Handling Potent Active Pharmaceutical Ingredients
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APIs: The importance of occupational health and safety
The World Health Organization (WHO) defines an active pharmaceutical ingredient (API) as: “Any substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings."
APIs are a critical component of the pharmaceutical supply chain and are a fundamental part and cornerstone of medical therapies! API pipelines have become more potent and toxic in the last 10 years, and continue to do so, this could not be more evident than in the antibody drug conjugate (ADC) space. It remains important that biopharmaceutical companies integrate potent API management and handling concepts in to their daily operations. For almost 20 years, Justin Mason-Home, founder of HPAPI Project Services Limited, has been a recognized expert in supporting pharmaceutical companies in the delivery of potent API projects.
We spoke to Justin Mason-Home, to learn more about HPAPI Project Services Limited and the importance of applying robust occupational health and safety processes to the drug discovery, development and delivery pipeline.
LM: Could you tell us more about your professional background and HPAPI Project Services Limited?
Justin Mason-Home (JMH): I am an organic chemist and Fellow of the Royal Society of Chemistry. I started out in pure research, synthesizing new chemical entities (NCEs) in the fragrance and flavor sector (Holland), before moving on to development and scale-up work in the chemical sector in the UK. In the 1990’s I moved to corporate environmental management, when new laws on Integrated Pollution Control required a whole new environmental permitting regime. I was subsequently headhunted into environmental consulting by one of the largest global environmental consulting firms and during my time there, a large pharmaceutical company presented with a number of pharma researchers who had a serious occupational disease. In collaboration, notably with John Farris and Robert Ku of what was subsequently to become SafeBridge, the ultra-potent causative agents were identified and numerous complex steps were undertaken to recover the business. After working with a biotechnology company in Holland, I became a founding shareholder of SafeBridge Europe, Limited in 2005.
After 10 years with the company, I wanted a new challenge, so I resigned from SafeBridge and formed my new company in July 2017. One of HPAPI Project Services Limited’s core objectives is to support (bio)pharma companies in planning for, designing, and delivering potent and highly potent active pharmaceutical ingredient (API) projects in a systematic, scientific and business-like manner. By their very nature, capital costs for such projects are high, yet all too often, facilities are being put together based on little or no empirical containment or control performance data, rather with assumption and non-evidence-based guesswork dominating. Sound chemical and pharmaceutical process understanding, supported by scientific, data-driven decision making, at conceptual, scoping, planning and delivery stages, should mean that companies design, invest and deliver better.
Highly potent APIs: Factors to consider during pharmaceutical development
LM: You emphasize the importance of integrating occupational health and safety within drug substance and drug product projects. Thinking about highly potent APIs, what factors should be considered during pharmaceutical development?
JMH: Processes involving handling potent and highly potent APIs (PAPIs/HPAPIs) follow the same fundamental scientific principles and are governed by the same health and safety laws as processes involving other hazardous substances. Maybe the most important differentiators between PAPI/HPAPI processes and processes involving “regular” hazardous substances are 1) that toxicological hazards are usually higher and 2) there is an absence of “tools” that are available to manage PAPIs/HPAPIs safely. As an example, phosgene, a highly toxic material used widely in chemical synthesis, but also used as a chemical weapon in the past, has an occupationally safe limit of 80,000 ng m-3 (UK); the government sets the limit and it can be monitored for straightforwardly, in real-time and at relatively low cost. In contrast, a potent drug may have an estimated safe limit below 1,000 ng m-3 (or even much lower), no formal legal limit will be available and certainly no real-time monitor exists. In the former example, one may have relatively high hazard and high risk, but the availability of good tools may mean that one has high certainty. In the latter, one may have higher hazard, higher risk, and very high uncertainty.
Any operation that involves handling a potent drug, whether it be an API chemical substance (or intermediate!); drug product manufacture; or dosage form preparation, must be subject to formal, structured, scientific and systematic health and safety assessments, not least because the law demands it.
A detailed review of all the health and safety factors that should be taken into account can’t be dealt with in a short space, but they include:
1. Effective occupational toxicological hazard assessment
If API hazards are assessed incorrectly, poor and expensive consequential business decisions may follow. This could be manifest in over-designing facilities at too high a cost or not putting in place sufficient worker and product protection measures, which again can translate into business liability and cost.
2. Detailed chemical and pharmaceutical process understanding
This includes important concepts of actions that can impact worker exposure potential, facility and wider environmental contamination and product cross-contamination. Mass transport factors, the forces and operational activities that affect mass transport, must be understood, scientifically and preferably quantitatively. Any health and safety risk mitigation gains at the process end are going to be the most cost-effective in terms of risk reduction. However, it is critical that risk factors are not dismissed or discounted “emotionally”.
Commonly heard “emotional” positioning includes:
- “It’s only a small amount”
- “This is the way we always did it” or “Party X are worse than us”
- “It should be OK” or “we did a risk assessment and it’s OK”
- “Nobody got hurt yet”
None of these make for good business decision making and certainly would not constitute any form of defence within the law.
3. Fundamental facility and equipment design features (“hardwear”), intended to control or contain to a suitable and defined level, include:
- Materials and personnel transitions
- Rooms, airlocks, room pressures and HVAC system details
- Facility layouts and materials of construction
- "Closed" processing
- Engineering control and containment “close to the action”
4. Excellent potent drug safety management systems (“software”), intended to provide upfront control and to demonstrate control, health, safety and compliance:
- High quality, scientific and systematic hazard and risk assessments
- Excellent procedures
- Excellent worker training and awareness
- Empirical workplace occupational hygiene monitoring (control equipment performance and worker exposure assessments)
- Medical surveillance
A useful exercise may be to contemplate what level of overall control you would be happy with were it to be you or your son/daughter handling the PAPIs/HPAPIs within the process. What level of confidence would be enough?
Antibody Drug Conjugates
LM: You are leading a workshop entitled ‘Safely Handle Highly Potent Payloads’, could you tell us more about what will be discussed?
JMH: The workshop is offered as part of Hanson Wade’s excellent World ADC Programme. How ADCs function has been the subject of many talks; the following Nature video provides a good overview of how ADCs function for the uninitiated.
Credit: Nature, Animation by Nucleus Inc.
Having run many workshops and conducted many potent compound safety training sessions, you just never know where the topics will range.
It must be noted that ADC toxicants are some of the most potent and toxic materials in the history of the pharmaceutical sector and the risks to worker health must not be under estimated. In ADCs we have the meeting of two great branches of science; biology and chemistry, yet biological agent hazards versus chemical agent hazards can be quite different and the means to take hazard and process information and then identify and control risk can also be quite different.
The means to assess hazard, identify risk, put in controls and manage health and safety overall are set out above, but as in all projects of this type, the devil is in the detail. No doubt we’ll have the usual questions over hazard assessment (especially occupational health categorizations (aka “banding”!)) and we’ll have to try and imagine hazard and risk in a world where these things are rather beyond human perception, but we might get into some of the detail, such as whether ultra-filtration in downstream ADC purification needs to be within a control device or can it just be done on the open floor?
Laws of the world require us to establish and maintain safe working environments for our (healthy!) workers. The good news is that a healthy, safe, informed and engaged workforce is also good for businesses and their shareholders. Further good news is that the disciplines around potent drug safety are those of science; the same discipline that underpins biopharma businesses and so the capacity to manage potent drug safety well, should not be unfamiliar..
I invite attendees to come armed with lots of questions and issues that we can debate and explore around the framework set out in the agenda. All questions are welcome, from the obvious to the esoteric!
Justin Mason-Home was speaking to Laura Elizabeth Mason, Science Writer for Technology Networks.