The drug development process is becoming increasingly complex.
Broadly, the industry operates in an evolving space with complex disease areas being studied, alongside ever-changing regulatory requirements, and the advancement of breakthrough treatments. Specific to active pharmaceutical ingredient (API) development is a whole set of other challenges related to chemistry complexity, the successful scale up of manufacture, analytical challenges, and safety and toxicity assessments, among many other factors that require attention.
In short, drug development has never been so challenging. For small to mid-sized biotech companies, it is nearly impossible to successfully manage all of these factors in-house. The drug development process is a costly and time-intensive process where success or failure can have major consequences for companies – this is why there has been a rise in working alongside a contract development and manufacturing organization (CDMO) partner. The expertise, efficiency, and cost savings that are enabled make bringing in an experienced CDMO partner the common route for many companies as they develop their compounds. However, this also makes the choice of the right partner more important than ever.
One of the most critical factors for biotech companies to consider when choosing the right CDMO partner is whether they offer an integrated service. For smaller biotech companies, it was previously common to sell or license their potential product to a larger company early in the development cycle. The larger company would then be the one to handle the drug development process and launch commercial activities.
Today, smaller and mid-sized companies are more likely to pursue development into later stages or handle the commercialization process themselves. The capabilities required to handle this process in-house are usually not an option, necessitating outsourcing of the process. Contracting individual partners to take care of each step involved in the process is a possibility but is an inefficient use of time and resources. This is why partnering with a CDMO that provides an integrated offering is the logical step for most companies in this position.
An integrated offering model allows the CDMO to guide the molecule through the full drug development journey, from API and HPAPI support, to bioavailability enhancement, to drug delivery, and commercial scale manufacturing. If one of the barriers to successfully completing drug development is complexity, then working with a partner that has expertise in each of these areas is one efficient way to navigate the issue. A CDMO that is able to work with the asset at each step of development is also more likely to achieve faster timelines, which can be crucial in the race to commercialization.
At Lonza Small Molecules, there have been many instances in which having a deep expertise across a range of areas has helped when working with partners to overcome difficulties in the development of a potential treatment. Here are three case studies that demonstrate some of the potential of working with a fully integrated drug development service provider:
Flexible early phase development - Case study #1
In this example, Lonza Small Molecules worked with a partner that was hesitating between two potential crystal forms of the final API. Previously, the product had been developed to the point of needing supply for a Phase II clinical study, but the client discovered that they needed to change the final API solid form free base to HCI salt. The decision then had to be made between two different crystal forms of the final API, and the freebase process had to be re-developed to adapt to the final HCI salt formation.
In response to the requirement to select the appropriate HCI salt form, Lonza created processes for both polymorph forms of HCI salt. Once this had been achieved, the physical-chemical properties and stability of both forms were analyzed, and, in discussion with the client, a final decision was taken to choose the more stable form.
In order to fulfill the project timeline, Lonza Small Molecules had to then produce 10kg of API, which could be achieved through the capacity to utilize kilo lab production. The process was then quickly shown to be efficient, and a demo sample could be provided to the client in just two weeks.
This demonstrates the flexibility and efficiency that is gained by working with a CDMO that has sufficient scale and knowledge to quickly adapt to the regular challenges that occur in the development process.
API development to improve yield - Case study #2
For this client, the issue was that the original bromide intermediate was not stable in workup and even in storage, leading to low purity and challenges in purification. The project had been taken on for Phase I supply when this was discovered, with the purity issues causing further negative impacts on the next API step, resulting in low reaction yield (58%), and low purity of crude API. The process, as delivered to Lonza Small Molecules, required cryogenic capacity and would necessitate installation and qualification of new equipment that compromised the project timeline.
As a result, Lonza Small Molecules carried out route scouting that found a chloride analogue could undergo the same substitution chemistry, providing advantages on process manufacturability. Importantly, the change led to increased stability of the intermediate and a process that allowed for over 97% purity of the intermediate, comparing favorably to the low purity (~80%) of the bromide intermediate. The switch of intermediate led to an increased yield of API formulation to 77%.
Due to the work of the Lonza Small Molecules team, the cryogenic conditions were no longer required, and no upgrades were required to the kilo lab facility. This meant that the projected timelines could be shortened, improving the overall process for production in later stages.
Scaling from med chem to clinical supply - Case study #3
In another case working on Phase I supply, there were numerous challenges that had to be overcome. With a timeline of six months, the task was to scale from a med-chem procedure at 10g scale to a Phase I batch supply. One of the difficulties was the low overall yield (14%) of the procedure established at med-chem scale, which involved an eight chemical step process.
With a variety of hurdles to navigate, Lonza Small Molecules leveraged its integrated services network to meet the timeline requirements of the projects. This involved working with API development and kilo lab manufacture in Nansha, China, API micronization in Monteggio, Switzerland, and formulation development in Tampa, Florida.
Due to the cooperation across the Lonza Small Molecules network, the team was able to develop and optimize the eight-step process. This allowed for the kilo lab scalable process to be created, and 3kg of final API to be delivered, all within the six-month timeframe. This was achieved by using a mass balance study to optimize overall yield; by changing the sequence of material charging to reduce impurity; and by slurrying instead of acid washing allowed for the improvement of yield.
The difference a team makes
This last case study was made possible because of the broad expertise that can be brought together by an integrated service, with the advantage that comes from Lonza’s global network. Lonza Small Molecules possesses five global locations and has a presence on three continents worldwide. Having this global network means that capacity can be provided to challenging projects working against shortened timelines. This is one of the reasons Lonza has invested into its site in Nansha, China, and is looking at further expansion in the future. The location provides a full range of API services, allowing for the development of molecules to Phase I.
In each of the case studies mentioned, it was the joined-up effort of Lonza Small Molecules integrated service that allowed for a solution to be found efficiently and effectively. In these cases, if the client had opted to contract many service providers covering each phase, the likelihood of delays and greater expense would have been increased. By partnering with a CDMO providing an integrated offering, the risks to a drug development program can be reduced, ensuring the treatment moves as quickly as possible to the patients.