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Early engagement with the client to understand goals and timelines –

• Enabled strategic risk management, reducing development time and ensuring a seamless transition into GMP manufacturing.

Strategic route scouting and Design of Experiments (DoE) approach –

• Optimized key intermediate synthesis, enhancing scalability and robustness for GMP production.

Safety assessment before GMP manufacture –

• Identified and mitigated risks, ensuring a safe and compliant manufacturing process.

Advanced analytical capabilities and method validation –

• Ensured high-quality API with well-characterized impurity profiles, meeting regulatory requirements.

Frequent client updates and structured technical transfer protocols –

• Facilitated smooth knowledge transfer and ensured alignment with client expectations.

Process development

We utilized the HEL PolyBlock 4 to:

• Rapidly assess process variations, identify critical process parameters, and perform precise heating, cooling, and liquid additions.
• Achieve precise and repeatable mixing, which enabled the identification of raw material particle size criteria impacting a key heterogeneous coupling reaction.
• Optimize the key intermediate synthesis step using a Design of Experiments (DoE) approach, improving both yield and purity for GMP manufacture, with a xx% increase in yield and significant impurity reduction.

Challenges with final crystallization, caused by an unidentified impurity, were resolved by modifying conditions with co-solvent and seeding techniques. This resulted in a more robust and repeatable crystallization process. We also explored the use of flow chemistry to manage a fast and highly exothermic reaction step in the intermediate synthesis, demonstrating its potential scalability.

Process safety

Before GMP manufacture, we conducted a comprehensive process hazard assessment to ensure all safety aspects were addressed. Key activities included:

• Utilizing DSC, TSU, and reaction calorimetry to evaluate exothermic reaction hazards and gas evolution.
• Performing RC1 and TSU testing to gather critical data on adiabatic temperature rises, gas generation, and reactant accumulation.

These insights enabled the determination of safe operating parameters for the process. The process safety data was instrumental for further scale-up and supported Hazard and Operability Assessments (HAZOP), increasing confidence in route selection and minimizing risks.

Manufacture

For manufacturing, we employed specialized equipment tailored to the needs of this process:

• A 20 L Büchi jacketed Hastelloy GMP vessel was used for a key transformation, mitigating potential in-situ HF generation. This material provided excellent corrosion resistance and a seamless transition from kilo to pilot scale.
• A 60 L jacketed Büchi GMP vessel equipped with a Huber 161W thermoregulation unit was utilized for larger volume steps and the final API crystallization. The vessel was modified for in-process monitoring and sampling.

An additional smaller header vessel enabled manipulation of highly air-sensitive reagents, while hazardous intermediates were transferred and isolated using a contained filter system. Key impurities were identified and trended, providing valuable data for the client. Throughout the project, frequent updates were provided by a multi-disciplinary team, supported by dedicated program management. Technical Transfer Protocols (TTPs) were developed to incorporate process knowledge and improvements gained during kilo-scale manufacture.

Analytical / release testing

We ensured consistency and reliability by executing test method transfers for in-process control (IPC) methods. Key activities included:

• Testing registered starting materials (RSMs), raw materials, and intermediates, coordinated by the quality team.
• Developing and validating analytical methods to support specification setting and final API release.

A wide range of analytical techniques was employed:

• HPLC/UPLC
• Headspace Gas Chromatography (GC-HS)
• Ion-chromatography (IC)
• Particle size distribution (PSD)
• X-ray powder diffraction (XRPD)
• Inductively coupled plasma-optical emission spectrometry (ICP-OES)

To ensure effective cleaning of manufacturing equipment post-API manufacture, we developed a cleaning verification method, providing additional assurance of product integrity.

We accelerated hit-to-lead to candidate nomination, supported by robust analytical data that facilitated informed decision-making. Our successful route scouting and DoE experiments improved yields and significantly enhanced the purity profile of the API.

Process development and optimization delivered a chromatography-free, convergent synthesis, while comprehensive safety data provided greater confidence in route selection and necessary engineering controls. Additionally, our manufacturing approach utilized specialized and validated processing equipment representative of pilot and commercial plants.

By addressing common transfer issues early, such as mass transfer, reaction kinetics, and material properties, we mitigated risks associated with scaling up from lab-style glassware. The API was delivered on time and in full, meeting the agreed quality specification. This empowered the client to progress to clinical trials with confidence.