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Eliminating risk: evaluation and mitigation of hazards of intermediates created during pharmaceutical processing.

Chemical processes and drug development in the pharmaceutical and fine chemical industries often deals with synthesis of highly complex molecules. Due to the novel nature of the materials, all the information required for safe scale-up, storage etc. is not readily available. Drug and fine chemical manufacture often involves a multistep process. Some of the intermediates formed during the process can be reactive and hence it is critical to understand their stability. Without information regarding the potential risks of intermediates (which can be highly complex molecules)--including toxicity, flammability, explosivity, corrosivity, chemical reactivity, thermal stability, etc., it can be hazardous to scale-up from laboratory to manufacturing scale. These hazardous characteristics are often difficult to evaluate due to the very limited quantities produced in the early stages of product development and even in actual production.

A recent paper presented by Mr. Delmar Morrison at the AlChE 2010 Loss Prevention Symposium, March 22-24, 2010, San Antonio, TX discusses a thermal runaway incident involving an organic peroxide intermediate during a power outage. The power outage was caused by a nearby lightning strike. The damage due to the lightning strike to several of the electrical distribution systems, local controls and instrumentation systems was not clear. Plant personnel tried to identify the issues with the control systems and repair them. However alarms associated with the control systems were disabled due to the power outage. One of the reaction vessels contained sufficient enough quantity of hot organic peroxide (cumene hydro peroxide, CHP). Since there was no cooling available, the intermediate started to undergo a self-sustained thermal decomposition. The decomposition products of the thermal runaway reaction were then vented and ignited, resulting in an internal flash fire. This was followed by a large pool fire in the operating unit. Several personnel were injured and significant property damage was caused by this incident.


In addition to the inventory of potentially hazardous intermediate materials that are created and handled during the scale up of a chemical process, there are changes in heat and mass transfer characteristics that may affect the progression of a reaction. It is therefore critical to characterize these intermediates. Identification of the decomposition of the intermediates is essential especially for:

* those associated with exothermic reactions (i.e., where heat is liberated during the reaction) and

* those which generate non-condensable gas To ensure safety, each process hazard must be mitigated with a defined basis of safety. There should be a definitive safety measure/s which should either minimize the likelihood of an event occurring to an acceptably low level or, where this is not possible, provide a method for protection of personnel, the equipment, and/or environment from the manifestation of the event. There are a number of potential hazards with intermediates which must be considered via a strategic assessment procedure including:

* the thermal-stability characteristics of the intermediates

* the thermodynamics of the intermediates

* the kinetics of the desired chemical process and possible undesired reactions

Critical parameters which must he defined prior to handling intermediates include:

* the safe handling temperatures for the intermediates

* the maximum and minimum allowable temperatures to effect the desired chemical conversion

* the rate of gas or vapor generation during the desired process Additional potential issues relating to intermediates which can cause problems include:

* Changes in heat-transfer rate as compared with small-scale equipment (reactor surface-to-volume ratio)

* Changes in mass transfer (power-to-volume ratio)

* Changes in the purity of process materials

* Changes in the materials of vessel construction


It is therefore critical to obtain chemical reactivity data under the desired and undesired process conditions via experimental testing, to ensure the safety of a chemical process. When processing exothermic chemical reactions involving reactive intermediates it should be remembered that the hazard arises from heat and pressure generation. Below is a list of some of the equipment that can be used to gather process-safety related information.

Differential Scanning Calorimetry (DSC): This is a contained, ramped-temperature screening test on a small sample of material (normally 2 to 10 mg) which provides an indication of the onset temperature and, more importantly, the magnitude of any heat release (A1-0.

Carius Tube: This test is similar to a DSC test; however, it uses slightly higher sample mass (normally 10 to 15 g) and is designed to collect temperature and pressure data. The test provides the reaction-onset temperature, the maximum temperature and pressure that can be attained, the rates of reaction (dT/dt) and (dP/dt), the onset temperature for gas generation, and the quantity of gas generated.

Accelerating Rate Calorimetry (ARC): This is a test that is performed in a heat-wait-search mode under pseudo-adiabatic conditions. The test determines the onset temperature of any self-accelerating exothermic reaction activity, the rate of temperature rise (dT/dt), the rate of pressure rise (dP/dt), and the volume of gas generated in a chemical system under conditions normally encountered during large-scale manufacturing and/or transportation. The sample mass is in the range of 2 to 5 grams.



Micro-Stirred Reaction Calorimetry ([mu]Cal): This reaction calorimeter can be used to determine the heat of reaction under isothermal conditions and identify the effects of changes in feed rate, temperatures, and concentrations on the instant-by-instant behavior of a reaction system. The heat of reaction (AHr) can be used to predict the adiabatic temperature rise in case of loss of cooling.

Reaction Calorimetry: Reaction calorimetry can be used to determine the heat of reaction under isothermal (constant sample temperature) or isoperibolic (constant temperature of the surroundings) conditions and identify the effects of changes in feed rate, temperatures, and concentrations on the instant-by-instant behavior of a reaction system. The extent of reagent accumulation can be quantitatively determined, and the heat of reaction (?Hr) can be used to predict the adiabatic temperature rise in case of loss of cooling.

Vent Size Package (VSP): The VSP is a pressure-compensated adiabatic calorimeter, and it can be used to determine the onset temperature, thermodynamic (heat of reaction, ?Hr), reaction pressure, and pressure-increase rate (dP/dt) for the reaction associated with the process.

Adiabatic Pressure Dewar Calorimetry (ADC II): This equipment is used to determine the stability of materials under adiabatic conditions. The thermal inertia of this system is very low and the test results are generally directly applicable to large-scale process vessels (e. g., up to 25 m3). The test provides direct measurement of temperature and pressure as a function of time, and time-to-maximum-rate data that can subsequently be used in the specification of maximum allowable handling temperatures, vent sizing for protection against runaway reactions for batch and semi-batch processes. Also, the test results aid in determining whether a reaction is "gassy" or if vaporization of a reaction component can be used to "temper" (control) the reaction. Additionally, blowdown tests can be conducted to determine if the vented materials are single-phase or two-phase (foamy) fluids.

BAM Fallhammer and Friction: The ignition sensitivity of solids, pastes, and gels to impact and frictional forces can be tested by the BAM Fallhammer and BAM Friction Apparatus, respectively. [BAM = German Institute for Materials Testing] The methods yield quantitative results in the form of limiting impact and friction energies. Chilworth Technology performs BAM Fallhammer and Friction Testing in accordance with the UN Recommendations on the Transport of Dangerous Goods - Manual of Tests and Criteria (ST/SG/AC.10/11/Rev.2 - 9/95).

* By Swati Umbrajkar, Chilworth Technology


Swati Umbrajkar, Ph.D. is the Manager of the Chemical Process Evaluation Group at Chilworth Technology. Dr. Umbrajkar consults with clients on a variety of process safety issues including high-pressure DSC cell tests, adiabatic calorimetry (ARC and ADC), reaction calorimetty (RC-1), all of which allow for the safe scale-up of batch and semi-batch processes. She has expertise in determining self-acceleration decomposition temperature and time to maximum rate, which are critical issues associated with the storage of bulk materials. She has authored several articles in the subject of chemical process safety. She is a member of the American Institute of Chemical Engineers.
Equipment Scale Data recorded

Differential 2 - lOmg Thermal activity, onset
Scanning temperature, magnitude of any
Caiorimetry heat release ([DETA]Hr)

Accelerating 2 - 5 Onset temperature, rate of
Rate Caiorimetry grams temperature rise (dT/dt), rate
(ARC) of pressure rise (dP/dt) and
 volume of gas generated,
 magnitude of any heat release

Carius Tube 10 - 15g Onset temperature, rate of
 temperature rise (dT/dt), rate
 of pressure rise (dP/dt) and
 volume of gas generated

Reaction 70mL - Heat of reaction
Caiorimetry 1.5L ([DETA][H.sub.t]) and
 adiabatic temperature rise

Micro-Stirred 1 - 100mg, Heat of reaction
Reaction [micro]L ([DETA][H.sub.t]) and
Caiorimetry adiabatic temperature rise

Adiabatic 800mL Onset temperature, rate of
Pressure Dewar temperature rise (dT/dt), rate
Caiorimetry (ADC of pressure rise (dP/dt),
II) volume of gas generated and
 vent sizing information for
 runaway reactions.

Vent Size 100mL Onset temperature, rate of
Package (VSP temperature rise (dT/dt), rate
II) of pressure rise (dP/dt),
 volume of gas generated and
 vent sizing information for
 runaway reactions.
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Title Annotation:RISK MANAGEMENT
Author:Umbrajkar, Swati
Publication:Pharmaceutical Processing
Date:Jan 1, 2014
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