The safe handling of hazardous reactions

Transcription

1 The safe handling of hazardous reactions A variety of chemical and engineering controls can be employed to contain the risks associated with the use of hazardous reagents. Dr Thomas Archibald, NextPharma Technologies* Many new drugs are now synthesised using hazardous reagents that would have been unthinkable in the past *Formerly Aerojet Fine Chemicals Discovery scientists are continually inventing increasingly complex target drug molecules. Making enough of these future drugs to support clinical trial requirements under increasingly short development times presents a challenge to the ingenuity of the manufacturing chemist. Additionally, the marketplace demands that the eventual commercial process be low-cost and have the same purity profile as the early development material. These factors are causing a re-evaluation of assumptions as to which chemical processes can be conducted industrially and have led to modern processes that look more like discovery routes than mature manufacturing schemes. Many new drugs are now synthesised using hazardous reagents that would have been unthinkable in the past. Safer processes using less hazardous reagents could be developed but time constraints mandate the use of these reagents, while at the same time containing the risks through use of a blend of chemical and engineering controls. A hazardous but clean reagent that saves two or three steps in a multi-step process is valuable, and the time saved can be directed at solving other critical issues. While the developers of new chemical processes wish to employ more hazardous reagents, corporations, regulators and the general public are becoming less tolerant of the perceived risks associated with chemical processes. What is considered hazardous tends to be determined by non-scientific reasoning, with the result that one finds little consistency from one company to another. For example, one multinational pharmaceutical company might opt to use Villsmeyer reagents which are banned by another company. Further complicating the use of hazardous chemicals is the nonavailability of many hazardous reagents - such as methyl isocyanate or phosgene - because of existing or pending shipping restrictions. Moreover, the cost of setting up the required infrastructure for generating and handling such materials within pharmaceutical companies may be prohibitive in view of the relatively small quantities needed for the development of a drug substance. Another disadvantage to the use of hazardous chemistry is the potential threat to the local surroundings. The rapid growth in chemical infrastructure in many pharmaceutical manufacturing plants has brought many types of chemistries together in one location. What may once have been an isolated building is now surrounded by many other vulnerable plants. Many older chemical reactions still being conducted in pharmaceutical plants may not pass current hazard analysis screening. Furthermore, because of growth, plants are often located in urban areas close to schools, shopping centres and housing developments. 124 Innovations in Pharmaceutical Technology

2 The rapid growth in chemical infrastructure in many pharmaceutical manufacturing plants has brought many types of chemistries together in one location It is a challenge to reconcile the needs of the neighbouring community, other plant processes, worker safety, governmental regulations and many other considerations with the need to bring new drugs to the market in a rapid and cost-effective manner. Outsourcing hazardous chemical processes to specialist fine chemical manufacturers which are well-equipped to handle the hazards is often the best option. Identification of potentially hazardous chemistries The need to manufacture in a timely fashion, combined with the ever-increasing complexity of new drug synthesis routes, leads to the issue of how to identify potential hazards effectively. Of course, the best way to identify a chemical hazard is to have experienced staff who have worked with the materials and are aware of the potential problems. Unfortunately, in a ten-step reaction sequence, it is unlikely that any single chemist will have such experience for all reagents and reactions. Once a problem step has been identified, standard screening by thermal analysis (such as DSC, ARC and other calorimetric methods) is useful, especially in the design of facilities. Thermochemical methods are widely used, but they can miss some potential problems and overstate others. For example, a loaf of bread generates more energy (5,100 kwh) than a stick of dynamite (2,000 kwh) on combustion, yet the preparation of toast is usually safe. Certain reagents such as Villsmeyer Reagent show the onset of decomposition at less than C above the usual reaction temperature. These reagents have been extensively used in a safe manner, even though they are banned in many companies where standard practice only allows reactions with an onset at C above the reaction temperature. One possible way of screening hazardous chemicals is to use existing accident data (Table 1). This data demonstrates that nitrations and sulfonations are similar in their hazardous characteristics, while hydrolysis and salt formation are more dangerous than halogenation. Some chemicals or processes have a greater potential for causing catastrophes in pharmaceutical manufacturing plants (Figure 1). Nitro compounds, nitrate esters and nitramines can act as oxidisers for the remainder of the molecule. Azides, diazo compounds, hydrazines, nitriles and acetylenes provide positive heats of formation and increased energy. Strained rings, such as epoxides and aziridines, are also potential sources of energy. Any molecule containing these groups should be carefully investigated on a case-by-case basis (2). There are a few rules of thumb that can be helpful in identifying problems in molecules containing these groups. If the weight of a troublesome group exceeds 25-30% of the total molecule weight, then problems may occur (easily detected by counting the number of carbons per energetic group). Six carbons or more per energetic functional group can provide sufficient dilution such that materials containing these groups are relatively safe (although there are exceptions). The greater the number of functional groups or combination of groups, the greater the potential hazard. For example, AZT contains an aliphatic azide group diluted by ten carbons and several oxygens and nitrogens, such that the azide group is not significantly hazardous. On the other hand, Table 1. Causes of chemical plant accidents (1). 126 Innovations in Pharmaceutical Technology

3 Figure 1. Selected troublesome functional groups. Figure 2. Typical use of diazomethane at industrial scale. The greater the number of functional groups or combination of groups, the greater the potential hazard diazidomethane (frequently encountered in azide reactions when methylene chloride is used as a solvent) is a very hazardous material. An exception to the "rule of six" occurs when the azide group is attached to an olefin or aromatic group - in which case care must always be exercised. Certain reagents are also potentially hazardous and require special handling. The manufacturers of these materials generally provide information to ensure that the user is aware of the potential dangers. However, many new pharmaceutical chemicals are not fully characterised; they may be custom orders or come from inexpensive third world sources. Detonability Detonability represents a potentially hidden hazard that few pharmaceutical manufacturers are prepared to handle properly. In some cases, reactants are not hazardous individually, and nor is the end-product, but when all are present together they create a dangerous condition. Detonation is a rapid decomposition in which a supersonic shock-wave is created. As a general principle, a mixture of an oxidiser and a fuel can detonate when the balance between them reaches a specified limit and some initiating event occurs. This explains the prohibition many companies have on the use of solvents (fuels), such as diethyl ether; ether can also form peroxides that can decompose with friction to initiate an explosion. A common feature of all safety analyses is a consideration of the potential of solvent spills and the risk of a possible fuel-air explosion. The fuel-air scenario is to be avoided, but because of the relatively low amounts in the gas phase, the hazard can be mitigated by deluge systems, air handling, explosion-proof equipment and so on. 128 Innovations in Pharmaceutical Technology

4 The potential for disaster in a reactor full of a detonable material (such as the acetic anhydride/nitric acid mixture) is high because of the large amounts of material present. For example, a partially filled 100 gallon reactor would be capable of generating a similar energy output to a 500-pound bomb filled with high explosives. Although detonability can be tested for by the card gap or other tests, this is not a readily available test for most pharmaceutical companies. A simple method for screening for detonability is to look for "zero oxygen balance" situations. Zero oxygen balance occurs when a fuel and an oxidiser are present in concentrations such that the carbon and hydrogen present have enough oxygen to generate water and carbon monoxide or carbon dioxide. Most chemical reactions are fuel rich because of the presence of solvents, but oxidiser rich situations can occur, such as when nitric acid is used as a solvent. If a reaction starts initially with a fuel-rich mixture and then goes on to an oxidiser-rich state, it must inevitably go through zero oxygen balance. Such situations occur frequently during the quenching of nitrating mixtures. Sometimes, zero oxygen balance situations cannot be avoided. In such cases, the risks require remote operation in appropriately bunkered facilities. The presence of zero oxygen balance must be accompanied by an initiating event to cause a transition to detonation. The initiation can come from energy inputs such as friction, a spark (often caused by electrostatic discharge), heat or a shock-wave. An example of this type of hazard is found in simple halonitro compounds, such as bromonitromethane, used in pharmaceutical manufacturing. This class of compound has zero oxygen balance in the neat form: As would be expected from the oxygen balance between carbon monoxide and carbon dioxide, this material is detonable. In fact, the energy output of bromonitromethane is similar to TNT (trinitrotoluene, a high explosive). Clearly, this is not a pure compound that should be manufactured or used in unprotected facilities near homes or other factories - yet it was manufactured in suburban laboratories before the dangers were realised. Shipping drums of neat bromontromethane would be equivalent to shipping high-explosive bombs. The most useful method for overcoming the zero oxygen balance problem is to dilute the mixture by adding more fuel (or sometimes more oxidiser). For the safe handling of bromonitromethane, an easy solution exists. Addition of a hydrocarbon to the bromonitromethane reduces the oxygen balance, and the mixture is no longer detonable. The diluted material can be used in further reactions without isolation and thus without danger. Diazomethane - a case study Diazomethane is an explosive gas believed to be impossible to use on an industrial scale. Recently, however, even this difficult material has been scaled up for pharmaceutical use in the production of high purity intermediates for HIV protease intermediates (3). Although other approaches have been developed, the original route using diazomethane remains the lowest cost in several cases. The route provided by the discovery chemists was carefully evaluated and a complete safety assessment was undertaken. Based on experimental data, an understanding of the potential hazards was gained and used to design a plant. Engineering controls for the critical reaction conditions were installed and small-scale runs were completed. With an experience-base of hundreds of runs over seven years, better-designed and larger-scale facilities were installed such that there is now a multi-metric ton capacity available (Figure 3). This experience shows that almost all chemistries can be practised safely and demonstrates the degree of facilitisation, experimentation and operational care that is required to do so successfully. A new general-purpose plant has been constructed in Sacramento to handle azide and other hazardous chemical reactions in a cgmp pharmaceutical environment. Safety principles When a risk assessment leads to the conclusion that a reaction or reagent is unusually hazardous, then there are three principles required for success in the safe handling of hazardous chemicals: experienced personnel, appropriate facilities and operational excellence. First, the selection process should start with an evaluation of whether the chemistry fits a facility's experience-base. Which similar compounds have been handled before, at what scale and over what periods of time? Are any of the chemists who did In some cases, reactants are not hazardous individually, and nor is the end-product, but when all are present together they create a dangerous condition Innovations in Pharmaceutical Technology 129

5 Figure 3. Production capacity of diazomethane per month. A simple method for screening for detonability is to look for "zero oxygen balance" situations the work still on staff and, if so, will they be working on this project? Are appropriate lines of authority in place so that experts will be in charge of controlling the project? Second, does the project fit the process equipment and facilities? Are the materials of construction correct? Are containment and material-handling systems properly designed? Is there a risk that inappropriate facilities might be used to meet schedule or economic goals? How close are the facilities to other process equipment or to high-profile sites such as schools and residential areas? Finally, is the organisation known for its high level of operational excellence, such that a hazardous process will be operated safely in exactly the same manner every time. Is the proper risk management structure in place and is it used? Is on-site testing available and how are environmental, safety and health issues evaluated? Is there a formal design review, process safety management, action item close-out and change control system? What failure or error mode analysis is used and how are records maintained? How are workers trained and, especially, how are they trained in handling hazards? Finally, is there an internal audit system in place to ensure that all facets of these systems perform as they should? Dr Thomas Archibald is Director, Business and Technology Development, at NextPharma Technologies (formerly AerojetFine Chemicals). After receiving a PhD from Tulane University, he taught at the Illinois Institute of Technology for four years before entering industry. He has 30 years' experience in agricultural, pharmaceutical and defence-related industries, where he served in research and development, management and technology development positions. Dr Archibald's expertise in the scale-up of unusually reactive chemicals and hazardous reagents has resulted in over 70 publications and patents. References 1. Chem Eng Res Des (1989), 67, Gustin JL (1998). Organic Process Research & Development, 2, Archibald TG, Barnard J, Huang DS et al. (1998). US Patent 5,817,778. Large scale batch process for diazomethane. 4. Archibald TG, Barnard J and Reese H (1998). US Patent 5,854,405. Continuous preparation of diazomethane. 130 Innovations in Pharmaceutical Technology