By Sue Wollowitz, Ph.D., President, Wollowitz Associates, LLC
It is always interesting to see how the march of technology and changes in business intersect in drug product development. Unfortunately, at times we don’t recognize the appropriate course corrections needed to best respond to the new paradigms. As an example, consider how new solubility-enhancing technologies and expanding outsourcing options can provide for new development efficiency but should also spur a reconsideration of how we address formulation development tactics.
NEW PARADIGMS, NEW CHALLENGES
Today, we know that many new drug candidates are considered poorly soluble. I would argue that one of the reasons for this is because poor solubility is no longer the barrier to drug development that it used to be. Previously, development of solubility-enhancement technologies was driven by poorly soluble drugs. Now the wider availability of such technologies has lessened the physical property demands — and perhaps dose demands — that might have been part of drug candidate selection in the past.
In addition, we now place higher demands on product performance, for example, accepting no restrictions on dosing with respect to meal intake (again, a demand that is possible because scientific and technology advances can often address the problem). Combined, these advances provide an opportunity for less time in drug discovery and smoother drug development. However, it does mean that gathering preformulation information should be done early.
In a fully integrated in-house model of drug development, those responsible for the drug product are engaged early to assess the characteristics of the API as it relates to potential formulations. Thus, the sequence of events: Carry out preformulation studies from a minimal amount of API, decide on formulation strategies for nonclinical and clinical use, and then engage the right resources based on the demands of the selected technologies.
In outsourcing, CMOs represent the two halves of manufacturing: drug substance manufacturing and drug product (pharmaceutical) manufacturing. As drug development itself became outsourced, it aligned with the facilities the manufacturers supported, i.e., drug product CDMOs (DP CDMOs). With the expertise responsible for preformulation residing in the pharmaceutical development side, the chronology of formulation decisions for virtual companies has drastically changed.
Today, DP CDMOs are often selected without knowledge of key physical and chemical properties of the drug candidate that might affect important formulation decisions. So, while previously a sponsor was identifying risks and issues in advance, now the sponsor selects and engages a DP CDMO, provides well-characterized material, and waits for analytical method transfer before any preformulation activities take place. Aside from the fact that the chosen CDMO may not be the best place to address the challenges of the particular product, this can extend development time by many months.
In addition, toxicology formulations are left with little support, since these are often decided before a DP CDMO is selected. A poorly soluble compound may not achieve the desired plasma levels in a simple powder-in-capsule or powder-in-bottle formulation. Inconsistent toxicology and pharmacokinetics’ results may be seen as well. Understanding the molecular and physical properties of the material that affects in vivo solubility before dose range-finding studies not only can speed up development, but can change clinical dose selection and even decisions on drug candidate viability.
Today, pharma companies of all sizes have limited patience for delays in development and need to rapidly determine the relative risks of formulation decisions.
THE OUTSOURCING COMMUNITY RESPONDS
The DP CDMO community understands the delays and impact caused by holding off on preformulation activity. The most noticeable response is the rise of the conglomerate CDMO that offers multiple manufacturing technologies, often at different sites, with specialized expertise in each area. These companies can assess and recommend appropriate technologies that all reside within their stables. But not all facilities are alike, and not all expertise is alike. Going with a conglomerate does not always lead to the best expertise in the one area that is needed for the specific compound.
It would be much better to have a window into formulation needs before engaging a DP CDMO. This allows the sponsor to better select the nonclinical formulation and the DP CDMO. It allows the DP CDMO to understand the needs of the product and the risks before bidding on a project, and it should allow for faster start-up of pharmaceutical development.
Small pharma development lab/Phase 1 facilities are one option. Engaging early helps plan toxicology formulations, as well as assessing the potential success of powder-in-capsule/bottle formulations for Phase 1. Solid-state characterization companies are often engaged during the same time frame that API process research takes place and often have expertise to also provide excipient compatibility and solubility studies. Finally, some analytical services companies provide such services.
OPPORTUNITIES FOR MORE-EFFECTIVE SUPPORT
I have long advocated for API CDMOs to provide basic preformulation data packages. They are already collecting data that is similar to typical preformulation studies. Why can’t they do both? Process research samples are available long before well-characterized lots are available to provide to a DP CDMO. The API CMO already has an analytical method in place and should have some solid-state characterization in-house or through a close third party. And they are much better- positioned to isolate and identify significant degradants and their formation pathways. They are perfectly situated to give the sponsor an early window into formulation needs for both tox and clinical formulations.
What kind of information are we talking about? Information that will clarify BCS (biopharmaceutics classification system)/DCS (developability classification system) classification, such as solubility in aqueous media as a function of pH, including biorelevant media using appropriate methods, is an easy and significant first step. Evaluating tox formulation options to increase bioavailability reduces the time and cost of experimentation at toxicology CROs. Even looking at things like wettability and excipient compatibility is possible.
Why don’t API CMOs do this more today? It does not serve as a means to carry out and/or support GMP manufacturing of API, which essentially all other development activity is directed toward. Because of that focus, they have limited or no expertise in pharmaceutical science and formulation. And we need expertise; understanding how molecular properties impact bioavailability and formulation design needs people who can apply both new and proven approaches to assessment. However, I believe moving such information-gathering forward and concurrent with early process development is possible.
An alternative to the horizontally integrated conglomerate CMO is the vertically integrated organization. Several conglomerate CDMOs have both API and drug product facilities which, with good project coordination, may allow some use of the pharmaceutics’ expertise while doing API process research.
The point is not to obviate the need for some preformulation work at the DP CDMO, but rather to provide a relatively inexpensive means to improve development. Having knowledge in advance of making decisions on DP CDMOs has many benefits, with the obvious one being that the sponsor can use the information in formulation and DP CDMO selection decisions. It also allows the DP CDMO to better understand the specific needs and challenges of the molecule, discuss formulation options more meaningfully, and provide a more tailored proposal. It does not negate the value of the multitechnology conglomerate CDMOs as one way to approach formulation decision making; they can often better coordinate early- and late-stage formulation and manufacturing that might require different technologies or offer technology “sampling.”
We should always be reassessing our needs, our decision making, and our available resources. The outsourcing community continues to respond to new paradigms and create their own to better serve their customers. But there are still more opportunities to improve the way drug development occurs to best address the needs of small pharma sponsors.