By Vince Ammoscato and Sean Lapekas, Ash Stevens
While much of the emphasis on safety in the pharmaceutical industry relates to ensuring patient safety, as should be the case, often other crucial aspects of safety — in particular process safety — receive less attention than is appropriate. With in- creasing pressure to deliver faster turn- around times and lower cost, the performance of comprehensive process safety evaluations, which are time consuming and expensive, can be glossed over by contract development and manufacturing organizations (CDMOs), most often due to a lack of awareness and understanding of their importance. Inattention to process safety can, however, lead to devastating consequences.
It is essential that CDMOs conduct all pharmaceutical manufacturing processes in a safe manner. To do so requires an effective process safety management system and strategy within a culture that emphasizes safety. Prior to acceptance, proposed projects must be evaluated to determine whether the capabilities of the CDMO are adequate, and only those projects for which suitable facilities, equipment and skilled personnel are available should be accepted. Once a project is underway, both theoretical and physical analyses must be conducted to determine the thermodynamic and kinetic proper- ties of all materials involved in the process and the process itself, both under normal and worst case scenario conditions. Only with access to this information can the behavior of a process be fully understood with appropriate engineering, safety controls and procedures implemented. The failure to establish an effective basis of safety can lead to inadequate process design and protection of opera- tors and, in the most severe cases, the surrounding community and environment.
The types of processes conducted by CDMOs range widely, and consequently so do the potential hazards and risks they pose. Some processes, such as those that involve the use of unstable raw materials, exothermic reactions and / or the production of non-condensable gases, are more hazardous than others. In addition, as reactions are scaled from the lab to the pilot plant and then commercial volumes, the risk they pose increases.
Not all CDMOs are equipped to safely manage every possible process required for the production of pharmaceuticals. Therefore, the first step in establishing an effective process safety strategy is determination of the company’s capabilities — and limitations — with respect to handling process hazards. In general, a paper assessment of the hazards presented by a potential new project, including the potency of the compounds and the potential for highly energetic chemistry / highly hazardous reactivity, should be suitable for determining whether the process presents hazards beyond what the CDMO is equipped to safely manage. A willingness to reject potential projects based on such a safety evaluation is the foundation of an effective safety management strategy.
If a project is deemed within the bounds of the CDMO’s capabilities, the proposal / quote submitted to the client should include an outline of all anticipated process safety testing (and associated costs) needed to establish an appropriate basis of safety and potential safety measures.
Comprehensive safety evaluations should begin immediately once a project is accepted and run parallel to process development activities. The benefits of this approach are numerous — not only is the identification of any potential risks / hazards achieved prior to scale-up; any necessary changes to the process can be completed prior to process scale-up.
The comprehensive hazard evaluation should identify both desired and undesired potential material and reaction hazards. Thermal stability testing of the materials and mixtures used in the process is completed using instruments such as a differential scanning calorimeter (DSC), a thermal screening unit (TSu) and / or accelerating rate calorimeter (ARC). The enthalpies of the intended synthetic reactions can be obtained by either estimation techniques using available thermodynamic data, or measured with a reaction calorimeter. The generated data is then used to identify any process hazards and establish a defined basis of safety for each that will minimize the likelihood of adverse events and, where necessary, provide protection to operators and the environment from any potential event that may occur.
Once a project is accepted, the CDMO should conduct a more thorough paper assessment, considering all of the functional groups of the molecules involved and the process conditions. If the reaction is sufficiently simple, this phase may include estimation of the heat of reaction using heat of formation data for analogous reactants and products taken from the literature. If no concerns are raised, then reaction calorimetry testing may be deferred until later in process development, so the testing will reflect the process as it will be scaled-up.
If there is any question about the potential stability of the materials in a process, DSC is performed on individual starting materials / reagents / products and / or re- action mixtures. The sample is heated at a constant rate, and the heat flows to (endothermic change) and from (exothermic change) the sample are recorded as a function of temperature and time. A DSC scan provides information about phase changes, decomposition or other self-reactivity behavior of the sample and whether these events occur exothermically or endothermically. For reliable results in safety testing, it is crucial that closed pressure rated crucibles be used for these types of DSC experiments.
There are limitations to DSC methods, however. First, the “onset” temperature can vary depending on the instrument sensitivity and the conditions under which the test was conducted.2 Second, DSC does not provide any information on changes in pressure, and it is pressure buildup after an energy release due to solvent vaporization or the release of gases that often leads to undesired consequences.
Therefore, analysis using a TSu or other similar pressure recording screening tool is imperative for evaluating both temperature and pressure responses, which can be studied under either isothermal or ramped temperature conditions. There are cases, in fact, where only slight exotherms or even endotherms are observed in DSC scans, but measurable pressure events are detected during a TSU analysis (SEE FIGURE 1).
Kinetic data and the heat of reaction of the desired process chemistry are then obtained using a reaction calorimeter. Traditionally, the Mettler Toledo RC1 has been the industry workhorse used for reaction calorimetry. A disadvantage of this system is that many users have it equipped with a 500-mL or larger reactor, and requires substantial quantities of material. Microreaction calorimeters have been recently developed, however, that utilize 1.5-mL to 20-mL vials and require minimal material, making the test quicker and more feasible for regular testing of all processes, regardless of development phase. It is important to note, however, that while a properly designed and executed microcalorimeter experiment will provide a reliable heat-of-reaction value, it may be difficult to determine the heat-release profile that will be observed during a slow addition that is typically employed on scale-up. If the microcalorimeter uncovers a large exotherm that will require strict temperature control via addition rate, further testing in larger equipment may be appropriate.
To establish the most appropriate basis of safety therefore requires the ability to know which tests to conduct and how to effectively interpret the obtained data. The experience and expertise of the CDMO’s process safety personnel are thus crucial to successful evaluations. Both an under- standing of the potential reactivities of molecules based on their structures, and extensive experience conducting safety evaluations of many different processes, are needed to be able to identify the best series of tests that will fully elucidate the reaction behavior for a given process.
For instance, if a screening test con- ducted on a reaction mixture uncovers a decomposition event, quite often the practice is to assign a default safety mar- gin, below which the reaction must be executed. However, one must remember that the screening test is performed in a sealed system, in which vaporization of the sol- vent is suppressed. If the “onset” of the de- composition event is above the atmospheric boiling point of the solvent, then to reach that secondary decomposition event, all of the solvent would first need to be vaporized. Before simply adding a 100°C safety margin (a common practice) that would re- quire cooling of the reaction further than necessary, leading to excessive energy consumption, carbon emissions and additional expense, it would be prudent to first evaluate the rate of decomposition at the atmospheric boiling point, and deter- mine the modes of failure that could lead to evaporation of solvent (i.e., the adiabatic temperature rise of the desired reaction, equipment failures, etc.), and base a safety margin on these findings.
The rate at which energy is released, and not just the amount of energy, should also be considered. Information on the time to maximum rate can be gleaned from DSC scans. From a pure qualitative perspective, a broad decomposition peak suggests that energy may be released following nth order kinetics, while a sharp peak indicates a rapid release and possible autocatalytic decomposition. In the latter case once the initiating event is triggered, there is much less time to correct the situation before a full-blown runaway occurs. If ARC testing is not readily avail- able, conservative Time to Maximum Rate information can often be estimated by conducting DSC analyses at multiple isothermal temperatures or scan rates and applying advanced software to develop scalable models of reactions that can be used to predict stability under different heating conditions. 
If the results of such an analysis raise any flags, more accurate data can be obtained using an accelerating rate calorimeter. Given the large instrument footprint and expense, ARCs are not typically owned by smaller CDMOs. Samples must there- fore be sent to an external testing laboratory for ARC analysis. The test provides in- formation about the relationships between time, temperature, pressure and kinetics for exothermic reactions under adiabatic conditions, such as those generally experienced in process equipment during loss of cooling.
Finally, it is not sufficient to consider only the desired reaction conditions. The behavior of the process under various un- desirable conditions — worst-case scenarios such as loss of cooling or other equipment failure (i.e., stirring, feed pumps, etc.) — must also be evaluated in order to deter- mine the most effective basis of safety.
Vince Ammoscato currently serves as Vice President of Operations for Ash Stevens Inc. in Riverview, Michigan. With extensive experience in multi-step regio- and stereoselective synthesis, including synthesis of nucleosides, peptide-based compounds and heterocycles, Ammoscato has served as the prime technical contact between Ash Stevens and external clients. Ammoscato holds a B.Sc. chemistry, 1988, and a M.Sc. organic chemistry, 1990, from the University of Windsor, Canada.