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Determining how much containment is needed for API handling requires evaluation of multiple factors.
Highly potent drugs represent a growing proportion of medicines, including therapies in development and those commercially available. As older products reach patent expiry, generic-drug companies are also moving into this space, creating an increasing demand for capability and capacity to manufacture highly potent APIs (HPAPIs), particularly for contract manufacturing organizations (CMOs).
A significant proportion of HPAPIs are in the oncology field, and as approximately one-third of all new drug approvals are currently cancer medicines, this represents a substantial market opportunity. Other therapeutic areas where drugs may be highly potent include asthma and pain management.
The chemistry to make these molecules is not necessarily difficult; however, the greater challenge is in the handling and containment of them to ensure operator and environmental safety. It is vital that a careful assessment is made of the hazards posed by each individual product, reagent, and intermediate involved in the synthesis ahead of manufacture. If the risks are underestimated, people within and around the plant will be in danger. Conversely, if the risks are overestimated, the result will be excessive amounts of money spent on containment and an increase in project costs.
A compound is deemed to be potent in pharmaceutical terms if it has an eight-hour, time-weighted average occupational exposure limit (OEL) of 10 µg/m3 or less. There is, however, no formally agreed definition of the OEL level that constitutes a “highly potent” compound. To add to the confusion, the same compound might be classified differently by individual risk assessors. This variability in classification is exemplified by a study carried out by Cambrex in which a panel of 38 molecules was sent to three risk assessors. Three different results were provided: one assessor deemed five of the 38 to be highly potent, one assessed 37 of the 38 to be highly potent, and the third fell somewhere between the two extremes.
The subjective nature of these results highlights that any CMO managing a facility to manufacture multiple APIs that may, or may not, be highly potent should consider each project on a case-by-case basis. A flexible approach allows manufacturing techniques, equipment, and containment options to be tailored to the molecule’s properties, and the requirements of each individual step of the synthesis. The result should be increased safety, lower costs, and enhanced capacity for the manufacturing of HPAPIs.
When determining risk, the starting point is the OEL and other safety-related properties of the molecule determined as part of the drug development process. Once an investigational drug reaches the large-scale manufacturing stage, extensive safety data will have been compiled, including results from preclinical toxicology assessments, animal studies, and early-stage clinical trials.
These data on potential hazards and dose–response effects are used as a basis by experts in risk assessment to generate OELs and occupational exposure bands (OEBs) that allow informed decisions to be made about engineering strategies and industrial hygiene requirements. Appropriate containment and personal protective equipment should be supplemented by comprehensive training to ensure their proper use.
There is an important caveat. Although toxicological data offer a useful starting point, there is a difference between potency and toxicity. Potency is a measure of how much of the API is required to have a therapeutic effect; toxicity is a measure of its adverse effects. A cytotoxic drug to treat cancer may be extremely toxic but its potency might be low, and therefore, side-effects are likely. Conversely, for some drugs that only require very small doses to have a medical benefit, the dose that causes side-effects may be substantially larger. The handling requirements in the manufacturing plant will be very different for the two.
Toxicology data gleaned from preclinical research or clinical trials are not designed for direct application to OELs, either. The aim of an early-phase clinical study is to determine optimal doses, balancing therapeutic benefit and what patients can tolerate. There is a huge difference between exposure in this context, and the inadvertent inhalation of dust in a manufacturing facility; there is no direct correlation between these clinical trial data and the safe exposure level for operators.
The data will, however, provide indications to issues that might occur with acute exposure. If they highlight issues such as respiratory problems, lachrymatory issues, adrenergic concerns, or somnolence, for example, acute problems might be anticipated in manufacture. There may be indicators toward chronic exposure issues, also, if there are indications that the compound might be carcinogenic, mutagenic, a sensitizer, or a clastogen.
With this information in hand, the next step is to identify any critical effects that exposure might have, such as target organ toxicity or pharmacological effect, and the dose-response curve. However, inter-person variation makes it difficult to make a definitive risk assessment.
At the lower end of the dose–response curve (Figure 1) is no-observed-effect level (NOEL), where the chemical causes no effect at all. The next point moving up the curve is the no-adverse-event level (NOAEL), which is commonly cited in risk assessments. Next, there are the analogous low-effect level (LOEL) and low-adverse-effect level (LOAEL), and then doses that are well tolerated, followed by the maximum tolerated dose (MTD). Past this point, the APIs are likely to be hazardous. In animal tests, at the ED50 point, half of the animals will experience an effect; at the TD50 point, half will experience toxicity; and at the LD50 point, half the study animals will die at that level of exposure.
OEL (μg/m3) =PoD x BW/UFc X MF x V
OEL is occupational exposure limit
PoD is point of departure for extrapolation (mg/kg-bw/day)
BW is body weight (kg)
UFc is composite uncertainty factor
MF is modifying factor
V is volume of air breathed during work shift (m3)
The OEL equation (Equation 1) includes uncertainty factors (Table I) that compensate for unknowns. The numerator comprises factors that will increase occupational exposure, while the denominator includes those that will reduce it, including uncertainty factors. Those components that can contribute to uncertainty include variation between species and between subjects, the duration of the study, the severity of the effect, bioavailability and bioaccumulation, and pharmacokinetics.
|Area of uncertainty||Uncertainty factors|
|Low-effect level (LOEL) to low-adverse-effect level (LOAEL)||10|
|Severity of effect||1–10|
Modifying factors are also considered by some risk assessors, including the slope of the dose–response curve, and the choice of critical effect and its clinical significance, its reversibility, and its relevance to workers. Susceptible subpopulations and read-across similarity may also be considered, as may a lack of independence for uncertainty factors.
This uncertainty is at the root of the variability in risk assessments. Depending on the magnitude of uncertainty values that are applied, and whether modifying factors are given weight, there is the potential for as much as eight orders of magnitude of difference in the OEL determined by individual assessors. Reconciling this variability in the final risk assessment is a major challenge.
The solution lies, at least in part, in applying real-world context to the uncertainty factors. Perhaps the most important is the acceptable exposure risk for an individual operator, and even for the most conservative risk assessor, a one-in-one-thousand risk may well be more realistic than the one-in-one-million risk to be an appropriate likelihood of an exposure happening. The one-in-one-thousand risk is not without context: it is commonly cited as the chance of a severe injury in a hazardous work environment.
Three orders of magnitude difference in acceptable exposure risk can represent a major difference in cost. If an API is placed in a higher OEB in the absence of data and with a large weight placed on uncertainty factors, then far more costly containment will have to be employed, and the manufacturing process will take longer. How necessary is it that the API is treated as so much more hazardous? And what about the intermediates involved in its production? It is less likely that there will be a calculated OEL for those intermediates.
It is important to carefully consider exposure modifiers. Is the process likely to generate dust? If so, the likelihood of airborne hazard is far greater. How long will the operator be exposed to the material? Theoretical OELs are based on an eight-hour exposure; however, the time of potential exposure may be only a few minutes. A case-by-case assessment of the actual facility, process, and procedures will give a far more realistic picture of the hazard. There may be limits on how long people can work on individual projects because of the potential for chronic effects. If an API is a known teratogen, it may be advisable for pregnant women to keep well away.
Occupational exposure bands are a useful tool for matching a hazard with containment requirements. APIs that fall into OEB1 are non-toxic, and a standard exposure level of 500 µg/m3 will suffice. OEB2 compounds will have special hazards, such as carcinogenicity, and the OEL will need to be lower.
At OEB3, where the hazards are greater but not extreme, the opportunity to customize handling to account for real-world situations is greater; this is where the greatest cost and time savings might be anticipated. Here, the containment could-and should-be designed around the process itself. The existing plant may suffice; alternatively, safety requirements might be met by introducing high-efficiency particulate air (HEPA) filters or soft-sided isolators, a more conservative approach than simply using personal protective equipment. The risk assessment should also consider the solvents and whether they can degrade processing or containment equipment. A program of surrogate testing is required to prove that the containment strategy is appropriate and working successfully before the hazardous material is introduced.
OEB4 APIs are more highly potent and toxic, and special handling and careful containment will be required. An additional band, OEB4+, encompasses compounds that are so potent that their OEL falls below 0.1 µg/m3. For OEB4 and OEB4+ compounds, the opportunity for customization is limited, and the process must be designed around the containment, and not the other way around. Dedicated isolators will most likely be employed, and rapid transfer ports for APIs deemed to be OEB4+.
This type of complete containment is extremely expensive, and while the conservative approach would be to use such containment for all highly potent compounds, in reality it may be overkill for OEB3 APIs. Instead, it may be more realistic to start out with the assumption that full containment is required, but then relax the handling requirements as further data become available, if the data suggest this will be safe. This level of flexibility will allow a CMO to offer its customers a more cost-effective solution, and faster timelines.
Jeff Pavlovich is senior process safety engineer at Cambrex.
Supplement: Outsourcing Resources
Pages: s18–s20, s33
When referring to this article, please cite it as J. Pavlovich, "Classifying Potent and Highly Potent Molecules," Pharmaceutical Technology Outsourcing Resources Supplement (August, 2018).