Safety/Environmental Report pubs.acs.org/OPRD
Merck’s Reaction Review Policy: An Exercise in Process Safety Ephraim Bassan,*,† Rebecca T. Ruck,*,‡ Erik Dienemann,† Khateeta M. Emerson,† Guy R. Humphrey,§ Izzat T. Raheem,∥ David M. Tschaen,§ Thomas P. Vickery,† Harold B. Wood,⊥ and Nobuyoshi Yasuda§ †
Environmental and Process Safety Engineering, Merck Manufacturing Division, Rahway, New Jersey 07065 Process Chemistry, Merck Research Laboratories, Kenilworth, New Jersey 07033 § Process Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065 ∥ Discovery Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486 ⊥ Discovery Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065 ‡
S Supporting Information *
2. REACTION REVIEW POLICY DETAILS General Considerations. Before 2009, there was no formal safety review process at smaller than Pilot Plant scale. If an individual chemist had process safety concerns, s/he would ask Merck’s Environmental and Process Safety Engineering (EPSE) group to review the planned chemistry. A paper exercise would be completed, and if deemed necessary, EPSE would also conduct thermal testing to assist the evaluation. However, this informal safety review proved highly under-utilized, especially if the reaction were not being run at prep lab scale. Beginning in 2009, EPSE partnered with Process Chemistry to develop a formal review process that would improve safety while not slowing down the pace of research. In 2012, this process was expanded to also include Discovery Chemistry. A two tier system has been developedbench (typically lab hood) and prep lab (0.5−5 kg) scales. Prep lab scale operations have been deemed inherently more hazardous than bench scale for three reasons: (1) The amount of material used is larger, so the potential for serious consequences from an undesired event is greater. (2) Heat removal is typically less efficient as scale increases. Heat generation is proportional to the volume of the batch, while heat removal is proportional to the cooling surface area. Unless special provisions are made for better cooling on scale-up, this dichotomy means that heat removal vs batch size is roughly proportional to the surface/volume ratio. Thus, in order to maintain constant batch temperature for exothermic operations when scale is increased 10×, the temperature difference between batch and cooling fluid needs to be about twice as large, or the reagent addition time needs to be about twice as long. (3) Time cycles are normally longer with increases in scale, e.g., longer heat-up, cool-down, and distillation times. Because the time−temperature exposure profile is increased in some cases, a decomposition exotherm can be triggered at a temperature that did not trigger it at smaller scale. For these reasons, a formal reaction review is now required for all prep lab reactions.
ABSTRACT: Process safety is an important consideration not only when conducting reactions on manufacturing scale, but also on lab and kilo lab scale. This contribution presents a discussion of Merck’s Reaction Review policy, originally specific to Process Chemistry and now applied broadly across the whole chemistry organization. Details of the policy and case studies are included.
1. INTRODUCTION Merck’s Process Chemistry department has always operated with an eye toward safety when carrying out chemistry. As such, a formal, comprehensive review for all procedures being carried out in the Pilot Plant has been in place for many years. Prior to 2009, only an informal, ad hoc safety review occurred for processes to be conducted in the Rahway prep laboratories (typically, 0.5−5 kg scale on a process intermediate/API basis). In 2009, the decision was made to formalize this process to complement the Pilot Plant review and better ensure the safety of all chemists running reactions on prep lab scale. An additional element of the new review process was a formal Hazardous Reaction Review, which applied to a much smaller scale than that employed in the prep laboratories. The necessity of this component was realized when a senior-level scientist in the department incurred a serious hand injury upon isolating a diazonium salt on 50 °C (5) azide formation, diazomethane, diazonium salts (6) dinitro or trinitro compounds (7) hydrazine These categories were originally selected because they are fairly common reaction classes and have unusually high potential for rapid energy release. It has been made clear to the chemists that other reactions that appear to have a comparable level of hazard should also be reviewed, per the chemists’ professional judgment. In practice, roughly one-third of the reactions reviewed as highly hazardous have not been from the automatic categories listed above, highlighting that Merck Chemistry has established a culture where process safety is foremost in the chemists’ minds.7 For highly hazardous reactions, a review by EPSE is required in addition to review with the scientific supervisor. In many cases, this review is simply a paper exercise. Sometimes, it leads to DSC or advanced specialized testing to better understand the specific hazards and properly define a safe operating envelope. Reactions in flasks ≤100 mL are not required to undergo a review.8 The risk of a serious incident at this smaller scale is relatively low as long as standard chemical handling precautions are taken. Furthermore, routinely including these small experiments in the Reaction Review process would consume limited resources without meaningfully improving process safety. Nevertheless, chemists have been provided with formal Reaction Review training and have been encouraged to exercise professional judgment for these smaller-scale reactions and engage the reviewers as appropriate. The training supplemented the standard chemistry safety training taken by all employees before conducting lab experiments. The Reaction Review training is mandatory for all chemists, providing details of the Reaction Review Policy as well as a high-level overview of process safety. The criteria for review, based on scale and reaction type, are illustrated in Figure 1. Highly toxic reactions use or produce chemicals that are particularly toxic. Cyanide, phosgene, HF, iodine, diborane, organotin, and mercury are representative of this class. Dangerous reagents include pyrophoric materials, such as butyllithium and lithium aluminum hydride. For reactions in these classes, a chemist is required to consult with his/her scientific supervisor to review hazards and procedures. If needed, additional input can
Although prep scale operations are more hazardous than bench scale operations, the latter can also pose significant hazards. This notion supports the second tier of the Reaction Review policy. At bench scale, formal reaction review by process safety experts is required for specific highly hazardous reactions. This practice leverages the time and experience of the process safety experts with those experiments where they are most likely to have constructive input. Reviewing all bench scale reactions would represent a significant burden on the experts and lead to delays, with minimal benefit or safety improvement. Prep Lab Scale. Prep lab scale is defined as reactions run in a vessel >5 L, even if the actual reaction volume is less.2 Note that the largest vessel size available for Merck prep lab use is 100 L. All prep lab scale experiments that involve a chemical reaction are covered by this policy. The policy requires the chemist to do the following prior to running the reaction: (a) Discuss with supervisor. (b) Complete a “Paper Assessment”: Consult literature, Bretherick’s,3 MSDSs. Consider reaction type, functional group instabilities, known hazards. (c) Chemistry Assessment: Complete probe reactions, documenting exotherms, addition times, cooling used, workup procedures, etc. (d) Acquire Differential Scanning Calorimeter (DSC) data on starting material(s) and product(s).4 (e) Submit completed “Reaction Review and Approval Form”. (f) Obtain approval from both one SAC (Scientific Advisory Committee)5 designee and one EPSE (Environmental and Process Safety Engineering)6 designee before performing the experiment. The approval form is simple. The first part contains some basic administrative information, e.g. name of chemist and supervisor, batch size and location, and timing. The second section requires a balanced equation, proposed experimental procedure, DSC traces of starting material(s) and product(s), any significant observations from probe runs or literature (e.g., addition highly exothermic, reaction generates gas, etc.), any special equipment or controls to be used, and approval boxes for SAC and EPSE with an area for any comments they wish to provide. For roughly one-quarter of the submissions to date, the EPSE and/or SAC reviewer has requested additional testing to further evaluate the potential hazards of the proposed experiment. The most common follow-up has entailed screening preor postreaction mixtures by DSC, and with more advanced tools as warranted. Drop weight testing for shock sensitivity has been done for unusually energetic materials. Turnaround time for approval has typically been ≤24 h when no additional testing has been needed. Generally, only one additional day has been required for follow-up testing. The initial concerns of some chemists that the review system would slow down research have proven unfounded, as the chemist normally knows at least several days in advance what the plans are for syntheses at prep lab scale. For those infrequent cases where more extensive testing has been required, turnaround time has been longer. Nonetheless, these experiments are precisely the ones with the highest risk of incidents, fully justifying the delay to allow thorough evaluation. In some cases, approval has been contingent upon implementation of minor process modifications or special controls. These B
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Figure 1. Merck Reaction Review Policy.
Figure 2. Highly toxic and dangerous reagents.9
While the general best practices can and should be applied to all classes of reactions being run in the lab, they fail to cover specifics for reactions that require the most significant safety precautions. Each of the Highly Toxic or Dangerous Reagents specified in Figure 2 carries its own set of safety concerns for handling, use, quench and disposal. Moreover, each of the Hazardous Reactions identified earlier in the paper has similar concerns, in addition to the highly energetic considerations. To address the Highly Toxic or Dangerous Reagents themselves, the team created what have come to be referred to as the “Before, During and After Slides”. These slides are
be requested from Merck’s Global Safety and the Environment group or from EPSE. Seven categories (Figure 2) have been defined and examples of corresponding reagents identified. As with the Hazardous Reactions, chemists have been encouraged to seek additional guidance if using a reagent outside the purview of this list but which may pose similar dangers. Viable starting points and best practices for conducting any Hazardous Reactions or reactions involving Highly Toxic/ Dangerous Reagents were developed as described above. In addition, general reaction safety best practices were established (Figure 3). C
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Figure 3. General best practices.
Figure 4. Representative Best Practice slide.
For each of the Hazardous Reactions, a Word document capturing the specifics of the particular reaction class, as well as links to prior internal large-scale examples, is provided. There are also links to literature examples of reactions in that class that went awry. For example, in the azide class, there is guidance concerning the Curtius reaction using diphenylphosphorylazide (DPPA), in which chemists are encouraged to avoid build-up of the acyl azide species (and concomitant uncontrollable exotherm) by adding DPPA to a preheated organic solution of the requisite carboxylic acid compound.
linked directly from the main Reaction Review policy by simply clicking on the particular toxic/dangerous reagent listed. These slides include details on how to prepare yourself and your lab mates for working with the particular reagent (including any precautionary safety measures to take), how to limit exposure during the reaction, and how to work up the reaction and dispose of the corresponding waste streams. They also provide links to relevant Safety Data Sheets. When appropriate, a warning sign (e.g., Cyanide in Use) is provided for the chemist to hang on the fume hood and lab doors. A representative slide for Cyanide Use is included in Figure 4. D
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3. CASE STUDIES This section presents several case studies that highlight the value of the Reaction Review process. These examples span a range of chemistries and scales, as well as different types of outcomes for the ultimate path forward. The issues and corresponding recommendations from the review process are described in each case. Blaise Reaction (Prep Lab Scale, eq 1). A chemist experienced a runaway reaction at small scale when carrying out a Blaise reaction. EPSE found that this runaway can be easily reproduced if the bromoester is added rapidly. Calorimetry testing with slow addition showed that the decomposition was unusually vigorous, with an adiabatic ΔT of ∼200 K, and that there can be a delayed and autocatalytic initiation of the desired reaction. Approval was given to run this reaction on prep lab scale with the following provisions to prevent an overly vigorous delayed initiation: (1) After 3% of the acetate has been added, assay the batch for both consumption of starting material and formation of product (no quantitative assay was available for the intermediate). Do not add more acetate until confirming that the desired chemistry has been initiated. (2) Repeat after the addition of acetate is 10% complete, and again after it is 40% complete. (3) For deployment at pilot plant and manufacturing scale, investigate use of online instrumentation to monitor the reaction. Dess−Martin Oxidation (Bench Scale, eq 2). DSC of the reaction mixture after periodinane addition identified an unsafe decomposition at elevated temperature. The proposed procedure added all the Dess−Martin periodinane at once. The highly exothermic reaction could raise the batch temperature very close to triggering the dangerous decomposition. Approval was given to run this reaction at bench scale with the following provisions that provide a larger safety margin to avoid the decomposition: (1) Run the reaction more dilute to ensure more thermal mass of solvent is present to absorb the heat of reaction, and hence lower the adiabatic ΔT for the desired oxidation. (2) Charge the periodinane in several portions. 2-Iodoxybenxoic Acid (IBX) Oxidation (Bench Scale, eq 3).
A chemist was designing a process using IBX, since it afforded better selectivity and conversion than other oxidation reagents. Pure IBX was found to be shock-sensitive10 even at an impact of only 50 kg·cm, as well as thermally unstable with a violent decomposition. Its use as a solid reagent was not allowed. Two additional forms of IBX were investigated: a 1.5 M solution in DMSO and a 45% blend with benzoic and isophthalic acids. Although both showed large, rapid exotherms by DSC, neither gave a violent decomposition, nor were they impact-sensitive at 100 kg·cm. Approval was given to the run the reaction at bench scale using either diluted IBX mixture with the following provisions: (1) Store the IBX solution or blend at or below room temperature, under inertion and away from light. (2) If employing the solid 45% blend with benzoic and isophthalic acids, tools should be plastic or rubber, but not metal. It should be noted that, while both the DMSO solution and acid blend of IBX were effective in the oxidation, the chemist opted for the DMSO solution as it would transition more readily to future scale-up opportunities. Azide Formation (Prep Lab Scale, eq 4).
A proposed process made an azide compound as a process intermediate, but also generated isopropyl azide as a reaction byproduct due to residual isopropanol mesylated in the prior step.11 Since the solvent was DMF, which has a relatively high boiling point, concerns were raised about potential condensation of isopropyl azide, which could be shock-sensitive. Initial guidance was provided to attempt the removal of isopropanol from the prior step. When this option proved unsuccessful, EPSE suggested adding ∼5% THF to the reaction, so that any condensate would be primarily THF with only a small concentration of isopropyl azide. The chemist found that this modification did not adversely affect the reaction, and the modified process was approved for prep lab and pilot plant usage. Percarbonate Reaction (Bench Scale, eq 5). The proposed procedure used sodium percarbonate as reagent and acetone as solvent. Such a system can form explosive acetone peroxide compounds. The reaction was rejected, and the chemist was instructed to identify an alternative solvent or, if necessary, a different reagent. This instance was one of the very few times a proposed reaction was rejected, as opposed to being permitted with operating restrictions and/or minor modifications. E
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(2) The 5-L flask was deemed the maximum appropriate size to use in a standard lab hood for safety and ergonomic considerations. (3) Urben, P. G., Ed. Bretherick’s Handbook of Reactive Chemical Hazards; Academic Press: Amsterdam, 2006. (4) For safety screening, a special DSC cell that can withstand a significant amount of pressure is used. The standard crimped Al pan may leak at relatively low pressure, enabling the volatile components generated to escape the system. However, when a very rapid exothermic decomposition occurs at larger scale, the gases will often not have time to escape the system (even if it is not rated for pressure) before the remaining reaction mixture further reacts at higher temperature, which can lead to additional heat and pressure generation. In order to best balance resources and expertise, two to five chemists per research site were trained to run DSCs with the special cells. These cells are made of Hastelloy C rather than Al, as Al reacts with many chemicals, thereby generating false positive or false negative results. (5) SAC (Scientific Advisory Committee) is a group of senior, experienced process chemists. Some of them have a particular interest and expertise in process safety. (6) EPSE (Environmental and Process Safety Engineering) is a group of process safety professionals, including chemists and chemical engineers, in the Chemical Process Development and Commercialization department. EPSE provides process safety testing and analysis support for all of Merck, including lab development, pilot plant scaleup, and full-scale commercial manufacturing. The EPSE lab has a large set of specialized testing equipment to evaluate process safety, including DSC (differential thermal calorimetry), ARC (accelerating rate calorimeter), RSD (reactive screening device), ARSST (advanced reactive systems screening tool), VSP (vent sizing package), drop weight test, calorimeters, and dust explosivity testers. EPSE utilizes its expertise and experience in evaluating the process safety hazards of the proposed reaction, as well as scale-up of the entire process. As appropriate, EPSE may also do additional literature review, and may determine (by modeling or experimentation) the adiabatic temperature rise of desired or undesired reactions. (7) No consistent theme has been present among that one-third of reactions to recommend inclusion of another default category among the hazardous reactions, but we continue to review these data and will modify the list if indicated. (8) There was considerable discussion around the appropriate minimum flask size for Hazardous Reaction Review. Chemists were once again reminded that reviews can take place at smaller volumes, a fact particularly relevant in instances of neat reactions. (9) OEB stands for Occupational Exposure Band. OEB 5 compounds are highly potent and, as solids, must be handled in isolators due to their low occupational exposure limits. For additional information, see: Maier, M.S.V. Toxicology Mechanisms and Methods; 2011; Vol. 21, p 76. (10) Plumb, J. B.; Harper, D. J. Chem. Eng. News 1990, 68 (29), 3. (11) Note that the presence of HN3 in reaction headspace is also of concern in azide displacement reactions. This scenario was mitigated by the presence of DIPEA in the reaction mixture.
Decarboxylation Reaction (Bench Scale, eq 6). This decarboxylation reaction was carried out by aging at 130 °C. DSC showed a large and rapid exotherm initiating at
160 °C, with concomitant pressure generation. This exotherm could be triggered by extended aging close to the reaction temperature. The chemist was asked to either identify decarboxylation conditions that would be conducted at a lower temperature and/or without DMSO, or to develop alternative chemistry that avoids this step. Ultimately, the latter approach proved successful.
4. SUMMARY Merck’s Chemistry departments, in consultation with Merck’s Environmental Process Safety and Engineering group (EPSE), have implemented a Reaction Review policy to address two potentially perilous scenarios: (1) reactions that could become dangerous on scale-up from bench to prep lab scale and (2) hazardous reactions that could be dangerous even at bench scale due to the high energy inherent to the system. This policy has simultaneously provided specific guidance and detail for the chemists on both the hazardous reactions and toxic/dangerous reagents. Since establishment of the original Reaction Review policy, no hazardous reaction-related injuries have occurred, and preventable incidents have been minimized. The Merck Chemistry Safety Network will continue to evaluate efficiency, compliance, and content over time to ensure the current and future safety of all Merck chemists.
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ASSOCIATED CONTENT
S Supporting Information *
Sample submission forms are provided. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
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[email protected] *E-mail:
[email protected] Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Karen Whitaker of Global Safety and the Environment and the members of the Merck Chemistry Safety Network for their assistance in developing and implementing the Reaction Review policy.
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REFERENCES
(1) The published procedure he was following was somewhat ambiguous, only specifying not to use a metal spatula, with no indication of the serious hazards of isolating the diazonium salt. While scraping the material on the fritted funnel with a Teflon spatula, the material exploded, leaving the chemist with multiple lacerations requiring sutures to mend and nerve damage requiring surgery to fix. F
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