During the development phase of a new drug, great pains are taken to characterize the molecule and to run a myriad of laboratory and animal tests to determine the product attributes, toxicology profile, and other matters that lead to showing that the mechanism of action is understood as well as possible. This early development phase is also characterized by an attempt to understand the most effective dosing level for a promising drug candidate that is safe and excites the developing scientists. The excitement stems from the realization that this particular molecule is an attractive candidate over others being considered by the R&D team as an extension of the business objectives of the corporation.
These elaborate development programs start with understanding the API, then lead to developing a formulation used to deliver the drug in an efficient, physiologically acceptable manner. A key to successfully moving to the clinical trial phase is control of the delivery of the API at bioavailable particle size. At some point, the die is cast regarding how the drug will be delivered and how the API is characterized for delivery. Or is it?!
What about this all important concept of bioavailability? The developing scientists are usually very focused on maximizing the bioavailability of the main compound with regard to a particular indication. This awareness is, of course, critical to the ultimate potential success of a given drug. Everyone assumes that as the formulated drug works its way to pilot level manufacturing and clinical supplies manufacturing, that the key characteristics of the API as delivered through some delivery vehicle will be preserved. As the process of formulating and manufacturing the final product goes from laboratory to small batch pilot manufacturing to larger scale Phase III clinical trials and on to full commercialization, the failure to verify that the key characteristics of the API remain intact can lead to unfortunate clinical trial outcomes. This can cost a sponsor millions of dollars and even lead to an unfortunate decision to discontinue what could be a very promising drug.
One key factor associated with bioavailability is particle size. This is well known by many teams of clinical and formulation scientists. Yet, as we will see, even this ball has at times been fumbled as the product passes through different hands responsible for the integrity of the final bioactivity of the product.
This becomes even more important in the world of nanotechnology drug delivery. In the case of ophthalmology pharmaceutical products–whether as an oral drug or topically administered drug, whether for anterior segment administration or posterior segment administration–bioavailability is the holy grail. It is also very difficult to achieve and maintain in some cases. Because certain drugs for the back of the eye include, in some cases, targeted API to specific layers of the retina, predictable and consistent bioavailability is mandatory as an underlying factor for the initiation and conduct of all phases of the clinical trials. In fact, controlled bioavailability is likely to determine the clinical success or failure of a drug when particle size is optimized and targeted based on the precise indication of use. In practical use and fact, key characteristics such as particle size, within clinical supplies provided for the clinical trial are assumed to be demonstrably in control. However, no such control can be demonstrated if the particle size distribution is not specified.
A personal experience with just such a circumstance presented itself during my career prior to joining ProPharma Group while I was the Principal Strategist for Ophthalmology at a large CRO. A sponsor had completed an extensive product development program that led to very successful pre-clinical testing that showed excellent bioavailability and safety of the product. This back of the eye treatment to restore the function of a certain layer of the retina offered great promise. The effectiveness and safety of the product was further proven in the Phase II clinical trials leading to great hopes for major positive outcomes for the Phase III studies, which had been awarded to the CRO because of perceived Phase III ophthalmology clinical trial capabilities.
As the Phase III clinical trials proceeded, the exuberance associated with the Phase I–and particularly Phase II studies–began to turn to disappointment as the results that came in were rather anemic, showing decidedly lower results for efficacy at the chosen dose. The clinical trial was put on pause and the drug was nearly abandoned until the clinical team from the CRO began to pursue the question of bioavailability. A review ensued that included knowledgeable process engineers and the original formulation team.
The outcome of the review was stunning. Apparently, the original small batch product developed for the early pre-clinical and Phase I and Phase II studies was created at the same small, boutique type manufacturer known for its skill and accuracy at making clinical supply batches of this type of drug. The sponsor, who was essentially virtual, decided to abandon the boutique manufacturer in favor of a “bigger,” more “sophisticated” and “experienced” contract manufacturer to make Phase III clinical supplies and primary stability batches. This new CMO assured the sponsor that it could scale up the product with little attention to the process that preceded its involvement, relying primarily on the “knowledge” contained within the boutique manufacturer’s batch record.
This “approach” to technology transfer failed to pass on the knowledge developed by the boutique manufacturer that API particle size, in the 30-70 micron range, was critical to product performance and clinical success. Thus blinded, the larger, more “sophisticated” manufacturer happily produced (repeatable, no doubt) a product wherein the API particle size was approximately 500 microns … a size that was never going to work at the level of the retina envisioned by the developers. The futile next steps were to try to “shave” the large, unwieldy particles into a usable drug. Any good formulation and process engineering team would know that this fire-fighting attempt was wasteful and not going to work.
Eventually, the Sponsor was convinced by way of investigation to go back to the process development drawing board and restructure and optimize the API, formulation, and process, with particle size as a key and vital aspect of the final specification for the final drug. Though very disappointed that the Phase III clinical trial had to stop and the drug reassessed, the sponsor was happy to know that the original prospects for the drug candidate still had great promise. This snafu cost millions of dollars and ultimately well over a year in their program. Nevertheless, the millions invested and the hopes of the original investors was not in vain. Particle size reigns supreme!
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