Journey of an API: Evaluating and mitigating process hazards

The use of very hazardous materials and processes in a pharmaceutical manufacturing project typically is not an organisation’s first choice, but there are scenarios when a more hazardous approach may be extremely optimal or inevitable. No matter the project, thorough hazard evaluation is a critical step in an API’s journey, responsible for ensuring a process scales safely and efficiently without putting product quality, equipment, or—most importantly—people at risk.

As we cover this stage of the API’s journey to market, we’ll take a closer look at hazard evaluation’s role in maintaining product quality, adhering to regulatory requirements and protecting operators. Read on to explore some of hazard evaluation’s key objectives and potential roadblocks along the way, and get a glimpse into our hazard evaluation approach at Sterling.

Breaking it down: Understanding and limiting risk

Hazards can come in various forms in API development and manufacturing, and risk only increases as a process scales. Hazards can arise due to toxic, energetic or unstable intermediates that are indirectly involved in synthesis, or due to a specific manufacturing process that can create the potential for explosion, heat release, ignition and other incidents.

Hazard evaluation aims to fully understand the potential safety risks that exist in a process early on and evaluate their potential impact, so that scientists can then take measures to eliminate the risk altogether or implement the controls necessary to support the process without compromising safety. Given the potential risks of bringing a hazardous chemical process onto the plant, hazard evaluation marks one of the most important components of an API’s journey.

Measuring success: Key objectives for hazard evaluation

Fundamentally, the success of any hazard evaluation effort is measured by the safety of the project as it scales. However, there are specific objectives and metrics scientists can use to evaluate the success of their hazard evaluation work.

Hazard evaluation should enable scientists, engineers and production staff to gain a comprehensive understanding of the potential hazards in a programme. Even more importantly, it must uncover the extent of any hazards that are present. Will the amount of heat released create a risk from an uncontrollable reaction or decomposition. Could an explosion occur and at what scale? Scientists require insight into the full range of hazards before they can take effective measures to eliminate or contain the risks.

How it’s measured: A multitude of tests can be leveraged in hazard evaluation to measure the level of risk involved. Reaction calorimetry is used to identify the potential for heat generation or absorption in a chemical process. Dust explosion testing, such as minimum ignition energy (MIE) identification, and electrostatic testing aid in understanding a powder’s susceptibility for ignition or explosion under given conditions. Differential Scanning Calorimetry (DSC) and Accelerating Rate Calorimetry (ARC) may be used to evaluate thermal stability and decomposition behaviour at certain temperatures. A comprehensive hazard evaluation programme typically involves a combination of these approaches, and more, to deliver a full picture of risk.

When a hazard cannot be removed altogether, hazard evaluation seeks to identify and quantify hazards, and support the design and implementation of appropriate engineering controls. The hazard evaluation team provides comprehensive data to the project team, allowing them to define engineering controls and outline strategies to minimise risk. Engineering controls vary based on the types of hazards involved. For example, health hazards and toxic materials may necessitate personal protective equipment (PPE), fume hoods and ventilation measures, while the threat of heat release may require emergency shutdown systems, isolated production suites and other controls.

How it’s measured: Specific engineering controls are evaluated using several techniques. Containment efficiency testing, which uses non-hazardous materials to measure concentration both within and without the contained system, may be used to gauge the effectiveness of containment measures. Leak monitoring and testing is also important for ensuring containment measures are working properly. In addition, an onsite hygiene programme involves monitoring activities to determine if chemical concentrations remain below designated occupational exposure limits (OEL). The use of personal protective equipment that is appropriate for the level of hazard present may also be used in conjunction with engineering controls.

Ultimately, hazard evaluation’s core objective is to identify chemical reaction hazards, then work with project teams in reducing the risk involved in an API manufacturing programme, eliminating hazards altogether when possible. In some cases, that means taking the less hazardous of two potential approaches. For example, if one approach requires a toxic reagent, but another approach involves a less toxic alternative, the less hazardous approach may be used, even if it requires an additional step. In other cases, however, hazards cannot be avoided, making ongoing monitoring and controls critical.

How it’s measured: Perhaps the most obvious measure of success for hazard evaluation is whether any safety incidents occur as a process scales. If any accidents do occur, no matter the size, scientists should conduct a thorough investigation to understand why the accident occurred and how it can be prevented in the future.

Overcoming obstacles: Addressing common hazard evaluation challenges

Obstacles related to hazard evaluation are more than inconvenient to the programme. Failing to adequately address them can have substantial implications for the safety, compliance and quality of a project. Below are some of the most common challenges that can arise at this stage of the API’s journey.

Successfully scaling a process is challenging for many reasons, but it is especially challenging from a hazard perspective. Hazard increases significantly with scale; while a process may present minimal risks at the lab scale, these risks become much more substantial on a plant scale. Therefore, hazard evaluation must proactively account for risks that might occur at larger production volumes. In addition, the equipment used to evaluate a process at the lab scale should mimic plant conditions as closely as possible, ensuring that the process is compatible with the equipment on plant while maintaining safety.

Process changes are another project element that can present challenges to hazard evaluation. As a project progresses, process changes may be considered to enhance efficiency, contain costs, improve environmental sustainability or deliver other advantages. Whenever a change occurs, no matter the size or significance, scientists must ensure that no new hazards are introduced as a result. This is important not only from a process safety perspective, but also from a regulatory one, as all elements of the process must be properly documented to ensure ongoing compliance.

While a designated hazard evaluation team is typically responsible for conducting hazard testing and raising potential safety issues, cross-departmental team members all play a role in maintaining continued process safety. For example, the hazard evaluation and chemistry team must closely collaborate during the early stages of a project to ensure that they are developing a process that is as safe and scalable as possible. The engineering team must be made aware of any specialised containment measures or ventilation requirements early on, so that they can make the necessary adjustments before the project transitions to the plant. On a broader scale, team members across the entire facility should have emergency response training to know how to efficiently and effectively respond in the event of a safety incident. This level of collaboration and integration across teams can be difficult to achieve and maintain, but it is imperative from a safety perspective.

Back to the big picture: Integrating hazard evaluation from the start

Hazard evaluation plays an important role from a project’s onset, as scientists aim to identify potential chemical and physical hazards, understand their potential impact, and evaluate toxicity and operator exposure. Generally, identifying hazards earlier is better, before they become larger issues on plant.

However, effective hazard evaluation does not end in the early stages of a project, nor does it occur in a silo. Anticipated hazards should be revisited as the project scales, and continuous monitoring should be carefully employed to observe process conditions. From the earliest stage to the latest stage, maintaining safety in processes involving hazardous steps or materials requires active participation and expertise from multiple subject matter experts across functional teams.

Hazard evaluation at Sterling

At Sterling, we recognise the critical importance of hazard evaluation, which leaves no room for an oversight. That’s why we leverage a proactive, integrated approach to hazard evaluation, which begins as soon as we introduce a new product on site and extends through scale up and ongoing optimisation. We carefully evaluate every project for potential risks in order to navigate our customers’ programmes as safely and effectively as possible while protecting our people.

Our 50+ years’ experience in hazardous chemistry enables us to safely support our customers’ hazardous projects with exceptional efficiency and agility. In addition, we’ve continued to test and implement new processes and purpose-built equipment to handle highly hazardous materials, such as diazomethane.

If you’d like to learn more about our approach to hazard evaluation or speak more about your programme, contact us today.