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Effective risk management is a paramount consideration in the realm of early-stage pharmaceutical development. As the pharmaceutical industry races to bring innovative therapies to market, the potential for risks and uncertainties looms large. This makes it imperative for pharmaceutical companies to adopt robust risk management strategies to navigate the challenges associated with drug development. As the saying goes, “Failing to plan is planning to fail,” highlighting the significance of early-stage risk assessment and mitigation. This article explores the importance of effective risk management in early-stage pharma development, drawing insights from industry experts and established methodologies to help ensure the successful progression of promising small molecule drug candidates.


In the highly competitive field of pharmaceuticals, time is of utmost importance for the successful development of new products. In the initial stages of product development, pharmaceutical experts face enormous pressure to determine the optimal molecule form, formulation, and final dose form. They must meticulously design exemplary studies, acquire precise outcomes, and make informed decisions while facing mounting time constraints. However, these challenges are only the beginning of the complex process of early-stage product development. In addition, there are limitations such as limited availability of active pharmaceutical ingredients (APIs) in small quantities ranging from milligrams to grams and restricted funding to attain the first clinical Phase 1 milestone that further exacerbate the complexity of the process.

In this context, the fusion of state-of-the-art technology and the expertise of renowned pharmaceutical researchers presents a promising solution to surmount these challenges. A recent study, conducted independently by a respected research institute, unveiled that an impressive 92% of participating R&D leaders encountered significant hurdles stemming from bioavailability limitations. Bioavailability refers to the rate and extent at which a drug is absorbed into the bloodstream, influenced by factors such as formulation, individual patient physiology, and route of administration.


Bioavailability limitations can give rise to various issues, including:

  • Diminished efficacy: When a drug fails to be absorbed into the bloodstream adequately, it cannot reach the target tissues in sufficient concentrations to exert its desired effects.

  • Increased side effects: If a drug is rapidly absorbed into the bloodstream, it may attain toxic levels within the body, leading to adverse reactions.

  • Reduced patient compliance: In instances where patients do not observe the desired outcomes from a medication, their likelihood of adhering to the prescribed treatment regimen may decline.


Encouragingly, several approaches can enhance bioavailability, including:

  • Altering the drug’s formulation: Modifying the drug’s composition by incorporating surfactants or other excipients can enhance its solubility, thus improving bioavailability.

  • Modifying the route of administration: For instance, if a drug exhibits poor oral absorption, alternative methods such as injection or inhalation can be explored.

  • Utilizing drug delivery systems: Employing specialized drug delivery systems can safeguard the drug from the harsh gastrointestinal environment or facilitate targeted delivery to specific tissues.

Overcoming Bioavailability Challenges for Safer, More Effective Drugs: A Commitment to Excellence

By effectively addressing bioavailability limitations, pharmaceutical researchers can develop more potent and safer drugs that significantly enhance patients’ quality of life. Even in the case of poorly soluble molecules, the solubility barrier plays a crucial role in enabling a proper Single Ascending Dose study in Phase 1. Despite the challenges faced by sub-optimal delivery technology coupled with poorly soluble molecules, we remain committed to achieving success at Renejix.


To achieve favorable outcomes, pharmaceutical development organizations have devised standardized selection patterns/decision trees and developed unique enabling platforms and models. Each organization sets its own rejection criteria for compounds based on specificities and patterns in the model. We have the necessary tools to succeed and help our clients overcome the challenges of pharmaceutical product development. For those exclusively focused on non-solubility-constrained molecules, reducing the selection pool of successful candidates is key to success. Leverage our expertise at Rene Pharma to help you navigate the complex landscape of pharmaceutical product development and achieve optimal outcomes without any plagiarism.

Strategies to Mitigate Risks: The requirement for improved scientific and technological foundations

Choosing the right platforms and models is vital in early pharmaceutical development risk assessment. Getting accurate and comprehensive data at this stage is crucial for a strong foundation for future development. This data helps in deciding the best development strategy by assessing stability, biopharmaceutical risks, and scalability.

Renejix emphasizes three critical factors for achieving early clinical success:

Firstly, it is essential to obtain appropriate and targeted pre-formulation data to assess chemical and physical stability risks. This includes not only automated data collection but also solid-state characterization and advanced detection methods.

Secondly, utilizing relevant biopharmaceutical models associated with the most suitable drug delivery technology platforms to provide systemic exposure is crucial.

Finally, being mindful of the Phase 1 objectives and later stage equipment trains is necessary to bridge formulation concepts with future scalability.

Assessing Physical and Chemical Stability Risks through Pre-formulation Platforms


To begin the pre-formulation stage confidently, it is critical to identify the physical and chemical properties of the drug substance that could significantly affect the performance and manufacturability of the drug product. However, small and innovative companies may lack the necessary physicochemical characterization for their new drug candidates, resulting in increased physical stability risks for the drug product. To address this challenge, comprehensive candidate profiling concepts like the 100 mg approach have been developed to identify potential development issues with drug candidates and allow for early risk mitigation.


Renejix Pharma utilizes high-throughput screening platforms for polymorph and salt screening, offering swift results that substantially reduce potential risks for developers. The platform screened 1,000+ molecules, providing Renejix Pharma with the experience and expertise necessary to elevate your drug product.


Renejix’s platform expands beyond the drug substance to cover formulation development, such as lipid formulations and amorphous solid dispersions produced through hot-melt extrusion or spray-drying processes. These protocols? combine physical and stability studies to bridge risks, guaranteeing that the final product meets the expected standards and performs well in the market. Our commitment to cutting-edge technology and unmatched expertise in drug development make us the perfect partner to ensure your drug product’s successful entry into the market.

Improving Drug Effectiveness: Innovations in Models and Delivery Technologies


Various models estimate drug absorption in the GIT. The MAD model considers solubility and permeability. The DCS model uses FaSSIF to link solubility and permeability for dose calculations. It classifies compounds as IIA or IIB, needing different solutions. IIA uses size reduction; IIB requires complex methods like solid dispersions or lipid-based systems.

When using animal models, we must be aware of potential biases that can affect our decisions. Sometimes, animal models are stricter than human tests, leading to incorrect assumptions about a drug. For example, a human problem (IIA) might be wrongly seen as an animal problem (IIB) due to testing differences. This can lead to unnecessary complex solutions. At Rene Pharma, we’ve created DCS models for each animal species and use AI tools to speed up testing and formulation development.

Building and sustaining technical proficiency in drug delivery systems is crucial for the development of both simple and intricate drug delivery technologies. While certain pharmaceutical companies opt to concentrate on their internal capabilities, such as their established manufacturing network, and exclude certain approaches from their internal models, Renejix holds the belief that co-micronization represents a domain that warrants deeper investigation and advancement.

Building a Quick and Efficient Phase 1 Bridge: Assessing Feasibility


To efficiently move a drug form from the initial stage to Phase 1, we need clear formulation goals, flexibility in design and manufacturing, and a focus on getting to clinical trials quickly. At Renejix Pharma, our R&D team has streamlined the process, creating various drug forms rapidly, including simple injections, powdered capsules, liquid solutions, and more complex options like lipid-based forms or spray-dried mixtures.

Summary

Development is widely acknowledged as complex and challenging. To prepare for later-stage clinical development, it is critical to mitigate various variables, such as chemical stability, physical stability, biopharmaceutical properties, and scalability risks.

In all cases, precise product design is necessary to meet the specific needs of patients and intended product performance. Strategies can differ significantly depending on the company and the product, ranging from an empirical approach to a more systematic and structured approach.

Collaborating with an expert company like Renejix Pharma can greatly benefit firms seeking to expedite the entry of their new drug candidates into clinical trials. Renejix has optimized and automated pre-formulation platforms, proven models, extensive expertise in development utilizing an enabling delivery technology toolkit, an excellent track record in scaling up concepts to Phase 1, and a tool kit, the industry’s most talented machine learning engineers and R&D professionals. As a result, Renejix is a valuable partner for companies looking to de-risk their drug development process and hasten the path to market.

References


1. ICH Q8(R2) Pharmaceutical Development, August 2009

2. P.Y. Chen et al, A Fit-for-Purpose Strategy Toward Solid Form Screening & Selection, Drug Development & Delivery, 11(1), 38-40, 2011.

3. T. Pointeaux et al., Fast-Tracking Time to Market in the Early Stages of Drug Development, Drug Development & Delivery, 11(8), 60-66, 2011.

4.  L.X. Lu et al, An integrated model for determining causes of poor oral drug absorption, Pharm. Res, 16, 1883-1887 (1999)?

5. J.M. Butler et al., The developability classification system: application of biopharmaceutics concepts to formulation development, J. Pharm. Sci, 99(12), 4940-4960 (2010)

6. ICH Q8(R2) Pharmaceutical Development, August 2009

7. An industrial case study: QbD to accelerate time-to-market of a drug product”, AAPS Open).

8. ICH Quality Guidelines: Present Initiatives & ISPE Involvement”, Pharmaceutical Engineering

author avatar
Sridhar Gumudavelli
Sridhar Gumudavelli serves as the Vice President of Formulation R&D at Renejix Pharma Solutions, where he brings a wealth of knowledge and experience to the table. His leadership is instrumental in navigating the complex process of drug formulation, leveraging a variety of technologies to enhance drug absorption, bioavailability, and patient compliance.Sridhar’s expertise is not just limited to his hands-on experience; he is also an innovator with several patents filed under his name. These patents reflect his contributions to advancing drug delivery systems, showcasing his ability to tackle some of the most challenging problems in pharmaceutical sciences for the past 30+ years.

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