Developing biologics can be challenging. Their development protocols are significantly different from small molecule drugs, which provide a general response and comprise as much as 90% of the pharmaceutical drug market. Biologics are more complex, though, with targeted mechanisms and potent pharmacological impacts. Nonetheless, their rising popularity – eight of the top 10 best-selling drugs internationally in 2016 were biologics – underscores their increasing importance.
Large Molecule Therapeutics: Complex Diseases
Large molecule therapeutics are where modern drug development is at, especially for complex diseases like cancer. Small molecule drugs are chemically synthesized and are low molecular weight. Large molecules like monoclonal antibodies and recombinant proteins are produced in living organisms like mammalian cells. These drugs target disease pathways with more specificity, which is key in cancer, where you need to target cancer cells without harming healthy tissue.
Producing big molecule therapeutics is challenging due to their size, complexity and sensitivity to environment. Advanced process development ensures these biologics stay stable and effective throughout the process. This also means overcoming molecular weight and cell membrane penetration hurdles, often requiring sophisticated formulations and delivery methods to get big molecule drugs into the body.
5 Key Steps in Large Molecule (Biologics) Development
Target Identification
Drug discovery involves identifying biological targets relevant to diseases. Traditional discovery methods are costly and slow, but computational techniques now offer cost-effective alternatives. Network pharmacology and systems biology advancements enable the prediction of drug-target interactions, facilitating multi-drug, multi-target, and multi-disease strategies. This shift from a linear to a network approach enhances the potential for one drug to target multiple sites.
Structure-based drug design has evolved, facilitating the exploration of novel chemical probes and lead compound potency, and molecular docking utilizes target structures to predict interactions and offers simplicity and speed. Ligand-based pharmacophore modeling is employed when target structures are unavailable, and network-based methods employ algorithms to predict new drug target genes or repurpose existing drugs. New methodologies provide insights into protein thermal stability across the proteome and in biological systems.
Cell Line Development
Demand for biologics has impacted the cell line development (CLD) market, expected to reach $1.7 billion by 2028. Adhering to CLD best practices is time-consuming, labor-intensive, and costly, but streamlining strategies for accelerating timelines include screening technologies and purpose-fit cell lines to balance speed, quality, and compliance while optimizing cell culture conditions. This improves productivity, scalability, and stability of cell lines, while reliable data sharing propels timelines and goals.
Optimal cell lines are fundamental to fast and effective CLD, and proprietary lines with existing data and product development can expedite the process further. Leveraging high throughput and advanced analytical tools streamlines early-stage development and scale-up.
Upstream and Downstream Processing
Upstream and downstream processing are part of producing biologics. Upstream focuses on cell growth and product production, while downstream involves product purification and filtration. Both processes are evolving to enhance product development and output.
Upstream processing advancements encompass fed-batch processes, improved cell culture media, advanced feeding strategies, and tailored bioreactor control. Downstream optimization targets increased throughput, reduced costs, and improved product quality maintenance.
Technology-driven analytics enable real-time monitoring to prevent errors, enhance efficiency, inform decision-making, and meet regulatory data requirements. Ongoing innovations for full online integration are in the early stages, and industry professionals are striving to achieve that ambitious goal.
Formulations
Formulating biologics is vital to ensure therapeutic efficacy, stability, and conformation during production, shipping, and storage. Biological materials present unique challenges, but the primary goal is to discover a solution that maximizes stability, preserving the molecule’s structure and delivering the highest proportion of active protein.
Formulation involves subjecting biomolecules to different conditions and incorporating stabilizing additives, followed by concentration studies to determine aggregation limits. Biophysical characterization aids in identifying optimal formulations for further development and entails long-term stability testing and accelerated degradation studies, emphasizing the importance of understanding the inherent, intrinsic, or extrinsic nature of particles in the process.
Regulatory Considerations
An Investigational New Drug (IND) application must be approved before starting human clinical trials. A regulatory expert well-versed in chemistry, manufacturing, and controls (CMC) is crucial for navigating the application and compliance process, including meetings with regulatory investigators. Expert guidance beforehand helps identify gaps in the application and address them. Regulators will oversee the process through clinical trials and commercialization and are valuable resources themselves.
The IND submission focuses on the clinical research plan, toxicology studies, and CMC related to drug manufacturing. The clinical plan addresses indication, mechanism of action, anticipated effects, and disease impact. Toxicology covers preclinical animal studies, safety validation, and dosing for Phase 1 trials. CMC considers manufacturing, analytics, and ensuring drug consistency and purity.
Process reliability and product consistency are critical during scaling up to commercial production, necessitating comprehensive documentation of process parameters, analytic results, and manufacturing data. This documentation supports process control, and optimization, and serves as a regulatory record of reliability and repeatability.
Manufacturing Challenges in Large Molecule Development
Manufacturing growth factors, cell therapies and large molecule injectable drug market requires very different processes to small molecule drugs. Biologics derived from living cells are more complex and require more monitoring and optimisation to ensure consistency and quality. Process development is key to scaling up large molecule drugs from research labs to commercial production.
The challenges come from the size and complexity of the molecules, especially in keeping the molecular structure intact through cell culture, purification and formulation. Regulatory approval also requires proving that the manufacturing process is robust enough to deliver batch-to-batch consistency. With big molecule manufacturing, the use of mammalian cells and advanced bioreactors has changed the game for companies, allowing them to produce high molecular weight compounds at scale.
A Promising Future for Every Stakeholder
The development of biologics has a long history, and it continues to pose unique challenges and requires a multidisciplinary approach. From target identification to formulation and regulatory considerations, each step plays a crucial role in ensuring the efficacy, stability, and quality of new drugs. Advancements in structural biology, cell line development, upstream and downstream processing, formulation techniques, and regulatory compliance are driving progress in this field. The future of biologics holds great promise, with continued advancements shaping the landscape of healthcare. By embracing technological innovations and new best practices, companies can meet the rising demand for biologics, and improve patient outcomes, and the bottom line.