First-in-Human clinical trials are one of the first critical milestones in drug development life cycle. The race to this milestone is underscored by the rise in expedited programs such as Fast Track designation, Accelerated Approval, Priority Review designation and Breakthrough Therapy designation. For drug developers, these accelerated timelines highlight how crucial it is to reduce the time from initial product concepts to production and then Phase I clinical trials. Numerous factors can slow down this process such as redundant verification testing, formulation, and technology selection. These challenges can be solved by partnering with one manufacturer rather than several who can provide integrated services from proof of concept to commercialization. With a single project manager who oversees all development activities, companies can shorten their development timelines and meet critical clinical deadlines while reducing cost- and time- inefficiencies.

Challenges in meeting accelerated timelines

Shortening development timelines is especially important for small, emerging and even virtual pharma companies who bring most of the small molecules into the development pipeline. The challenge is their lack of resources and access to in-house equipment and expertise to enhance and manufacture their compounds, as well as the limited funding if the company is a start-up. However, their continuous innovation is an incredibly important contribution to the industry as they often develop treatment options for unmet clinical needs, where it is important that they get the support needed to succeed.

To reach early clinical trials, small and emerging companies traditionally work with several contract development manufacturing organizations (CDMOs) to ramp up production. However, each partner in this value chain will sample, test, and release the product using their own methods before moving forward – creating redundant activities that consume more time and resources. One study showed that interacting with a single CDMO service partner may shorten the first-in-human clinical timeline by an average of 14 weeks, reducing costs by nearly $21 million and increasing net revenues by almost $24 million. 

Another challenge that may elongate development timelines is the increasing complexity of drug compounds that require special processing or enabling technologies to meet target drug product profiles. This is the result of more than 70 percent of the small molecules under development requiring bioavailability enhancing technologies to increase their effectiveness. Solving these problems before Phase I clinical trials is important during solid-state characterization, technology selection, API development and supply, as well as identifying the right drug product.

While navigating accelerated development timelines, it is critical for pharma companies to strategically choose their partners. The right one can help meet important clinical deadlines that can be the difference in successfully launching their life-saving drug product to the market.

Navigating manufacturing and regulatory hurdles

CDMOs play an integral role throughout the entire process from the early stages of development all the way to commercialization. These strategic partners help alleviate concerns regarding aggressive development timelines, especially for candidate molecules targeting specialty and orphan applications, by acting as the project manager thus easing communication between facilities and scale up of production.

The challenge when engaging with multiple manufacturers is replicated activities across different stages that can rack up costs and time. In addition, many issues can occur during different stages of manufacturing, including packaging requirements, quality control and quality assurance, liability questions, optimizing schedules and timelines to avoid full retesting. Working with a single integrated partner acting as the project manager means that they have a bird’s eye view of the processes and thus reduce complexity, effort, time, and costs across every development stage. Other potential advantages include a streamlined contract process; consistent reporting mechanisms; coordinated design and development for the active pharmaceutical ingredient (API), drug-product intermediate(s), and finished drug product; and simplified data sharing, technology transfer, and validation.

On top of manufacturing expertise, a CDMO with regulatory expertise can immensely help companies advance their drug products through commercialization, especially those under an accelerated program. Many small and mid-sized biotech companies do not have the capacity, or the regulatory affairs experience needed to develop an appropriate regulatory strategy. All too often, this can cause delays throughout the development process.

Involving a CDMO partner with an extensive development and manufacturing network with Subject Matter Experts (SMEs) to advise in early development discussions may help structure a program that meets the expectations of regulators, helping secure approvals at each phase.

Some of the biggest regulatory challenges when developing drug products are the varying national requirements as well as its different interpretations. While the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) application and inspection expectations are aligned based on the international guidelines, they may not always be fully identical. Furthermore, other countries such as China may have different guidance from their own respective regulatory agencies, which requires additional insights. Given the necessity the work across and understand the guidelines of different regulatory bodies, an experienced CMO or CDMO is invaluable in navigating the differences between these agencies and their input and insights have the potential to reduce cost and time in the long run.

Collaborating with a CDMO who has the capabilities to deliver your small molecule product from proof of concept to commercialization on top of navigating complex regulatory frameworks can make a huge difference. In the following case studies, I will outline several success stories of how an integrated partner can help meet important early-stage clinical deadlines and enhance small molecule compounds.

Case study one: clinical manufacture with a breakthrough therapy designation
Lonza was asked to meet a rapid clinical- phase timeline for a HPAPI oncology drug that had promising results in Phase I work. The drug had been granted “breakthrough therapy” designation by the FDA, so the development timeline was accelerated. A different CDMO had been used for early kilogram-scale manufacturing using a multi-step process, so the goal was to transfer this process to Lonza, scale it up, and mount a campaign to manufacture hundreds of kilograms of material for Phase III clinical testing, which was scheduled to start within 4 months.

After working closely with the pharmaceutical company, we created clear project objectives and a phase-appropriate plan that was adapted as the development moved forward. HPAPI experts led the entire effort where they clearly communicated with the pharma company and facilitated the transfer and clinical manufacture. As HPAPI manufacturing requires a very close eye on containment and handling, manufacturing these across different CDMOs would’ve meant that every touch point in that value chain had to verify their facilities. In this case, as it was Lonza handling the scale up, the technology transfer between different stages of development was much quicker and still ensured the safety of the engineers and Manufacturing team.

Within 10 months, clinical material was ready when the Phase III tests began and a successful amount of Phase III clinical material was manufactured and delivered. This was followed immediately by a successful Product Validation campaign. The timeline from dosing of the first clinical patient to commercial approval was only 2 years and 8 months.

Case study two: technology selection and drug product

In this second case study, our approach was focused on choosing the correct technology to improve the bioavailability of a high-dose, poorly soluble molecule in a single unit dose.

Based on the physical-chemical properties of the molecule and measurements of its solubility in water and select solvents/lipids, the solubility of the molecule in select lipid vehicles was sufficiently poor that a lipid approach would not lead to a single unit dose. Similarly, based on dissolution rate measurements of a micronized sample, a physiologically based pharmacokinetic (PB/PK) model predicted micronization would not overcome the bioavailability challenge.

To determine the suitability of an amorphous solid dispersion approach to improve the molecule’s bioavailability, an amorphous solubility measurement was performed. This measurement showed a ten-fold improvement in solubility in simulated intestinal fluid (SIF) relative to that of the crystalline compound. By subsequently measuring drug solubility in the presence of select concentration-enhancing polymers, several lead ASD compositions were identified.

These compositions were manufactured on a scalable, small-scale spray dryer and evaluated using in vitro dissolution tests and rapid physical-stability tests. From these evaluations, a 50% drug: Eudragit-L100 formulation was chosen for further scale-up and inclusion into a high-loaded dosage form (HLDF) that contained an equivalent amount of hydroxypropyl methylcellulose acetate succinate (HPMCAS-H) as a concentration-enhancing polymer. Using this composition, the required dose could be administered in a single dosage form that increased exposure in an animal model two-fold relative to the crystalline compound.

In just eight weeks, the technology selection program and drug product development provided a clinical-image formulation and in vivo animal supplies. There was no technology transfer needed from one CDMO to another to create the formulation and drug product – reducing the timeline by months and by extension decreasing development costs.

Identify problems early for a more successful product launch

As outlined in the case studies, solving challenges in early stages is critical to a success product launch. Characterizing the target drug product profile before the clinical stage will help choose enabling technologies and drug delivery platforms among other elements. Pharmaceutical companies and their CDMO partners must work closely to define key problem statements early on to design robust processes for the entire development program, beyond the first stages. Thoughtful processes cut inefficiencies from the bud and prevent them from snowballing to later phases of development. This can potentially save months, if not years, in manufacturing, saving millions of dollars along the way and potentially getting the medicine to the patients who need them sooner.

Technical competence, collaboration and flexibility are vital qualities in a productive partnership. A CDMO partner with a synergetic approach knows how to make the next stage of development more efficient.