Mitigating risk,
maximising reward
Balancing the use of hazardous chemistry in API development and manufacturing
INTRODUCTION
Safely handling
hazardous chemistry
As more complex molecules enter the pipeline, the demand for hazardous chemistry has seen a significant increase. While the use of certain hazardous processes or toxic intermediates has the potential to increase yield, minimise waste or reduce the number of process steps, they can also introduce new risk and safety concerns if not properly understood and managed.
When hazardous chemistry cannot be avoided altogether, thorough hazard evaluation, comprehensive controls and continuous monitoring all play an essential role in maintaining safety throughout the project lifecycle. Maintaining safety while using hazardous chemistry requires extensive experience and resources. This makes outsourcing a compelling avenue for organisations who are either considering or actively embracing hazardous approaches in their programmes.
If you are a pharmaceutical or biotechnology organisation pursuing a programme with hazardous chemistry requirements, keep reading. We’ll explore reasons for using hazardous chemistry, key considerations, steps to success and more.
Speak to one of our hazardous chemistry experts
Why hazardous chemistry?
Because of its reactive nature, hazardous chemistry is not a first course of action. It is typically only applied when other chemistries have been attempted first. There are two key reasons that organisations may choose to apply hazardous chemistry in their projects:
- A hazardous step may be the only viable option to achieve a structurally complex molecule or an intended therapeutic effect. Some syntheses simply require more extreme conditions or more hazardous intermediates.
- Hazardous chemistry may also deliver a more efficient and effective route, such as a higher yield or fewer process steps than other alternatives. In any event, it is critical to carefully assess the level of risk associated with a hazardous step or material, and ensure that the necessary controls can be implemented to safely support the process.
As molecule complexity continues to rise and as equipment and engineering controls become more sophisticated, the prevalence of hazardous processes within the industry has grown. Customers and regulatory authorities alike are committed to maintaining high safety standards in all projects involving hazardous materials and processes.
Insight, applied
During process development on a project at Sterling, a screening identified DAST (diethylaminosulfur trifluoride), a fluorinating agent, as the optimal material for one of the chemical steps.
DAST is known to be highly energetic and potentially explosive. Therefore, Sterling carried out an extensive series of thermal stability experiments in its hazard evaluation lab. In addition, Sterling commissioned specialist explosive screening tests to supplement its internal work and establish safe operating limits for process scale-up.
Identifying the risk
Assessing and mitigating risk begins with understanding the type of hazard present. Hazards can be health-related, involving the use of toxic or potent compounds. Hazards can also be physical, with the potential for explosion, ignition and heat release, among other incidents. Each type of hazard necessitates a thorough approach to mitigate risk and maintain process integrity.
For health hazards
Minimising operator exposure is the key focus when it comes to health hazards. Personal protective equipment (PPE), specialised containment measures like fume hoods and ventilation, and appropriate training and emergency response plans are critical to protecting plant operators from toxic and potent materials.
For physical hazards
Engineering controls, standard operating procedures (SOPs) and regular safety audits are key to ensuring physical hazards are properly contained. Condition monitoring and equipment upkeep are also essential, as they help to ensure consistency over the course of a project and prevent environmental changes that could alter the safety profile. Well-defined response plans and appropriate training are equally critical when working with physical hazards.
TAKE A POLL
Loading ...It is important to note that as scale increases, so does risk. While a process may pose no safety issues at the lab scale, it can prove to be quite hazardous as it scales up and moves to the plant. Proactively considering this potential early on is crucial to maintaining safety. Explore the process below to see how safety impacts can naturally rise as scale increases.
Lab scale
Lab scale
The reaction generates a toxic byproduct, but when handling just a few grams at a time, everything is safely contained using fume hoods and standard PPE. Any incident can be managed relatively easily due to the small volume of material.
Pilot plant
Pilot plant
The volume of toxic material produced increases to tens or hundreds of kilograms, necessitating ventilation systems, more significant containment measures and emergency response protocols.
Manufacturing plant
Manufacturing plant
With the greatest volume of material handled throughout the process, manufacturing also poses the greatest level of risk. Handling the material requires advanced scrubbing systems, and even more extensive containment measures and emergency response planning than at the pilot plant scale.
Regulatory implications of hazardous process design
When harnessing hazardous processes, thorough documentation and controls are key not only from a safety perspective, but also from a regulatory perspective. A number of guidelines and regulations, both specific to the pharmaceutical industry and more general in nature, focus on the safe handling and disposal of hazardous materials. Some of these include:
The Control of Major Accident Hazards Regulations (2015) apply to the EU and UK. These regulations focus on preventing accidents with a designated list of substances, reporting requirements, emergency response plans and more.1
In the US, the Occupational Health and Safety Administration (OSHA) is focused on workplace safety. Its Hazard Communication Standards requires chemical manufacturers to evaluate hazards, provide appropriate labels and safety sheets to employees handling hazardous materials, and train employees to properly handle hazardous chemicals.2
Current Good Manufacturing Practice (cGMP) guidelines cover every aspect of pharmaceutical manufacturing, and include specific guidelines for products involving hazardous substances.3
The United Nations’ Globally Harmonized System of Classification and Labelling of Chemicals (GHS) provides a framework for classifying and labelling chemicals based on the type of this hazard and making this information readily available.4
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) includes safety guidelines that are focused on toxic materials within drug substances.5
Maximising safety and success in hazardous process design
When an organisation decides to pursue hazardous chemistry, whether out of necessity or due to its incremental benefit, it can do so safely and successfully by taking the following steps over the course of its project.
Start early
In order to maximise efficiency and mitigate risk, hazard evaluation should be conducted early in a project, prior to scale-up and manufacture. During these early stages, organisations should look out for potential chemical and physical hazards, assess toxicity and evaluate the operator’s level of exposure to a hazardous substance. Changing processes at later stages can be costly, burdensome and risky, so identifying and accounting for hazards early on can help to avoid setbacks down the line.
Test thoroughly
Hazard evaluation can involve a range of testing, from calorimetry, to powder testing, thermal stability analysis and more, depending on the substance and the type of hazard present. An experienced team should understand which tests to conduct based on the nature of the project. Then, scientists must take care to analyse results to assess the hazard’s full extent, identify the most appropriate controls and recommend next steps.
Leverage an integrated approach
Hazard evaluation and hazardous process design cannot exist in a silo, instead requiring close collaboration with other teams that will be involved in the project from business development to procurement and engineering. For example, the engineering team can provide guidance around what may be needed to safely and successfully fit the project into the site’s existing equipment. By harnessing this multi-disciplinary approach, organisations can ensure everyone involved in the project remains on the same page and considers everyone’s perspective.
Implement controls
The right engineering controls are imperative for containing hazardous materials or processes, avoiding operator exposure and ensuring safety. For example, a process that has the potential for explosion may warrant remote operation and monitoring to keep operators away from the material. Continual process monitoring is also critical to avoiding changes in temperature, pressure, and other conditions that could increase risk.
Account for process changes
Any change introduced to a process can come with potential new hazards that must be accounted for. Changes to environmental conditions, reagents, solvents and other components can impact both safety and compliance. When implementing these changes, it is critical to reassess risk and ensure that the appropriate safety thresholds are still being met.
Want to learn more about hazardous process design in action?
Diazomethane is a highly reactive compound that can detonate even in the absence of air. Our team performed extensive research and testing to set an upper exposure limit and implement thorough engineering controls, enabling us to support processes involving diazomethane with zero safety incidents.
A diazomethane deep dive with Sam Brogan, Global Director of Research and Development
Why is hazardous chemistry so prevalent within the pharmaceutical industry? What does hazardous process design look like in action? We asked Sam Brogan, Global Director of Research and Development at Sterling, to hear her perspective.
Q:Why is hazardous chemistry so important in the industry right now?
Hazardous chemistry has always had a role across chemical industries. The pharmaceutical industry is no exception, in fact, we’ve been supporting hazardous substances and processes for our customers at our Cramlington site for more than 40 years now.
Obviously, if people are willing to take on this risk rather than avoiding hazards altogether, there must be a reason people are using hazardous processes or materials in their projects. On projects where we use hazardous chemistries with our customers, other materials or routes have generally been explored before determining that the hazardous process is the most effective one, for one reason or another.
For example, a hazardous route may simply be the most efficient means to achieving a desired molecule. Maybe that means higher yield. Or maybe it’s that the process can be completed in fewer steps, delivering greater efficiency and cost-effectiveness. No matter the reason, a hazardous route may deliver significant advantages over alternatives that might make it worth taking on the risk, assuming that an organisation can safely support the process.
Other times, the more hazardous way may be the only way. This can come up with more complex molecules in particular. We’ve had customers who have tried a variety of routes to achieve their intended molecule or therapeutic effect, and they find that the hazardous route is the only way that’s working as desired.
Q:Can you provide some background on Sterling’s work to support diazomethane projects?
Diazomethane is a powerful methylating agent, so it has many potential uses in pharmaceutical development and manufacturing. But, few people are using it. That’s because it is highly reactive and highly explosive, with the potential to detonate even in the absence of air.
On top of that, diazomethane is also a highly toxic respiratory irritant, and can also be harmful if absorbed through the skin. So not only is it a significant physical hazard, but it’s also a potential health hazard. It’s not even commercially available—because it is so explosive and unstable, and can decompose quickly in storage, it’s generally prepared for immediate use.
As you can imagine, that makes it very difficult to work with at the manufacturing scale. Any existing literature we were able to find on it came from academia and dealt with quite a small scale.
Our team has extensive experience in hazardous chemistry, but we don’t take on any work before we’re 100% confident we can handle it safely. A significant amount of research and testing went into being able to support diazomethane reactions at scale.
Q:What happened when the project was ready to move to the plant scale?
After initial explosion testing, we performed additional testing and assessed the explosivity in air and nitrogen. After numerous tests, we were able to determine how much material we could have in a reaction vessel at a time while still maintaining safety. We included a large safety margin in this estimate to mitigate risk as much as possible, then ultimately brought the process on plant. To date, we’ve had zero safety incidents and have supported diazomethane processes on plant up to a 100 kg scale.
Q:What sets Sterling’s approach to hazardous chemistry apart?
Our hazard evaluation team is involved from the earliest stages of a project, which is not something you see all the time. We have a say in what projects we take on and how we go about them, as do all of the teams that will be involved in a project throughout its lifecycle. This is key because it ensures we will be able to support the entire project with confidence.
Of course, the collaboration doesn’t stop in those early stages. We maintain consistent communication with chemists, engineers and others to make sure we are aligned on project requirements and progress at all times.
Another one is our breadth of expertise. We can support reactions involving phosgenation chemistry, carbonylation chemistry, hydroxylamine reactions, materials like carbon monoxide, cyanide, and highly potent APIs, and the list goes on. If a customer comes in with a type of material or process we aren’t as familiar with, it’s likely that we’ve worked with a similar hazardous process that involves many of the same principles and controls. And this range of expertise is always growing as we take on new projects.
Supporting hazardous processes with Sterling
When it comes to hazardous chemistry, working with the right partner is as important as having the right equipment and controls.
At Sterling, we deliver more than 50 years of expertise in hazardous chemistry. By leveraging multi-disciplinary expertise, close internal collaboration, state-of-the-art equipment, and a range of testing approaches, we set our customers’ hazardous processes up for success.
Here are some of the things that set us apart:
-
A dedicated hazard evaluation team that works closely with our chemistry, engineering and procurement teams, and reviews every project, to maximise safety across the full molecule lifecycle. -
A range of testing capabilities, including reaction calorimetry assessment, thermal stability analysis, emergency relief design and dust explosion measurements. -
Experience in projects involving diazomethane, fluorination, cyanide, carbonylation and other hazardous materials and processes.
Helpful resources on hazardous chemistry
Explore the resources below to learn more about hazardous chemistry and our approach at Sterling.
Poster Presentation
Making sense of hazardous chemistry
Scenario Sheet
Designing a safe and scalable diazomethane process
Technology Page
Diazomethane
Technology Page
Hazard evaluation
Technology Page
Hazardous chemistry
Blog
Journey of an API: Evaluating and mitigating process hazards
