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Discovery & Development Ingredients, Small Molecules

Three Gurus of HPAPI Hazards

John Farris

President and CEO of SafeBridge Consultants. He has extensive expertise in executive management, industrial hygiene, laboratory safety, control of potent pharmaceutical compounds, environmental protection and environmental remediation. John was part of the team who put together the first categorization systems for pharmaceutical hazard categorization and control in the late 1980s.

John Roosa

Associate Director, New Technology Development/Industrial Hygiene Lead within the Pilot Plant at Merck & Co. He has over 20 years’ experience in process development and project management, with responsibilities balanced between managing small to large scale capital projects and leading teams to optimize production equipment, improve user interfaces, and increase asset reliability.

Greg Baker

Associate Director EH&S and Enterprise Risk Management at Eisai. He has over 18 years of pharmaceutical industry experience, with expertise in the areas of environmental, health & safety as well as business continuity management. With his background as a certified industrial hygienist, and in his current role as a multi-site EH&S/business continuity leader, he has been very involved in various facets of potent compounds, such as facility design, safe handling, and supporting uninterrupted product supply to patients.

How do you define “highly potent”?

JF: Before you can define “highly potent”, you must first define “potent”. I actually don’t support “highly potent” as a generic term. It has been picked up by the uninitiated within the industry and used somewhat inappropriately. All pharmaceutical substances have pharmacologic potency and it is a continuum of potency from low potency, to moderate potency, to potent, to highly potent. All must be controlled in the workplace and controls get more sophisticated when you get to “occupationally potent”. From my point of view, the term highly potent is reserved for the stuff that should never see the light of day. It’s a small category of things that really needs to be buttoned up in isolation and full containment. Occupational health categorization of a drug should be driven not just by a set of toxicity and potency criteria but by what you have to do to handle the drug safely.

Occupational hygiene is not keeping up with the development of new and ever-more toxic drugs, and not enough resources are being put into it.

GB: I absolutely agree. And to expand on that, there’s been a lot of confusion over the years on different terms such as cytotoxic and cytostatic. These buzz words have the potential to cause fear and confusion, where some companies may feel they can’t manufacture these drugs safely and with high quality. Actually, they can be manufactured very safely and with very high quality, with the right understanding and controls. So I definitely agree that if we’re going to use the term highly potent, then more specific understanding of what that terms mean would benefit the pharmaceutical industry, both from a drug product quality standpoint and also an Environmental, Health and Safety (EH&S) standpoint.

JR: The precautions we take may also depend on where in the lifecycle of a new drug we are. The further the chemistry and toxicity studies, the more likely it is that we will know what classification the compound is in. Early on, when the compound is just discovered in the lab, or in early clinical trials, we may not know exactly how potent the material is, so we adopt a ‘better safe than sorry’ approach.

Potent Numbers

Highly potent compounds typically have an occupational exposure limit under 10 microgram per m3.

The global HPAPI market is expected to reach $17.5 billion by 2018, from $9.1 billion in 2011.

Analysts estimate that 25% of the drugs in development globally are highly potent.

 

Briefly, what are the advantages of more potent drugs?

GB: The biggest advantage is the potential benefit to the patient – we’re seeing drugs that have greater pharmacologic activity, targeted to a specific disease and to a specific part of the body.

JR: If a drug is more potent, that translates to a lower dose, with fewer impurities being delivered to the patient.

JF: Another potential benefit to the patient is the characteristic of these drugs having a longer duration of action in the body. If a drug lasts longer, a patient doesn’t need to take it as often and is more likely to stay on the required dosing regimen, which can be critical to drug efficacy.

How is the trend towards increasing potency changing how we manufacture drugs?

JF: We are starting to move away from the traditional “bakery equipment” into more closed and contained processing equipment. There are more dedicated facilities for potent drug work and the beginnings of consistent approaches to facility design and emission control, but there is a long way to go yet.

GB: The trend towards increasing potency leads to a greater potential risk of exposure to the worker, and greater risk to the company if aspects such as cross-contamination and exposure prevention for employees aren’t effectively managed. I believe there is growing understanding that these risks can be very effectively managed, with appropriate expertise, prior planning, and implementation of tiered and science-based risk control strategies.

What are the challenges associated with potent drug manufacture?

JF: Potent drug manufacture is not for everybody. You have to contend with worker fear of exposure (after reading a Safety Data Sheet), actual over-exposure, and potential for cross-contamination of products as lower levels become more significant.

GB: It’s a very small quantity per unit dose. So another challenge for companies is to make sure that they have that appropriate uniformity of the dose, given that such small amounts of the active ingredient are going into the batch.

How great are the risks of working with highly potent drugs?

JR: If you’re doing the work in a rigid isolator, there’s a reason why it’s being done there – the person absolutely cannot be exposed. The risks can be tremendous.

JF: Depending on the therapeutic class of drugs, the consequences of exposure could be anything from allergic sensitization to hormonal effects, such as development of breast tissue in men, to infertility or even death.

GB: I agree that the risks can be very high. Also, it is important to ensure that personnel understand the difference between hazards and the risk, as sometimes the terms can be confused. A hazard could be thought of as the potential for harm – whereas risk is the probability of harm. It is important for employees to have a detailed and strong understanding of a compound’s acute and chronic hazards. Similarly, they need to understand the various risk control measures in place to protect them, such as engineering controls, written procedures, personal protective equipment (PPE) requirements, and occupational medical surveillance programs. Also, it is important to enable employee confidence and understanding by making them aware of qualitative and quantitative risk assessment results.

What are the core elements to reduce risk?
No one is working on the next aspirin; they’re working on the next highly-targeted, potent, toxic payload.

JR: The goal is relatively straightforward, but attaining it is not always so easy. In simple terms, the first goal is to make sure the API is nowhere near the breathing zone of the operator. The second is that you really do not want the powder touching the operator anywhere, particularly the hands. It’s just fundamental common sense, but to meet those goals you need proper facility design and engineering controls, such as conditioned space, contained processing or use of flexible/rigid isolators. You also need to have procedures and proper training in place, because the level of skill an operator uses is very important; everything from the technique used to scoop up the powder to how quickly they move can have an impact. The last layer of defense is PPE.

JF: A systematic approach is needed. First, the hazard must be evaluated properly (how much will trigger what health effects?) and exposure limits and air monitoring methods must be established. As John Roosa notes, a facility must be designed that both controls migration of material and enhances appropriate behaviors in workers, with controls at the sources of exposure to prevent unacceptable airborne and surface levels of contact. The next steps are:

  • implementing an effective PPE program
  • training workers in the abstract concepts of potent drug safety awareness
  • conducting air monitoring studies
  • improving controls based on data
  • feeding back monitoring data to workers
  • instituting an appropriate medical surveillance program
  • having effective procedures and techniques to limit exposure
  • instituting an emergency response program.

GB: In addition to the EH&S related measures, it is also vital for companies to assess and control quality/GMP-related risk. It needs to be clearly illustrated that risk is well controlled through facility and operational design, and science-based approaches to risk management. The controls in place for worker protection, such as containment technology and facility/room ventilation design, also have a great benefit in preventing risk of cross-contamination. Companies must also make strategic and regulatory decisions on which products are manufactured in which areas, and decide whether product contact equipment must be dedicated or if it can be shared between products with science-based cleaning limits. Various factors will be closely considered by companies as they make business decisions to control patient risk.

What safety aspects do we need to improve?

JF: All of the above. Occupational hygiene is not keeping up with the development of new and ever-more toxic drugs, and not enough resources are being put into it. Pharma is a highly competitive arena, and there are some people who view their health and safety approach as a competitive advantage, so they don’t want to share it with their competitors. I would argue that some things are too important not to share.

GB: In addition to the occupational health measures we have been speaking of, it is also important for companies to do a very thorough process safety analysis, where they look at their equipment, their process flows, and the flammable/explosive characteristics of the given materials. This ensures protection of the employees, proactively prevents equipment/facility damage, and also helps to reduce the likelihood of a product supply interruption as a result of a safety incident. These types of process safety analyses start in the early stages of drug development, and progress up through scale-up and commercialization.

JF: As a health and safety professional, my job is to protect workers. But an aspect that is often lost on people in EH&S is the business impact of safety. It costs around $1,000,000 a day to develop a new drug, so for every day that the drug isn’t being developed or manufactured, you’re losing this investment. There’s also a major impact on staff morale and productivity if an incident occurs. Proper safety measures can be expensive, but they are vital – not just to protect your people, but also to protect your investment.

JR: When it comes to safety, you always strive for continuous improvement. You never want to be satisfied because when you become complacent, that’s when incidents happen, so strive for improvements across the board.

 

Dangerous Chemistry

To understand just how vital effective EH&S measures are, you only need to look at some of the potential risks to workers. The good news is that while the effects of exposure can be serious, with the correct safety measures the risks are minimized. Several studies have found no increase in mortality amongst pharmaceutical workers compared with the average population (1–2)

Hormonal Hazards

When oral contraceptives first hit the mass market, the effects on workers weren’t understood, and many were exposed to what we now know to be unsafe levels of hormones, primarily by inhalation (3). Among the first reported problems include development of secondary female characteristics in male workers, including breast enlargement and decreased potency and libido. Other effects include potential testicular atrophy in men and menstrual irregularity, pseudo-menopause, and blood clotting in women.

Sensitive Issue

Apart from the direct effects of therapeutic drugs, workers can also suffer from sensitization to a specific API. Sensitization refers to ‘priming’ of the immune system by exposure to an allergen, leading to (sometimes serious) allergic reactions to the compound. Exposure to opioids can have a particularly severe effect on the airways, leading to respiratory arrest, as it not only acts as an allergen but also triggers release of the inflammatory molecule histamine (4).

“Knockdown” Power

Beyond potent, or even highly potent compounds with chronic effects, there have been rare instances in which a pharmaceutical compound in early development has been found to cause acute reactions including nearly instant collapse.  In some cases, given the difficulty of establishing safe cleaning limits in the absence of data, companies have been forced to demolish a contaminated area entirely. For now, such compounds may be too hazardous to be developed further, but in future, it’s possible they could be managed in isolation units, using robotics to manipulate the drug.

 

What are the limitations of current occupational health categorization systems?

JF: The five companies that created the system (Merck, Lilly, Abbott, Upjohn and Syntex) could not come up with a “one size fits all” defined system for each of the five companies, so instead they took a general “hand in glove” approach, similar to biosafety levels, where the “hand” is evaluating the compounds based on a hazard assessment using drug potency and toxicity data and the “glove” is matching workplace exposure control descriptors shown to be effective for similar categories of drugs based on experience and air monitoring data. There are now roughly 35 different systems in the industry, which are mainly variations on the four- and five-category schemes. Some would argue that the number of different systems is a problem but I don’t think so. The people that think it’s a problem want things organized into neat bundles, but the occupational health categorization system was never intended to be a cookbook with step-by-step instructions. Rather, the categorization process presents a guideline or a road map.

GB: Industrial hygiene and EH&S professionals and toxicologists at the various pharmaceutical companies understand how the different categorization systems relate to each other, and they collaborate when there are business relationships between companies. Whether a company has a four- or five-band system, there are occupational exposure limit (OEL) ranges that apply to those bands, so companies can see how a given material fits into their company-specific bands. At the site level, a categorization/banding system is beneficial in the uniformity it creates for employees to understand basic guidelines for safe handling, based on a material’s band. That said, a categorization system should never be a substitute for activity/product-specific risk assessments supported by EH&S professionals.

JR: I don’t personally get too crazy about the banding systems. If it’s potent, or it’s close to being potent, it’s potent to me and we’re going to treat it with every precaution out there.

What does the sector need from regulators?

GB: I would say that continued collaboration and being open-minded to risk-based (vs hazard-based) approaches is key. There is evidence that companies and regulators are coming together to develop more common understanding of risk-based approaches which have strong scientific foundations. One example is the ISPE baseline guide “Risk-based Manufacture of Pharmaceutical Products” (Risk-MaPP), which touches on both EH&S and quality-related aspects of pharmaceutical manufacturing. It was a great effort, which brought together a lot of industry representatives and regulators to provide clear guidance.

JF: Personally, I don’t think more regulation is needed, but I do think that there should be more education and understanding about hazardous drugs. I remember as a child that I used to ride around in my parent’s car, which had no seat belts, and no-one ever gave it a thought. But now of course I would never travel anywhere with my kids unless they were securely belted. We don’t necessarily do that because of regulation, but because today there is an increased awareness of how seatbelts can save your life.

The trend towards increasing potency leads to a greater potential risk of exposure to the worker, and greater risk to the company.
What are the key points to consider when planning a safety training program for staff?

JR: Reading documentation or even watching a video is not enough – the more shop-floor training the better. We involve the whole team, we film videos, and then we’ll watch the videos and see what can be improved. It’s also crucial that the training covers the entire process from start to finish. In other words, you can’t have the equipment all set up and have everybody show up and give the training on it. Rather, you need to have everybody show up and have them set up the equipment. They need to fully understand all the detail of set up, use, breakdown and cleaning of the equipment.

JF: You need to clearly convey that what you can’t see, taste, feel or smell can hurt you. If you’re dealing with scientists you cannot assume that they already had some focused laboratory safety training in their university years, particularly in the area of potent compound safety. In fact, in the US only about 10 percent of graduate programs in chemistry require laboratory safety as a part of the curriculum. On the flipside, when it comes to the line operators, who typically have a high school or college-level education, some managers assume that because they are not scientists, they won’t understand the potent compound safety concepts – and that is also wrong. It’s up to us to convey the information in a way they can understand.

What do pharma companies need to consider when outsourcing production of potent drugs?

GB: When outsourcing, it is very important that a thorough risk assessment be completed in partnership with the prospective/selected CMO. Not only things like their regulatory history and their financial stability, but also looking at things like their facility design, equipment design, and their procedures and policies. They must be able to produce a high-quality product, with the appropriate health and safety protection of their workers.

JF: To add to Greg’s input: there are contenders and pretenders – you need to be sure you know the difference.

Responding to Risk

By John Farris

I’ve spent many years training scientists and operators to safely handle potent compounds and I think it’s fair to say that people tend to fall into three groups when it comes to their attitude to potent compound exposure risk…

  1. “On the floor”
    These are often the old timers, or those who are cavalier about the risks. They may think they know more about this than you do, have worked with potent compounds before and find the training an inconvenience. These people need to be brought to a higher level of appreciation for the risks they face based on candid presentation of case studies where severe effects have occurred.
  2. “On the ceiling”
    Often people who are newer to the job, and who are inquisitive and educated. These individuals read the safety data sheets, look at the health effects and, understandably, get very worried by the potential impact on their own or their loved ones’ health. You can peel them off the ceiling by explaining that everything can be done safely, and showing them exactly how, based on understanding what levels are safe, how exposure occurs and the mitigating factors that control exposure.  
  3. The “safe driver”
    Almost everyone thinks they are a safe driver – a much safer driver than all those other idiots on the road! In the laboratory, the ‘safe driver’ effect manifests itself in comments like, “I conduct myself safely. But this idiot working next to me is leaving a mess and putting me at risk because of their behavior.”  The safe driver needs to understand that by tolerating this behavior, rather than speaking to the culprit or their supervisor, they are themselves creating a hazardous situation – one must take responsibility for one’s own safety, in combination with a company management system that requires accountability in this area.

The next SafeBridge Potent Compound Safety “Boot Camp”® is in June in Edinburgh, see http://www.safebridge.com for details.

 

How do you see the market evolving over the next 5-10 years?

JR: I see this market growing and I see the equipment vendors constantly striving to improve the engineering controls. We’re getting smarter and we’re coming up with novel ways to isolate the APIs from the handler. It’s so important now to never stop learning; you always have to keep your finger on the pulse of industry trends and improvements that are coming down the line.

GB: I think there’s going to be a growing awareness by companies and regulators on risk-based assessments and control measure decisions. And, like John, I believe there will be increasing specialization in engineering and containment control. I also think we will continue to see more and more specialized, disease-targeted formulations.

JF: No one is working on the next aspirin; they’re working on the next highly-targeted, potent, toxic payload. As Greg indicates, every year drugs are getting more targeted, doses are getting lower and scientists are finding creative ways to deliver drugs to receptor sites on diseased cells. Take chemotherapy – at present it’s usually a brute force treatment where you try to kill the tumor before you kill the patient. But now there are products on the market – and many more in development – that target only the cancer cells. Antibody–drug conjugates are designed not to release their toxic payload on healthy cells, so they only kill tumor cells – like “silver bullets”. These delivery technologies have allowed pharmaceutical companies to attach even more toxic payloads – drugs that in the past would have been scrapped because they would kill the patient. Now, they could offer wonderful, breakthrough therapy for cancer patients. The problem we’re facing is that somebody has to work with this stuff.

What challenges lie ahead?

JF: The emerging nanoparticle delivery systems that are now being developed pose special challenges for occupational health. These nanoparticles can contain a whole cocktail of different chemo drugs, creating a risk of what’s known as the mixture effect. Let’s say you have two drugs, each of which has an OEL – it’s no longer acceptable just to meet the individual exposure limits. You now have to meet a mixture limit, which is a fraction of the OEL that has to be met for each one, because of the additive effects of the different drugs. Plus, there are risks associated with the nanoparticles themselves. Owing to their small size, they can enter the body through many different routes, some of which are unknown.

GB: There are an increasing number of companies producing highly potent active ingredients because they are trying to focus on unmet medical needs. So from a business standpoint, companies will be put under increasing pressure to make a decision on whether to manufacture in-house, use a CMO, or engage in some kind of hybrid partnership with a CMO. Companies need to ensure the best decision is made for the patient, company, and protection of employees.

JR: When it comes to safety, you have to constantly strive for improvement. Keeping up with technology and implementing it is definitely a big challenge; technology is exploding and part of my job is to explain to everybody why we need it, and then to assimilate the new technology into the business.

There is tremendous pressure on the industry to lower costs, and understandably so, but there must be a balance between lowering cost and maintaining both the intended functionality for patients, and a safe working environment for employees.

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  1. G. M. Marsh et al., “Mortality Patterns Among Workers in a US Pharmaceutical Production Plant”, Ann. Epidemiol. 15(2), 112–122 (2005).
  2. D. G. Dolan et al., “A 50-Year Historical Cohort Mortality Study of Workers in a Pharmaceutical Plant”, Journal of Occupational & Environmental Medicine 46 (2), 161–166 (2004).
  3. K. D. Tait, “Chapter 79 – Pharmaceutical Industry”, In: Encyclopaedia of Occupational Health and Safety (4th Edition). www.ilocis.org/documents/chpt79e.htm
  4. R. J. L. Heron and F. C. Pickering, “Health Effects of Exposure to Active Pharmaceutical Ingredients (APIs)”, Occupational Medicine 53, 357–362 (2003).
About the Author
Charlotte Barker

As an Editor at Texere, I’m working closely with our audience to create vibrant, engaging content that reflects the hard work and passion that goes into bringing new medicines to market. I got my start in biomedical publishing as a commissioning editor for healthcare journals and have spent my career covering everything from early-stage research to clinical medicine, so I know my way around. And I can’t think of a more interesting, challenging or important area to be working in.

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