like we have at Homology serves our programs regardless of the modality or transgene and allows us to advance all programs as expeditiously as possible. Not having to reinvent the system for each new product candidate allows for greater efficiencies and can benefit patients over time by reducing product development and potential commercialization timelines.
A Look Ahead
There are two FDA-approved gene therapies for monogenic diseases that are helping patients today, hundreds of genetic medicines clinical trials currently underway and many more in the pipeline. These should help to bridge the gap in the learning curve and experience that exists in AAV technology today. At Homology, we are focused on accelerating this curve by leveraging our unique internal vector capabilities, using our data to challenge our thinking, and understanding and continuing to utilize our inherent expertise while growing our talent base. It is incumbent upon the field to continue to innovate in process development and manufacturing instead of holding onto what has been done in the past. We need to embrace new technologies and processes that are better suited to meet the unique challenges in developing genetic medicines to help patients, and with an urgency that can improve the lives of people and families who suffer from rare diseases.
 Kolata, G. (2017, November 27). Gene Therapy Hits a Peculiar Roadblock. The New York Times. Retrieved from http://www.nytimes.com.