Introduction

Since the 1970s, occupational toxicologists, industrial hygi-enists, and other occupational health professionals in the pharmaceutical industry have recognized that occupational exposure to active pharmaceutical ingredients (APIs) can cause unintended health effects in workers handling these substances (Romer 2003). Chemical compounds that are routinely handled in the pharmaceutical industry are unique from other chemicals in that these compounds are designed to have an effect on the human body. In an occupational setting, if an employee provides a pathway of exposure to a potent compound, there is a high probability that the com-pound is going to elicit the designed response. Occupational health professionals in the industry have responded to this hazard recognition by employing strategies for the risk evaluation and control of potent APIs, otherwise known by the term potent compounds. The purpose of this paper is to provide an overview of the necessary strategies for prevent-ing occupational exposure to potent compounds.

The strategies for preventing occupational exposure to potent compounds consists of anticipating and evaluating the hazards of potent compounds; determining those proc-ess activities that pose the highest risks; evaluating those risks; and, finally, controlling potential exposures primarily through engineering devices. These strategies should be applied at all stages of pharmaceutical product development

including discovery, pre-formulation, initial test batches, pilot plant, scale-up, and production. These strategies can be applied to initial discovery of a potent compound by an innovator company or to the development of a product coming off patent by a generic pharmaceutical company.

There are four definitions routinely utilized in the phar-maceutical industry to determine if a chemical drug sub-stance should be considered a potent compound. These definitions can be extended to cover biotechnology products as well. First, a potent compound is a pharmacologically active ingredient or intermediate with biological activity at 15 g/kg of body weight or below in humans or a daily therapeutic dose of 1 mg or below per day. Second, a chemi-cal drug substance is considered to be a potent compound if it is an active pharmaceutical or biotechnology ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 g/m3 of air as an 8-h time weighted average. Thirdly, a potent compound must be a pharmacologically active ingredient or intermediate with high selectivity (as in the ability to bind to specific receptors or inhibit specific enzymes) and/or have the potential to cause cancer, muta-tions, developmental effects, or reproductive toxicity at low doses. The final definition of a potent compound is that of a novel compound of unknown potency and toxicity.

From a risk management standpoint, failure to control occupational exposure to potent compounds can result in

ISSN 1537-6516 print/ISSN 1537-6524 online 2011 Informa Healthcare USA, Inc.DOI: 10.3109/15376516.2010.484621 http://www.informahealthcare.com/txm

R E S E A R C H A R T I C L E

Strategies for preventing occupational exposure to potent compounds

Dean M. Calhoun, Angela B. Coler, and Joe L. Nieusma

Affygility Solutions, LLC, Broomfield, Colorado, USA

AbstractOccupational exposure to active pharmaceutical ingredients in a manufacturing or laboratory environmental can cause unintended health effects in workers handling these compounds. Occupational health professionals in the pharmaceutical industry have responded to this hazard recognition by employing strategies for the risk evaluation and management of potent APIs, otherwise known by the term potent compounds. The purpose of this paper is to provide an overview of the necessary strategy components for preventing occupational exposure to potent compounds.

Keywords: Potent compound safety; occupational exposure pharmaceuticals; occupational toxicology; risk assessments

Toxicology Mechanisms and Methods, 2011; 21(2): 9396Toxicology Mechanisms and Methods

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10.3109/15376516.2010.484621

Address for Correspondence: Dean M. Calhoun, CIH, President, Affygility Solutions, LLC, Broomfield, Colorado, USA. Tel: 303-884-3028. E-mail: dcalhoun@ affygility.com

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94 D.M. Calhoun, A.B. Coler, and J.L. Nieusma

delays in product development, production stoppage, and employee illnesses.

Strategy component 1: Evaluating the hazards of existing and new compounds

Prior to the introduction of new APIs into the workplace, a thorough scientific literature search on the specific or similar compounds should be conducted. In addition, for a com-pany first establishing a potent compound safety program, a thorough literature search should be performed on pharma-ceutical products already in the companys portfolioeither in development or already on the market. The occupational health professional needs to gain an understanding of the potential hazards of all of the companys products. While retrieving literature and understanding the hazards may seem like a fairly simple task, for new compounds early in the development process it is often challenging to find infor-mation that is relevant to an occupational exposure scenario. However, the primary focus should be to identify sufficient information to allow preliminary classification of the potent compound into a banding strategy such as those proposed by Naumann et al. (1996). This classification scheme in principal has been widely accepted across the pharmaceutical industry with minor revisions. The most common modification to the classification scheme described by Naumann et al. is typically in the number of classification bands individual companies utilize for their products. The number of bands that a com-pany chooses to employ depends on the range of pharmaceu-tical products in the companys portfolio and the number of control options that the company has implemented. Figure 1 describes the Affygility Solutions banding scheme.

Potential literature sources of information can originate from both inside a company and from published scientific literature. Primary articles, as well as the many high qual-ity databases from the National Library of Medicine of the National Institute of Health, provide published resources on numerous chemical substances. Additionally, non-govern-mental databases can also be found online. For discovery compounds, the internal toxicology studies will provide the most useful information. If the chemical entity has been on the market for a significant period of time, the literature can possibly provide all the necessary data to complete a potent compound classification. Once the data has been assembled, professional judgement must be exercised to evaluate the data and determine the critical toxicological end-points.

When evaluating the data, the following guidelines have been recommended by Leung (2002, 64771):

a no-observed-adverse-effect level (NOAEL) should be 1) selected over a lowest-observed-adverse-effect level (LOAEL);

studies with the same route of exposure are preferred;2) human data, in general, should take priority over animal 3) data;chronic studies, which reflect long-term repeated expo-4) sure in an occupational environment, are usually more appropriate than acute studies; andThe most sensitive endpoint that is biologically relevant 5) to humans is preferred;irreversible effects such as carcinogenic, teratogenic, or 6) reproductive effects generally take priority over revers-ible effects such as irritation or elevated liver enzymes unless the LOAEL of a reversible effect is much lower than the NOAEL of an irreversible effect.

Once a relevant dose has been determined, an estimated occupational exposure limit (OEL) can be calculated using the methodologies such as those presented by Sargent and Kirk (1988). Briefly, a NOEL or LOAEL is multiplied by body weight followed by division by uncertainty factors, a modify-ing factor, and any relevant pharmacokinetic parameters. The amount of air breathed during a typical shift (10 m3) is also a factor in the denominator of the OEL equation. Uncertainty factor values are as unique as the companies that set them. Internal policies usually provide criteria for setting uncer-tainty factors ranging between 110. Examples of the criteria typically used are shown in Table 1. The criteria shown in this table is not meant to be a comprehensive as to factors covered by uncertainty factors, but rather to demonstrate the complexity of the issue to be considered in setting an OEL for a potent compound.

Any comprehensive programme will have established procedures detailing the relevant uncertainty factors and how the numbers are set according to the risk acceptance philosophies of each company. The modifying factor is included to account for an estimate of how complete the data set appears to be for the chemical. Assignment of this factor is based mainly on professional judgement of the toxicologist performing the compound evaluation. Relevant pharmacokinetic parameters utilized in the equation include bioavailability, volume of distribution, and various half-lives of the drug.

In the case of a drug nearing patent expiration, a more direct exposure limit calculation can be completed based on the lowest daily therapeutic dose of the drug. This dose is divided by a safety factor, generally between 10100, and the amount of air breathed on a typical 8-h work shift (10 m3). The appropriate safety factors are determined through an extensive literature review from the sources previously mentioned. Because of the wealth of available information, a generic drug company formulation rarely requires any additional toxicology studies to be performed on a previ-ously marketed drug.

Table 1. Criteria used for uncertainty factors.Interspecies differences Route of administration

LOAEL vs NOAEL Length of critical study

Sensitivity of target populations Irreversible effects

Human variability

I II100 20 5 0.5

Occupational Exposure Limit (g/m3)

III IV V

Figure 1. Affygility solutions control banding system.

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Strategies for preventing occupational exposure to potent compounds 95

Strategy component 2: Conduct risk assessments on all potential exposure scenarios

After an understanding of the potential hazards of the com-pound has been acquired and an OEL has been calculated, the occupational toxicologist should perform a detailed risk assessment. Risk assessments are often an overlooked, but extremely important, component of a potent compound safety program. The risk assessment will contain a number of risk factors that will define the probability of exposure. These risk factors are shown in Table 2. A comprehensive potent compound safety program will have completed detailed risk assessments on every step of the process. In addition to manufacturing processes, risk assessments should also be conducted for non-routine activities, such as emergency repair activities, spill situations, or equipment failure. In order to appropriately conduct a risk assessment, representatives from a number of departments will need to be involved. These departments can include: industrial hygiene, occupational toxicology, occupational health, and operations.

Strategy component 3: Evaluate potential exposures

After risk assessments have been completed, a risk-based monitoring strategy will need to be developed. Exposure assessment strategies such as those proposed by Hawkins et al. (1991) are useful. For instance, exposure assessments are utilized to identify the need for engineering controls or, in the case where engineering controls alone are not adequate to control occupational exposure, if personal protective equipment (PPE) is required as an additional means of pro-tection. Data from an exposure assessment will determine the level of containment achieved and if other means of controlling exposure are required.

When conducting air monitoring for potent compounds, it is frequently the case that air sampling and analytical methods will not be available and will need to be developed by specialty industrial hygiene analytical laboratories. While total dust methods may be appropriate for low hazard APIs, total dust methods dont offer the sensitivity and specificity needed for high hazard compounds with OELs in the low g/m3 range.

During the interval of method development for a potent compound, the integrity of the containment strategy can be tested. It is common practice in the pharmaceutical industry to use either lactose or naproxen sodium to perform surrogate

monitoring on the equipment train prior to inclusion of the more potent API (Mehta & Tait, 2002). The data obtained from these evaluations will provide insight into how the contain-ment strategy will perform when the potent compound is in the equipment train.

After receipt of the exposure assessment results, the occu-pational health professional will need to carefully evaluate the data and compare to the field notes to determine the activities and operations that contribute to increased expo-sures. The results should be communicated in writing to affected personnel. Exposure assessments are a critical tool for performance verification of engineering controls. Operator effects are numerous. Even the most sophisticated engineering controls can be ineffective due to poor opera-tor technique or failure to follow established procedures. The authors of this paper have shown that a single instance of inappropriately using a compressed air hose to remove spilled dry powder from the top of a container can result in an 8-h time weighted average exposure that is 400% higher than another who did not use a compressed air hose. High quality, comprehensive training is critical to decrease or eliminate variability in operator technique. Consistent tech-niques, attention to detail, and proper use of the available engineering controls is critical in preventing occupational exposure to potent compounds.

Strategy component 4: Implement risk management and control measures

The primary focus of a comprehensive potent compound program is to prevent occupational exposures through effective process containment. When handling highly potent compounds, containment must be provided during all steps in the process. Typical containment devices include the use of downflow booths during weighing or dispensing activities, the use of high containment or split butterfly valves during product transfer between containers, local exhaust ventila-tion near dust generating activates, closed systems, vacuum transfers, and the use of isolators to enclose the process. These are just a few examples of containment devices and many others exist. The engineering controls need to be a workable design, ergonomically correct, and user friendly or they will quickly be relegated to the backroom by operators. The operator interface is one main aspect that is controllable. Minimizing operator interaction in a process will minimize exposure potential.

In addition to engineering controls, other risk manage-ment strategies may need to be utilized. These strategies may include administrative controls such as compound-specific hazard communication training and product-specific medi-cal surveillance. However, these aspects cannot be consid-ered as a substitute for the previously mentioned engineering controls. Other examples of administrative controls include time limits for operator exposures, gender restrictions, bio-monitoring protocols, and process changes to eliminate operator variability due to inconsistent work practices. The

Table 2. Risk factors for probability of exposure.How the API is handled Frequency of the exposure

Physical form is the API (powder, liquid, or gel)

Previous reports of adverse health effects

Quantity of the API Previous industrial hygiene results

Duration of the exposure Extent of existing engineering controls

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96 D.M. Calhoun, A.B. Coler, and J.L. Nieusma

use of personal protective equipment should only be used as a tertiary means of exposure control.

Strategies for preventing occupational exposures to potent compounds require that all elements be considered. Failure to control exposures to potent compounds can result in costly program missteps, delayed production schedules, or potentially hazardous exposures to workers. A compre-hensive potent compound program will have contributions from occupational toxicology, industrial hygiene, safety, engineering, and operations. The primary goal for the pro-gram is employee safety and increased productivity.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Mehta TM, Tait K. 2002. Validation of dust control efficiency using lactose as a surrogate at a pharmaceutical company in India. Paper presented at the meeting of the American Industrial Hygiene Association, San Diego, CA. Abstract available online at: http://www.aiha.org/aihce02/handouts/pf120mehta_files/frame.htm (last accessed 19 May 2010).

Naumann BD, Sargent EV, Starkman BS, Fraser WJ, Becker GT, Kirk GD. 1996. Performance-based exposure control limits for pharmaceutical active ingredients. Am J Ind Hyg 57:3342.

Romer T. 2003. Containment of potent compounds at Bristol-Myers Squibb: an overview. Presentation for the International Society of Pharmaceutical Engineers Chapter on September 10, 2003. Available online at: http:www.ispe.org/newengland/09102003Romer.pdf (last accessed 7 December 2004).

Sargent EV, Kirk GD. 1988. Establishing airborne exposure control limits in the pharmaceutical industry. Am J Ind Hyg 49(6):309313.

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Strategies for preventing occupational exposure to potent compoundsAbstractIntroductionStrategy component 1: Evaluating the hazards of existing and new compoundsStrategy component 2: Conduct risk assessments on all potential exposure scenariosStrategy component 3: Evaluate potential exposuresStrategy component 4: Implement risk management and control measuresDeclaration of interestReferences