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Safety Guidelines for Continuous Processing

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Continuous Pharmaceutical Processing

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 42))

Abstract

This chapter gives safety guidelines for continuous chemistry experimental work in the laboratory. It also applies to continuous manufacturing of small-volume products using laboratory fume hoods. Pressure relief devices are needed on the discharge of positive displacement pumps. They are needed immediately downstream from back pressure regulators, at the inlet and outlet of plug flow reactors (PFRs), and on all pressure vessels that are not always open to an atmospheric pressure vent. Venting should be sufficient so vessels do not pressure up when filling, with vent paths free of block valves. Vent knockout vessels should be present and appropriately sized to catch process materials in case vessels overfill and also catch bubbler liquid in case of suck back. Plugging and fouling can be minimized by using a large enough tubing size, monitored with pressure transmitters, and managed with strategically placed valves and tees. Inerting is a primary line of defense against fire. Grounding and bonding is used when flowing from one vessel to another to prevent static charge buildup and sparking. Nonconductive liquid flowing through nonconductive tubing at high velocities should be avoided. Heat exchange rate should be sufficient for exotherm removal and chemical reaction safety, and chemical reaction safety analysis should be done, including calorimetry and thermal stability. Secondary containment should be provided, as well as sensors, to detect leaks and hazardous concentrations. Materials of construction must be compatible with the chemistry under reaction conditions. Automated alarms, interlocks, and/or auto-shutoffs should be included based on temperatures, pressures, and fill levels. Emergency stops should be installed. Reactant accumulation or total mass accumulation; overfilling product collection vessels; undesired phase changes; backflow into feed vessels, vents, or utilities; and static electricity buildup should all be prevented.

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Notes

  1. 1.

    “Catch-and-weigh” means to collect the pumping liquid for a measured time period in a tared container or graduated cylinder. If collecting in a tared container, then measure the mass of liquid pumped. Measured mass per time is the actual pumping rate.

  2. 2.

    A low set pressure is especially advantageous for runaway reaction scenarios, as it provides a better chance of turning around the pressure rise before the maximum allowable pressure is reached.

  3. 3.

    Piping components are assigned a design pressure, while ASME pressure vessels are assigned an MAWP; ASME pressure vessels also have a design pressure, but this may be different from the final assigned MAWP.

  4. 4.

    ASME (American Society of Mechanical Engineers) B31.3 Code for Pressure Piping provides guidance on the design of piping systems. Section VIII of the ASME Boiler and Pressure Vessel Code is commonly used to design and test pressure vessels. For equipment designed to the ASME BPVC, the allowable accumulated pressure (pressure above the MAWP) is generally 10% for non-fire scenarios, and 21% for fire scenarios.

  5. 5.

    API 521 is American Petroleum Institute Standard 521 on Pressure-Relieving and Depressuring Systems.

  6. 6.

    API 520 Part 1 is American Petroleum Institute Standard 520 Part 1 on Sizing, Selection, and Installation of Pressure-Relieving Devices in Refineries. Its guidance is widely applied in the process industries.

  7. 7.

    NFPA 69 Standard on Explosion Prevention Systems.

  8. 8.

    See for example, OSHA 1910.101 on Compressed Gases.

  9. 9.

    See the pressure relief section for more on leak testing.

Abbreviations

A/V:

Surface area per unit volume

API:

American Petroleum Institute

ASME:

American Society of Mechanical Engineers

BPVC:

Boiler and Pressure Vessel Code

CCPS:

Center for Chemical Process Safety

CSTR:

Continuous stirred-tank reactor

DIERS:

Design Institute for Emergency Relief Systems

GC:

Gas chromatography

LOC:

Limiting oxygen concentration

MAWP:

Maximum allowable working pressure

MOC:

Materials of construction

MSMPR:

Mixed suspension mixed product removal

P&ID:

Process and instrumentation diagram

PFR:

Plug flow reactor

PI:

Pressure indicator

PPE:

Personal protective equipment

PT:

Pressure transmitter

SAChE:

Safety and Chemical Engineering Education program

SURF:

Scale-Up Review Form

References

  • Allian AD, Richter SM, Kallemeyn JM, Robbins TA, Kishore V. The development of continuous process for alkene ozonolysis based on combined in situ FTIR, calorimetry, and computational chemistry. Org Process Res Dev. 2010;15(1):91–7.

    Article  Google Scholar 

  • American Institute of Chemical Engineers. Guidelines for pressure relief and effluent handling systems. New York: American Institute of Chemical Engineers; 1998.

    Google Scholar 

  • Baxendale IR. The integration of flow reactors into synthetic organic chemistry. J Chem Technol Biotechnol. 2013;88(4):519–52.

    Article  CAS  Google Scholar 

  • Braden TM, Gonzalez MA, Jines AR, Johnson MD, Sun W-M, Eli Lilly and Company. Reactors and methods for processing reactants therein. United States patent application WO 2009023515 A2. 19 Feb 2009.

    Google Scholar 

  • Braune S, Poechlauer P, Reintjens R, Steinhofer S, Winter M, Lobet O, Guidat R, Woehl P, Guermeur C. Selective nitration in a microreactor for pharmaceutical production under cGMP conditions. Chim Oggi. 2009;27(1):26–9.

    CAS  Google Scholar 

  • Britton LG. Avoiding static ignition hazards in chemical operations. New York: AIChE; 1999, ISBN 978-0-8169-0800-4.

    Book  Google Scholar 

  • CCPS. Inherently safer chemical processes: a life cycle approach. Hoboken: John Wiley & Sons; 2009, ISBN 978-0-471-77892-9.

    Google Scholar 

  • CCPS. Guidelines for engineering design for process safety. Hoboken: Wiley; 2012.

    Google Scholar 

  • Crowl DA, Louvar JF. Chemical process safety: fundamentals with applications. 3rd ed. Upper Saddle River: Prentice-Hall; 2012.

    Google Scholar 

  • Expert Commission for Safety in the Swiss Chemical Industry (ESCIS), SUVA. Static electricity: rules for plant safety. Plant/Oper Saf. 1988;7(1):1–22.

    Article  Google Scholar 

  • Fisher HG, Forrest HS, Grossel SS, Huff JE, Muller AR, Noronha JA, Shaw DA, Tilley BJ. Emergency Relief System Design Using DIERS Technology: the Design Institute for Emergency Relief Systems (DIERS) project manual. New York: American Institute of Chemical Engineers; 1993, ISBN: 978-0-8169-0568-3.

    Book  Google Scholar 

  • Gutmann B, Cantillo D, Kappe CO. Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew Chem Int Ed. 2015;54(23):6688–728.

    Article  CAS  Google Scholar 

  • Hessel V, Kralisch D, Kockmann N, Noel T, Wang Q. Novel process windows for enabling, accelerating, and uplifting flow chemistry. ChemSusChem. 2013;6(5):746–89.

    Article  CAS  Google Scholar 

  • Johnson MD, et al. Development and scale-up of a continuous, high-pressure, asymmetric hydrogenation reaction, workup, and isolation. Org Process Res Dev. 2012;16(5):1017–38. https://doi.org/10.1021/op200362h.

    Article  CAS  Google Scholar 

  • Johnson MD, et al. Continuous reactors for pharmaceutical manufacturing. In: Nagy ZK, El Hagrasy A, Litster J, editors. Continuous pharmaceutical processing. Cham: Springer International Publishing; 2020. (this volume).

    Google Scholar 

  • Johnson MD, May SA, Kopach ME, Groh JM, Cole KP, Braden TM, Shankarraman V, Merritt JM. Design and Selection of Continuous Reactors for Pharmaceutical Manufacturing. Chapter 16 in Chemical Engineering in the Pharmaceutical Industry, Second Edition – Drug Substance/API. 2019. Edited by David J am Ende and Mary Tanya am Ende.

    Google Scholar 

  • Kletz TA. What you don’t have, can’t leak. In: Chemistry and industry. Richmond: The National Archives; 1978. p. 287–92.

    Google Scholar 

  • Kopach ME, Murray MM, Braden TM, Kobierski ME, Williams OL. Improved synthesis of 1-(azidomethyl)-3,5-bis-(trifluoromethyl) benzene: development of batch and microflow azide processes. Org Process Res Dev. 2009;13(2):152–60.

    Article  CAS  Google Scholar 

  • Li B, Widlicka D, Boucher S, Hayward C, Lucas J, Murray JC, O’Neil BT, Pfisterer D, Samp L, VanAlsten J, Xiang Y. Telescoped flow process for the syntheses of N-aryl pyrazoles. Org Process Res Dev. 2012;16(12):2031–5.

    Article  CAS  Google Scholar 

  • May SA, Johnson MD, Braden TM, Calvin JR, Haeberle BD, Jines AR, Miller RD, Plocharczyk EF, Rener GA, Richey RN, Schmid CR. Rapid development and scale-up of a 1H-4-substituted imidazole intermediate enabled by chemistry in continuous plug flow reactors. Org Process Res Dev. 2012;16(5):982–1002.

    Article  CAS  Google Scholar 

  • Obermayer D, Balu AM, Romero AA, Goessler W, Luque R, Kappe CO. Nanocatalysis in continuous flow: supported iron oxide nanoparticles for the heterogeneous aerobic oxidation of benzyl alcohol. Green Chem. 2013;15(6):1530–7.

    Article  CAS  Google Scholar 

  • Osterberg PM, Niemeier JK, Welch CJ, Hawkins JM, Martinelli JR, Johnson TE, Root TW, Stahl SS. Experimental limiting oxygen concentrations for nine organic solvents at temperatures and pressures relevant to aerobic oxidations in the pharmaceutical industry. Org Process Res Dev. 2014;19(11):1537–43.

    Article  Google Scholar 

  • Proctor LD, Warr AJ. Development of a continuous process for the industrial generation of diazomethane. Org Process Res Dev. 2002;6(6):884–92.

    Article  CAS  Google Scholar 

  • Rincón JA, Barberis M, González-Esguevillas M, Johnson MD, Niemeier JK, Sun WM. Safe, convenient ortho-Claisen thermal rearrangement using a flow reactor. Org Process Res Dev. 2011;15(6):1428–32.

    Article  Google Scholar 

  • Sahoo HR, Kralj JG, Jensen KF. Multistep continuous-flow microchemical synthesis involving multiple reactions and separations. Angew Chem. 2007;119(30):5806–10.

    Article  Google Scholar 

  • Tilstam U, Defrance T, Giard T, Johnson MD. The Newman−Kwart rearrangement revisited: continuous process under supercritical conditions†. Org Process Res Dev. 2009;13(2):321–3.

    Article  CAS  Google Scholar 

  • Wada Y, Schmidt MA, Jensen KF. Flow distribution and ozonolysis in gas-liquid multichannel microreactors. Ind Eng Chem Res. 2006;45(24):8036–42.

    Article  CAS  Google Scholar 

  • Wang Z, Richter SM, Gates BD, Grieme TA. Safety concerns in a pharmaceutical manufacturing process using dimethyl sulfoxide (DMSO) as a solvent. Org Process Res Dev. 2012;16(12):1994–2000.

    Article  CAS  Google Scholar 

  • Webb D, Jamison TF. Continuous flow multi-step organic synthesis. Chem Sci. 2010;1(6):675–80.

    Article  CAS  Google Scholar 

  • Ye X, Johnson MD, Diao T, Yates MH, Stahl SS. Development of safe and scalable continuous-flow methods for palladium-catalyzed aerobic oxidation reactions. Green Chem. 2010;12(7):1180–6.

    Article  CAS  Google Scholar 

  • Yoshida JI, Kim H, Nagaki A. Green and sustainable chemical synthesis using flow microreactors. ChemSusChem. 2011;4(3):331–40.

    Article  CAS  Google Scholar 

  • Zhang P, Russell MG, Jamison TF. Continuous flow total synthesis of rufinamide. Org Process Res Dev. 2014;18(11):1567–70.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Edward Mark Davis for his consulting on this manuscript. We thank Bret Huff for leading and promoting the continuous process design and development at Eli Lilly.

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Authors and Affiliations

  1. Eli Lilly and Company, Indianapolis, IN, USA

    Martin D. Johnson & Jeffry Niemeier

Authors
  1. Martin D. Johnson
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  2. Jeffry Niemeier
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Corresponding author

Correspondence to Martin D. Johnson .

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Editors and Affiliations

  1. Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, USA

    Zoltan K Nagy

  2. Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Arwa El Hagrasy

  3. Department of Chemical and Biochemical Engineering, The University of Sheffield, Sheffield, UK

    Jim Litster

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Johnson, M.D., Niemeier, J. (2020). Safety Guidelines for Continuous Processing. In: Nagy, Z., El Hagrasy, A., Litster, J. (eds) Continuous Pharmaceutical Processing. AAPS Advances in the Pharmaceutical Sciences Series, vol 42. Springer, Cham. https://doi.org/10.1007/978-3-030-41524-2_13

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