Scaling-up drug development processes from small lab-based synthesis to full-scale manufacturing comes with significant challenges. Not least are the numerous safety risks involved, the majority of which arise from changes in heat-loss behavior when materials are handled at scale. To manage such thermal and pressure hazards, a safety orientated approach needs to be adopted that ensures threats are identified, assessed, and mitigated at every stage of the development pipeline.

Ensuring that complex, high-hazard environments can run over consistent periods without causing serious accidents or catastrophic failures exemplifies a Highly Reliable Organization (HRO). Nuclear power plants, air traffic control systems, and naval aircraft carriers are textbook examples for applying HRO theory, but these fundamental principles can equally be applied to a wide variety of other industries and settings. The pharmaceutical sector is one such practitioner, adopting HRO methodologies in many scale-up manufacturing processes.

Process safety: the critical consideration for safe scale-up
Hazard assessment along the product development journey needs to be extensive and rigorous to achieve a successful scale-up. Hazard evaluation must be adopted early and conducted throughout the entire development process. A systemic approach is needed so that colleagues from discovery, process chemistry, and commercial teams can effectively work together. HROs only achieve the highest standards of reliability by relentlessly prioritizing safety over other performance criteria and ensuring safety is maintained as the top priority.

Process safety can be broken down into three broad areas with each being an essential step to reducing manufacturing risks. Completing all stages helps to achieve a safe and efficient scale-up while keeping the organization focused on safety. The three stages are:

• Screen for potential hazards;
• Evaluate main reactions, including possible unintended side reactions, and mitigate the hazards present; and
• Recognize the impact of “what if” scenarios to implement appropriate safety and control strategies.

Mitigating hazards with organizational safety mindfulness
Karl E Weick and Kathleen M Sutcliffe1 argued that a critical quality of HROs is their success at continually reinventing themselves. Weick and Sutcliffe found implementing five characteristics gave HROs a “mindfulness” that sustains safety levels when unexpected situations have to be faced (see Figure 1).


HROs are aware that new threats to safety continuously emerge, uncertainty is endemic, and no two accidents are exactly alike. They take an ever-questioning mindset to process safety in the context of product development challenges.

Pharmaceutical manufacturing and scale-up extensively benefit when adopting these five strands of safety mindfulness. Not only will it lead to well-implemented process safety, where hazards are mitigated at each stage, but it will also help build a robust safety culture into all operational activities. It is worth appreciating, a process can be designed to have low severity of hazards but could still be high risk and dangerous if not operated correctly.

Taking a comprehensive approach to testing
Considering product development systematically, the pre-manufacture journey falls into clear stages — discovery, process development, and scale-up. Each stage requires high safety mindfulness with extensive testing throughout each workflow (see Figure 2).


Discovery testing will be broad and typically happens at pace. Leaving too much lab-based safety testing to the process development phase is too late, as this testing usually takes more time, thus impacting the time to market. Manufacturers should gain sample understanding at a small, cost-effective scale to identify significant risks and prevent delays during process development. The knowledge gained here is expected to shape all future decisions around how further testing is carried out on desired reactions and synthetic routes.

For the most impact, discovery testing extends from raw materials and processes through to prototypes and end products. The desired primary reaction is assessed and characterized, and any possible additional thermal and pressure hazards during operation are identified.

This screening across various metrics is achieved by taking many candidate molecules and reaction processes from a large group of samples. Outcomes need to be supported with sufficient data to allow for impactful, rapid decision-making. These outcomes could be which synthetic route is chosen or which solvent the final product will be stored in. This early stage is the preferred time to evaluate potentially unsafe materials or synthetic routes and inform the selection of alternative, lower-risk options.

To meet discovery testing targets, micro-scale calorimetry can quickly screen the thermal properties of raw materials, but it is incapable of providing critical information on pressure change rate—a vital metric for assessing possible explosion hazards. The challenge to obtain representative samples of raw, pure materials and reaction mixes must also be faced to avoid a negative impact on rapid, extensive sample size screening during process development. Preferred solutions should allow fast temperature and pressure screening on the same platform to speed up the time to manufacture. For example, a device such as the TSu Thermal screening unit enables rapid, simultaneous screening of both the temperature and pressure characteristics of a sample. It can be considered a complementary or even alternative technique to the classical DSC/DTA (Differential Scanning Calorimetry / Differential Thermal Analysis) methods. In comparison to methods such as DSC/DTA, the TSu data includes sample pressure changes, which have the potential to be more hazardous than thermal changes.

Demands for further testing and retesting made by those in process safety are not intended to slow down discovery, but rather to improve process development and scale-up as a whole. As reagents are used in very small amounts, retesting is possible and should be common practice. Completing such high levels of testing in early discovery may create time and scheduling conflicts, but it is a requirement to keep simultaneous projects moving at speed.

Extensive analysis for a comprehensive understanding of the process
Process development helps determine a more complete understanding of the desired synthetic route. It is relied on to deliver a comprehensive approach to hazard evaluation and mitigation against these consistent scenarios:

• Full exploration of the desired reaction;
• Avoidance of reaction thermal runaway; and
• Modifying operating conditions to reduce or eliminate identified hazards

Hazard screening and reaction calorimetry should both be applied. This testing identifies and measures hazards involved in selected synthesis reactions and determines the manufacturing plant’s necessary cooling capacity to maintain safe operating conditions. Usually, the manufacturing plant’s cooling capacity is a fixed value, and it is the process that is designed and modified around the existing hardware limitations. This could ultimately mean that sub-optimal chemical processes are utilized due to the hardware’s limits but would ensure a robust and safe manufacturing process.

Instrumentation must deliver scale-up functionality with HRO thinking
The breadth of scale-up testing should always extend to simulate different reaction scenarios and produce a robust results comparison. The most effective testing tools need to illustrate various outcomes: from the worst-case scenario to those with far less impact.

The scale-up challenge here is that large-scale reactors, like those utilized in manufacturing and pilot plants, typically behave adiabatically, meaning they lose very little heat to their surroundings. This behavior is very different from smaller, lab-based vessels that proportionally lose far more heat. Such variants in heat retention are a significant potential problem for scale-up. If left unaddressed, at the manufacturing scale, the system could retain too much heat, which at best would result in more plant cooling required for temperature control, and at worst, trigger a thermal runaway reaction.

Specialized adiabatic calorimeters can use low thermal mass test cells, providing a low Phi-factor. The Phi-factor is based on the ratio of a vessel’s total heat capacity to that of its contents. The sample then responds very similarly to how a large-scale manufacturing plant would. Proportionality, less of the heat produced during reaction and runaway, is spent warming up the test cell, as the test cell has less thermal mass. The thermal energy then goes back into the sample, heating it further, which increases the kinetics of the reactions and further increases the heat release rate. Because of this, a low Phi-factor system will closely mimic the behavior of process-scale vessels but at a lab-scale. The data generated from low thermal mass test cells provide the basis for calculating critical safety systems, such as vent sizing.

Replicating HRO achievements with a robust process safety culture
The need for all lab, bench and production stages to have a good process safety culture in place is strongly evidenced. Investigations of catastrophic events repeatedly identify that safety culture weakness is a factor in serious incidents. The U.S. Chemical Safety Board (CSB) investigated multiple sulfuric acid releases at the Tesoro Martinez Refinery in California in 2014.² The first of these caused approximately 84,000 pounds of acid to be released. Less than a month later, a second incident occurred in the same unit. Following investigations into both incidents, the CSB concluded that the plant’s weak safety culture created conditions that made incident recurrences far more likely. It then transpired that over several years in the run-up to the major event there had been various minor safety incidents causing worker injuries.

“A strong process safety culture is necessary to help prevent process safety incidents and worker injuries.” —US Chemical Safety Board

Top to bottom safety culture
To bring about significant changes in safety, a rigorous safety culture must be embedded at corporation, facility, and team levels. It comes about by taking calculated and consistent action and recognizing that long-term effort is required to maintain the culture for the organization’s lifetime. What’s needed is the creation of a new normal, one that extends across all staff changes and management concerns.

Effective communication
Effective communication is key for cultural changes to be adopted and maintained. As speed constraints and harder challenges are increasing pressure for those working in pharmaceutical discovery, this is not the time to work in isolation. It is essential that everyone involved in the process, especially those with safety expertise, understand results and outcomes as they happen. Any safety-related data should be extensively shared.

Expertise and insight
Process safety expertise from experienced professionals working across the process scale-up workflow must be a feature in decision-making. Their insights in risk mitigation can provide great support from a manufacturing perspective and shape material testing constructively. Applying the concepts of safety mindfulness helps steer the workings for all professionals throughout the workflow.

These changes in the safety culture will ultimately improve the company’s efficiency and reliability. Process safety can help design a very safe process with as few hazards as possible. However, it is ultimately the company’s safety culture that dictates a safe and effective route to market for a product.

Summary
There are many hazards with bringing a lab-scale process to the manufacturing scale. These hazards need to be identified, assessed, and mitigated at each stage of product development. By designing safety into the development process and building a strong safety culture in the company, these hazards and their associated risks can be significantly reduced. This helps deliver confidence in a safe and efficient scale-up process. 

References

1. Karl E. Weick, K. M. (2015). Managing the Unexpected, Third Eddition. Wiley.
2. U.S. Chemical Safety and Hazard Investigation Board, C. (2016, October). Tesoro Martinez Final Case Study. Retrieved from CSB: https://www.csb.gov/tesoro-martinez-sulfuric-acid-spill/

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As Application Leader, Joseph Willmot works with H.E.L customers helping them solve complex challenges and find the best solution for individual applications. For this, Joe calls on his three years of experience as Project Manager at H.E.L where he gained insight into the functionality of the company’s range of scientific instruments and software. Prior to joining H.E.L, Joe worked as an Analytical Chemist at BP for two years after gaining his degree in Chemistry from the University of South Wales.