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Process Safety in the Pharmaceutical IndustryPart I: Thermal and

Reaction Hazard Evaluation Processes and Techniques
Ayman D. Allian,* Nisha P. Shah, Antonio C. Ferretti, Derek B. Brown, Stanley P. Kolis,
and Jeffrey B. Sperry

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ABSTRACT: Process safety groups in the pharmaceutical industry are important components of active pharmaceutical ingredient
(API) development through its life cycle from discovery to commercial scale. The pharmaceutical process safety laboratory staff
Downloaded via 212.119.46.179 on October 24, 2020 at 14:33:56 (UTC).

conduct a series of tests to identify chemically unstable reagents, intermediates and solvents, and mixtures to ensure that the
proposed operating conditions provide a sufficient safety margin from the onset of undesired and potentially catastrophic thermal
decomposition. Across several pharmaceutical companies, the methods used for these assessments and how results and conclusions
are made are widespread (vide infra). A working group was created with members from several pharmaceutical companies within the
International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the goal of precompetitive
collaboration and to understand each of the participating companies’ procedures and assessment regarding process safety. Each
company was invited to provide input using a blind survey format. This was done in the interest of making this knowledge accessible
for the participating companies and the wider community of other pharma and chemical companies and even academic institutions
in the US and throughout the world. This article provides the results of this in-depth survey of the members of the IQ Consortium
thermal hazard working group. General issues around different tools used to assess thermal hazard risk and questions regarding
staffing and tech transfer of process safety data/information from development to manufacturing were addressed. A snapshot of how
various assessment strategies are employed as a function of stage of development (early, mid, and late) is also presented.
KEYWORDS: process safety, thermal stability, thermal hazard, pharmaceutical, calorimetry, safety

1. INTRODUCTION to enable their respective companies to run potentially

Most large pharmaceutical companies have a process safety
laboratory (PSL) group that is accountable for the under-
standing of the thermal hazards associated with reagents,
chemicals, and reactions at hand.1,2 Their work focuses on
minimizing risks associated with handling hazardous chemicals,
waste streams, and running hazardous reactions. A lack of
understanding of chemical hazards can potentially expose these
reagents and/or mixtures to conditions, temperatures, and/or
mechanical stress that can trigger unsafe conditions such as
fire, deflagrations, and explosions, which will lead to significant
material loss, delay, supply chain disruptions, injuries, and/or
loss of life. Process safety groups conduct a series of tests to
identify chemically unstable intermediates and reaction
mixtures and ensure that the proposed operating conditions
provide a sufficient safety margin from the onset of undesired
and potentially catastrophic thermal decompositions.3 There
are several illustrations available in the literature where
pharmaceutical process safety groups successfully managed to
avert catastrophic incidents by stopping dangerous chemistry
from being scaled-up.4,5 For example, potential safety hazards
associated with the violent thermal decomposition of dimethyl
sulfoxide in the presence of an acid were identified and
mitigated prior to scale-up.6 Other examples include the use of
continuous operation that was championed by their PSL staff
hazardous chemistry such as ozonolysis.7−19
Drug development is an iterative process that requires many
years to complete.20 During the journey of a drug from the
bench to the market, different phases of development require
increasingly larger amounts of material for clinical assessment,
and the scales at which manufacturing processes are executed
may increase from milligrams of the limiting reagent in a
round-bottom flask to metric tons of the limiting reagent in
2000 gallon (US) equipment. The hazards of operating with
flammable solvents and energetic materials/reactions drasti-
cally increase with the increase in scale. Therefore, most
pharmaceutical companies have a PSL. PSL staff are tasked
with the assessment of thermal and reaction hazards in order to
ensure the safety of the personnel handling these materials in
the lab and plant operators who will be executing the process.
The most seasoned practitioners of process chemistry and
engineering would agree that safety is of paramount
importance in running on scale and cannot take a back seat
Received: May 13, 2020

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.oprd.0c00226

A Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 1. Pharmaceutical research and development process overlaid with the phases of drug substance process development used for the survey.
Reproduced from the PhRMA website with permission.
to any other process characteristics (yield, cycle time, cost,
etc.),21 as any incidents can lead to significant capital loss and
human loss and can be very damaging to a company’s brand.
Outsourced processes also need appropriate attention, as an
incident at a strategic contract manufacturing organization
(CMO) can lead to significant business interruption, supply
chain delays, injury to staff, and damage to equipment
executing the chemistry on the innovator company’s behalf.
Over the past decade, the pharmaceutical industry has faced
many new challenges from both a cost and timing
perspective.22 Patient needs and market pressures have
increased the need to run at speed, and as a result, cycle
times for development have decreased. In addition, many large
pharmaceutical companies have outsourced chemistry and
typically one CMO works with multiple pharma companies at
the same time. Given each may have a different approach to
process safety assessment and risk tolerance, this may cause
confusion and potentially lead to decreased safety perform-
ance. Collaboration in the field of process safety can bring
tremendous benefit to the pharma companies; however, there
have been limited venues and appropriate platforms to allow
such collaboration. It is in this vein that the IQ thermal hazard
working group set out on a survey of member companies
designed to answer some fundamental questions. Specifically,
questions arose around the common “best practices” at each of
the member companies with respect to assessment of thermal
hazards at all stages of development. Finally, a dissemination of
the pharmaceutical industry practices could have the effect of
harmonizing language for the industry and creating less
confusion for our partners.
2. METHODOLOGY AND SURVEY QUESTIONNAIRE
CRAFTING AND DESIGN
In order to achieve our goal of understanding how different
pharma companies approach thermal hazard evaluation, a
significant effort was initiated to draft a comprehensive set of
questions to be distributed among the participants. It was
quickly recognized that process safety practices vary signifi-
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cantly based on the scales of operation involved, which parallel
different stages of drug development. Figure 1 shows a
snapshot of the typical research and development dynamics
which occur when transforming a molecule into a drug. During
the early stages, a very large number of molecules are screened,
and their structure is subsequently modified and optimized
through a diverse array of chemical transformations carried out
at a small scale (mg). Many molecules do not progress to early
development, and therefore, very limited resources are devoted
to optimizing and understanding the synthetic chemistries
involved. Process safety experiments may be evaluated for
reactions that are known to be hazardous, but in general
reactions are not screened or evaluated by the process safety
group (vide inf ra). As a molecule transitions to early
development and is introduced in the clinic, larger amounts
of active pharmaceutical ingredient (API) (g to kg) are
required to support clinical and product development studies.
At this stage, process chemistry groups become involved and
new chemical routes and scalable processes are invented and
developed. At this stage, it is atypical to execute at this scale
without an appropriate process safety assessment. At this stage,
processes may be fit-for-purpose to supply the clinical program.
As clinical trials progress, the attrition rate is still high and only
a small fraction of programs advance to late-stage develop-
ment. The chemical processes at this stage need to be further
developed to be commercially viable, that is, highly optimized,
well characterized, robust, sustainable, with established proven
and acceptable ranges, efficient, and cost effective. At the late
stage, the process safety aspects must be deeply characterized
and understood.
The survey was constructed with input from all 15 of the
working group member companies.1 During the design phase
of the survey, we elected to create three subsections of the
survey that roughly paralleled the traditional stages of
pharmaceutical drug substance development (Figure 1).
From the perspective of operational definition and guidance,
the following definitions were used to demarcate the stages for
the survey:
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 2. Key differentiators considered in the hazard evaluation of chemical processes.
• Early stage: programs conducted in a laboratory
environment, at the discovery/medicinal chemistry scale.
• •Mid-stage: programs that either progressed from
discovery to process research and development, first-
in-human and/or are in process characterization in the
development lab, kilo lab, and/or pilot plant.
• Late stage: programs that either progressed from the
mid-stage to tech transfer, engineering runs, validation,
and commercial delivery.
In addition to these three sections, a general overview
section was used to capture items that span all three stages of
development. The final survey that was sent to the working
group members consisted of 91 questions distributed
(unevenly) among the four different sections and consisted
of free response questions, menu drop down choices, and
option selection types of questions. The survey was sent to 15
companies and participation rate was 100%. In this paper,
results and analysis of the survey are discussed and described.
2.1. Process Safety General Approach. It is generally
accepted that a chemical process cannot be executed at large
scales without a proper process safety assessment.23 PSL staff
are accountable for evaluating the thermal and pressure safety
of chemical processes throughout all unit operations. The
outcome of an experimental process safety study may enable a
process to be scaled as proposed, which lead to recom-
mendations on process changes and/or necessary specialized
equipment, reducing the scale of the process, or determining
that the process is not scalable and needs to be redeveloped. In
this section of the survey, we focused on general information
such as (a) when PSL staff are typically engaged, (b) general
criteria used to assess risk, (c) how PSL staff are involved in
the tech transfer process, and (d) literature references utilized
to identify hazardous reagents and reactions.
First, the participating companies were asked to choose
between two options when the PSLs are engaged:
• For known hazardous chemistry, PSL staff are involved
in the early phase and potentially contribute to route
selection
• Only after the process chemistry is “locked”
Only 2 of the 15 companies surveyed indicated that their
PSL has an active role in route selection, providing data to
inform the decision on which route to pursue. This can be due
to the fact that resources are limited during the early phase and
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the high attrition rate of clinical programs (see Figure 1).
However, this makes the PSL role more critical as potentially
dangerous chemistries can move forward from discovery
groups with little to no attention to thermal hazards.
The PSLs are commonly a part of chemical development
organizations and composed of highly trained dedicated staff
with a background in either chemistry or engineering.
Pharmaceutical companies also outsource various safety tests
especially when advanced equipment or expertise are not
available internally. Companies were asked if staff outside the
process safety group, but within the same company, also carry
out dedicated safety experiments. Six of the 15 companies
indicated that process development chemists or engineers may
run initial process safety screening by differential scanning
calorimetry (DSC). In these cases, the PSL staff is still
responsible for the overall process safety evaluation (PSE),
interpreting the results generated by partner groups (either
internal or external), providing recommendations, and
deploying more advanced thermal hazard assessment techni-
ques as needed.
As a clinical program moves toward late-stage development
and commercialization, the scale at which the manufacturing
process needs to be executed may increase significantly. As a
result, the level of experimental depth of the process safety
study also increases. In addition to the scale, (vide infra), there
are several “triggers” which may initiate a PSE or increase the
level of experimental scrutiny. Companies were probed for
which factors, excluding the scale, can alert the PSL staff when
evaluating a new process: the most cited (top 4 out of 8)
criteria, as shown in Figure 2, were the presence of highly
energetic materials, energetic reactions, gas evolution, and the
use of highly corrosive and highly hazardous materials (e.g.,
toxic or low flash point)
The presence of highly energetic functional groups or
energetic reactions are key factors mentioned by all 15
companies. These are identified using a combination of
literature and internal knowledge on hazardous chemistries.
Among the widely used literature resources are Bretherick’s
Handbook of Reactive Chemical Hazards24 and Stoessel’s
Thermal Safety of Chemical Processes.25 Also, the list of
recommendations on transport of dangerous goods by the
United Nations26 along with other publications27,28 have been
referenced.
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 3. Triggers for repeating a PSE on a process.
Gas evolution is another highly cited factor because of
potential pressure hazards. Companies were asked whether
they have a written list of reactions which generate gas. The
choices available were:
A No
B Yes, we have standard list (please share)
C Chemist is asked for a balanced equation
According to the survey, option B was not selected,
indicating that none of the companies possess comprehensive
literature lists to flag reactions that either generate gas as a side
product of the desired chemistry or as an undesired
decomposition product that may be generated under off-target
conditions. The potential for gas generation is initially assessed
by analyzing the balanced chemical equations (11/15, option
C) relative to the process, which is provided by the
development scientist. Only one company screens every
process for unexpected pressure events.
The presence of corrosive or highly hazardous reagents was
cited by 13 out of 15 companies as a significant hazard
concern. In this context, it is worth noting that the choice of
equipment in terms of the material of construction also has
process safety implications, as side reactions can either be
initiated or have lower onset temperatures because of
interactions between equipment and the process streams.
Furthermore, incompatibility of reagents with equipment can
lead to significant corrosion and damage. Incompatibilities can
also compromise product quality by introducing metal
contamination into the product. Nine pharmaceutical
companies indicated that they have references that are used
to the screen materials of construction compatibilities. The
main references are the Cole Parmer chemical compatibility
database,29 Schweitzer Tables,30 Corrosion Data Survey,31
ASM Handbook,32 and The Pilot Plant Real Book.33
Typically, a PSE is only valid for the exact process that has
been tested, and changes to the reaction (temperature,
concentration, reagents, solvents, order of addition) can
cause a dramatic change in the outcome of the PSE. Because
the PSL staff operate in a space where processes are constantly
being improved and optimized, there are questions on how to
address process changes and whether a full PSE, both
experimental and paper, is needed because of a single process
change. Figure 3 shows companies’ responses on what might
trigger a new PSE evaluation.
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Figure 3 shows that changes in the amount or type of
reagent and/or solvent, the addition sequence, or conditions
trigger an additional PSE because the latter changes can
drastically alter the thermal hazard profile and thus require
further testing. In terms of handling minor changes in the
process that are deemed too small to have an impact, 5 out of
the 15 companies at the commercial stage would still repeat a
full experimental hazard evaluation. At the small scale, 7 out of
the 15 companies indicated that an experimental re-evaluation
might not be necessary and only a paper exercise could suffice.
The PSLs are typically equipped with an array of calorimetry
tools to measure the heat generated by (a) the desired reaction
at the process temperature, (b) runaway reactions, and/or (c)
thermal decompositions that might occur at higher temper-
atures. Criteria to classify the severity of the latter thermal
events, based on adiabatic temperature rise (ΔTad), were
proposed by Stoessel, as shown in Table 1.34 ΔTad is a key
Table 1. Severity of an Exothermic Event Based on Heat
Released and the Corresponding Adiabatic Temperature
Risea
adiabatic temperature rise (°C) energy released J/g
high >200 >400
medium 50−200 100−400
low <50 <100
a
Adopted from Stoessel, F., Thermal Safety of Chemical Processes:
Risk Assessment and Process Design. Wiley-VCH: Weinheim, 2008.
quantity used in the field of process safety to evaluate the
exothermic behavior of a process and can be calculated
through the following equation
Q rxn
ΔTad =
m × Cp (1)
where Qrxn is the total heat evolved by the chemical reaction
(Joules), m is the mass of the reaction (g), and Cp is the heat
capacity of the reaction mixture (J/g·K). The adiabatic
temperature rise is a conservative estimation of the severity
of the hazard; it assumes that all heat generated by the reaction
is retained in the reaction system to increase the temperature
of the reaction mass. As such, the ΔTad is the largest
temperature increase one could expect to see if the reactor
cooling was to malfunction.
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 4. (a) Classification of exotherms in terms of adiabatic temperature rise as low (green), medium (yellow), high (red). Each line corresponds
to the criteria given by a single company. (b) Stoessel criticality classes, used by 12 out of 15 companies.
For example, if a reaction exhibits a ΔTad of 200 °C and is
operating at room temperature, 22 °C, it can potentially
increase the temperature of the reactor contents to 222 °C if
cooling failed. Clearly, this can be catastrophic as the
temperature increase could lead to further speed up of the
reaction rate, solvent evaporation, and initiate other thermal
decompositions. Based on the Stoessel classification criteria
(Table 1), a thermal event that exhibits a ΔTad of 200 °C or
higher is considered a high severity event. On the other hand, a
ΔTad of 50 °C or less is considered low severity, while a ΔTad
of 50−200 °C is considered medium.
Surveyed companies were asked to express severity in terms
of the energy associated with an exotherm and/or in terms of
the adiabatic temperature rise (ΔTad) associated with that
exotherm. Figure 4a shows what is considered a low exotherm
(green), a medium exotherm (yellow), or a high exotherm
(red) in the 10 companies that answered this question. Figure
4a indicates that most companies consider an adiabatic
temperature rise below 50 °C as a low severity exotherm,
while a ΔTad higher than 200 °C would be classified as a high
severity exotherm which reflects the classification proposed by
Stoessel. However, three companies were on the conservative
side and considered ΔTad higher than 50 °C as high severity.
The probability of reaching a thermal decomposition is
measured using the Stoessel Criticality classes25 that is widely
used in the pharmaceutical industry, as was mentioned by 12 of
the 15 companies surveyed. These criticality classes rank a
process relative to the probability that a runaway reaction may
be initiated in the worst-case scenario of the loss of cooling to a
reactor. The classification goes from class 1, the safest, to class
5, the most dangerous where the probability of triggering a
runaway reaction is very high.
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The criticality class is assigned only based on temperatures
that are descriptive of the process. It starts by identifying the
conditions of the intended process, namely, the temperature of
the process (Tp). Then, typically the heat of the desired
reaction is measured by reaction calorimetry and the ΔTad is
calculated using eq 1. The maximum temperature of the
synthesis reaction (MTSR) is defined as shown in eq 2
MTSR = Tp + ΔTad (2)
In addition to the MTSR, two other figures of merit are
considered important for the assignment of the Stoessel class.
First, the maximum technical temperature (MTT) is typically
defined as the solvent boiling point for an open system. For a
closed system, it is the temperature that corresponds to the
pressure to which the safety valve is set. Second, the TD24 (vide
supra) is defined as the temperature at which the time to the
maximum rate of a runaway reaction is 24 h under adiabatic
conditions. With these temperatures in hand, the Stoessel
criticality class can be determined.
For a Stoessel class 1 reaction, the heat of reaction is
insufficient to cause the reactor content temperature to reach
the solvent boiling point (MTT) and therefore reaching the
TD24 is very unlikely. However, for a class 5 reaction, the heat
of reaction is capable of causing the temperature to reach the
TD24, which is below the MTT. As such, the boiling of the
solvent cannot act as a barrier to prevent the temperature from
reaching the TD24, and the probability of triggering a thermal
decomposition is very high.
Across industries, the discipline of process safety seeks to
quantify the risk inherent to executing a process. A Stoessel
criticality class can be used as a guideline for the probability of
a thermal hazard event occurring, as shown in Figure 4b.
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 5. Process volumes that trigger thermal hazard evaluation in the early stage.
Pharmaceutical companies tend to be conservative. For
example, if the probability of an exothermic event is high,
(Stoessel class 4 and 5), there is a consensus that these
processes would not be allowed to move forward. There is the
constant objective to design processes that are inherently safe
(i.e., Stoessel class 1 or 2), where the probability of triggering
an uncontrolled exothermic event is low regardless of the
severity of the event.
A series of questions were asked regarding how the PSLs
engage with internal or external manufacturing plants. When a
process is scaled-up within the same organization, it needs to
be determined what group is ultimately accountable for
process safety. For 7 out of 15 companies, the central PSL is
fully accountable. However, 3 out of the 15 companies
indicated that the receiving site is accountable while the
remaining 5 indicated that it is a partnership between the two
sites.
For a process that is transferred to an external CMO, there
are often questions relative to how to share safety data
generated at the innovator’s thermal hazard lab. A majority of
the surveyed companies (10/15) have responded that the
available process safety data are shared without providing
interpretation or recommendations. It is then the responsibility
of the CMO to determine whether the process is safe for their
facility and how the process needs to be run based on their
own internal risk tolerance. Indeed, 5/15 companies
responded that they require the CMO to also generate their
own thermal hazard data. Only three companies indicated that
in addition to sharing data, they provide recommendations on
how to translate the data into process design or equipment
setup. It is worth mentioning that four companies selected two
or three of these choices, indicating that some companies do
not have a unified policy in terms of sharing data and their
approach can be CMO or program specific.
Instances where the central PSL and the CMO have
disagreements on whether a process is safe to scale are rare but
do occur. In some instances, there might be a conflict between
the way the PSL interprets the data and SOP of the CMO. An
example that was mentioned was a case where the CMO used
the 100 °C rule35 to determine safety margins as a part of their
SOPs, while the innovator company did not. The rule requires
100 °C between the MTSR and the onset temperature of a
significant exotherm as detected by DSC or a similar
technique.25
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Because pharmaceutical companies often acquire external
programs that have already advanced to the mid- to late-stage
development, there might be cases where process safety data
have already been generated. In such cases, 7/14 companies do
not adopt the data and repeat the PSE, while the remaining 7/
14 might use the available data on a case-by-case basis.
When assessing the overall safety of a chemical process,
there might be the need to investigate concepts beyond
thermal hazards. For example, there might be issues regarding
the toxicity of certain reagents, side products, or byproduct,
and in order to produce a comprehensive safety assessment,
there might be the option to involve experts from an
environmental, health, and safety group (EHS). Surprisingly,
the majority (8 out of 15) indicated that EHS is not consulted,
while 4 out 15 companies mentioned that EHS is involved in
the PSE and/or participate in writing the process safety report;
the remaining 3 companies responded that EHS is somewhat
involved.
2.2. Process Safety Approach at the Early Stage. This
section will focus on PSL staff’s approach to thermal hazard
analysis in early development. Knowing that several labs do not
evaluate thermal hazards at this stage, we asked the participants
if their safety labs support the medicinal chemistry group. Five
companies indicated that either their organization does not
have medicinal chemistry, or they have it but strategically
elected not to support it; these participants were exempted
from the remaining questions in this section.
At the early stage, as discussed in the introduction, medicinal
chemistry is typically carrying out a large number of small-scale
reactions. Therefore, companies are taking a risk-based
approach to minimize thermal hazard evaluation at this stage.
The 10 companies that do support early stage have minimal
involvement and experimental work. Two companies indicated
that the medicinal chemistry staff are equipped with a DSC
and test their own samples, rather than relying on the PSL.
However, it is worth mentioning that, as stated in Section 2.1,
while the staff outside the PSL are permitted to gather their
thermal hazard data, the PSL staff remains accountable for the
overall PSE. Furthermore, to keep the experimental work to a
minimum at this early stage, in 7 out of the 10 companies, the
PSL staff rely on desk screening performed by the medicinal
chemistry staff. The medicinal chemistry staff then engages or
consults with the PSL staff only when dealing with energetic
functional groups and/or potentially hazardous reactions. To
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 6. Materials tested by DSC in the early stage.
understand if there is a scale that prompts PSL staff
engagement, participants were asked if there is a threshold
above which the PSL staff involvement is required. Most
companies did not report a scale threshold to trigger PSL
involvement and simply react to medicinal chemistry requests
irrespective of scale. The response from the few companies that
reported a scale threshold is shown in Figure 5. It is worth
mentioning that companies that reported these thresholds
indicated that there are cases at a small scale, less than the
threshold, where testing may be done if energetic material is
present or a significant amount of gas is expected. For example,
two companies specified that they still would perform thermal
hazard testing before scaling to ≥1 g if flagged as high energy
or potentially hazardous.
In cases where testing is deemed necessary, we asked the
participating companies the type of thermal tests that are
deployed at this stage. By far, the primary method of testing (6
out of 9) is DSC.3 DSC provides fast thermal stability data for
components of reactions, while requiring only milligram
quantities of samples. This is important at this early stage
where the material is very valuable and scarce. One company
uses thermal screening unit (TSu)36 and reaction calorimetry
(RC) in certain scenarios. The remaining two companies who
responded to this question do not do any thermal testing at
this early stage. At this point, the PSL staff’s hazard evaluation
is mainly focused on isolated reagents, starting materials, and
products, as shown in Figure 6. Waste stream and distillation
concentrates are less likely to be evaluated. This is probably
because processes, solvents, and unit operations at this stage
are not fixed and still being investigated. One company only
tests streams that contain known explosive functionality.
After gathering DSC data, most companies do not set a limit
on an acceptable window between the operating temperature
and the onset of a significant exothermic event because the
associated risk is low at this small scale. However, three of ten
respondents restrict the operating temperature to at least 100
°C below the decomposition onset by DSC. Another company
went further and dictated a full calorimetric evaluation and
requiring a 100 °C window between the MTSR and the
decomposition onset by DSC. Of course, the latter is not just
conservative but also requires additional testing as MTSR is
typically determined by reaction calorimetry.
DSC screening is the main platform for thermal stability
investigation at the early stage. However, accelerating rate
calorimetry (ARC)37 is consistently used for further inves-
tigation when red flags such as large exotherms are determined
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by DSC. The goal of using the ARC is to get more quantitative
measurement of the heat generated and more accurate onset
temperatures. Also, ARC allows pressure measurement, a
capability not available in the DSC. Four companies use DSC
exotherm energy as a trigger for ARC. Specifically, two
companies mentioned that the presence of an exothermic
event by DSC in the amount of 100 and 800 J/g, respectively,
will trigger an ARC run.
In addition to triggering ARC testing, seven of the ten
respondents use DSC to prompt impact sensitivity and
explosion propagation testing, using Yoshida correlations.38
The Yoshida correlations are an empirical method of
predicting a material’s hazard potential when subjected to
low energy stresses based on onset temperature and
decomposition energy measured by DSC. These correlations,
or a modified form thereof,5 are used by five companies to
trigger additional testing. One company uses the Yoshida
correlations but also carries out impact sensitivity and
explosion testing for materials that did not trigger Yoshida
correlations if the DSC has an exotherm energy of ≥800 J/g.
Two companies do not use the Yoshida correlations; rather,
further testing at one is triggered by the exotherm onset and
energy (<500 °C and >500 J/g, respectively) and at the other
solely by exotherm energy (>800 J/g). We asked the
participating companies to specify the type of test used if
Yoshida correlations were positive; two companies specified
Fallhammer,5 one of them in conjunction with high rate Carius
Tube,a as the next test to perform. Unfortunately, the
remaining six companies did not specify the impact or friction
sensitivity tests of choice.
Heat of reaction is an important parameter to measure, as a
part of the overall assessment of the thermal hazard (see
Section 2.1). However, experimental heat of reaction measure-
ment can require amounts of materials that might not be
available at this early phase. Not surprisingly, seven
respondents do not measure the heat of reaction at this
stage and two will if the DSC indicates energetic decom-
position and/or a large exotherm is observed in lab
experiments. With the experimental heat of reaction not
widely used at this stage, we asked the participants the type of
desktop methods commonly used to estimate heats of reaction
in lieu of testing. Participants indicated using estimates based
on similar chemistry, CHETAH,39 and quantum methods.40
One participant has developed their own proprietary heat
estimation tool. Because most respondents do not evaluate
heats of reaction experimentally at this stage, there are no
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Figure 7. Materials tested for pressure hazards in early stage.
Figure 8. Scale that triggers thermal hazard testing in the mid-stage.
triggers for further advanced calorimetric testing. We will show
later in the article that advanced heat of reaction testing is used
in the later phases of drug development. Two companies may
perform further measurements if desk screening indicates high
heats of reaction.
Next, participants were asked questions related to gas
evolution inherent to desired chemistry. The participants were
given the following options.
A No, no gas measurement is done at this stage
B No, we just assume that the theoretical amount is
liberated
C Yes, but only for reactions that are known to generate
gas (please describe how this is measured)
D Yes, only if the screening tool gives red flags (please
describe)
E Yes, all reactions are screened for pressure (please
describe how it is measured)
None of the responders picked choice E, as that would be
experimentally exhaustive. Eight companies do not exper-
imentally measure total gas generated, option A and B. It is
either not considered at this stage or they assume the
theoretical amount is liberated. The remaining two companies
will investigate if gas evolution appears severe, uncontrolled, or
hazardous in lab experiments. In general, rates of gas evolution
and maximum pressures are not examined at this stage.
For undesired/unintended reactions, eight respondents do
not investigate gas generation in early development. The
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remaining two conduct pressure screening if DSC indicates a
severe exotherm, and then they move to more advanced
techniques if the pressure screening indicates uncontrolled off-
gassing. Next, participants were asked if pressure increase or
rate of gas evolution is examined. In agreement with the
discussion earlier around the desired gas evolution, most
companies (9 out of 10) do not investigate these parameters at
this early stage. One company looks into gas hazards only if
reaction is known to generate gas, or if the scale is large
enough to warrant testing. It is worth mentioning that we
asked the participants to indicate if red flags from the pressure
screening test will trigger more advance testing; as expected, 8
companies said “no” as most companies at this stage do not
even conduct the initial screen, let alone deploying an
advanced gas hazard test. Figure 7 shows the types of samples
tested if pressure hazards are deemed worthy of investigating at
this stage. Most of the companies select samples based on
hazard potential, with 4 companies testing any streams
expected to be highly hazardous. Waste streams and distillation
concentrates are rarely considered at this stage.
Finally, survey participants were asked if any results or
outcomes would prompt the process safety lab to require
modifications to the chemistry prior to moving forward.
Although open-ended, the responses were relatively consistent.
Four of the ten companies listed a positive impact or friction
sensitivity as a justification to require process modifications.
Additionally, six of the ten will stop reactions from moving
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Figure 9. Material subject to thermal hazard testing in the mid-stage.
forward if DSC and/or ARC data indicate high energy (see
Section 2.1 for definition of high energy) and low onset
exothermic activity that is close to the operating temperature.
The responses were also consistent with our previous
discussion on the appropriate safety window, with companies
indicating that they will not allow chemistry to move forward if
a significant exotherm is within 100 °C of the operating
temperature measured by DSC. Another interesting response
referenced the increase of flow chemistry to enable chemistry
that is hazardous in cases where an exothermic event is very
close to the operating temperature.41
2.3. Process Safety Approach at the Mid-Stage. This
section is aimed at understanding the IQ members’ thermal
hazard testing in the mid-stage. The participants were asked
some similar questions to those in the early stage in order to
examine the increase in complexity of process safety testing
with the increase in scale.
As in the early stage, the participants were asked two
questions. First, is there a scale where little to no testing is
done? Second, is there a scale above which a level of thermal
hazard evaluation/testing must be done? Then, we asked the
participants to select one of these options:
1) No, all reactions are tested in a similar fashion
2) Yes (please specify)
3) Yes, but other factors are also considered (please
specify)
Only two companies selected option (1), which indicated
that most companies (13 of 15) are using the scale to guide
when the PSL staff need to conduct thermal hazard testing, as
shown in Figure 8. The use of the scale as guidance appears to
help PSL labs prioritize their work even when the programs
transition from the early stage, especially when the scale is still
small. In other words, the majority of the companies are taking
a risk-based approach to reduce the testing burden on the PSL
personnel, especially when the scale is small, even at early- and
mid-stages. In the early stage, Section 2.2, limited involvement
was observed from the PSL staff and their engagement was
dictated by the medicinal chemistry staff needs. However,
clearly at the mid-stage, the PSL staff now drive the decision
on their involvement in thermal hazard evaluation. Similar to
the early stage, ass shown in Figure 5, the scale that would
trigger thermal hazard testing in the mid-stage also varied
significantly. For reactions free of energetic functional groups,
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based on the responses from the survey, the scale varied from 2
L to pilot scale, see Figure 8. The data suggest that certain
pharmaceutical companies are leaning more conservative and
running thermal hazard testing even at a scale less than or
equal to 2 L. On the other hand, other companies appear to be
more risk tolerant and will not do testing until the process is
scaled-up in reactors above 100 L. It is worth mentioning that
3 companies indicated that even though they are committed to
a scale at which a level of testing is needed, some testing will be
done even below that threshold if the reaction is deemed risky
due to the presence of high-energy functional groups. A similar
approach by the pharmaceutical companies was discussed in
the early stage as well, indicating that these thresholds serve as
guidelines but are not set in stone.
Next, we asked participants to describe the thermal tests
used and materials being tested. The participants were giving
the following options:
A None
B Quick screening tools, (please specify).
C Full safety evaluation with calorimetry, (please specify).
Not a single company picked choice (a) that no work is
done at this stage. This is understandable, as at this stage, the
volume is large enough to pose more risk and some form of
testing is needed. Indeed, some testing was deployed at the
early stage, see Section 2.2. It is worth reminding the reader
that in the early phase, apart from one response, testing was
largely limited to screening tools like the DSC. At this stage, 13
out of the 15 picked choice (c), meaning that companies did
not stop at screening tools and deployed other advanced
calorimetric tools as needed. However, 2 companies indicated
that they still rely strictly on quick screenings. These results
provide solid evidence for a sharp increase in the complexity of
thermal hazard tools utilized once the program progress from
the early to mid-stage.
At the early stage, as shown in Figure 6, the types of
materials subjected to thermal hazard screening showed that
the focus was limited to the isolated material and product.
When the same question was posed to the participants on their
approach in the mid-stage, the response is starkly different, as
shown in Figure 9. At this stage, IQ members did not just test
isolated reagents and isolated products, but workflows evolved
to include other streams. Now, the majority (13 out of 15) will
test the initial and final reaction mixtures and streams that were
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Figure 10. Acceptable safety window for operating temperature of the reaction.
less likely to be tested in the early stage. Similarly, distillation
concentrates and waste streams rarely tested in the early stage
now are being evaluated by most participants. One company
goes further and tests the wet cake for thermal hazard.
Once reagents and reaction streams were tested, the
participants were asked what constitutes an acceptable safety
window from the operating temperature, as shown in Figure
10. Based on the DSC exotherm onset data, the 100 °C degree
rule was the most common approach, with 7 companies using
this approach. The use of the 100 °C degree rule is also
popular in the early stage, see Section 2.2. Interestingly, in the
mid-stage two companies diverted slightly from the 100 °C
rule, using a slightly more relaxed approach, where the 70 °C
degree rule or 2/3 of the onset was used. With the use of
advanced calorimetric techniques in the mid-stage, compared
to the early stage, PSL has access to more data to analyze and
extrapolate. The use of time to maximum rate (TD24) along
with Stoessel criticality classification is gaining momentum to
determine the safety window, as four companies are using this
approach, see Section 2.2 for more details. Companies that use
Stoessel criticality classification indicated that class 4 and 5
reactions will not move forward, and rarely class 3 will be
allowed to be scaled-up (Section 2.2). For ARC data, two
companies indicated they use the 50 °C rule, which is because
of the increased accuracy of the ARC versus the DSC.
However, it should be noted that ARC testing requires more
material and is much slower than DSC. It is worth mentioning
that in the early stage, companies did not define a safety
margin; however, at this stage, they now have an internally
well-defined safety window that they enforce.
Next, IQ companies were asked what kind of results would
trigger further testing beyond the screening tests mentioned
above. It appears that 8 companies do not have a quantitative
measure for deployment of further tests and rely on process
safety expertise to trigger it. However, 7 companies indicated
that if the operating temperature is within 100 °C of the onset
temperature measured by DSC, further testing, most likely in
the form of ARC and/or DSC isothermal hold, will be
deployed. Other techniques such as the use of modeling
(example AKTS) were also mentioned when the operating
temperature is close the onset measured by DSC.
In the early stage, see Section 2.2, the survey showed that
pharmaceutical companies are already deploying impact
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sensitivity and explosion propagation testing. We posed the
same question for the mid-stage, namely, what kind of results
would trigger impact sensitivity and explosion propagation
testing and the following options were given:
A Yes, please describe.
B No, not at this phase
The majority of the companies (12 out of 15) selected
option A. However, three companies indicated that it is still
too early to deploy these tests at this stage. The authors
assume that the shipment and handling of large quantities of
solids are not expected and that explains why these companies
elected to delay testing until assets are commercialized. The
twelve positive responses can be divided into two groups. The
first group, 5 companies, relied on the process safety
personnel’s prior experience to trigger these tests such as the
presence of certain functional groups. The other group, the
remaining 7 companies, was using quantitative triggers to
initiate impact sensitivity and explosion propagation testing,
either using DSC data alone (3 companies) or DSC data with
Yoshida correlations (4 companies). The companies that use
DSC data alone relied solely on the decomposition energies
observed. These energy thresholds were 400, 500, and 800 J/g,
respectively, above which warrant further testing. The
remaining 4 companies utilize the Yoshida correlation to
examine if further testing is needed. It is worth mentioning that
impact sensitivity was deployed when necessary by 7
companies in the early stage. At this mid-stage, impact
sensitivity is more widely used with clear internal guidelines
on when to deploy it.
Heat of reaction is a key component of the thermal hazard
assessment. In the early stage, see Section 2.2, the heat of
reaction measurement was not done by most companies and
instead they relied on desktop methods to estimate it. Again,
we posed the same question here to see if the increase in scale
affected thermal hazard and impact sensitivity measurement. In
that spirit, participants were asked if heat of reaction is
measured and were asked to pick from these options:
A No, no heat of reaction is measured at this stage
B Yes, always. Please specify instrument
C Yes, only if heat is expected or previous screening tests
indicate that this is necessary (please describe)
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Figure 11. Material tested for pressure hazard in the mid-stage.
Figure 12. Will companies deploy additional testing to justify long hold times of reaction mixtures.
None of the IQ companies picked option A, indicating that
at this stage of development, heat of reaction is a topic of
concern. Indeed, 10 out of 15 will always measure heat of
reaction, while 5 companies indicated that the heat of reaction
is only measured if necessary, that is, based on prior
knowledge. Again, these responses are strikingly different
than those obtained from the early stage, where most
companies said that the heat of reaction is not measured.
Companies’ responses indicate that there is a plethora of tools
that can be used for this measurement, namely, RC1, EasyMax
HF, Omnical, ARSST,b Setaram, and THT microcalorimeter.
It is worth mentioning that the measurement of the heat of
reaction, Qrxn, is required to be able to calculate ΔTad and
MTSR using eqs 1 and 2, respectively. These values are used to
assign a criticality class to the reaction using Stoessel’s
methodology (see Section 2.1). With more companies using
this approach, one can see why the measurement of heat of
reaction is more prevalent. Next, the participating companies
were asked if the maximum heat of reaction is a parameter that
is examined to make sure that the heat generated from the
reaction at any point during the course of the reaction is within
the vessel’s ability to remove heat, preventing undesired
heating of the reactor contents. Four companies said that this
parameter is not examined, and nine companies do examine it.
Two of the nine companies that indicated looking into this
important parameter said that they have guidelines for
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preventing scale-up when maximum heat flow is above 25−
30 W/L (i.e., typical value for heat removal capability of
reaction vessel at the scale), otherwise the process needs to be
modified. Four companies indicated using commercially
available advanced modeling software like DynoChem to
understand a vessel’s suitability to handle the reaction at hand.
Surprisingly, 9 out of 15 companies appear to have no criteria
or consideration of this parameter at this stage.
The use of desktop methods, as in the early stage, is still very
popular at this stage with 9 out of the 15 companies using heat
estimating techniques, literature, and/or internal archived data
of similar reactions to estimate the heat of reaction. However,
the remaining six companies will only do experimental work to
eliminate risks. Next, we asked the participating companies an
open question, namely, in the mid-stage, can red flags from the
heat of reaction screening trigger further calorimetric measure-
ments? The authors’ intent was to check if the companies that
measure the heat of reaction using screening tools will
eventually go back and use more advanced calorimetric
techniques if a significant exotherm was observed during the
screening. Several companies indicated that if the adiabatic
temperature rise is above 50 °C from screening tools then
advanced techniques like RC1 will be deployed to quantify the
heat of reaction more accurately. Other companies strictly use
RC1 calorimetry and do not utilize the fast screening tools to
start with.
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Questions in this section thus far focused on thermal
hazards; the survey at this point pivots and focuses on pressure
hazard screening as it did in the early stage. We asked
participating companies, in the mid-stage, is gas generation of
the desired/intended reaction measured?
A No, no gas measurement is done at this stage
B No, we just assume that theoretical amount is liberated
C Yes, but only for reactions that are known to generate
gas (please describe how this is measured)
D Yes, only if screening tool give red flags (please describe)
E Yes, all reactions are screened for pressure (please
describe how this is measured)
At the mid-stage, most companies’ PSL are striving to
understand gas generation. Of the positive responses, option C
was dominant with 10 companies. This means that while the
pressure hazard is a concern, only samples that are known to
generate gas will be tested, probably to reduce the workload,
that is, taking a risk-based approach. Four companies will test
gas evolution for all reactions in any case, and the remaining
company does not measure but assumes that the theoretical
amount of gas is liberated (option B). This is in contrast to the
early stage where 80% of companies picked option A and B,
that is, do not measure gas evolution because theoretical
amount is assumed, or it is not considered. Interestingly,
option D was also not selected which indicates that the use of
pressure screening tools are not widely used. For companies
that measure gas generation, the majority (8) use a mass flow
meter coupled with their calorimetric setup. Other companies
indicate using ARSST and RITTER clocks for gas measure-
ment.
Besides the desired reaction, participants were asked if
individual process streams are also tested for pressure hazards
in the mid-stage. As shown in Figure 11, the response was
widespread with at least 4 companies testing all streams, and at
least one company indicated that no pressure hazard testing is
done unless there are specific data highlighting a potential
pressure hazard. The majority of companies (11) subject
reaction mixtures to testing. Other streams like waste streams,
distillation concentrates, and end-of-reaction mixtures are also
of concerns and tested by 4−7 companies for pressure hazard.
In addition, gas generation can also be due to an upset
scenario where loss of cooling can trigger a decomposition that
releases gas, or the heat generated can drive solvent
vaporization. The survey is attempting to probe best practices
to identify these potentially very hazardous scenarios. In this
regard, the survey asked the participants if the rate of undesired
gas evolution is measured and the following options were
given.
A No, not at this stage
B Yes, but only if DSC indicates significant exotherm
(please describe)
C Yes, all undesired chemistry is screened for gas
generation (please describe)
Similar to the question on the desired reaction gas evolution,
three companies do not consider pressure hazards at this stage
(option A). Among the remaining 12 companies, 5 companies
do so only if a significant exotherm is found in the process
(option B), and 7 companies measure gas generation of
undesired chemistry (option C) regardless. Next, and as in the
early stage, participants were asked if values of the gas
evolution rate or maximum pressure increase can be used to
designate a process safe to run. The reader is reminded that for
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the same question in the early stage most companies, 9 out of
10, do not check this. However, in the mid-stage, 13 out of the
14 companies that responded to this question indicated that
these parameters, gas evolution and pressure increase, are
being carefully examined. Most companies are now concerned
with pressure limitation in the vessel and its ability to vent the
generated gas. One interesting response was a defined
threshold of 2 ft3/min for gas generation above which the
process will be deemed unacceptable.
For the question whether more advanced gas measurement
techniques are used whenever pressure screening tests find any
red flags, 8 companies answering yes and 7 answering no at this
stage. The 8 companies with the positive answers indicated
that they typically deploy TSu or ARC for quick screening, and
if a significant pressure event was observed, they follow it up
with advanced testing like Vent Sizing Package (VSP). While
the latter techniques focused on the volume of gas generated, it
is worth mentioning that authors are aware that certain
pharmaceutical companies have implement on-line technique
to identify the composition of the generated gas.
Gas generation during reactions poses another hazard
besides over pressurization, namely, fire risk when the
generated gas is flammable. Pharmaceutical companies are
conservative, their first safety layer is making sure that there is
an absence of ignition sources. The second safety layer
deployed is inerting the reaction system. In order to achieve
this goal, companies target bringing the flammable gas
concentration below its lower explosive limit (LEL) or
reducing the oxygen concentration below the limiting oxygen
concentration (LOC) which then renders the headspace
inflammable even when an ignition source is present. Because
of potential inaccuracies in the quantitative measurement of
LEL and LOC, many companies develop their own safety
window between the measured or known LOC/LEL level and
what they require in practice. We have asked each company
what their acceptable level is, that is, the typical threshold they
target to ensure safety. Only 10 companies responded to this
question. Four companies target dilution to 25% of the LEL,
two companies target 50% of the LEL. One company took the
conservative approach of reaching 10% of the LEL. One
company targets LOC and another two will use enough inert
gas to keep O2 below 5%.
Several questions were asked regarding extended hold times
for reactions, waste streams, and storage of starting materials
and intermediates. First, is additional thermal testing required
for reaction mixtures to justify long hold times? Three
companies responded that testing for stability is not done at
this stage. On the other hand, three companies always do
additional testing to justify long hold time, while the majority
(9) only do such testing if there are red flags in the process that
warrant it. One of these red flags is if the hold temperature is
within 50 °C of a significant exotherm. Some companies listed
what specifically the additional tests were, which included a
variety of isothermal calorimetry tests, (e.g., TSu, ARC, and
DSC) and one company does kinetic modeling.
Next, the same question was asked to justify long hold times
of waste streams. Six companies do not do additional testing in
this case, where 9 do it if there are red flags in the process that
warrant it. These red flags include the waste generating gas or
showing a significant exotherm from screening tests. Next,
companies were asked whether tests are done to justify storage
conditions of starting materials, intermediates, or products and
what would trigger these tests. Approximately half, 8, said that
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Figure 13. (A): Number of companies who responded that they consider MOC compatibility. (B): Further breakdown of the “yes” responses.
they do no such testing, while 7 do. Further testing is usually
triggered by the thermal stability data collected in routine
screening. Examples of scenarios where testing would be
needed include (a) low onset temperatures and/or (b) high
decomposition energies.
Figure 13 shows that the majority of companies (14)
consider material of construction compatibility with chemicals
or reaction mixtures. The 14 participants with positive
responses were asked to describe their approach. Eleven
companies responded and their responses were fairly evenly
divided between using online databases and literature data
versus actual tests, where coupon corrosion tests are
performed. Five companies indicated deploying both desktop
and experimental methods.
Many of the ubiquitous solvents used in the pharmaceutical
industry are nonconductive and thus there is a risk of building
static especially when solution is mechanically agitated or from
friction because of flowing in a pipe. This electrostatic
discharge can lead to a spark which can start a fire or/and
cause damage to the reactor.41 The survey shows that slightly
less than half of companies (7) consider stream conductivity as
a potential for electrostatic hazards. A closer look at the
positive responses shows that companies either use literature
values for conductivity or experimentally measured values
when data are not available. The remaining 8 companies did
not consider conductivity at this stage.
For shipment of hazardous materials, the self-accelerating
decomposition temperature (SADT) is a value that is widely
used to determine whether the material must be transported
under temperature-controlled conditions. The SADT is
defined as the lowest environmental temperature at which
the center of the material within the package heats to a
temperature 6 °C greater than the environmental temperature
after a seven-day period or less.26 This period is measured from
the time when the center of the package reaches 2 °C below
the environmental temperature. Six out of the 15 companies
responded that they consider SADT for the shipment of
material. Those who use SADT mentioned that they typically
deploy this measurement when there is an onset temperature
below 125 °C or to ensure compliance with DOT and UN
transportation standards. The method of determining the
SADT can vary; usually this is done with isothermal screening
tests, or by using DSC data and modeling methods to predict
the kinetics of decomposition.
Companies were asked what results or outcomes would
prompt them to stop a reaction from moving forward and
propose changing the chemistry to mitigate the observed risks.
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Answers to this question were across the board but could be
collectively summarized by the following themes:
• Stoessel classification of 4 or 5
• Decomposition detected close to the operating temper-
ature
• Large exotherm (i.e., adiabatic temperature rise >50 °C)
• Uncontrolled gas generation
• Potential for explosivity
The fact that reactions with a classification of 4 or 5 are not
allowed to move forward is consistent with the companies’
response in Section 2.1, where there is a consensus among
pharmaceutical companies that these reactions are too
hazardous and will not be permitted to move forward.
Considering whether a formal process hazards analysis
(PHA) is performed when scaling-up to a kilo lab or pilot
plant, five companies responded yes and eight responded no.
Out of those who responded yes, one company performed
PHA if the process is very high risk and another company does
so if the process is over 200 L scale.
With more pharmaceutical companies these days doing
chemistry in flow,42 the question was asked whether further
thermal hazard tests are conducted if a reaction is done in
continuous mode. Surprisingly, ten companies responded no
or N/A, with only five companies responding yes. This shows
that the PSL approach to evaluating thermal hazard with flow
chemistry is still evolving.
The use of modeling in thermal hazard safety evaluation was
another topic of interest that the survey aimed to probe. When
failure modes are likely, participants were asked whether they
experimentally evaluate them or rely on models to understand
that failure. Only four companies answered no, while the
majority 11 companies answered yes, which indicates that the
use of modeling is becoming a very integral part of thermal
hazard evaluation. Situations that are likely to be modeled are
reactor and condenser cooling failure scenarios, heat of
reaction at upset conditions, and reactions with high adiabatic
temperature rise.
Finally, participants were asked if thermal hazard data were
utilized for kinetic modeling. Three companies indicated
modeling reactions using the heat flow data using DynoChem
and also using AKTS to study kinetic of decomposition. On
the other hand, ten companies indicated that they do not use
data for kinetic modeling at this stage, which is unfortunate
because heat flow data can be used to better understand
reaction kinetics and mechanisms.43,44
2.4. Process Safety Approach at the Late Stage. This
section will focus on the last portion of the drug journey (the
late stage). It is worth mentioning that several pharmaceutical
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Figure 14. Material subject to thermal hazard testing in the late stage.
companies indicated that much of the thermal hazard
evaluation has been done before arriving at this stage. Most
pharmaceutical companies partner with external CMOs for
manufacturing both the drug substance intermediates and drug
substance. This partnership between the two organizations
becomes increasingly critical with respect to the process safety
assessment of chemical processes. Each IQ member company
was asked to answer a series of questions pertaining to their
process safety testing practices for commercial scale
production. Five out of the 15 companies who took part in
the survey noted that all commercial manufacturing is
externalized, and therefore, only minimal process safety testing
is performed in-house. Because the CMO partner is ultimately
responsible for the safety of their plant and people, the CMO
will gather any additional process safety data not provided by
the pharmaceutical company with which they are working.
These five companies skipped this section and the remaining
analysis is done on the remaining ten companies who support
thermal hazard testing at the late stage.
The ten remaining IQ members were asked a series of
questions that are similar to those asked for the mid-stage to
capture the increased complexity as the program progresses to
the commercial and manufacturing phase. The first question is
“which thermal tests are employed for assessment of late-stage
processes?” and the following options were given to the
participants:
A None
B Quick screening tools (please specify)
C Full safety evaluation with calorimetry (please specify)
D Evaluation is similar to what is done for the mid-stage
Not surprisingly, half of the companies indicated that the
evaluation is similar to what is done in the mid-stage, option D,
as typically the chemical processes do not change significantly
from the mid-stage to commercial stage. In addition, the
process safety tests do not necessarily change from the mid to
late stage. This answer shows that process safety tests are
widely applicable to the assessment of early stage to late stage
chemical processes. The remaining half of the participants do
full evaluation with calorimetry, option C. The open responses
indicate that companies will do additional testing related to
changes in the process, take a closer look at the waste streams,
and also analyze authentic samples from the commercial sites.
In the mid stage, two out of 15 companies were still using
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quick screening tools, but now at this late stage, this is not an
option which is expected.
The next question asked each company to identify the
specific reagents, materials, and/or streams that were tested at
the late stage. The 8 companies who responded to the question
indicated that they perform testing on isolated reagents and
starting materials, isolated products, initial and final reaction
mixtures, as well as the distillation end point. Seven of the eight
companies perform testing on waste streams (Figure 14). The
response is very similar to the mid-stage, the only noticeable
difference is waste stream evaluation, where 8 of the 15
companies in the mid-stage do it, but at the late stage it is 7 out
of 8.
The next question polled the participants about acceptable
safety windows for operating temperatures based on available
thermal hazard data. Of the ten companies that do in-house
testing for late-stage processes, two said that only Stoessel class
1, 2, or 3 reactions will be performed. Two companies
mentioned that there are site-specific rules regarding safe
operating temperatures, and one company said they apply 2/3
of the DSC onset temperature. Finally, three companies noted
that they use 100 °C below the DSC onset temperature and/or
75 °C off the TSu onset temperature as these are the common
margin of safety adjustments for these instruments. The
response is in good agreement to the question asked earlier in
the mid-stage (Figure 10). This suggests that these safety
margins are set and are consistent across stages.
After thermal hazard testing is performed, oftentimes the
data lead to additional testing. The ten member companies
who did internal late-stage manufacture were polled: “can red
flags lead to additional testing?”. Four companies said the
approach is the same as their mid-stage evaluation. One
company noted that if the exotherm is >100 J/g and within the
MTSR then additional testing would be required. The
remaining four companies noted that internal guidance
governs what additional testing may be required, for example,
testing of upset scenarios like mischarge or thermal stability.
This could include ARC testing and vent sizing calculations. It
is worth mentioning that in the mid-stage, about half of the
participants did not have a quantitative trigger for deploying
advanced testing, but that is not the case here at the late stage.
The participants were asked if red flags trigger impact
sensitivity and explosive propagation testing, and the following
options were given to the participants.
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Organic Process Research & Development
A Yes, please describe these criteria and any further tests
that are done
B No, not at this phase
C Evaluation is similar to what is done for mid-stage
Majority (seven out ten) responses were very similar to what
is done in the mid-stage, namely, option C. Only one company
noted that this would not be done presumably because the
company simply outsources this testing, and participants
meant that this test is not done internally. Finally, two
companies noted that a full testing package (impact, friction,
and dust explosivity) would be performed for all late-stage
commercial manufacturing processes regardless of whether or
not the tests were triggered by a screen. Among the triggers
discussed in the response were DSC decomposition >500 J/g,
>800 J/g and peak shape. The response is similar to what has
been discussed in the mid-stage and the early stage.
The next four questions addressed gathering calorimetric
data for reactions performed at a commercial scale. First, the
participants were asked if the heat of reaction is measured and
the following options were provided.
A No, no heat of reaction is measured at this stage
B Yes, always. Please specify instrument used (example:
Omnical, RC1, THT).
C Yes, only if heat is expected or previous screening tests
indicate that this is necessary (please describe)
D Evaluation is similar to what is done for the mid-stage
All companies answered yes (option B and D) which is not
surprising as most companies measure the heat of reaction
even at the mid-stage. The 10 positive responses were equally
split between option B and D, that is, half of the companies do
this testing in the mid-stage and if it was not done, they will
definitely do it at this stage. The participants were asked to
provide the type of instrument used to measure calorimetry,
and the following platforms RC1 and C80 were mentioned.
Again, the response is similar to the mid-stage but excluding
some screening tools like microcalorimetry. Not surprisingly,
option (A) was not selected, that is, all companies that perform
internal commercial manufacture note that calorimetry is (or
has been) performed at this scale. Even option C was not
selected, indicating that the pharmaceutical companies at this
stage will measure heat of reaction irrespective if a screening
triggers it or not.
Next, the participants were asked if the maximum heat flow
was determined. Nearly all participants (nine out of ten)
indicated using the same approach as the mid-stage, where the
participants have a rule of thumb of not scaling up a reaction
where the maximum heat flow is >30 W/L, see Section 2.3.
Several companies indicated relying on their chemical
engineering group to ensure that the heat generated from
the reaction can be removed.
For heat of reaction measurements, the majority (7 out of
10) will rely on experimental results which is understandable
because of the increased risk at this scale. Only three of the
participants noted that desktop methods for screening heats of
reaction were used at a commercial scale but indicated that
only if the comparable reactions are sufficiently similar to the
one performed at scale. The use of desktop methods was more
popular in the mid-stage where 9 out of the 15 companies are
using CHETAH or literature to estimate the heat of reaction.
Next, companies were polled if heats of reaction screen
measurements could trigger additional calorimetric measure-
ments. The responses indicated that companies at this late
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stage do not use screening calorimetric techniques and by
default exclusively use advanced calorimetry. Other companies
indicated that the need for advanced calorimetric techniques
would have been addressed earlier in the mid-stage.
The next set of questions addressed the measurement of off-
gas for reactions performed at a commercial scale. For gas
generation from the desired reaction, the following options
were given:
A No, no gas measurement is done at this stage
B No, we just assume that the theoretical amount is
liberated
C Yes, but only for reactions known to generate gas, please
describe how this is measured.
D Yes, only if screening tool give red flags (please describe)
E Yes, all reactions are screened for pressure (please
describe how is measured)
F Evaluation is similar to what is done for the mid-tage
Six of the ten companies indicated using the same strategy
used at the mid-stage. Two companies indicated that all
reactions are tested at this stage regardless of the screening
results. Two companies noted that the measurement of off-gas
is only determined for reactions that are known to specifically
generate pressure during the reaction. This is drastically
different than the response from the mid-stage, where 11 out of
15 companies indicated the measurement of off-gas only for
reactions known to generate gas. This suggests that at the late
stage companies conduct gas measurement even for reactions
that are not known to generate gas. It is worth mentioning that
the tools described in this section for the measurement of gas
evolution are the same as that described in the mid-stage.
The member companies were asked to specify which streams
undergo analysis for pressure generation as we did in the mid-
stage, as shown in Figure 11. Seven of the companies
responded that the same streams undergo testing at this
stage as for pressure generation as for mid-stage. The
remaining 3 companies indicated testing every stream on the
list, namely, isolated reagents, starting materials, isolated
product, reaction mixtures, end of the reaction, distillation
concentration, and waste streams. In the open response,
companies were encouraged to list other streams that they
might look into, and we want to highlight that the companies
focused on reactions with potential gas generation like
intermediates with a tert-butyloxycarbonyl protecting group
(BOC) group. Intermediates with a BOC moiety are known to
release isobutylene and CO2 gas.
In terms of gas generation measurement for unintended
reactions or decompositions, companies were given the
following options:
A No, not at this stage
B Yes, but only if DSC indicates significant exotherm
(please describe)
C Yes, all undesired chemistry is screened for gas
generation (please describe)
D Evaluation is similar to what is done for mid-stage
The answers suggest that the approach here for the
undesired gas generation is similar to what is done in the
mid-stage, where most companies (seven out of 10) picked
option D. Two companies indicated being conservative where
all undesired chemistry will be screened. One company picked
option B, namely, testing for unintended gas generation will be
done only if DSC data indicate a significant exotherm. Next,
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
participants were asked if gas evolution and/or maximum
pressure are examined, the following options were given.
A Yes, please describe
B No
C Evaluation is similar to what is done for the mid-stage
All ten companies noted that the rates and total pressure are
a concern and examined, option A and C. The fact that
pressure and gas evolution are examined by all companies is
not surprising at this stage, as these parameters are already
examined by 14 of the 15 companies even in the mid-stage.
Looking closer at the open responses to see if there are criteria
on what is an acceptable pressure rise and/or gas generation
threshold, the respondents did not provide a quantitative
answer but indicated that there are concerns around not
exceeding the maximum allowable pressure of the vessel and
the need to do vent calculations to ensure safe operating
pressures.
When asked if red flags that arise from the pressure
screening tests could warrant additional, more advanced
testing, and the following options were given:
A No
B Yes (please describe)
C Evaluation is similar to what is done for mid-stage
It is worth mentioning that 7 of the 15 companies at the
mid-stage responded yes to this question. However, at this late
stage all companies selected options B and C, that is, additional
testing would be deployed. Three companies picked option B
and the remaining seven companies, option C, meaning that
the red flags would have been picked up and additional tests
performed at earlier stages. Taking a closer look at the open
answers, one company noted that ARC testing would be
performed and one said that vent sizing calculations would be
done at this stage.
With respect to flammable gas generation during the course
of a process, if the flammable gas is diluted with nitrogen, four
companies noted that the margin of safety is 25% of the LEL of
the mixture. One company targets 10% of the LEL. The other
companies that responded noted that the margin of safety is
site specific. Overall, the responses are very similar to the
responses from the mid-stage (Section 2.3).
The next series of questions covered protracted hold times.
This included reaction mixtures, waste streams, and the storage
and transportation of materials. All companies noted that the
testing needed to cover protracted reaction hold times, which
would have already been completed at the mid-stage.
Interestingly, at this late stage, participants were given the
option of “testing only if there is a red flag”; however, that
option was not selected which suggests that these tests are
deployed regardless. It is worth mentioning that this option of
testing only when there are red flags was the predominant
choice, 9 out of 15, in the mid-stage, as shown in Figure 12.
For waste stream hold, the same question was asked and the
response was again all positive. Seven companies said this
would have been performed in the mid-stage, and as with the
reaction hold, none of the companies said that the red flags
would trigger these tests, which suggests that at this stage these
streams are tested regardless. The response is significantly
different than the approach in the mid-stage, where 6
companies said these streams are not tested and 9 said these
waste streams will only be tested if there are red flags in the
screening process. Taking a close look at the open responses
for companies that perform the testing, one company said that
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extended storage times could be justified with DSC and ARC
testing, one company used ARC testing alone to cover
extended storage times, and another one used isothermal TSu
experiments.
For raw materials, all companies except for one said that
storage conditions are examined for late-stage development.
Among the eight companies that responded positively, three
companies performed storage evaluations at earlier stages and
five companies said that the evaluation would be performed
based on the available thermal stability data. This response is
much higher than that observed in the mid-stage, where 8
companies responded negatively to the question, that is, no
testing was done (Section 2.3).
Participants were also asked to describe the type of tests
deployed to justify storage conditions and what triggers them.
Companies used a combination of DSC, TSu, and ARC data
for thermal stability. Beyond thermal stability, one company
indicated conducting dust and explosivity testing on their
stored materials. For raw materials, intermediates, and
products, companies were asked again, as in the mid-stage, if
SADT is used to assess risks for decompositions during
shipping. Of the ten companies that do internal late-stage
manufacturing, eight use SADT at this stage while two
companies said no. Again, in the mid-stage, 9 out of the 15
participants did not use SADT which suggest that the use of
SADT is more predominant in the late stage. Looking closer at
the open answers for the companies that answered positively,
three companies determined SADTs at earlier stages. Two
companies determined the SADTs of materials if deemed
appropriate by EHS during the HazOp. One company used
SADT if a material exhibited an exothermic decomposition
below 125 °C. Two of the eight companies used advanced
software packages (model-free kinetics or AKTS) to determine
a material’s SADT, which is again similar to the approach in
the mid-stage.
The participants were asked whether or not MOC
compatibility was considered. All responses were positive
that testing is done which is not surprising as virtually all
companies (14 out 15) are doing this testing in the mid-stage,
as shown in Figure 13. The positive responses include two
companies that use coupon testing. Two companies also stated
that if incompatibilities are known, then additional testing
would be performed. One company said that the receiving site
is responsible for all MOC considerations. Finally, one
company stated that the process safety labs study how MOC
affects thermal hazard testing results. Again, the responses are
very similar to those seen in the mid-stage.
Next, we asked if stream conductivity is considered for
potential electrostatic hazards, and all responses were positive.
Five companies noted that this data would have been gathered
at previous stages. One company said that conductivity testing
is done for all processes. One company said that the data are
pulled from literature sources. Finally, one company said that
the data are gathered at an external vendor. Overall the
response suggests an increase in scrutiny of the electrostatic
hazard at this stage as 8 out of 15 companies did not even
consider the streams’ conductivity in the mid-stage.
For process safety testing requirements for continuous flow
processes, four companies said that the evaluation of flow
processes would have already been completed at an earlier
stage. Two companies said the evaluation of a flow process is
identical to batch processes and no additional testing is done.
Two companies also said that no late-stage processes are
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Figure 15. Survey results about specific techniques used for PHA.
performed in continuous mode. Overall the response is similar
to what is observed in the mid-stage.
Companies were next asked “what results/outcome would
prompt your lab to stop a reaction from moving forward and
propose changing the chemistry to mitigate the observed risk”.
As in the mid-stage answers varied and here are the key
responses.
• One company said a reaction’s Stoessel classification
would be used to give a go/no go decision.
• One company noted that if adequate protection
measures could not be implemented to contain the
consequences of the event then the reaction would
require further development.
• The remaining six companies said that all issues that
would prevent a reaction from being executed at a
commercial scale would have been resolved at earlier
stages.
All companies were asked if a formal PHA is required. At
this stage, all companies responded positively that PHA is
required with the exception of one who said that it depends on
the CMO. This is a significant increase compared to only 5 out
of 15 companies in the mid-stage that deploy a PHA.
Companies stated that multiple PHA methodologies could
be implemented within the same company. Six perform Hazard
Operability (HAZOP) methodology. Four use failure mode
and effects analysis (FMEA). One company used layers of
protection analysis. Four companies did not disclose the
specific PHA techniques they employed (see Figure 15).
If a failure mode is identified, the companies were asked how
these modes were evaluated, with experimental data and/or
modeling. Seven companies use experimental data to evaluate
failure modes and one company did not gather any additional
data. There was no indication that modeling was used to study
these failure modes. Modeling was slightly more popular in the
mid-stage (11 out 15); it appears that late-stage companies are
more cautious in terms of adopting modeling which is
understandable. As for general kinetic modeling use, three
companies said they will not use modeling for studying upset
scenarios. Three companies also stated that they will only use
modeling for low-risk activities. Two companies said that these
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data would have been gathered at earlier stages of develop-
ment.
Process development of the unit operations in the
pharmaceutical industry presents a design space where
variability in the process parameter and input variables (like
temperature, reagent equivalent) are permitted as it would still
provide assurance of quality. These variations within the design
space are typically not evaluated during thermal hazard
evaluation, and safety tests are done at the intended center
point. In the next question of the survey, companies were
asked how they evaluate safety when operating with the design
space, although experimental evaluation and results might be
limited to the center point. The five companies that perform
commercial-scale manufacture noted that they would not carry
out further testing beyond the center point. The companies
that considered the safety of the process over the design space
mentioned doing the testing at the worst-case scenario and
some companies use a paper exercise based on FMEA.
When asked about assessing the mixing of waste streams,
only one company that performs commercial manufacturing
stated that they did not assess the mixing of waste streams.
This could be due to the location specific requirements for
waste handling (i.e., waste is shipped off site for incineration).
The other seven companies perform some type of waste mixing
assessments. Some companies will perform waste neutraliza-
tion if required by the site.
The final question asked the participating companies how
they keep track of changes made to processes post validation.
Two companies said they do not track changes to processes
post validation. In this instance, the manufacturer is
responsible for assessing the safety of any proposed changes.
Two companies track changes made to processes through
written reports that are archived within the respective
company. Four companies rely on their external sourcing
groups to reach out when changes to processes are proposed.
3. CONCLUSIONS
The IQ thermal hazards and process safety working group
completed a survey of its membership to assess approaches to
process safety development. Participation rates among the
member companies was excellent, and the information
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
gathered covered all phases of development and manufactur-
ing. While many commonalities exist, it should not come as a
surprise that each company has a different approach for
gathering and developing process safety information, and these
approaches are likely reflective of the individual member
companies’ cultures and risk tolerance. In addition, there were
very few commonalities noted among the way member
companies interact with CMOs and share their thermal hazard
results.
The key findings from the survey in terms of engaging PSL
throughout the drug development lifecycle is the following. At
the early phase, some companies reported not having
medicinal chemistry groups to support, whereas others are
either supporting the early phase in a scaled-back manner or
not at all. Most companies surveyed have a threshold that
triggers an evaluation by PSL; however, that threshold varies
significantly from company to company. The “mid-stage” of
development (roughly corresponding to the execution of drug
substance campaigns in the kilo-lab or pilot plant) is where the
majority of companies surveyed are executing process safety
work. Almost half of the companies’ PSL are not providing
process support in the late phase, which likely reflects a desire
to have most process safety risks understood and discharged
prior to transfer to manufacturing.
Among the common themes among the companies, they all
indicated that exothermic and pressure generating reactions are
their prime area of focus regardless of the stage of
development. Also, most member companies will closely
examine any process changes and most likely any change will
trigger an experimental thermal hazard examination of the
change on process safety. Across the member companies, the
Stoessel criticality classification system is becoming a common
language for assessment of thermal risk. On the other hand,
when it comes to establishing a “margin of safety”, variation
was noted among companies that participated in the survey.
Finally, the authors’ desire is that this article will be used by
the pharmaceutical companies and other institutions that
handle chemicals including and not limited to CROs,
universities, and other chemical industries to evaluate their
current PSE programs. However, the reader should be
reminded that approaches discussed in this paper might not
be the best practices and are subject to change as they
represent the current state of how surveyed companies conduct
their hazard evaluation. Changes in the current state can come
from learning from incidents and/or evolution of testing
methodologies. Indeed, we plan to conduct a follow-up survey
in the future to assess how surveyed companies change their
safety testing methodologies.
■
AUTHOR INFORMATION
Corresponding Author
Ayman D. Allian − Process Development, One Amgen Center
Drive, Amgen Inc., Thousand Oaks, California 91320, United
States; orcid.org/0000-0002-1604-6738; Email: aallian@
amgen.com
Authors
Nisha P. Shah − Process Development, Gilead Sciences, Inc.,
Foster City, California 94404, United States; orcid.org/
0000-0001-7524-5959
Antonio C. Ferretti − Chemical Process Development, Bristol
Myers Squibb, Summit, New Jersey 07901, United States
R https://dx.doi.org/10.1021/acs.oprd.0c00226
pubs.acs.org/OPRD Article
Derek B. Brown − Process Development, One Amgen Center
Drive, Amgen Inc., Thousand Oaks, California 91320, United
States; orcid.org/0000-0002-7909-0867
Stanley P. Kolis − Small Molecule Design and Development, Eli
Lilly and Company, Indianapolis, Indiana 46285, United
States; orcid.org/0000-0001-6268-9470
Jeffrey B. Sperry − Vertex Pharmaceuticals, Boston,
Massachusetts 02210, United States; orcid.org/0000-0003-
0365-5646
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00226
Author Contributions
The manuscript was written through contributions of all the
authors. All the authors have given approval to the final version
of the manuscript.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors are grateful to the entire IQ thermal hazard team
that worked together to craft and design the questionnaire and
subsequently took the time to answer them. That includes
Nelson Landmesser (TEVA), Brian D. Phenix (Vertex), Simon
Leung (Bristol-Myers Squibb), John D. Weaver III (Pfizer),
Frank Dixon Jr. (GlaxoSmithKline), Lady Mae Alabanza
(Genentech), Megan Roth (Merck), Chris Mitchell (Takeda),
Charles Papageorgiou (Takeda), Zhe Wang (Abbvie), Steve
Richter (Abbvie), Max Sarvestani (Boehringer Ingelheim),
Shasha Zhang (Bristol-Myers Squibb Company), Mark Hoyle
(AstraZeneca), and Christopher Tickner (Bristol-Myers
Squibb Company). The team appreciates the support of the
International Consortium for Innovation and Quality in
Pharmaceutical Development (IQ, www.iqconsortium.org)
throughout the process. We would especially like to thank
Maja Leah Marshall for her support of the project during the
rollout of the Survey, and her expertise in SurveyMonkey was
crucial to the success of this effort.
■
NOMENCLATURE
ΔHrxn (a) the desired reaction at the process temperature,
(b) by runaway reactions and/or (c) thermal
decompositions J/mol
ΔTad adiabatic temperature rise associated with that
exotherm, °C (K)
Qrxn thermal Energy of the reaction J
AKTS advanced kinetics and technology solutions
ARC accelerating rate calorimetry
BOC tert-butyloxycarbonyl protecting group
CMO contract manufacturing organizations
Cp heat capacity of reaction mixture J/g °C
CRO contract research organization
DSC differential scanning calorimetry
LEL lower explosive limit
LOC limiting oxygen concentration
m mass g
MTSR maximum temperature of the synthesis reaction °C
MTT maximum temperature for technical reasons °C
Phi (ϕ) correction factor used to account for the thermal
mass of a sample bomb. ϕ = 1 + (mbCpb/msCps),
where m and Cp are the mass and heat capacity of
the bomb and the sample. Unitless
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
PSL process safety laboratories
RC reaction calorimetry
Tp temperature of the process °C
TSu thermal screening unit
TD24 temperature at which the time to maximum rate for a
decomposition reaction is 24 h °C
VSP vent sizing package
■
ADDITIONAL NOTES
a
The Carius Tube test is used to determine the onset
temperature for decomposition of reagents and the rate of gas
evolution from such decomposition.
b
Advanced reactive system screening tool.
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