Process Optimization & Scale-up

Late-stage development is a critical phase for optimizing and scaling up the manufacturing process of small molecules, ensuring that the drug substance can be efficiently produced at a commercial scale. At Aragen, our Process Development & Optimization services are designed to ensure that your small molecule is developed efficiently, with a focus on improving yield, repeatability, minimizing costs, and enhancing product quality. We follow RFT (Right First Time) approach by using Quality by Design principle during process development. Our team work closely with you to refine each step of the process, from the initial synthesis to final manufacturing, to ensure your product is ready for the complexities of large-scale production.

By leveraging advanced technologies like DoE, BlazeMetrics, Flow chemistry, rigorous testing, and a deep understanding of pharmaceutical manufacturing, we help you achieve a seamless transition from clinical phases to commercial-scale production. Our expertise ensures that your process is not only scalable but also optimized to meet the growing demands of the market while maintaining product quality and regulatory compliance.

Process Development & Optimization Services

We specialize in refining and enhancing processes that are already in development, focusing on safety, optimizing yield, purity, and efficiency as you transition from clinical phases to continuous large-scale manufacturing.

Comprehensive Process Analysis

Our experts follow DMAIC methodology in all the process development activities. Our experts continuously interact with your team to understand the process in detail and identify the problem statement (potential inefficiencies, bottlenecks) to finalise the objective for the study.  We use advanced modelling and simulation tools, in-line PAT (Process Analytical Technology) tools to track the process and predict how small changes might affect large-scale production allowing us to proactively address issues before they arise. This process includes:

• Establish baseline performance of process:  We assess the current process past data and analytical measurement system to access the process capability to meet desire specification and analyse the frequency of problem or cause. important factors such as yield, cycle time, cost per unit, and purity to create a baseline for optimization.
• Root-cause analysis: A deep dive into your current process and historical data to identify specific root cause to the failure/problem to plan the mitigation strategy.
• Risk assessment:  Using our extensive knowledge of industry standards and historical data, we identify risks associated with scale-up and regulatory compliance.
• Process Improvement by DOE: We follow scientific, and data driven approach by using DOE tools for process optimization by identifying the critical process parameter and developing the optimum design space to meet desire specification.
• Control strategy: Once the process is developed, we identify the risk associated with the process with respect to scale-up and implement appropriate control strategies to mitigate/avoid the risk.

Process Improvement/ Refinement

Our process improvement/refinement services focus on optimizing key aspects of the manufacturing process to improve yield, purity, efficiency, and scalability while minimizing costs and environmental impact. To achieve them, our experts follow scientific and data-driven approaches including:

• Process understanding: Detailed process discussion to understand the problem statement followed by appropriate root cause analysis to identify the cause.
• Reaction Optimization: We use Design of Experiment (DOE) tool considering critical process parameters Like, temperature, pressure, solvent, catalyst etc. for process development and to create optimum design space. Our expert crystallization team focus on robust crystallization process development to achieve targeted specific physical attributes. We use advance PAT tools to monitored entire process inline to understand the process kinetics to improve process efficiency and reduce unwanted by-products. 
• Reaction Optimization: Refining reaction conditions (e.g., temperature, pressure, solvent, catalyst choice) to improve reaction efficiency and reduce unwanted by-products using Design of Experiments (DoE).
• Purification Streamlining: Developing scalable purification techniques like crystallization, silica treatments to improve product purity and reduce waste.
• Waste Reduction: Minimizing solvent consumption, recycling, reducing environmental impact, and lowering overall production costs through process redesign.
• Solvent & Material Selection:
  • Solvent Selection: Choosing environmentally friendly, cost-effective solvents that improve reaction efficiency at larger scales.
  • Raw Material Sourcing: Identifying reliable, cost-efficient suppliers for key materials to ensure a consistent supply while optimizing cost.
  • Green Chemistry: Applying sustainable practices such as solvent recycling and the use of renewable materials to improve the process’s eco-friendliness and long-term viability.
  • Establish Design Space: Establishing an appropriate design space for the process, using DoE and PAR/NOR studies, which helps define acceptable operating ranges for process parameters and ensures robust, scalable operations.

Scale-Up Services

Successful scale-up is critical for moving a small molecule from the lab to large-scale commercial production. We are experts in managing the challenges of scaling, from volume increase to process consistency, while ensuring product quality and regulatory compliance are maintained at every step. Our scale-up services ensure that your production process maintains consistency and efficiency at every stage.

Lab-to-Pilot and Commercial-Scale Transition

Our team excels at translating lab-scale processes to pilot- and commercial-scale production, maintaining the integrity and performance of your small molecule throughout. We manage this process through:

• Process Engineering studies (Scale-up/down studies): We perform detailed process engineering studies on the optimized process before manufacturing to check the process robustness in terms of scale-up parameters like occupancy, mixing, addition rate, cooling rate etc. The data obtained from these studies ensure smooth scale-up with any process failures.  
• Process Simulation and Modeling: We leverage advanced modelling tools like Dynochem to simulate potential scale-up challenges and identify solutions early. This approach optimizes process parameters, reduces risks, and ensures smoother transitions.
• Pilot-plant Trials: Our pilot-plant facilities enable us to test new process parameters, fine-tune reaction conditions, purification steps, and overall process flows while maintaining cost-effectiveness and operational efficiency.
• Process Documentation and Tracking: Detailed process documentation is maintained throughout the scale-up journey to ensure all changes are traceable, enabling regulatory compliance and smooth inspections. We use Electronic Laboratory Notebooks (ELNB) for seamless data recording and management, ensuring that all experimental data, process parameters, and adjustments are captured electronically. This provides a secure, accessible, and auditable record of your process development and scale-up activities, supporting 21 CFR Part 11 compliance and simplifying the regulatory submission process.

Production Volume Management & Capacity Optimization

Scaling a process goes beyond expanding batch size and is about ensuring consistent quality and reliability across all stages of production. Our scale-up services include:

• Capacity Assessment: We assess your current and future production needs, determining whether additional resources, equipment, or facilities are necessary for optimal production.
• Process Cycle Time Optimization: We fine-tune each step of the production process to reduce cycle time, increase throughput, and maximize productivity to enhance efficiency, lower costs, and meet critical deadlines.
• Automation and Monitoring: Cutting-edge automated systems are used for real-time monitoring of key process parameters (temperature, pressure, flow rates, etc.), ensuring real-time adjustments and consistency during scale-up.

Minimization of Impurities and Variations During Scale-Up

One of the most critical challenges during scale-up is minimizing process variability and ensuring consistent product quality. Our approach includes:

• Critical Process Parameter Monitoring: We continuously monitor key process parameters (temperature, pressure, flow rates, etc.) to ensure they remain within acceptable limits during scaling.
• Variation Control: We implement strategies to reduce the impact of minor variations in raw materials, equipment, and environmental conditions that can lead to differences in product quality.
• Quality by Design (QbD): By implementing QbD principles, we build robustness into your process from the beginning, anticipating risks and optimizing at each stage to ensure a predictable, scalable, and high-quality process.

Advanced Reactor Systems for Large-Scale Production

Our Scale-Up Lab is equipped with a range of state-of-the-art reactors and equipment designed to handle the increased volume and complexity of late-phase drug substance production. We offer reactors from 60L to 630L and utilize a variety of associated utilities to optimize your manufacturing process.

• Reactor Types: We use a combination of All Glass, SS-316, and Hastelloy reactors (ranging from 50L to 250L) to accommodate a wide array of chemical reactions and conditions. These reactors are designed for flexibility, durability, and high performance across different scale-up activities.
• Temperature Range: Our reactors operate across an extensive temperature range of -78°C to +200°C, which allows us to handle both low-temperature and high-temperature reactions effectively.
• Associated Utilities: Specialized utilities such as nitrogen supply, breathing air, and hot water systems support the reactors, ensuring optimal operation. These utilities are critical for managing temperature, pressure, and environmental conditions, which guarantees consistent and reliable production.

Additionally, our facility is equipped with a range of advanced systems designed to handle a variety of reaction conditions and production scales, from small-scale synthesis to kilogram-scale manufacturing. These include:

• Double-Jacketed Radley Process Reactors (1L to 20L)
• Heidolph Rota-Evaporators (up to 20L) 
• PAR Hydrogenators (250mL to 2L)
• Autoclave/Pressure Vessels (up to 20L, 100 bar, 250°C) for multi-gas reactions
• Vacuum tray driers for controlled drying processes 
• Centrifuges with Halar coatings for efficient separation
• Nutsche filters for precise product purification and filtration