Q: Vertex was founded in 1989 on a desire to do things differently. Does the company still strive for innovation and, if so, where can that be seen in the company practice and structure?
Innovation is in everything we do at Vertex — from drug development to the continuous manufacturing (CM) process for our medicines. An example is our cystic fibrosis (CF) research and development programme, a model for both precision medicine and manufacturing, with innovation in the areas of genomics/genetics, cell biology, chemistry and continuous manufacturing/real-time release.
Continuous manufacturing is an innovative process that
- enables manufacturers to better monitor quality throughout the production process
- enables manufacturing and process development timelines to run in parallel with rapid clinical development
- provides significant flexibility throughout the entire manufacturing process.
Continuous manufacturing requires a small equipment footprint and can therefore be located in close proximity to the company’s R&D facilities, which can stimulate further innovation and foster collaboration between manufacturing and R&D efforts
Q: Has the overall mission changed much, is the company still driving towards developing drugs that can improve the lives of people with serious illnesses?
Vertex continues to be committed to discovering, developing and commercialising innovative medicines for a number of serious diseases.
Our work in cystic fibrosis brought to patients three medicines so far to treat the underlying cause of the disease – the first medicines to ever address the cause of the disease and not only the symptoms.
In addition to our clinical development programmes focused on CF, Vertex has numerous additional research programmes in progress including in Sickle Cell Disease, pain and several others.
Continuous manufacturing is well suited to manufacturing personalised medicines and those with breakthrough therapy designation, when development timelines may be short and there are many patients in need of transformative new medicines.
Q: How much difference does it make to the business to be able to develop a drug in the lab and then move to production swiftly?
The speed of CM allows for the manufacturing of medicines on an “as needed” basis, such that medicines can be manufactured from active pharmaceutical ingredient (API) to commercial-ready tablets, including all quality testing required to release the product, in a few days as opposed to 4-8 weeks with a traditional batch process.
Under the traditional paradigm, manufacturing may not be able to keep pace with the short development timelines for precision medicines and breakthrough therapies.
Q: Is PAT a fundamental part of the practice and operation of the business in the development and manufacturing stages, both for field trials and bulk commercial production?
Incorporating PAT and parametric controls to allow for real-time release (RTR) provides a greater assurance of quality at multiple steps in the process, not just when final tablets are produced, as well as significantly reduced cycle times, which leads to lower inventories and more flexibility in responding to patient demands.
Upon completion, batch quality will have been confirmed using PAT and online monitoring of all critical process parameters and quality attributes throughout the manufacture.
The batch is therefore ready for release immediately. In addition, any quality issues with the manufacturing process are immediately identified and allow for action to be taken in real-time preventing the production of non-conforming material.
This minimises waste and unexpected batch losses owing to quality concerns being identified after the completion of manufacturing, which is the case for batch manufacturing with traditional post-manufacture quality control testing.
Unlike end product testing, quality is confirmed throughout the manufacturing process after each unit operation and across the entire batch. This is a more reliable quality approach.
The development of precision medicines where multiple, different formulations and/or doses of a single medicine may be needed is supported by CM since we can make different medicines on the same machine, adhering to very rapid manufacturing timelines.
Using CM, the formulation composition and process can be clearly defined early, on commercial-scale equipment, prior to Phase II (critical for breakthrough therapies), thus reducing or eliminating scale-up risk.
This also avoids late-stage formulation changes and the need for high-risk bioequivalence studies to bridge to the full-scale batch process.
Q: What are the key practical hurdles to deploying PAT in practice?
In the initial stages of planning our transition from traditional batch manufacturing to CM, we assumed that the key challenges would be regulatory hurdles and technological challenges.
In practice, we have found that the regulatory challenges have been less difficult to overcome than we anticipated. The FDA and EMA have been strong supporters of our efforts to advance pharmaceutical manufacturing technology, have been highly engaged, and have provided ongoing guidance and support to ensure alignment of expectations.
For the most part, the technological challenges have been less of an issue than we assumed; the technology is well developed and the machines run well.
One of the most challenging aspects has been developing the QbD control strategy in concert with the operational software to integrate both process control and PAT monitoring to achieve the desired end state.
We have defined concepts such as minimum sampling frequency, and redundant IPC systems, and have established a control strategy methodology that satisfies both regulatory needs and efficient manufacturing.
Vertex has made a strong commitment to continuous manufacturing, and to mitigate risk as we embarked upon this ambitious project, we made the decision to bring multiple facilities online to manufacture our medicines, including facilities that are fully continuous (Boston, MA) and other facilities globally that reflect both a CM and hybrid approach, ensuring a robust supply chain network for our manufacturing efforts.
Q: Are we on the crest of a wave when it comes to achieving continuous production and real-time release of drugs? And, if so, what are the potential benefits for the end user?
From speaking to colleagues in the industry, it is clear that the interest in CM is picking up momentum, with several companies making substantial efforts in this area.
Once a few companies have demonstrated that the perceived regulatory and technological hurdles of implementing this technology are not standing in the way of success by receiving approval for commercial products, we think this will reduce the risk substantially for others, and then the benefits of CM will be such that anyone not adopting this technology may be at a sufficient disadvantage.
It’s the wave of the future in pharmaceutical manufacturing, in our opinion. It provides the opportunity to monitor quality throughout the manufacturing process, enables manufacturing and process development timelines to run in parallel with rapid clinical development, and provides significant flexibility in the manufacturing process, ultimately benefiting patients.