Re-defining Process Safety To Accommodate Biomanufacturing Risks

Biomanufacturing is in the growth

Humankind has used different types of micro-organisms to produce goods since prehistoric times. Some very common examples include cheese, bread, wine and beer. Also, some “natural remedies” used before the development of scientific medicine involve fungus…leading to the discovery of penicillin, around 1928.

In the last decades, humans have learned to manipulate the genetic code of micro-organisms to “teach” them how to produce valuable goods. One of the first successes in this arena was the production of “human” insulin by a genetically modified strain of the bacteria E. coli.

This hormone replaces with some advantages the animal insulin used until the 1980s in the treatment of certain types of diabetes. Since then, the toolkit of techniques to edit the genetic code of micro-organisms has grown spectacularly. As a consequence, so has the number of solutions provided by the pharmaceutical industry by biomanufacturing.

Although the trend has been very successful in the pharmaceutical industry, it is by no means limited to it. Biologists have “taught” bacteria to metabolise things they usually would not, such as crude oil and toxic wastes.

The idea clearly being to disperse this bacteria over spills to eat them up. We call this “bioremediation”, and has been around for some decades now. There has also been intensive investigation on bacteria who can metabolise acidic compounds present in crude oil, thus replacing the costly and hazardous hydrodesulphurisation processes currently in use in most refineries.

Some other bacteria have been engineered to produce new types of foods (like some of the meat replacements we can find on the supermarket), or even “smart foods” with some added healthy properties, like lowering your blood cholesterol.

Today, most of us consume biomanufactured products, we observe biotech companies listed on the world’s stock exchanges, and even a growing number of universities offer specialised programs.

There’s no such thing as a free lunch

This popular adage was adopted by Nobel Economy Prize Milton Friedman as the title of one of his books, and has been ever since in widespread use in the economic sciences to refer to opportunity costs.

We could also recycle it to mean that every action we take has an impact on safety. For instance, during the 1970’s, it became increasingly popular to feed cattle with something called meat-and-bone meal. This new fodder was made of…well, meat and bones of other animals, including sheep and cows.

As a consequence, cows developed a new disease technically called bovine spongiform encephalopathy (BSE), and popularly known as “mad cow disease”.

At some point, BSE seeped through to human beings who consumed infected cow products, giving rise to its human version, known as modified Creutzfeldt-Jakob disease.

BSE and its human version are caused by a prion, a misfolded protein, that finds its way to the brains of patients and prevents them from working properly.

There have been other documented cases where mishaps of different types and sorts have led to the spreading of diseases. Thus, for instance, a loss of containment in a virology research laboratory in Marburg and der Lahn (Germany) in 1967 caused an outbreak of a haemorrhagic fever known ever since as Marburg disease, closely related to the infamous Ebola fever. Even today, the Chinese authorities have repeatedly denied that COVIR-19 has spread out of a biosecurity laboratory.

Going back to the title of this section, we can conclude that there is no such thing as a free lunch, and we need to be prepared to tackle the new hazards and risks posed by biomanufacturing.

There is nothing new under the sun

Another classical quote, this time from the Ecclesiastes. What sense can we make out of it in the context of biomanufacturing safety? Very clear: humankind has faced several similar situations before today.

For instance, the development of the chemical and petrochemical industries during the 20th century gave rise to major incidents such as Bhopal and San Juan Ixhuatepec. The nuclear industry, developed during the second half of the 20th century, gave us Three Mile Island, Chernobyl and Fukushima.

We have to admit, though, that Homo sapiens is a very resilient species. Time and time again we have been able to harness the risks associated with our inventions.

Will it be different with biomanufacturing? We don’t think so. Furthermore, we strongly believe that the frame for managing biomanufacturing risks is already there, and needs only minor tailoring.

The frame we mean is process safety management (PSM). Back in the 1980s, a series of catastrophic incidents (including Bhopal and San Juan Ixhuatepec) led the American Institute of Chemical Engineers (AIChE) to identify process safety as a discipline clearly distinct from industrial safety.

As a result of that insight, AIChE founded the Center for Chemical Process Safety (CCPS) and tasked it with the development of the newly defined discipline; that is, with the development of any tools required for a comprehensive identification, assessment and management of the risks.

PSM was the result of this task. We can think of it as what one needs to do to optimise one’s safety performance and minimise the probability of suffering major accidents.

To make sure that our biological hazards can be managed by PSM, we must verify that the following items are appropriate:

• The scope of the discipline.
• The elements, key principles and essential features.
• The tools.
• The experts.

We’ll analyse them in turn.

Definition

The CCPS defines process safety as[ CCPS (April 2020).] “

… a disciplined framework for managing the integrity of operating systems and processes handling hazardous substances by applying good design principles, engineering, and operating practices. It deals with the prevention and control of incidents that have the potential to release hazardous materials or energy. Such incidents can cause toxic effects, fire, or explosion and could ultimately result in serious injuries, property damage, lost production, and environmental impact.”

To include the risks associated to a loss of containment of hazardous biological agents we only need to replace “hazardous substances” by “hazardous substances and biological agents”.

Key elements and essential features

Table 1 shows the twenty elements identified by CCPS as pillars for a world-class process safety performance, as grouped in DEKRA’s Organisational Process Safety solution scheme into seven workstreams.

Table 1. Workstreams and CCPS elements

Every one of the elements and workstreams seems fully applicable, as long as its framework is properly identified. If you consider, for instance, compliance with standards: indeed you will need to keep track of any trade standards and regulations applicable and comply with them.

Another example, hazard identification and risk analysis: we ought to be able to identify the potential hazards of any new process and assess its risks. Indeed all elements continue to be valid, and we could not think of any additional element or workstream that could be needed.

Key principles are defined by CCPS as[ Center for Chemical Process Safety. Guidelines for Risk Based Process Safety. John Wiley & Sons, 2011.]

“a part of an RBPS element, which is often generic to all elements because of the nature of how management systems are defined in these Guidelines. For example, almost all elements include a key principle called maintain a dependable practice, which is further expanded into essential features and work activities that help ensure that appropriate actions are undertaken to provide the required level of dependability for activities related to the particular element.” Likewise, essential features are “a set of activities or actions that help support a key principle of an RBPS element (e.g., involving competent personnel is one essential feature that is required to maintain a dependable practice within most management systems)”.

As shown in Figure 1, key principles and essential features provide a top-down development of the expectation of the element; the expectation being understood as “what excellent looks like”.

Figure 1. Expectation, key principles and essential features

CCPS has identified a total of 78 key principles and 301 essential features for the 20 elements. It would be clearly too long for this paper to discuss in detail each one of them.

Just as an example, let us look at the key principles and essential features for element “management of change”, listed in Table 2.

Incidentally, one can easily pinpoint mismanagement of changes as one of the root causes behind the Creutzfeldt-Jakob disease explained above. When meat-and-bones fodder was fed to cattle, was there a management of change in place, with the key principles and essential features of Table 2 in place? Most likely, not.

Table 2. Key principles and essential features for element “management of change”

It seems clear that the top-down definition of the element, as provided by its key elements and essential features, is fully applicable to the new hazards originated by biomanufacturing. We have revised the remaining nineteen elements, and reached the same conclusion.

Tools

Clearly, we cannot expect every tool developed for process safety to be applicable to biohazards. In some cases this will be feasible with some minor changes.

For instance, we can envision applying techniques such as HAZOP or quantitative risk analysis to a biomanufacturing facility, but they will need at least some fine-tuning. We will also need to develop consequence modelling in line with the new types of hazards.

Going back to the example of the Creutzfeldt-Jakob disease, how could one assess the risk of changes in the feeding of cattle? The entire PSM toolkit will need to be refurbished to host the entirely new class of hazards.

Experts

Together with new techniques, we will need a whole new cohort of process safety experts, bringing knowledge on biological processes, to complement what we already have in terms of chemical processes. Needless to say, appropriate competence development programs will need to be deployed.

Conclusions

New bioengineering technologies are increasingly being applied to manufacturing of diverse types of goods: from food to pharmaceuticals to oil & gas.

On the other hand, a stream of incidents from the past clearly proves that exposing humans to new micro-organisms (for instance, engineered ones) can turn into a catastrophe with unprecedented consequences.

However, the risk of exposure to new hazards is not unknown in history. Humankind developed process safety as a way to identify, assess and manage risks caused by hazardous materials: from secular hazards such as flammable dusts (sugar, flour….) to those linked with hazardous industrial chemical reactions and new chemicals. The technological answer to harness these risks has been process safety management.

At DEKRA we believe that, despite its “chemical” origin, the framework of process safety management is sufficiently robust and flexible to accommodate the new risks.

We will need, however, to develop new tools or adapt some of the existing, as well as include new colleagues who bring the technical expertise on the new risks.