Risk Management of the Explosive Dusts in the Pharmaceutical Industry: A Practical Approach

The potential for dust explosions during pharmaceutical development and manufacturing is often overlooked. During processing and transporting, bulk powders can form airborne dust clouds and generate a static charge. In addition, the process containment systems designed to protect employees from potent compound exposure can create ideal conditions for high concentrations of airborne dust to collect inside processing vessels and equipment. These combined factors can lead to an increased risk for dust explosions during pharmaceutical processing operations.

Under the right circumstances, all materials can be explosive. Similar to hydrocarbon vapors, dust suspended in air can ignite and burn extremely rapidly. If these conditions occur in a confined area such as in processing equipment or in a manufacturing suite, a dust explosion may occur.

Moreover, dust explosions can release high pressures. Based on our experience, we found that it is common for active pharmaceutical ingredients (APIs) to be capable of releasing pressures in the 8–10 bar range, which is often considerably higher than the processing equipment's pressure rating.

Protection against dust explosions can be accomplished by preventing the explosion from occurring or by reducing the negative effects if the explosion occurs. This article focuses on a risk assessment approach and implementation strategy for engineering controls to prevent dust explosions in the pharmaceutical manufacturing environment. The scope of this article is limited to materials that can deflagrate. Materials known to detonate require additional control measures beyond the scope of those items discussed here.

Although the article is intended to be a practical guide to managing the risk of explosive dusts, it is not intended to be relied upon as a definitive risk management program. Pharmaceutical drug developers and manufacturers should create their own risk management programs with assistance from process safety professionals to address the specific explosive dust risks of their respective operations.

Hazard recognition

The first step in evaluating explosive dust hazards is to identify the parameters that can contribute to an explosion or a deflagration.

A dust explosion is a combustion process (see Figure 1). All components of the fire triangle—oxygen, a fuel, and an ignition source—must be present for a fire or an explosion to occur. If any one part is removed, the risk of explosion is eliminated. It is preferable to remove two sides of the fire triangle to provide a higher safety factor when managing dust explosion risk.

Figure 1: For a fire to occur, all components (ignition source, oxygen, and fuel) of the fire triangle must be present.

In the pharmaceutical industry, the fuel frequently is the API and, to a lesser extent, the excipients (e.g., binders, coatings). Nonetheless, APIs have a wide range of explosivity and sensitivity to an ignition source (e.g., between 1 and >1000 mJ).

Ignition source. An ignition source must provide sufficient energy to create an explosion. Ignition sources include open flames, exposure to hot surfaces, high temperatures, friction, mechanical impact (e.g., metal–metal contact), electrical sparks, and electrostatic discharge.

In the pharmaceutical industry, however, the main ignition source tends to be from an electrostatic discharge, which can be generated by processes such as sieving, milling, pouring, mixing, and pneumatic transport. The grounding and bonding of equipment and tools minimize the risk of ignition.

Oxygen. For an explosion to occur, an adequate amount of oxygen is required. For most organic materials such as pharmaceutical materials, oxygen concentrations that are less than 8% volume are unlikely to support combustion (1). By maintaining oxygen concentrations in process equipment at 5% or less, one can eliminate the risk of combustion while still allowing a 3% safety factor to account for any leaks in equipment that may allow the oxygen to escape.

Fuel. In many cases, the API is the fuel source. APIs have a wide range of explosivity or sensitivity to an ignition source. Explosive characteristics vary among materials and can depend on the properties of the material, particle size, impurities, and moisture content among other factors.

In our experience, most excipients (e.g., lactose and starch) have a low explosive potential, but there are some exceptions. For example, magnesium stearate has a low MIE (minimum ignition energy) at 1–3 mJ. When considering the fire triangle principles, the fuel or the API is always present and can rarely be eliminated.

Fuel must be present in a sufficient quantity and be airborne to be explosive in a dust cloud. Explosive dust testing of the fuel is useful for determining how sensitive a compound is to an ignition source or electrostatic discharge and the explosion severity.

Hazard evaluation

Although explosive dusts are hazardous, they can be processed safely. Nonetheless, safe processing requires a basic knowledge of the materials being handled and a hazard evaluation of the process conditions and equipment. This section describes tests and guidelines to help evaluate a hazard.

Explosive-dust testing. Using a risk assessment model, the following two core tests should be conducted on APIs and excipients that may have explosive properties:

• minimum ignition energy (MIE) (mJ);

• explosion severity (Kst) (bar m/s) (see sidebar, "Terms and definitions).

Terms and definitions.

An approximately 500-g sample is required to complete MIE and Kst testing. One should conduct testing using a recognized standard such as the ASTM E2019-99, Standard Test Method for Minimum Ignition Energy of a Dust Cloud in Air (2) and the E1226-00, Standard Test Method for Pressure and Rate of Pressure Rise for Combustible Dusts methods (3).

Particle size, moisture content, and humidity all can affect sample analysis. The sample should be tested in an environment that is as close to the processing conditions as possible (i.e., samples from the same supplier and with the same particle size).

Testing for minimum ignition temperature (MIT), minimum explosive concentration (MEC), and limiting oxygen concentration (LOC) may not be required based on process conditions and containment considerations. For example, the MIT typically is much higher than processing temperatures, even in fluid-bed dryers or heated jacketed vessels. In these cases, temperature is unlikely to be an ignition source.

It may be prudent to sample and test the formulation's blend as well as the active component, depending on the process train, the percentage active component in the blend, and the batch size. For example, if the material goes through a milling step, a sample of the milled material should be sent for analysis. If the API has a low MIE, then excipients with higher MIEs may act as a secondary fuel source, thereby contributing to the overall explosion severity.

Another challenge for the pharmaceutical industry is that 500 g of API may not be available for testing. In this case, several conservative assumptions must be made until test data can be collected (see Table I).

Table I: Explosive index.

Evaluating process equipment hazards. The evaluation of process equipment hazards should include dust capture, extraction, dust collection, and cleaning of contaminated equipment. In addition to explosive-dust testing, several assumptions and pieces of information are required to complete the hazard evaluation.

• MEC. The MEC of an active component is typically in the 30–100-g/m³ concentration range. This concentration can be achieved inside a process vessel or an intermediate bulk container, but it is unlikely to be achieved in workroom air where there is good containment.

• Batch size. The batch size is an important parameter because it relates to the MEC and can help researchers determine the feasibility of achieving the MEC during processing. For a batch size of less than 10 kg, for example, it would be difficult to achieve the MEC during a dispensing operation, depending on the size of the process container.

• Percent (%) API in blend or product. The drug load or %API is an important value when evaluating the process train and hazard level of the unit operations and the quantity of available fuel. In general, blends with a high %API (e.g., 75% or more) will be more hazardous than blends with a low %API (e.g., 1%). Exceptions may be made when the excipients are considered to be explosive.

• Particle-size distribution. Distributions with median particle sizes less than 100 μm may be more sensitive to energy and ignition sources (4, 5). For an explosion to occur, the material must be in a dust form (median particle size <400 μm) (4, 5) and be dispersed in the air in a higher concentration than the MEC. This consideration is important when evaluating the hazards of a process that causes size reduction such as milling.

• Maximum pressure (P_max). The P_max value can be calculated from Kst test data. This value can be compared with the pressure rating ofthe process equipment to determine whether equipment would be safely contained if an explosion were to occur.

• Process train. Higher risk processes such as milling or size reduction, fluid-bed drying, screening, and pneumatic transfer as well as the presence of flammable liquids may increase the risk of an explosion because of the nature of the processes. These processes tend to have an increased risk of mechanical spark, greater dispersion of powder in air, and a high-energy movement of particles contributing to a greater potential for electrostatic discharges.

• Potent compound containment. If the potent compound containment strategy involves closed-container processing, vacuum extraction, and pneumatic transfer, one must give special attention to the likelihood and the severity of a potential explosion (6).

• Cleaning practices. Additional consideration should be given to the routine cleaning practices of process equipment and general housekeeping. Where possible, water or inert solvent rinsing is preferable to vacuuming products that are an explosion risk. If vacuuming is required, then an explosion-rated vacuum system should be used.

Quantifying the risks. An explosive index and control strategy has been developed to assess raw materials used in the production of pharmaceuticals (both APIs and excipients) to determine the risk level and the appropriate controls and safety strategies required. Table I lists an explosive index to quantify the risk associated with explosive dusts.

Using the MIE of materials, the sensitivity to electrostatic discharge can be determined. The Kst is used to determine the consequences of an explosion. On the basis of these two factors, the overall risk of a dust explosion can be estimated.

Control strategies

General principles. In general, when the MIE is less than 10 mJ, one must consider reducing the oxygen concentration to prevent an explosion. The MIE can be reduced by inerting the process equipment with nitrogen or other inert gases, which removes the oxygen portion of the fire triangle. The oxygen concentration should be reduced to 5% or less. Special precautions must be taken when working with nitrogen because leaks could cause an oxygen-deficient atmosphere outside the vessel. Oxygen must be monitored in the room to protect employees who are working with the inert gases.

Grounding and bonding (see Figure 2) should be completed on all equipment to dissipate any electrical charge-eliminating electrostatic ignition sources. All equipment (e.g., scoops, process equipment, transfer liners, hoppers, product, bulk containers, antistatic tools, static dissipating shoes) that can accommodate a charge must be grounded or bonded.

Figure 2: All equipment that can build up a charge should be grounded and bonded.

Housekeeping and containment must be maintained within the processing suite and for process equipment to eliminate the fuel portion of the fire triangle. Concentrations of explosive dust in the air in the same range as the occupational exposure limit are well below the MEC and do not represent a hazard.

The following pharmaceutical processes are of higher risk for dust explosion: fluid-bed drying, vacuum drying, grinding, milling, sieving, hybrid mixtures, micronization, and pneumatic transport. In addition, cone discharges (i.e., electrostatic charges on the surface of the cone or powder) may be generated when filling a process vessel or intermediate bulk container. A higher safety factor such as inerting, may be required when dealing with high-risk processes. Table II identifies recommended control strategies for each explosive index category.

Table II: Control strategies for explosive dusts.

Conclusion

There are often unknown or unseen explosive risks when working with pharmaceutical compounds. One must understand, reduce, and eliminate explosive risks during drug development, scale-up, and all subsequent manufacturing processes.

Drugs and drug products identified as having a high explosive risk are manageable and require controls and understanding above and beyond conventional pharmaceutical development strategies. Failure to understand and control these risks could lead to consequences ranging from an interruption in product supply to serious plant damage or significant personal injury. A range of systems and measures presented in this article can be used for safely handling and processing explosive pharmaceutical compounds in a wide range of manufacturing process applications.

Jeffrey Dinyer* is a manager of environment, health and safety, Mark Turnbull is an associate director of PDS process development and Sandra Neale is a former senior manager of environment, health and safety, all at Patheon Inc. (Toronto Region Operations), 7070 Mississauga Road, Suite 350, Mississauga, ON, Canada L5N 7J8.

*To whom all correspondence should be addressed.

References

1. National Fire Protection Association (NFPA), NFPA 69: Standard on Explosion Prevention Systems (NFPA, Quincy, MA, 2002).

2. ASTM International, Method E2019-99: Standard Test Method for Minimum Ignition Energy of a Dust Cloud in Air (ASTM, West Conshohocken, PA, 1999).

3. ASTM International, MethodE1226-00: Standard Test Method for Pressure and Rate of Pressure Rise for Combustible Dusts (ASTM, West Conshohocken, PA, 2000).

4. R. Eckhoff, Dust Explosions in the Process Industries (Elsevier, New York, NY, 1997).

5. NFPA, NFPA 654: Standard for the Prevention of Fire and Dust Explosions from the Manufacturing, Processing, and Handling of Combustible Particulate Solids (NFPA, Quincy, MA, 2000).

6. NFPA, NFPA 61: Standard for the Prevention of Fires and Dust Explosions in Agricultural and Food Processing Facilities (NFPA, Quincy, MA, 2002.

7. NFPA, NFPA 77: Recommended Practice on Static Electricity, National Fire Protection (NFPA, Quincy, MA, 2000).

8. NFPA, NFPA 499: Recommended Practice for the Classification of Combustible Dusts and of Hazardous (Classified) Locations for Electrical Installations in Chemical Process Areas (NFPA, Quincy, MA, 2004).

9. NFPA, NFPA 68: Guide for Venting of Deflagrations (NFPA, Quincy, MA, 2002).

Other useful sources

J. Barton, Dust Explosion: Prevention and Protection (Elsevier, New York, NY, 2002).

NFPA, NFPA 30: Flammable and Combustible Liquids Code (NFPA, Quincy, MA, 2003).

NFPA, NFPA 91: Standard for Exhaust Systems for Air Conveying of Vapors, Gases, Mists and Noncombustible Particulate Solids (NFPA, Quincy, MA, 1999).