UNDERSTANDING PHARMACEUTICAL MANUFACTURING RISK ASSESSMENTS

Jérôme Taveau

Learn about the distinct hazards in the pharmaceutical industry at each phase of manufacturing.

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The pharmaceutical industry is often perceived as inherently safe. Its processes involve small-scale unit operations with lesser quantities of hazardous materials than typically found in the chemical industry. The industry is also subject to very strict operational and quality controls. Along with chemical hazards in the pharmaceutical industry, it would be a mistake to neglect the possibilities of fires and explosions in particular, as several accidents have highlighted in the past.

Pharmaceutical manufacturing indeed involves multiple hazardous unit operations, from the synthesis of the active pharmaceutical ingredient (API) to the solid processing operations such as milling, blending, granulation and drying, among others. It’s important to clearly understand the risks associated with pharmaceutical operations and propose right sized, cost-effective mitigation strategies.

What is the Pharmaceutical Manufacturing Process?

The pharmaceutical manufacturing process combines the API and excipients (e.g., binders, coatings) into a dosage form such as tablets or capsules. API is generally obtained via chemical or biological synthesis involving multiple liquid phase reactions in stainless steel pressure resistant reactors containing solvents. API is then filtered, crystallized, purified, dried and milled. Once API is isolated, it is blended with excipients into the right proportions to create the final dosage. The resulting powder mixture is then subject to several granulation (wet or dry), milling and drying steps (using conical or fluid bed dryers). Tablets are finally preformed, coated and packaged.

What Types of Hazards are in the Pharmaceutical Industry?

Throughout the pharmaceutical manufacturing process, there are unique hazards that pose a serious risk to operators, equipment and the facility in general.

Fire Safety in the Pharmaceutical Industry

The storage of combustible solids and flammable liquids implies fire hazards in the pharmaceutical industry. An uncontrolled fire can rapidly spread to other parts of the facility and escalate to even more serious, secondary accidents. It is therefore crucial to adequately address fire hazards in pharmaceutical operations.

Runaway Reaction

During the synthesis of API, an uncontrolled exothermic reaction can be caused by different process deviations, such as the introduction of incorrect material or the loss of coolant or agitation. This can result in a rapid elevation of temperature, triggering secondary decomposition reactions, leading to a thermal runaway. The heat produced is enough to vaporize the solvent present in the liquid phase, forming a flammable atmosphere that can ultimately cause the explosion of the reactor. Authorities believe that is what happened at the Teva API plant in Ramat Hovav, Israel, where one worker was killed, and 30 others were injured.

Dust Explosion

Most active pharmaceutical ingredients and excipients (e.g., magnesium stearate, lactose and starch) are combustible powders with low Minimum Ignition Energies (MIE), meaning they are particularly susceptible to ignition from common sources such as electrostatic discharge. The successive solid processing operations can generate fugitive dust and form dust layers and airborne dust clouds, creating fire, flash fire and explosion hazards. In addition, the transfer of combustible powders into a reactor that already contains flammable vapors can create hybrid mixtures, which can explode as well.

Bursting

Common industrial utilities, such as boilers or heat exchangers, also present a risk of explosion under a range of abnormal circumstances, such as fire exposure or clogging. In a recent incident in India, a boiler attached to a plant transformer caught fire, apparently due to a short circuit, causing an explosion.

Toxicity

Finally, it is worth reminding that APIs, which are produced to treat diseases or reduce their side effects, are generally highly toxic materials at relatively low doses. Any prolonged exposure to APIs may cause chronic health effects, serious incapacitation or fatalities.

Mitigating Your Pharmaceutical Manufacturing Risks

Multiple hazards must be considered in the design of a new pharmaceutical process, or when process alterations trigger a Management of Change review. By conducting a process hazard analysis and understanding any prevention or mitigation gaps in the process, the applicable hazards can be understood and managed.

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