Submitting the appropriate information for an IND application, especially the solid state aspects of the drug substance (DS), can accelerate new drugs into clinical trials. Having the appropriate information from a physicochemical perspective will reduce uncertainties about the solid state form, expedite the process, and openness with the FDA.(1)
Most Active Pharmaceutical Ingredients (APIs) exist in different crystalline arrangements, thereby exhibiting polymorphism. Polymorphs have different physicochemical properties, which may affect stability and solubility, consequently, the dissolution and bioavailability of the drug product (DP).
Not knowing if an API exhibits polymorphism could range from being a nuisance having to restart a laboratory study to financially catastrophic consequences if the API is already commercialized as a drug product, e.g., Norvir (2) and Neupro (3). These types of consequences can endanger patient lives and must be avoided.
Typically, the most thermodynamically stable polymorph should be identified as early as possible to reduce time to market and costs because it has the lowest propensity to transform during process development, formulation development, and storage.
There may be occasions a metastable polymorph would be used for drug product development demonstrating superior benefits over the stable polymorph whether it be for improving absorption, bioavailability, or processing.(4,5)
Based on several Guidance for Industry documents, the sponsor is required to provide a brief CMC description of the drug substance which includes the physical, chemical, or biological characteristics. Part of that brief description should include information about the solid state chemistry of the DS, typically an XRPD pattern and particle size information will suffice. Demonstrating that the same polymorph used in Phase I, as with the animal studies, should be demonstrated since different polymorphs may have different solubility and stability characteristics. (1,6,7)
Any differences between the chemistry or manufacturing of the DP used for animal toxicology studies and Phase I clinical studies must be discussed and how these differences may influence the safety profile of the DP. Knowing that the solid state form of the API does not transform into another polymorph is key to mitigating risks in the DP since different polymorphs may have different solubilities and stability which will influence the dissolution of the drug product and ultimately the bioavailability in a test subject. Understanding the particle size range may influence the dissolution profile of the DS and DP and should be included in the brief description of the DS.
The FDA understands that the manufacturing processes for the DS and drug product (DP) may change during the drug development process. It is important to establish phase-appropriate tests demonstrating that the DS and DP are consistent to ensure the safety of the subjects in the clinical study.
“The goal of manufacturing process development for the drug substance is to establish a commercial manufacturing process capable of consistently producing drug substance of the intended quality,” as stated in ICH Q11. The quality of the drug substance directly influences the quality of the drug product.
Stability data on representative samples of the DS and DP are required for all clinical IND phases by demonstrating acceptable chemical and physical limits for the duration of the study. Knowing the physicochemical properties of the API are critical for a successful IND application to move into a clinical phase.
By the end of Phase II, knowledge about the solid-state form must be provided to the FDA, including the propensity to exhibit polymorphism and if the different polymorphic forms can affect drug product performance which is based on Decision Trees 4–1, 4–2, and 4–3 found in ICH Q6A. Even when the drug product is an injectable, chemical, and physical stability and solubility should be considered critical quality attributes of the drug substance for an injectable drug product implying the need to manufacture the drug substance consistently.
Understanding the physical and chemical properties of an API early during development will be vital for continued discussions with the FDA as advised by the Guidance for Industry, INDs for Phase 2 and Phase 3 Studies, Chemistry, Manufacturing, and Controls Information.
“Given this preference for the most stable polymorph, it would be beneficial to discover and characterize this polymorph at the earliest possible stage of development.” (2)
The initial stages of drug development are crucial to identifying the most thermodynamically stable polymorph early on. Knowing if an active pharmaceutical ingredient exhibits polymorphism can help you avoid financial, time, and physical hindrances throughout the DP process. Submitting accurate data and information in an IND application can help reduce any risks and unknowns and aid pharmaceutical manufacturing companies in expediting new drugs into clinical trials.
Regis Technologies, Inc. can help pharmaceutical and biotechnology companies take and expedite their drug candidates to market. We offer a wide variety of services, including those that help support API manufacturing through solid state chemistry, process research and development, analytical development and stability services, and GMP API manufacturing.
If you’re interested in partnering with Regis Technologies Inc. for your next project, or if you want to learn more about how we can help your company, please don’t hesitate to contact us. We’d be happy to help answer any questions you may have and get the process started.