Pharmaceutical


Thorough Risk Assessment Supports At-Scale Process Safety


I


t goes without saying that in any manu- facturing environment no one sets out to design an unsafe process. However, it is not enough to ensure a process will be safe under normal operating conditions. Deviations from normal operating conditions must be consid- ered at every step.


Integration of risk analysis into process design at an early development stage helps provide the opportunity to design an inherently safe process, taking into account the question, “What if…?” Used correctly, this early-stage risk analysis becomes an iterative procedure that accompanies process development.


The rules for improving process safety through appropriate design may almost appear trivial: everything from “know your chemistry” and avoid unnecessary accumulation of exo- thermally reacting compounds to maximize heat transfer per reactor volume unit and avoid external runaway triggers. However, the nature of batch and semibatch reac- tions—frequently relied upon in the areas of pharmaceutical and chemical manufacturing— establishes additional variables that should be taken into account when designing processes to be intrinsically safe.


Batch mode is acceptable (and cost-effective) for nonhazardous reactions. However, if there is more than a moderate adiabatic temperature increase and exothermic decomposition at maximum reaction temperatures, it is preferable to run a semibatch process where addition of one or more reagents is controlled. Classic defensive safety measures (e.g., emergency/evaporative cooling, quenching, and pressure relief) should never be ignored.


What does it mean to adequately determine thermal risk and prevent unsafe conditions in the case of either batch or semibatch process- ing where steady state is never reached? This article focuses on obtaining the data needed to develop processes that will help ensure that


classic defensive measures are never required, while also improving processes with regard to cost-effectiveness and time-to-reaction.


Ascertaining thermal risk Chemical process risk and hazard potential


are affected by a number of parameters. These include heat transfer, mixing effects, kinetics, heat generation rate, overall heat balance, heat- removal capacity of the reactor, accumulation of reagents/energy, and physical properties such as reagent stability and reaction mass.


Thermal runaway scenarios in a chemical plant are ultimately tied to a condition in which an ongoing reaction’s heat generation has exceeded the heat dissipation capacity of the process equipment—for example, reactant (heat) accumulation during a simultaneous cooling system failure when energy potential is released adiabatically. The predominant hazard in the manufacturing process, however, is the loss of control of a desired reaction due to reactant accumulation, high sensitivity to impurities, initiation problems (long induction time), wrong kinetic assumptions, or other variables.


The energy balance is dominated by a low heat dissipation capacity and subsequent en- ergy accumulation. In a case such as this, even very weak undesired reactions can run away. Undesired operational conditions may lead to insufficient mixing, wrong feed rates/tempera- tures, etc., that contribute to runaway scenarios, or vice versa. As noted, either scenario can be bad for production and potentially unsafe.


For these reasons, it is critical to gain an under- standing of MTSR, the maximum temperature of the synthesis reaction, based on the amount of accumulated reagent, or MAT, the maximum achievable temperature in the worst-case sce- nario assuming 100% reagent accumulation. Starting from MTSR, further events—particular- ly decomposition reactions—can be triggered that may ultimately lead to an explosion. These


AMERICAN LABORATORY • 18 • JUNE/JULY 2014


events need to be defined and explored if intrinsic safety is to be reached (see Figure 1).


Understanding runaway potential To prevent unsafe operating conditions based on runaway scenarios, data are required to predict runaway scenarios. Because it is not feasible to model the reaction completely in practice, the analysis of thermodynamics and kinetics of the reacting system can be reduced


by Urs Groth


Figure 1 – Heat balance diagram. A typical semibatch is run at the unstable oper- ating point.


Figure 2 – Runaway graph from iC Safety soft- ware (METTLER TOLEDO, Schwerzenbach, Switzerland).


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