In the fast-paced pharmaceutical industry, the ability to swiftly and cost-effectively bring new drugs to market is critical. Early-stage assessments of developability, encompassing both therapeutic efficacy and manufacturability, are vital to identify viable drug candidates and eliminate less promising ones. Employing a quality-by-design (QbD) framework from the outset fosters the development of efficient manufacturing processes and flexible formulations that can adapt to evolving requirements. Mikart leverages its extensive experience across various molecule types, state-of-the-art R&D facilities, and a profound commitment to QbD principles to advance the development of oral dosage forms. This integrated approach not only accelerates production timelines but also enhances the overall cost-effectiveness of drug development, ensuring rapid adaptability to changing pharmaceutical landscapes.
The Importance of Developability
Developability is a critical factor in drug development, a process known for its complexity and high costs. For new drug products to gain approval, they must demonstrate not only safety and efficacy but also present clear benefits over existing treatments. These advantages could include enhanced effectiveness, lower costs, or improved patient adherence to the medication regimen. Moreover, there is increasing pressure from governments, healthcare payers, and investors to expedite development timelines.
A pivotal strategy for reducing these timelines involves rigorously evaluating the developability of drug candidates early in the process. This means focusing on identifying and progressing only those candidates that are not just potentially effective and safe at reasonable dosages but are also viable for cost-effective manufacturing. The rapid generation and analysis of precise, high-quality data during this phase are essential. It aids in distinguishing candidates with promising properties from those unlikely to meet the necessary criteria. Discontinuing the development of the latter early in the process can significantly conserve resources and redirect them towards more promising candidates, thereby reducing the time to market and enhancing overall development cost-effectiveness without compromising on the safety, quality, and efficacy of the drug.
In terms of specific focuses during developability assessments, two primary areas are emphasized: therapeutic efficacy and manufacturability. While the importance of efficacy is clear, the aspect of manufacturability is equally critical though less obvious. Early evaluations must assess whether a drug can be produced not only in a cost-effective and scalable manner but also in a way that the final product meets desired performance standards. This comprehensive approach ensures that both the production processes and the end products are optimally designed to meet rigorous health standards and market needs. Additionally, it is crucial to consider the selection of a dosage form that enhances the bioavailability of the drug. This involves choosing a formulation that not only ensures the drug is delivered effectively but also maximizes its absorption and therapeutic impact, providing the best chance for successful treatment outcomes.
Enhancing Drug Development with Quality-by-Design
The quality-by-design (QbD) approach is foundational in ensuring that quality is intrinsic to both the product and its manufacturing processes from the very beginning. By utilizing design of experiments (DoE) methodologies, QbD facilitates the definition of a precise manufacturing design space, which guarantees the consistent production of high-quality drug substances and products throughout the scale-up and regular manufacturing phases. Additionally, meticulous control over the supply chain secures the availability of high-quality raw materials and excipients.
Early in the development process, it's essential for formulations to be thoroughly understood. This includes determining precise specification tolerances for all excipients, as well as conducting rigorous tests to define stability limits and identify any potential undesirable interactions between excipients and the drug substance. The earlier these details are established, the quicker the optimal formulation can be determined, streamlining the later stages of development.
QbD is fundamentally a risk-based strategy that pinpoints critical production factors essential for achieving a high-quality final product that meets specific patient requirements. This methodical approach maximizes the efficient use of time and resources. Implementing a robust QbD program from the start not only facilitates scalability but also enhances the sustainability of the manufacturing process, providing long-term benefits in production efficiency and product quality.
Designing Advanceable Formulations
During formulation development, the objective is to pinpoint a formulation at an early stage that could potentially serve as the final product. Due to the myriad changes and variables that arise as drug candidates progress through development, achieving this final formulation early is rare. Nonetheless, the initial stages of formulation development should focus on creating advanceable formulations. These formulations are designed with an eye toward achieving a harmonious balance among key factors: bioavailability, scalability, stability, manufacturability, and compliance. This strategy ensures that even if adjustments are required as the product advances, the groundwork laid by these early formulations will facilitate smoother transitions and adaptations, maintaining the integrity and efficacy of the final product.
Benefits of Starting Simple
In the early stages of formulation development, it is advantageous to start with simpler formulations to minimize investment in candidates that may not ultimately prove effective. By considering the desired route of administration and the mechanism of action of the drug candidate, a straightforward dosage form is chosen that can reliably provide safety and efficacy data. Once these data are obtained, a detailed investigation into the interactions between the drug substance and the excipients is essential to ensure their compatibility. This thorough examination facilitates informed selection of the optimal dosage form, dosage level, and final composition, setting a solid foundation for further development.
The Importance of Continuous Developability Assessments
Continuous developability assessments are crucial not only in the initial phases of drug development but throughout the entire project life cycle. The pharmaceutical industry is inherently dynamic, with frequent changes in market demands, regulatory requirements, and clinical trial outcomes. These changes can necessitate modifications to the product, ranging from formulation tweaks to adjustments in the dosage form. Moreover, stability studies may indicate that certain excipients are incompatible over time, requiring alternative solutions. Regular and ongoing assessment of developability enables rapid detection of such issues, facilitating timely adjustments. This proactive approach not only accelerates the development process but also contributes to cost efficiency by allowing developers to adapt quickly to evolving requirements and data.
Sachets: Flexible Dosage Forms for Streamlined Development
Sachets serve as an excellent initial dosage form that offers potential for advanceable formulations. They are notably flexible, supporting formulation adjustments as a drug progresses from clinical trials to market readiness. The inherently dry nature of sachets, whether filled with powders for reconstitution or beads for sustained-release, offers advantages over liquid solutions or suspensions, particularly in terms of stability.
Furthermore, sachets are designed as controlled unit dose products, which ensures that patients receive the exact prescribed amount of active ingredient without the need for measurement. This precision is crucial for maintaining dosage accuracy and patient safety.
Sachets also offer significant flexibility in dosage levels, enabling quick adaptations to meet evolving clinical data. For example, they can be easily modified by back-filling with additional powders or beads to adjust the dosage strength, thus circumventing the need to restart the formulation process.
Despite these advantages, sachets are often overlooked in pharmaceutical development, frequently relegated to roles such as physician samples or associated with non-pharmaceutical uses like candy packaging. Moreover, the capability to manufacture sachets is not widely available among contract development and manufacturing organizations (CDMOs), which may limit their use despite their significant potential to streamline drug development timelines.
Innovative Technologies and Capabilities at Mikart
Mikart stands out as a CDMO dedicated to formulating and manufacturing patient-centric drug products that enhance usability, addressing challenges related to swallowing, taste, and palatability. Their expertise spans a wide array of dosage forms including liquid solutions, suspensions, multiparticulates, minitablets, sprinkle formats, orally disintegrating tablets (ODTs), chewable tablets, sublingual tablets, and various unit-dose forms such as sachets. They are also proficient in applying aqueous-based coatings and other advanced taste-masking and controlled-release technologies.
Packaging solutions at Mikart include high-density polyethylene and glass bottles, unit dose cups, and both cold form and thermoform blisters, which include options for child-resistant packaging that remains accessible to elderly patients. In the realm of innovation, Mikart is exploring cutting-edge technologies, such as a predictive model called a “compression simulator.” This tool predicts the performance of drug formulations during dry granulation and compression processes, accounting for variations due to different machine brands.
Further technological advancements at Mikart include the installation of a NanoTransformer™, developed by Nano PharmaSolutions, which significantly enhances the solubility and bioavailability of poorly soluble active pharmaceutical ingredients. This technology, originally derived from techniques developed by NASA for applying nanoscale coatings, allows for the precise deposition of drug substances onto nanoparticles of excipients like sugars. It is applicable across all stages from preclinical to GMP manufacturing of nanomedicines, offering a unique and innovative approach to solubility enhancement.
Mikart’s R&D lab is equipped to handle a diverse range of early formulation and process development tasks. Their non-GMP, small-volume formulation area enables the exploration of various excipient combinations and drug formats. This lab-scale capability, coupled with their extensive knowledge built over fifty years and numerous projects involving various molecule types, allows their experts to make rapid and informed decisions early in development with minimal data.
For drug candidates and formulations that show promise, the transition from R&D to production is seamless, supported by the close cooperation among Mikart’s analytical, formulation, and process development teams. Their integrated capabilities span from preclinical formulation evaluation through to commercial production and life-cycle extension for all oral dosage forms, establishing Mikart as a comprehensive resource for pharmaceutical companies aiming to develop optimal drug products with accelerated timelines and reduced costs. This comprehensive service offering is supported by a robust regulatory department, ensuring swift regulatory approvals and maintaining an impeccable track record with health regulators.