Importance of Establishing Q3 Microstructural Bioequivalence
Bioequivalence (BE) is a demonstration that two products are expected to act equivalently in the human body. BE must generally be assessed when qualifying a new generic to an already-approved originator (“brand”) product. It also frequently comes into play during the development of originator products, for example, when the sponsor conducts its clinical studies with an early prototype formulation, but then seeks to get approval for, and market an improved formulation. Bioequivalence studies are often used to “bridge” the two formulations.
Conventionally, BE is most commonly demonstrated via human pharmacokinetic studies. However, for drug products that act locally, i.e., at or near the site of application rather than via the systemic circulation, difficult and expensive clinical endpoint bioequivalence studies that test for clinical cure or improvement with hundreds or thousands of patients are the norm.
BE presently is denoted in “degrees” of similarities depicted in the table above. In recent years, FDA has made a concerted effort to find in vitro alternatives to clinical endpoint bioequivalence studies in order to help facilitate the development of generic drugs. Many of the products for which such in vitro bioequivalence studies could be done have complicated microstructural features that may not be fully elucidated with currently available technologies. In many cases, approval of the originator product predated modern analytical technology, and so the originator itself may not understand the microstructure of its own product.
DigiM: A Trusted Filing Partner
- Q3 BE for non-systemic treatments (highly variable) are highly desirable (> 50% of ANDA applicants in 2019-2020 received notice to send additional data to support claims)
- Top reasons ANDA are rejected: inadequate stability information, inadequate dissolution, and the drug product was not bioequivalent to the RLD. ANDA Filing Statistics
DigiM image-based pharmaceutical microstructure characterization technology is a proven tool to help demonstrate equivalence between two formulations, potentially eliminating the need for expensive and time-consuming human studies.
Application Areas and Case Studies
Q3 BE is routinely employed to grant biowaivers for accepting generic drugs into the market. This allows pharmaceutical companies to bypass the lengthy and costly process of approving new drugs through an Abbreviated New Drug Application (ANDA). However, the traditionally accepted format for evaluating Q3 BE, while employs a good amount of time and costs at the expense of efficiency, only works for drugs with systematic applications, such as oral solid dosage forms.
These common approaches include pharmacokinetics (PK) and/or clinical endpoint studies, fails when a drug is acting locally due to the large variations among different localized areas, and the interactions involved. Such intricacies are compounded with increasingly complex generics. Complex generic drug products are defined in the Generic Drug User Fee Amendments (GDUFA) II Commitment Letter as a product with:
- A complex active ingredient(s) (e.g., peptides, polymeric compounds, complex mixtures of APIs, naturally sourced ingredients)
- A complex formulation (e.g., liposomes, colloids)
- A complex route of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions or gels)
- A complex dosage form (e.g., transdermals, metered dose inhalers, extended release injectables)
- Complex drug-device combination products (e.g., auto injectors, metered dose inhalers); and
- Other products where complexity or uncertainty concerning the approval pathway or possible alternative approaches would benefit from early scientific engagement.
If a complex drug product is shown to be microstructure bioequivalent with the brand product, there is very high likelihood that they will reach the same therapeutic effect, or they are therapeutically equivalent. DigiM image-based pharmaceutical microstructure characterization technology answers directly to this urgent call from both the industry and the regulatory agency.
Stability represents a level of safety within the drug formulation process. Ensuring safety is one of the FDA’s guiding principles. Comparing two time points of the generic sample with the RLD through the DigiM's image-based pharmaceutical microstructure characterization technology would provide the consistency required to establish stability and/or identify the means to ensure it.
It is a critical factor in the ANDA application process. Particularly for polymeric drug products, such as Poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres and implants, the API is embedded within a biodegradable polymer matrix, which is sensitive to temperature, pressure, and drug-polymer interaction during formulation, processing, and manufacturing. Slight changes can greatly influence features such as particle size distribution and porosity, hence alter the drug stability. Each of these microstructural facets affect drug release and other physical parameters that are critically important for safe and effective treatments.
DigiM has assisted clients to determine the cause of instability and other unanticipated foibles by providing tools to identify, analyze and optimize formulation designs to reach microstructure bioequivalence.