The Role of Workers and their Management Teams in Establishing and Maintaining Confidently Safe Working Environments, for Workers Handling Potent and Highly Potent Active Pharmaceutical Ingredients (HPAPIs)

Potent/Highly potent API (‘HPAPI’) occupational health and safety (worker safety) may not be the most important element within a [bio]pharmaceutical project, but it is an important element. Whether it is a new HPAPI project, new facility design and build, existing facilities upgrading, processing and containment equipment selection, occupational health and safety SOP development, C-level executive through to all staff level potent drug safety training, or investigating worker real or perceived health effects, companies have a strict legal obligation to establish and maintain a safe working environment. Regulatory obligation or not, managing occupational health and safety well is good business. There is true commercial value to developing well-designed highly closed processes that protect product and workers, to develop facilities and management systems that are fit-for-purpose and to establishing and maintaining confidently safe working environments for workers handling potent and highly potent APIs; where workers are educated, informed, empowered and liberated, to deliver innovative biopharma therapies that are the hallmark of our industry. Confidently safe working environments with robustly confident workforces have high value and maintain valuable business continuity.

BioPharma companies invariably state in their highest-level Policies, Missions, Corporate Commitments and similar, that people (workers) are their most important asset. It’s not a difficult business decision. The Law says that every business must have a policy for managing [employee] health and safety – it has to be done anyway. But is worker health really the most important business matter?

Companies are required to provide accurate and reliable safety information, along with instruction and training for workers handling APIs. Workers must be provided with comprehensive and understandable details about APIs they are asked to handle, including substance identity, relevant safe limits, risks to health, what control measures to use, workplace monitoring results and other elements.

Management teams need to understand risk well, design facilities, processes, procedures and management systems that are effective, which manage operational liabilities and which deliver a safe working environment. All of this needs to be achieved whilst at the same time developing a workforce that is risk-aware (not ‘risk-‘blasé’ or ‘risk-scared/paranoid’) and set an environment to deliver therapeutic drugs for wider disease treatment and health protection.

With higher, complex and multiple uncertainties present, HPAPI occupational health and safety management can be a significant challenge, including employees who may not be confident that their safety is being protected at work. Worker concerns resulting from poor understanding and/or poor management can impact effectiveness at work, including hiring staff and staff retention.

The (bio)pharma sector, its turnover and its profits, more than any other sector, is underpinned by a rigid and scrutinized application of the scientific method, so why do some companies struggle with applying the same rigorous systematic science to API occupational health and safety as is applied say, to product safety (Quality)?

When faced with high-concern HPAPI safety matters (regulatory or worker exposure related or budgeting(!)), immediate responses from company management teams can be variable, ranging from excellent, to outright ‘emotional denial’ dismissiveness, to excessive and irrational concern. Subsequent poor responses can range from doing nothing, to improving operational procedures, to snap ‘put everything in containment’ responses, to try and apportion blame, right up to stopping operating. Potent drug safety professionals have pondered long and hard about often non-scientific operational management of potent drug safety, indeed including responding to worker concerns and over-exposure issues. Top of the list of factors are the somewhat non-intuitive nature of potent drug safety and a lack of the usual ‘tools’ that are available for other ‘regular’ high hazard substances (like toxic gases, volatile organic compounds, etc).

Handling APIs is a truly risky business (1).

For benchmarking, the Occupational Exposure Limit (OEL; a safe working environment limit) for cyanides (CN-) is 5000 µg m-3 (microgrammes per cubic meter) and the OEL for benzene is 3250 µg m-3 (2). In contrast, the OEL for paclitaxel (a first-line small-molecule chemotherapy drug (3)), has an OEL of circa. 1 µg m-3 (4), that is, 5000x lower than cyanide. Paclitaxel would be described by experienced potent drug safety professionals as a ‘potent’ drug (not ‘highly potent’ or ‘HPAPI’).

Benchmarking further and using Paclitaxel as a reference; to obtain a concentration of 1 µg m-3 in air, one would have to take 1g (gramme) of a powder – about a quarter of a teaspoonful -and distribute it homogeneously in a volume of 1,000,000 m3 (one million cubic metres) of air. Conveniently in the UK, the volume of Wembley Stadium is a little over 1,000,000 m3. The ‘safe’ limit for Paclitaxel then, is one quarter of a teaspoon of powder distributed homogeneously in Wembley Stadium. Analogies like this aim to try and give the reader a perspective of the magnitude of the risk and associated challenge.

For those with an Occupational Exposure Band (OEB) (5) system, incorporating an OEL limit value of 10 ug m-3, the equivalent challenge would be 2½ teaspoons of powder distributed homogeneously in Wembley Stadium. It should be apparent that the main factor driving risk (both occupationally for workers, and therapeutically from a patient safety perspective via cross-contamination potential) is high-hazard substance API potency and toxicity. The magnitude or ‘intensity’ of presented risk and associated control/protection challenge, whether the OEL is 1 µg m-3 (1/4 teaspoon of powder homogeneously distributed in a ‘Wembley’ volume) or 10 µg m-3 (2½ teaspoons of powder homogeneously distributed in a ‘Wembley’ volume), is essentially the same. OEB systems and the level of reliance that may be placed on them need to be understood in a strict scientific manner.

Even with higher risks and higher uncertainties than in other industries, the good news is that management of potent drug safety is a strictly systematic and scientific endeavour, and science-based companies should be able to apply their strict science skills equally to worker safety.

It all starts with the Hazard. OELs are (or should be) scientifically robust and are usually based on a toxicological Point of Departure (PoD), which may often be a No Observed Adverse Effect Level (NOAEL), plus a compound safety factor designed to be protective of worker health (6, 7).

After Hazard comes Risk. There is no such thing as zero risk. So you have to decide how much API it is OK to expose someone to. You can’t choose zero. The OEL as a maximum limit is a good start. Communicating risk is difficult at the best of times. Communicating risk in a non-intuitive, data sparse and uncertain biopharma world moreso. Further, communicating risk in this environment can be risky in and of itself! A delicate balance is needed to communicate risk effectively, whilst at the same time avoiding scaring people. It is well known that different people have different attitudes to risk – a further confounding factor.

In the final analysis, the only solution is to educate and inform at all business levels. Only with a ‘proper’ scientific appreciation and understanding of API hazard, exposure risk, effective control (including containment) and wider API safety management, can companies really make effective potent drug safety management decisions. There is no place for ‘emotional positioning’, ego and uninformed opinion.

Sensitive yet robust H&S training must be part of any operation involving handling APIs.
APIs are prima facie designed to affect human physiology – if health and safety provisions apply to hazardous substances, then they especially apply to APIs. Workers must be provided with suitable and sufficient information, instruction and training (8):

• the names of substances and the hazard and risk which they present to health
• any relevant workplace exposure limit (eg an OEL or OEB)
• access to any relevant safety data sheet (beware poor SDSs!)
• the significant findings of risk assessments
• the appropriate precautions and actions to be taken by the employee in order to safeguard himself or herself and other employees at the workplace
• the results of any monitoring of exposure and, in particular, the employee shall be informed forthwith, if the results of such monitoring show that the workplace exposure limit has been exceeded
• the collective results of any health surveillance undertaken
• and more!

The Role of API Occupational Health and Safety SOPs and Effective Corporate Management

It goes without saying that the ‘hardware’ in the form of well-designed ‘closed’ processes, well-chosen control/containment strategies, within excellently designed API processing facilities is essential. However, one can have the best ‘hardware’ facilities in the world, but if they are not operated and managed excellently, the full investment value may not be realised. The ‘software’ is just as important. Excellent SOPs and excellent operational execution under SOP control, by informed management teams, by excellent well-trained, risk-aware workers is critical to effective potent drug safety management.

In comparison to other industries involving other hazardous substances, API working environments are much more uncertain; no real-time monitors have ever been developed for speciated APIs in air and none are on the horizon. Arguably, monitoring is required to be done, but such work is much more difficult and much less reliable than in other industries. If one is to do monitoring, it would make sense to monitor a minimum number of strictly defined and well-bounded API handling unit operations. If workers are allowed a free hand to individually decide how to handle APIs, what does one monitor?

This needs to be done whilst simultaneously setting a motivating environment where workers (especially in R&D) can innovate, try different things, push the boundaries and deliver the next great therapeutic breakthrough.

Every foreseeable API handling and processing unit operation/activity that workers may come across cannot be captured. Certainly, many unit activities form subsets; in the lab many operations involve ‘small’ scale powder manipulations (note that if the OEL is 1 ug m-3, one gramme is not a ‘small’ amount!) and single control/containment solutions can be defined for such activities, but what about development scale particle sizing or diamond microprobe open-stage IR or open-stage XRF or OSD powder formulation development?

Though difficult, one can try and maintain easily accessible guidance for all workers for all activities, but it is inevitable that something different will come along the minute the latest version of guidance is issued! Alongside written, accessible practical real-world guidance, knowledgeable and well-trained workers can be developed, with an understanding of hazard, risk and control and what factors influence exposure potential (mass, quantity, frequency, physical form, mass transport factors, etc etc), and workers can be empowered to apply core knowledge to what faces them day-to-day. Management teams need to facilitate a working environment where workers are not stranded, not knowing what to do and with temptation to ‘improvise’; where open, risk-free communication can be had in a ‘no-blame’ environment, all with the intention of continuous improvement and protecting every person’s safety.

With ‘hardware’ put in place based on a systematic scientific position on toxicological hazard, proper risk assessment and effective engineering control/containment measures, plus ‘software’ put in place in the form of robust, useable occupational H&S SOPs and with well-trained, risk-aware workers, companies can deliver confidently safe working environments where workers can innovate, thrive and deliver successful HPAPI projects.

References and notes

1. J Mason-Home, Chimica Oggi – Chemistry Today; vol. 39(2) 2021.
2. EH40/2005 Workplace Exposure Limits, pursuant to the Control of Substances Hazardous to Health Regulations 2002, as amended (‘COSHH’); United Kingdom
3. https://www.cancerresearchuk.org/about-cancer/treatment/drugs/paclitaxel
4. Various sources consolidated
5. J Farris et al, Chimica oggi – Chemistry Today; Vol 24 (2), March/April 2006
6. Robert H. Ku, Chemical Health & Safety, January/February 2000
7. https://www.ema.europa.eu/en/documents/presentation/presentation-key-points-recognize-quality-health-based-exposure-limits-and-associated-monograph-e-lovsin-barle-pda_en.pdf
8. Paraphrasing COSHH Regulation 12