Solving Bioavailability Challenges Using A Molecule’s Target Product Profile (TPP)

What is the Target Product Profile (TPP)?

The Target Product Profile (TPP) describes the desired characteristics of the proposed drug product aimed at a particular disease. We consider the TPP to be a living document that may change as together we learn more about your molecule.  The TPP will commonly include the following information:

• Intended use
• Active pharmaceutical ingredient (API) characteristics
• Proposed critical quality attributes (CQAs)
• Target patient populations
• Dosing frequency
• API loading of the product

As such, the TPP provides the foundation for developing a product, allowing developers and stakeholders to understand what is required to be successful.

The key to achieving the TPP is to ensure optimum bioavailability of the API within the drug product. This means paying careful attention to factors, such as the route of administration, the characteristics of the API, and the dosage requirements. A “one size fits all” approach to improving bioavailability and delivering the TPP will not lay the foundations for a successful drug product formulation. The flexibility of the approach is key.

Laying the right API foundation

At the heart of every drug product is the API. Therefore, when embarking on a drug product formulation project, it is important to develop a clear understanding of the API and its characteristics, including the dissolution rate, the melting point (along with other thermal properties), the API density, and any other solid-state characteristics that are relevant.

• Dissolution rate is a critical parameter of pharmaceutical dosage forms – in vitro dissolution testing is performed to screen out formulations that don’t offer the right dissolution profile. In addition, the dissolution method should be considered in relation to the in vivo performance of the dosage form. Characteristics of the API, such as particle size distribution and surface area, all factor into the dissolution rate.
• Knowing the melting point of an API is equally important, as any chemical degradation of a drug during processing can create several issues. Particular care must be observed if an API or excipient exhibits a relatively low melting point or glass transition temperature in the case of non-crystalline substances. Once formulated, the API may undergo a polymorphic transformation into a different form with different physicochemical properties.
• Understanding the true, bulk, and tapped density of API is vital due to the impact on the compressibility, flow, and compaction properties of powders. This can depend on particle size distribution, particle shape, and cohesiveness, amongst other factors.

The route of administration with which the API will be delivered should be chosen and confirmed early into the development campaign. This will, in turn, inform other areas of development, such as the dose requirements. It will also determine factors regarding the bioavailability of the treatment; for instance, an IV dose will require sufficient aqueous solubility. Research suggests that about 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble [1]. As such, having the experience to understand such bioavailability issues and address them early and provide solutions is essential for any CDMO partner.

Designing an approach to tackle bioavailability challenges

The TPP helps develop an approach to tackle bioavailability and ensure the best possible project outcome. We offer several approaches to customers to address bioavailability issues.

One increasingly popular solution to insoluble compounds is high-energy media milling (nanomilling). This approach is particularly effective as it is suitable for oral, injectable, topical, and inhalable applications. Lubrizol Life Science Health (LLS Health) offers a nanomilling feasibility program, which unfolds in three steps:

1. Develop a target product profile and screen the API for nanomilling
2. Generate particle size distribution and short-term stability data for each formulation
3. Identify promising formulation(s) and provide material for animal PK studies

We can quickly determine if nanomilling is viable for a particular API, saving the customer both time and expense through the feasibility program. LLS Health is an expert in this area, being one of the only CDMOs capable of performing nanomilling under aseptic conditions.

The use of Amorphous solid dispersions is another approach that may be attractive due to the solubility enhancement achieved via this approach, which can be accomplished through hot-melt extrusion and spray drying. However, due to APIs’ chemical reactivity and hygroscopicity, this approach presents formulation challenges, so it is important to find a CDMO partner that has experience navigating these potential issues.

Formulation of APIs through excipients such as cyclodextrin complexes, used as complexing agents to protect the hydrophobic functionality of an API, is an option.  Further encapsulation provides a versatile option for fragile APIs and long-acting dosage forms.

Working with LLS Health to solve your bioavailability challenges

Many formulation techniques can help your product achieve the desired bioavailability, and LLS Health is well equipped to support you in finding the most appropriate approach for your asset.

We are experienced at harnessing both the TPP and data we gather at every stage of the development process to support you throughout the decision-making process for your product. For more than 20 years, we’ve developed the expertise and technology that ensures that we can take your asset, no matter how complex, and make progress towards the end goals as set out in the TPP.

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Written by: Robert Lee – President at Lubrizol Life Science Health – CDMO Division at The Lubrizol Corporation

Sources:

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629443/