Taking Your API to the Next Level: Three Steps to Consider Before Outsourcing
April 07, 2022 (10 minute read)
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Simplifying your APIs development journey
April 01, 2021 by Audrey Kelleman (7 minute read)
Category | Small molecule
The primary way new drugs are developed is changing. Historically, pharma companies—particularly large pharma companies—have developed APIs in-house. The goal of this development model is to take an API from discovery through development, in order to take a product to market. Typically, this strategy is self-funded, support is conducted in-house, involves large teams, and is equipped to take a molecule from discovery to commercial manufacturing.
Over the past several years, there has been an increased trend of smaller/virtual innovators who discover new APIs and bring them to Phase II, in hopes that they can sell their developed asset. These innovators are usually funded by venture capital funds, and staff members usually wear multiple hats—i.e., run multiple functions. Due to how lean these innovators are, they typically have little to no good manufacturing practice (GMP) equipment for chemistry, formulation, and analytics. Small developers may also employ the services of CMC consultants and often outsourcing partners to help develop their innovative API.
Now, those same type of innovators are realizing they don’t have to just develop and sell their precious API discovery. These companies are now holding onto their asset and utilizing contract development and manufacturing organizations (CDMOs) to help bring their API all the way from discovery to commercial manufacturing. The choice to outsource is a decision made of out necessity—smaller innovators are lean teams and do not have the capacity or the expertise to streamline an API’s journey from development to commercialization. On top of the that, the API market is highly competitive, making the race for innovators to get their molecule to market, all the more fierce.
Whether you find yourself engaging one or multiple CDMO(s) to partner with, it’s critical to determine how you will approach the clinical development of your API.
Clinical Development: Start with Your Endgame in Mind
When it comes down to it, the focus of early development for API innovators is this:
We need to develop an API that will succeed in clinical trials.
To get there, consider what Phase I clinical goals, objectives, and milestones you want to reach. By doing this and sharing them with a prospective CDMO(s), it has the potential to weed out CDMOs who aren’t as familiar with what a clinical development program should look like. Explaining your desired endgame should cultivate a stimulating conversation where a CDMO should follow up with questions to fully understand your clinical goals. These questions should include, but are not limited to:
- What is the most important thing we—the CDMO—need to know about your clinical goals before we offer a solution?
- When do you want the First-in-Human (FIH) results read-out?
- When is the first subject first dose (FSFD)?
- When is the Investigational New Drug/Clinical Trial Application (IND/CTA) filing due?
- What is the clinical protocol/synopsis?
- What should the final drug product do?
- Why can’t you just dose the API?
- What should happen or has happened in the preclinical studies?
- How have you developed the API?
When a prospective CDMO asks these types of questions, it will begin to reveal not only how they can tailor their offerings to your unique goals and objectives but stimulate a more meaningful conversation. More importantly, it will provide them with the necessary awareness of your clinical objectives as you plan your clinical study and align it with your chemistry, manufacturing, and controls (CMC) plan.
Strategy Options for Your API’s Development
Once you and your API are ready for Phase I clinical studies, there are different strategies you can choose from. Typically, the right strategy is chosen because of elements like budget, speed in which you need to get to clinic, and what regulatory steps need to be considered. At a high level, there are three options most API innovators can choose from before moving to Phase I clinical studies:
Option 1: Document all information expected for cGMP synthesis in a laboratory notebook. By doing this, batch records can provide assurance that API isolation takes place in a cGMP, appropriately controlled environment.
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Option 2: Synthesize an appropriate amount of drug substance API that will be used to support your non-GMP safety studies, as well as your FIH/Phase I studies.
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Option 3: Outsource non-GMP steps to a lower cost supplier and run cGMP steps in a cGMP facility.
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Regardless of which option you take, it’s important to remember why you’re strategizing in development early on—to better position the API for success in clinical trials. This early investment in development can yield downstream dividends in API development. Early investment in API development for clinical studies:
- Allows for smarter selection of RSMs,
- Creates a better synthetic process that avoids overly hazardous reagents,
- Avoids intermediates with genotoxic potential,
- Creates a better synthetic process that prevents problematic impurities,
- Allows for more scalable chemistry and convergent synthesis,
- Helps you in selecting a solid-state form early on,
- And assists in deciding on final isolation solvents.
Of the above list, one of the more commonly overlooked considerations is the selection of the solid-state form. This is important because in Phase II, the dosage form must be determined. So, if you don’t assess the solid-state form used in Phase I, you may not know how it will behave in your final dosage form.
For example, let’s say you go with a tablet form in Phase II. In Phase II, you scale up your API and it doesn’t have the desired compressibility, or you experience issues with flow properties. If this were to happen, you may have to assess a different synthetic process or investigate additional physical manipulation steps. For example, particle size engineering may have an impact on the validity of your Phase I data—which could result in additional time, cost, and waste in your program.
Many new chemical entities are inherently poorly soluble but there are numerous technologies—see the table below—that can address these challenges making Phase I the best time to set your formulation.
Getting your API in good shape before Phase II is monumentally important for its success in clinical trials, and oftentimes, your small virtual team may not have the expertise/resources to solve the problems that may arise in early API development. From process optimization and complex chemistry, to analytics, as well as finding the most efficient chemical route for your API—simplifying the complexities of early development, all while trying to get your API to clinical trials in a timely fashion, is no easy feat.
It will be easier to determine your formulation if your API and drug product (DP) teams are fully aligned at the start of the program. There are so many unknowns and what if’s with developing and scaling APIs, and if a CDMO already has a means of integrating the chemists with the formulators and analysts, your API’s journey to clinical trials will be much more streamlined.
Having a formulator involved in the process development of the API can help support what the chemical and physical attributes of the final API—i.e., Quality Target Profile—need to be by engaging in everything from early API characterization to the formulation enablement of the API. In conjunction with the right know-how as it pertains to the science of molecules and development of APIs, this type of team increases the probability of getting to clinical trials and ultimately the market, faster.
API Outsourcing Challenges
As previously mentioned, smaller API innovators have no choice but to outsource certain responsibilities to a CDMO. Historically, innovators have taken a multi-vendor approach to CDMO outsourcing to avoid “putting all their eggs in one basket,” which on the surface, can make sense. Especially if you’ve had a negative experience where a single CDMO did not deliver.
With all being said, a multi-vendor approach to CDMO outsourcing has its own fair share of risks—risks that may outweigh those of going with a single-vendor approach. Over the past several years, multi-vendor programs have shown they are prone to delays, miscommunication, and dropped handoffs. Innovators already have the challenge of discovering the next ground-breaking API, and due to their leaner teams, most of them don’t have the bandwidth to also play project manager.
API innovators who choose a multi-vendor approach must coordinate communication and cooperation between multiple vendors—many of whom are often competitors and don’t naturally coordinate and collaborate well with one another. Not only do innovators have to facilitate communication between CDMOs, but further organize the project transportation from one CDMO to another. Lastly, innovators who choose a multi-vendor approach often miss the opportunity to leverage a global experience across the entire supply chain.
Quick to Clinic™: Simplifying Your Drug’s Development Journey
Thermo Fisher Scientific’s Quick to Clinic™ offering allows you and your molecule to quickly reach that Phase I milestone, all while mitigating the various risks of API development. By leveraging collaborative teams across drug substance, drug product, and clinical services, Quick to Clinic™ can better characterize and position your API, before clinical trials.