Generic Drug Development

Using equivalence by design to evaluate RLD product microstructures and guide generic in house development towards successful ANDA submissions.

Issue

Developing an in house generic product of a reference listed drug (RLD) can be a lengthy, costly, and turbulent process. Beyond demonstrating Q1 and Q2 equivalence, the optimization of the product microstructure and Q3 equivalence can be a significant barrier. In addition the regulatory need to demonstrate this equivalence, microstructures are a driving force behind the product performance. This is especially true for complex drug products where controlled release and long-acting mechanisms dictate drug release. When a generic product is developed with quality by testing, and when microstructures are ignored, development costs can skyrocket.

Common Challenges

Difficulty optimizing the formulation and manufacturing processes to develop a product with same performance and quality as the RLD
Demonstrating in house product Q3 microstructural equivalence with the RLD for ANDA filing and data packages
Lengthy testing to demonstrate in vitro and in vivo performance in the development of long-acting implants, microspheres, and IUDs
Use of Q3 microstructural bioequivalence to file for a biowaiver in the development of topicals

Solution

To overcome the complexities of generic development and iterating manufacturing to get the right performance, we apply an equivalence by design approach integrating a microstructure feedback loop from the RLD. Before even developing an in house formulation, analyzing the RLD microstructure can pave a critical pathway to selecting the correct manufacturing parameters. We use advanced microscopic analysis such as FIB-SEM and X-ray micro-CT to quantify the size, distribution, and interaction of ingredients and porosity within the final drug product. Microstructure digitization provides a visual and quantitative demonstration of equivalence of RLD and the in house formulation. For controlled release platforms, we can predict a release profile in a matter of days, using the real digitized microstructures as a direct input. This eliminates the need for long in vitro tests during process selection stages. We also study post-partial release samples from in vivo and in vitro studies, enabling quantification of the drug dissolution front, polymer degradation, and other structural changes that can occur. This analysis can offer insights into the impact of the in vivo environment on release and can support the pharmacokinetic data.

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Our Approach

Reverse engineering the RLD with digital microstructure analysis for quicker time to market
Quantification of final API particle size and porosity within the final drug product
In silico image-based release prediction for controlled release platforms using the digital microstructure
In house vs RLD structural equivalence assessments to support ANDA data packages