Early on, the drug substance (DS) manufacturer will provide a wealth of preliminary characterization data. And if the drug is active in early nonclinical and preclinical testing, a larger quantity of the DS will be prepared for more comprehensive animal safety and pharmacokinetics studies. These studies may require up to several hundreds of grams (sometimes a kilo) of purified DS with low levels of impurities and residual solvents that meet global regulatory standards.
But changes in the DS process as it scales up can affect the drug product (DP). As processes change, many properties of the DS can also change: its purity, potency, by-products, particle size distribution, morphology (crystal shape and structure), and rate and extent of dissolution. Therefore, as DS manufacturers evaluate and optimize the synthetic route, process conditions, crystallization solvents, etc., they must understand and track these changes, and discuss them with DP formulators to anticipate challenges in formulation.
DS characterization is critical to DP formulation but characterization and formulation are often not integrated during drug development. This creates needless difficulties because if DS chemists and DP formulators collaborate on a formulation development strategy for early Phase I first in-human clinical studies, they can save time, money, and avoid rework.
Siloed development is neither efficient nor effective
Traditionally, DS and DP have related but distinct deliverables. The end-product for a DS development team is a pure chemical substance produced in 5-to-12 synthetic steps; the end-product for a DP development team is a patient-friendly drug. For DP formulators, the DS team’s end-product is their starting point.
Typically, the industry has been conservative in characterizing the full properties of the starting material for the DS: A minimum number of tests are conducted to suit the requirement of the immediate next step, such as preclinical toxicity or animal exposure studies.
This is unfortunate. As molecules become more difficult to formulate, this sequential, compartmentalized development model is no longer adequate.
DS and DP functions must collaborate on a sound formulation strategy
Early stage, pure DS is ideally suited for characterization tests which can catch problems early by identifying properties that could dictate future formulation choices. Yet developers routinely assume the preclinical period is too soon to consider formulation, reasoning that “We are not formulating yet; we are just identifying challenges before we trip over them.”
A systematic DS characterization should include a series of critical formulation-enabling tests, and establish a thorough understanding of a molecule’s properties to flag issues that can be addressed early in the clinical stages. A detailed DS profile can help DP formulators craft a strategy to make sure, for example, that the DS will not get degraded in the GI tract. A forced degradation study can ensure a molecule is protected via its formulation.
For example, recently a company produced a DP formulation in parallel with the human Phase I clinical study, based on a truncated DS characterization effort (shortened to reduce overall development time). The resulting formulation was a DS blend in a capsule, packed in blisters for stability. However, after one-month stability data showed that the DP had degraded, a thorough investigation and root cause analysis revealed that the DS was degrading due to alkaline conditions, and in response to exposure to a specific range of light.
Due to the rushed timeline and incomplete characterization effort, there were no baseline characterization data available that demonstrated the stability of the DS in different pH conditions, or in the presence of different intensities of light. This was an avoidable mistake that required reformulating the DP and slowed development. Systematic testing could have prevented it.
Data from forced degradation studies enable chemists and formulators to understand if a DS is stable under acidic or alkaline pH buffers, as well as in accelerated conditions of light, heat, humidity, and exposure to oxygen. If a systematic forced degradation study on the DS and DP had been carried out early on, the formulators could have designed the DP with excipients to stabilize the DS in an alkaline environment. And if a DS were sensitive to light, it could be formulated in a capsule with light protection, or in a tablet with an opaque coating. It may need to be manufactured under specific lighting conditions. For example, a recent case study of a DS revealed that it was stable under red light but not yellow. As a result, handling the DS in the lab, as well as during manufacturing, was only done under red light to maintain DS stability in the DP, and to avoid any degradation and the formation of photo-catalyzed impurities.