Developing ADCs? Here's A Refresher On HPAPI Occupational Health Risk Mitigation (2025)

A conversation with Justin Mason-Home, Director/Owner, HPAPI Project Services Ltd.

Developing ADCs? Here's A Refresher On HPAPI Occupational Health Risk Mitigation (1)

Amid the boom of antibody-drug conjugate (ADC) investment and research, one environmental health and safety expert wants to remind the industry about safety risks for frontline biopharma workers — all those highly potent drugs we’re linking up with antibodies and other novel biological targeting agents.

Justin Mason-Home of HPAPI Project Services Ltd. fortunately comes across only a handful of workplace accidents involving highly potent APIs (HPAPIs) each year, but when they do occur, they’re usually enough to seriously disrupt business and can change the relationship a company has with its workers and customers. He’s not an alarmist and sees no value in scaring people, he says. Instead, he encourages a measured, business-focused and thoughtful approach to risk mitigation. It’s technically complex, tricky but doable. It’s also the law.

We had some questions and asked for some practical advice on understanding and managing potent drug safety risk. He replied in an email and a video chat. His answers have been edited. Here’s what he told us.

With the surge of new investment and R&D into ADCs, what's your opinion of how the industry has kept front of mind the inherent risk associated with working with HPAPIs?

ADCs and HPAPIs more widely, are commercially “cool,” whereas I am quite confident in saying that API occupational health and safety is not! Health and safety are never going to be the top of the agenda in the industry; however, it is interesting to observe that companies often state that worker safety is their highest priority. After all it is the law, and you have to do it anyway!

Sticking to the science, some API payloads within the ADC world are some of the most potent and toxic in the whole history of biopharma. Strictly, ADC toxins are just hazardous chemical substances (as indeed are ADC biological elements, too). However, with potent and highly potent APIs, safe levels (usually manifest in the form of occupational exposure limits or OELs) are often many orders of magnitude lower than “regular” hazardous chemicals like toxic gases and hazardous solvents. Furthermore, we do not have the same tools that are available for managing health and safety of regular hazardous chemicals.

Risks when handling APIs, and even more so when handling HPAPIs, are demonstrably real and higher than when handling regular hazardous chemicals. One therefore needs to apply a set of skills in order to first understand the subject (and risks present and potential commercial impact), including toxicology, risk assessment, control/containment engineering, industrial hygiene, and other related skills, and then manage it effectively — practically, scientifically, systematically, and pragmatically.

Commercial risks and liabilities are clear, and include poor facility and process design, incorrect process assets selection and poor project design more widely, health effects in workers, loss of confidence within the workforce and with customers, and the ever-present potential commercial/criminal liability.

Overall, my experience is that potent drug safety management is highly variable and tends to be influenced heavily by individuals within projects/companies. The diversity of thinking and approaches that I see never ceases to amaze me!

Sometimes, parties are systematic, scientific, and logical, but sometimes they are not! I find it rather strange that some businesses, more so than in any other type of industry, and fundamentally underpinned by strict application of the scientific method (and regulated under GMP), can sometimes ditch the science book and use ‘emotional positioning’ instead — something that absolutely would not be allowed in the development and delivery of a drug to a patient!

Within GMP, a drug has to be proven to be safe and effective, with robust scientific evidence that must withstand external scrutiny. Poor potent drug safety management outcomes in companies manifest as poor project design, poorly designed facilities (expensive and over-designed and expensive and under-designed), and operational procedures and management systems that are not fit for purpose. I tend to see more over-designed facilities/projects with excessive containment (“stick everything in containment” is maybe a substitute for deeper understanding), which can become very difficult for frontline workers to operate in and can present long-term operational liability.

Given that there are no continuous air monitoring methods, what is your recommended strategy for workplace exposure testing?

This is maybe the hardest question I get asked! “How much monitoring should we do?”

First, we all need to understand that workplace monitoring for an API — a non-homogeneous particulate substance in the air — is very different from monitoring for a toxic gas or a hazardous solvent. The latter are diffusion-controlled, homogeneous gases and vapors in air, which fill space and, for which, continuous and often solid-state monitoring devices are available along with reference materials and calibration standards (they’re also low-cost and reliable). Furthermore, governments around the world set regulatory limits for these sorts of substances.

In contrast, we have no speciated chemical continuous air sampling devices of this type in the API world. I do not think we will get real-time speciated API air monitoring equipment in my lifetime.

This makes our world much more uncertain. One is therefore limited to discreet single-sample air monitoring, capturing particles onto a filter and subjecting the filter to speciated chemical analysis. The strict scientific answer to the question is that the more monitoring work you do, the higher confidence you can get — and conversely so. We will never get the same level of confidence that one gets when handling regular hazardous substances. It’s also worth noting that laws of the world demand monitoring for hazardous substances in the working environment. Do your risk assessments, start somewhere, and keep going. Use experts but maybe also do some work in-house yourself — make safety part of the process and try and seek this mysterious thing called “confidence” over time.

Pragmatically, I would recommend that companies have an industrial hygiene (IH) monitoring program (understand the subject first) that includes assessing the control/containment performance of control/containment devices (work with equipment vendors, too) and also includes measurement of workplace exposure levels to APIs. In this respect, this is no different from monitoring for solvents and gases in the chemical industry or monitoring for radiation in the nuclear industry — it’s just more difficult to do and outcomes are more uncertain.

As I said, start somewhere and keep going. Let risk be your guide — focus on higher-risk activities. Be aware that risk assessment in the uncertain potent drug world is difficult, too.

How do you interpret data, especially regarding time-weighted averages? Can you explain why time-weighted averages are not appropriate for managing control/containment performance target testing (CPT)?

The last question was one of the hardest to answer. This is an easy one!

Time-weighting is a convention used in hazardous substances monitoring regulations that tries to look at the daily dose that a worker might receive at work. OELs are usually expressed as an eight-hour time-weighted average (8-hr TWA). For a continuous monitoring device for a solvent one would integrate under the curve to get the mass (i.e., the dose), which is related directly to the OEL.

In the absence of continuous methods and monitoring calibration standards and other uncertainties in API air sampling, one does not have the robustness of data to time-weight it. In my opinion, time weighting should not be used to conclude exposure levels over a day for APIs. Testing against a CPT, or indeed testing worker exposure levels against an OEL, should be undertaken on a task-oriented basis, and the objective should be to be below the OEL or CPT limit value (i.e., the number) over the task duration.

If subsequent monitoring finds levels above the OEL/CPT limit value, then I would recommend using an expert to help interpret the data.

Developing ADCs? Here's A Refresher On HPAPI Occupational Health Risk Mitigation (2)

Can we talk about the balancing act of managing equipment and human behavior together?

Sure. Equipment is just engineered “stuff.” Water pumps have a water pumping performance that we can specify and easily measure. Light sources generate photons, which we can specify and easily measure.

We want our isolators and ventilated enclosures to have a particulate matter control/containment performance. The problem is we can easily specify it, but we can’t easily measure it. We do not know the control/containment performance envelopes of our devices — we can’t get the data to populate such envelopes. They have one, but we don’t know what it is.

We know that many things influence control/containment performance, including latent design, airflow, air pressure, maintenance, and many other factors, including human behaviors. The objective should be to specify and procure equipment that one has a reasonable expectation that a CPT can be met. Then, the challenge is to extract that latent performance using one’s own process and workforce.

Surely, it has to start with training and awareness of workers within an environment of excellent and robust SOPs. Consistent and excellent operational performance (underpinned by robust SOPs) opens up the possibility to measure effectiveness. In contrast, poor operational procedures/management – a wild West approach – can only make things more difficult to manage. Emotional positions such as, “Our people are smart and know what to do,” or, “Nobody got sick in the past,” are wishful thinking at best, and I can’t see this being defendable within the law, either.

I’ve made several mentions of the criminal law. I don’t really like referring to the law as it sounds very “consultanty.” The law is a blunt instrument in potent drug safety management — the general hazardous substances laws that regulate this area are more difficult legally when APIs are involved, but they are the only laws we have!

Laws require parties to establish and maintain safe working environments. They require toxicological hazard assessments, risk assessments, and controls (following a hierarchy of engineering, then administrative and, least effectively, personal or PPE controls). They require workers to be trained and worker health to be surveilled. Companies should apply the same level of systematic science to occupational health and safety as they do elsewhere in their businesses, such as, for example, in Quality. Running two different levels of science for commercial convenience is very difficult to defend.

Every company must have someone with assigned responsibility, a champion if you like, overseeing health and safety. At large biopharma companies, that will probably be a full-time health and safety officer. At smaller companies and CDMOs, those responsibilities are more likely to be folded in with another role.

How do control strategies change based on OEL? In other words, if my product's OEL is especially low, what should I do differently compared to one with higher OEL?

Again, this is an easy one and a common pitfall! The OEL (which is a measure of the hazard) should not be the only defining criterion. The risk should be.

If it was you or your son or daughter handling the API, would you rather pipette 1 mL of an ultra, megapotent API solution once a year or would you rather micronize 50 kg every day of a solid/powder lower OEL API? The latter is a lower OEL but higher risk.

Hazard forms part of the overall risk, but there are many other factors, including mass, frequency of handling, physicochemical properties and electrochemical behavior, competence of the workforce, the sort of control/containment equipment available and its effectiveness, wider facility-level controls, maintenance, the effectiveness of management systems, and many more factors.

Risk assessment is an area that is often poorly practiced — often more emotionally than scientifically. Data sparsity is at the core of our problems. Scientifically, one needs to have an appreciation of “mass transport (with very small masses) and how this can translate into exposure potential for workers — or indeed, cross-contamination risk for managing drug quality risk.

Can you explain how the OEB approach helps in the absence of a specific OEL?

Occupational exposure bands (OEBs) have most effective application for early-stage compounds (e.g., R&D, preclinical, early clinical) where there is insufficient toxicology data to develop a formal OEL. In these cases, few options are available.

Some classes of compounds have alternative methods of hazard assessment available, but the vast majority do not. If an API is at late clinical stage or beyond, there is generally sufficient information to develop an OEL, and one should seriously think about doing so.

It is worth noting that an OEL is of limited value unless a validated air monitoring method is also developed so that monitoring can take place versus the OEL. Otherwise, it can be a somewhat academic exercise.

Banding systems do serve a purpose to help manage and guide one toward a control/containment approach (engineering, administrative, and personal), and they can form a framework for managing potent drug safety and for administering an industrial hygiene monitoring program. All of these elements, including those discussed earlier, must be managed in a knowledgeable and integrated fashion.

Several organizations, notably ISPE, have guides for handling HPAPI. What standards do you recommend following?

A couple of guides stand out. We have the longstanding Assessing the Particulate Containment Performance of Pharmaceutical Equipment guide from the International Society for Pharmaceutical Engineering (ISPE), previously known as the SMEPAC guide, which is the only reference, as far as I am concerned, for measuring this type of performance. By the way, a next edition of this guide has just been released (December 2024) and reverts back to the SMEPAC name (Standardized Methodology for the Evaluation of Pharma Airborne Particle Emissions from Containment Systems).

In 2022, ISPE published its Good Practice Guide: Containment for Potent Compounds. The work built on earlier work of others and had a complex genesis, but it is a useful reference. The guide is notably data-sparse, and one may find it difficult to navigate to a solution that fits a particular project or process. I must state that this is my own personal view and not the view of ISPE.

A notable change within GMP in the last 10 years has been a move to use health-based exposure limits (HBELs) for managing API cross-contamination risk – i.e., levels of an API that are acceptable of one drug in another. OELs are HBELs!

This is one very good example of convergent science being used for API management overall.

Are we likely to see regulation shape up to better control HPAPI and prevent unwanted exposure?

I think not, and further, I do not see that there is any need for a change to health and safety Regulations, which have been established in the criminal law for a long time now. In my view, laws as they stand (in the U.K. (and elsewhere)) are fit for purpose. A reading of the law describes what has to be done, as I set out earlier – it’s just that each of the component elements when applied to APIs is more difficult, a difficulty exacerbated by a lack of tools that are present in other industries.

My advice is to engage with and understand the subject well and make decisions and advance positions on an informed, systematic, scientific basis. Ditch the emotional positioning. Sound, solid, science-based project development, API and facility design development and delivery, as well as practical and pragmatic potent drug safety management developed in a structured way are commercially wise, delivering cost-effective API/HPAPI projects and effective company commercial and regulatory liability management.

About The Expert:

Developing ADCs? Here's A Refresher On HPAPI Occupational Health Risk Mitigation (3)Justin Mason-Home, FRSC, is an organic chemist with 25 years of health, safety, environmental, and chemical engineering experience in senior technical, legal, and commercial aspects of the pharmaceutical, biochemical, and chemical industries. For most of his career, he has worked with potent and highly potent APIs, developing and managing technical and highly complex projects. He is a fellow of the Royal Society of Chemistry in the United Kingdom.

Developing ADCs? Here's A Refresher On HPAPI Occupational Health Risk Mitigation (2025)
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