To gain insight into this complex landscape, we spoke with Abbas Razvi, head of pharmaceutical development, and Sandro Holzer, head of process development bioconjugates at Lonza. In this Q&A, they share their expertise on accelerating development timelines, integrating new technologies, navigating regulatory hurdles, and ensuring high-quality standards. Discover how Lonza uses creative strategies and interdepartmental collaboration to advance the process development of these critical therapeutics.
Current landscape
What are the most significant challenges in accelerating timelines for the development of parenteral drugs?
AR: Accelerating timelines for parenteral drugs presents several challenges. One challenge is formulating complex molecules to ensure stability, efficacy, and safety. Overcoming low drug solubility, compatibility with excipients, and achieving desired release profiles is crucial. Acceleration often depends on extensive data on similar molecules. Stability is vital, with decisions based on stability data under various conditions. Obtaining stability data from normal storage conditions adds confidence before clinical programs. The challenge is mitigating the risk of insufficient stability data on the drug product. Manufacturing parenteral drugs aseptically is intricate, requiring specialized facilities and expertise. Scaling up for large-scale production adds complexity.
Strategies for acceleration
Can you discuss specific strategies or methodologies that Lonza employs to expedite the pharmaceutical development process for parenteral drugs?
AR: Lonza employs several strategies to accelerate development, focusing on efficiency and quality. One strategy is tailoring formulations early through screening conditions and automated analytical testing. This identifies characteristics impacting stability, manufacturability, or patient experience. Modeling tools and developability assessments streamline subsequent formulation and process development, avoiding roadblocks later. Our holistic approach combines drug substance/drug product formulation, manufacturing process development, presentation with a fit-for-purpose container-closure system, and an analytical testing panel identical to the eventual control system. Phase-appropriate solutions focus on critical aspects at each stage, ensuring efficient use of resources and time. Early development prioritizes stability, while later stages optimize formulation robustness and scalability. An integrated approach fosters clear communication and avoids silos, demonstrated in our Ibex® Design DNA-to-IND program. This integrated program utilizes advanced technologies for fast timelines, increased productivity, and enhanced yield. Lonza's enhanced Tox offering for monoclonal antibodies accelerates DNA to tox drug substance by two months, enabling toxicological studies before GMP manufacturing. Combining these strategies, Lonza expedites parenteral drug development while maintaining quality and patient safety.
Technological integration
How does the integration of new technologies, such as AI and automation, impact the development timelines of parenteral drugs?
AR: The industry is adopting digitalization technologies, robotics, and AI machine learning tools to develop therapies faster and more efficiently, reducing timelines and costs. Lonza uses digital technology and automation to streamline operations, decrease manual involvement, and improve data-driven decision-making. Initiatives like high-throughput developability studies and machine learning models for particle characterization shorten individual development steps, minimize material requirements, and reduce overall timelines and costs. New technologies in aseptic processing address industry-wide challenges, such as subvisible and visible particles in parenteral products. Adopting robotics and automated visual inspection systems for defect and particle identification addresses this issue. AI for image analysis and pattern recognition improves detection while minimizing false rejection rates. Coupled with automation, this process eliminates air bubble formation, reducing processing timelines. Remote parameterization stations expedite recipe creation, saving time and allowing earlier technical transfer integration into production planning. Maximizing line occupancy contributes to overall process time savings.
Regulatory considerations
What regulatory hurdles do you encounter most frequently, and how does Lonza navigate these to ensure timely development and approval of parenteral drugs?
AR: Preparing for regulatory submission, such as a Biologics License Application (BLA), is complex, especially for small biotech companies. Challenges increase for biologic drug products due to complex manufacturing processes and evolving regulations. Lonza leverages experience with numerous BLA programs and submissions to various regulatory authorities. Many regulatory hurdles occur early in development, so enlisting CDMO support to develop a BLA roadmap and scale-up is crucial. CDMOs have highly qualified scientists to ensure all requirements are fulfilled for complex submissions, from early pre-clinical to commercial stages. Best practices for de-risking the regulatory process include flexibility in providing CMC data and collaborating on a development strategy for a robust CMC package. This ensures a successful first submission and inspection readiness, minimizing RFIs and reducing efforts and timelines for license applications.
Technological innovations
Which technological innovations have been most impactful in advancing the process development of bioconjugates?
SH: Bioconjugates and antibody drug conjugates (ADCs) are revolutionizing treatment options for life-threatening diseases. However, these therapeutics introduce complex challenges in development and manufacturing, increasing costs and timelines. Collaborating with a strategic partner like a CDMO is essential for minimizing risk, cost, and supply chain complexity. Lonza's Ibex® Design ADC and Ibex® Bioconjugates Flex programs enable end-to-end development and manufacturing of cytotoxic and novel bioconjugate drugs. These programs integrate new technologies from the acquisition of Synaffix, including site-specific conjugation, spacer technology, and a validated payload platform. Non-ADC bioconjugates can access Synaffix's GlycoConnect™ platform for flexible bioconjugation applications, including oligonucleotide conjugates. AI and machine learning (ML) capabilities optimize manufacturing processes, facilitating predictive maintenance, streamlined product development, and proactive quality improvements. This enhances overall production efficiency.
Quality control
How does Lonza ensure high-quality standards are maintained while accelerating process development timelines?
SH: Lonza consistently creates effective, safe, and high-quality drug substances and products. The structural and chemical attributes of substances determine safety, efficacy, and quality. The manufacturing process impacts these characteristics, requiring systems to ensure consistent product quality across the product life cycle. Quality by Design (QbD) is a holistic and proactive approach to defining and controlling process impacts on product quality. This includes characterizing a design space, quantifying the potential impact on quality for process variations, and implementing a process control strategy to minimize risk or mitigate impacts on product quality. QbD shortens time and risk for development and commercialization, allowing process flexibility to support product quality as molecular formats evolve.
Scalability
What strategies does Lonza use to ensure that bioconjugates developed in small-scale are effectively scalable to larger production volumes?
SH: Lonza employs various strategies to ensure bioconjugates developed on a small scale are scalable to larger volumes. Key approaches include using standardized small-scale experimental setups representative of unit operations at scale to ensure facility fit early in development. Leveraging over 15 years of experience in large-scale bioconjugates manufacturing, Lonza conducts thorough scale-up risk assessments to avoid common pitfalls. Collaborations enhance capabilities, such as acquiring Synaffix, combining Lonza's expertise with Synaffix's ADC technology platform. This comprehensive service facilitates rapid discovery, development, and scaling up of novel ADCs, streamlining the path to clinic and commercialization.
Interdepartmental collaboration
How do different departments within Lonza collaborate to ensure efficient and accelerated process development for bioconjugates?
SH: Interdepartmental collaboration is essential to bioconjugate development and manufacturing, forming the core of Lonza’s integrated end-to-end offering, like Ibex Design® ADC. Lonza combines expertise in protein, small molecule, and bioconjugate drug substance/product development and manufacturing, including process development, supply chain, and program management, under a single quality system with an aligned goal. Collaboration across technologies, sharing best practices and knowledge, fosters innovation to accelerate the development of next-generation health solutions.
Future trends
What future trends or advancements do you predict will most influence the acceleration of process development timelines for bioconjugates?
SH: The future of bioconjugates, especially ADCs, is promising. Accelerated approvals of ADCs since 2019, along with new technologies like stable linkers and site-selective conjugation, will drive market success. Outsourcing of ADC manufacturing is increasing due to the complexity of handling cytotoxic substances and the demand for these therapies. Integration and technology platforms will be crucial for accelerating bioconjugate development timelines. Bioconjugates will remain a heterogeneous field with various modalities and technologies. Integrated offerings combining development capabilities into a single solution can significantly accelerate timelines to the clinic. Lonza’s Ibex® Design program, with flexible technology platforms like Synaffix GlycoConnect™, standardizes process and analytical development in a complex landscape.
Advice for process developers
What key pieces of advice would you give to professionals in process development looking to enhance their efficiency and reduce timelines?
SH: Considering manufacturability early in the product lifecycle is crucial, even during drug discovery. This proactive approach avoids detours and iterations on the path to clinical trials. Key factors like process scalability, reproducibility, and robustness should be integrated into the initial design of both the process and the product. This ensures a smoother transition through subsequent development stages, supporting faster time-to-market for bioconjugates.
