Any manufacturing process has inherent safety risks, so it is essential to identify and reduce potential hazards before production begins. At Teva api, we are always looking for ways to improve methods and ensure best practices, and that includes making our manufacturing plants even safer, to protect our employees and keep production on schedule.
Identifying, assessing, and characterizing intended and, more importantly, unintended chemical reactions are critical to ensure safe process scale-up and different unit operations. Two years ago Teva api R&D began developing an innovative method that would pinpoint risk factors early on – during the design process – so we could recommend preventive safety measures before production got underway. We call it Safety by Design (SbD) based on the methodology used for pharmaceutical Quality by Design principles, which use a scientific approach to control product quality and process robustness (FDA 2008, Guidance for Industry: Q8 (R2) Pharmaceutical Development). SbD follows a similar method, using computer-aided process design and simulation tools to integrate safety, quality and productivity throughout the product lifecycle.
While SbD is still in the early stages of implementation, results are promising in the pilot and production plants that are following this process. They are successfully using this comprehensive data to minimize hazards, control health and safety risks. Teva api’s commitment to target zero safety incidents with the implementation of this new model has distinct advantages for customers. In comparisons to API manufacturing facilitates without systematic safety procedures, SbD reduces development time, which helps make the process more efficient. It enables Teva api to continue producing the high quality products our customers expect and delivering them without interruption.
Simulations and modelling are the backbone of Safety by Design
Most organic API synthesis processes are exothermic, meaning they produce heat. During production, excess heat must be removed to prevent possible undesired scenarios. In addition to being a safety issue for workers, the facility and the environment, excess heat can produce impurities, which affect active pharmaceutical ingredient quality.
We use reaction calorimetry to measure the maximal temperature of synthetic reaction (MTSR) and differential and/or adiabatic calorimetry to measure the critical temperatures to find the temperature of decomposition. The measurement is rated on a scale with five (5) classifications (Francis Stoessel: Thermal Safety of Chemical Processes: Risk Assessment and Process Design, Wiley 2008.). For example, a Class 1 process is considered safe – a temperature increase would not be considered dangerous. Class 5 represents the highest level of risk. If a cooling failure occurred, the molecules could decompose causing a thermal explosion. In Class 5 scenarios, the process either needs to be redesigned during development to reduce the criticality level, or additional safety measures need to be implemented during production.
In creating Safety by Design, our goal was to take the traditional approach to the next level. We developed a more comprehensive method using process simulation tools and mathematical models to predict real case scenarios in production. We know that calorimetric measurement can also provide kinetic data, and when supported with other analytical tools it can be used to determine reaction rates and potential side or runaway reactions. Combining the heat and mass transfer, thermodynamics, and the kinetics of the reactions, models can determine whether a process will be safe or unsafe. We can then easily adapt the findings to the operating conditions and equipment in a particular plant in a specific country.
By developing sophisticated computer models with process simulators, we learned that in the early phase of process development, we could predict and prevent hazards, control risks and help optimize the overall process. A systematic approach helped us gain a better understanding of potential safety issues by considering the reactants used in the process, their physical and chemical properties, the process conditions, heat and gas evolution, the equipment used in the process during the development stage, and ﬁnally, scale-up to production.
Case studies: How SbD reduced risk in API production
In two early test cases, process evaluation and modeling validated the importance of identifying potential hazards and engineering solutions during lab development.
Removing thermal instability: After running a specific API product through a safety assessment, the adiabatic calorimeter results indicated that process criticality was Class 5 due to the decomposition of solvent, DMSO. Further simulations also predicted that the process criticality would reach the highest risk. Redesign of the process is performed using different solvents and SbD evaluations to make the process safer. When we substituted the solvent DMSO with DMAc, the heat and pressure generation from secondary reactions dropped significantly and lowered process criticality to a much safer Class 2. The recommended solvent change increased operation safety without impacting product quality.
Reducing reaction conditions: We experienced a similar outcome when we ran a specific API product, one step through the SbD process simulation. When the solvent DMSO was used in the reaction mixture, the models showed the rate of heat generation could quickly rise to unsafe levels, making the process potentially thermally unstable (Class 4-5). By replacing DMSO with DMF in the process simulation, the reaction mixture safely stabilized without any safety risk (Class 1) and avoiding production delay.
In both cases, comprehensive evaluation during process design provided a clearer understanding of the potential dangers and gave us the opportunity to develop much safer solutions. In production, the solvent changes were successful and much safer, without impacting product quality or cost.
Continuous improvement makes best practices even better
In order to help us bring to our customers the best quality product in the most cost-effective manner, Teva api continuously pursues better methods and more advanced technologies to stay ahead of the curve. Safety by Design is a different approach – it elevates process safety to the same level of importance as product quality and environmental impact. But most importantly, it provides a framework for saving lives, preventing injuries and producing safe, high quality APIs for the most efficient and timely product delivery for our customers worldwide.
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