Process Development
VI. PROCESSING RESPONSIBILITY IN BULK DRUG PROCESS DEVELOPMENT
All chemical processing, whether on a large or a small scale, whether for high value chemicals or commodities, or for bulk drugs, textile polymers, petrochemicals or household products, carries a risk to those that work in the industry, to people around the manufacturing sites and beyond, and to the environ-ment: locally, beyond the locality, and at large. Indeed, the risk comes about from multiple directions:
1. The hazards created by the chemistry itself: (a) intended and unintended energy releases, and (b) the various hazards of handling the materials involved. Bulk drugs often
present a peculiar hazard, i.e., the relatively high potency of the desired biological activities, as well as the collateral activ-ities of the intermediate compounds and, of course, of the drugs themselves.
2. The specific manner in which the chemical processes is implemented at scale. Most risks in chemical processing are a function of the process design, the equipment design, and the operating procedures used to manufacture the products.
In other words, the same inherent hazard can be implemented at various levels of risk depending on the specifics of imple-mentation, and often enough details matter.
Hazard—a source of danger, of possible injury or loss.
Risk—The probability of suffering a given loss or injury from a hazard.
3. The local context in which the manufacturing pro-cess is implemented. First, there are factors, such as the proximity to populated areas, the direct impact on sensitive receiving bodies of water or other valuable habitats, or a less apparent impact on remote parts of the environment at large. Then, as a lesser subset of those risks are the various statutory and regulatory constraints that create liability potentials or that may impede timely manufacture if not properly addressed.
It is one of the prime responsibilities of the bulk drug pro-cess development organization to seek propro-cesses of accep-table levels of risk in both the chemistry and its engineering, and to participate in the process design and manufacturing plans to see to it that their implemen-tation risk is sufficiently low. Of all aspects of technology transfer, none demands more in terms of the develop-ment team thrusting itself downstream and seeking the closest collaboration with the manufacturing organiza-tion. Clearly, the greatest opportunity for success exists at the developmental stage of the R&D process work, when the process is conceived and developed; engineering low risk into the implementation of a hazardous process is always the second choice for the bulk drug process development team and the collaborating process design
function. For example, much safer process alternatives seemed to exist for the process that led to the 1974 cata-strophe in Bhopal, India (24); one called for a different chemical route and the other for a different process design of the original chemistry.
Incidents such as Seveso, Italy, 1976 (24,25) and Bhopal illustrate the potential for catastrophic events from aber-rant chemical processing and design, sloppy operating practices and incomplete knowledge about probable unin-tended events and consequences.
Generally useful practices in this aspect of bulk drug process development are:
Early assessment to guide the process conception and choices. This implies availability within the pro-cess development organization of, or facile acpro-cess to, laboratory capabilities to evaluate thermochemical and environmental hazards. The evaluation of indus-trial hygiene hazards is aimed at the protection of per-sonnel, and is facilitated by the availability or access to adequate toxicology resources such as those generally available to a research drug firm. This industrial hygiene context, however, differs substantially from that of evaluating the risk to patients taking the drugs, and a different subset of skills and methods applies.
Continuing assessment as the process develops, including a vigorous interaction with the process design function and the manufacturing organization.
For example, issues such as the choice of manufactur-ing site, which influences the risk, cannot be settled by the process development team alone, nor can they be properly settled without the hazards assessed during development.
Reasonably early decision on the in-house vs. outside manufacturing choices, as the latter requires technol-ogy transfer and due diligence work, as well as the inevitably longer cycle for reaching the necessary technical and business agreements (more on this under VII below).
A. Thermochemical Process Safety
Most chemical processing operations have energy exchanges between process streams and the surroundings; process streams are heated or cooled for various purposes and such exchanges need to be safe. Heated streams must not exceed limits that generate undue pressures or undesired chemical events, whereas cooled streams must not freeze and interrupt process flows, or hamper a desired chemical reaction and accumulate unstable intermediates.
A distinction needs to be made between limits observed to maintain process performance and limits observed to avoid a hazardous operating condition. The above para-graph refers, of course, to the latter limits, as depicted in Fig. 19 using the safe processing envelope concept.
The thermochemical safety of chemical processing deals with the safe handling of the energy released from chemical reactions and with the prevention of unwanted releases of energy. Chemical reactants may, when converted to products, result in the transformation of chemical energy into heat, and during such exothermic reactions the heat release needs to be safely managed. In addition, chemical process streams may reach abnormal conditions that cause unintended exothermic reactions, with the attendant formation of unintended bypro-ducts and release of energy.
Hence, the objectives of thermochemical process safety as a distinct principal component of processing safety at large:
Identify all intended energy releases and determine their magnitude, rates, and byproduct releases, such as gas evolution and their composition. These deter-minations need to be made over the appropriate range of process conditions.
Identify unintended chemical events and energy releases for reasonable hypothetical situations (e.g., excess temperature by loss of coolant or runaway, excessive evaporation of solvent, interrupted reaction cycle, etc.) and assess their magnitude, probable rate, and consequences with respect to containment, gas
evolution and, when indicated, the composition and toxicity of the components of a plausible release.
Identify and quantify the hazards of handling the process streams and materials with respect to shock sensitivity, flammability, explosiveness in air mix-tures, dust=air explosiveness, etc.
Seek process development solutions to avoid or reduce hazards. For example, one might seek an alternative reactant, a reaction medium that permits a lower reaction temperature or, in the ultimate, a different synthesis scheme for the conversions at hand.
Provide process design solutions to those hazards that cannot be reasonably developed out of the process, thus reducing their risk to levels appropriately low for the operating context. For example, a hazardous Figure 19 Processing limits for performance and for safety. Pro-cessing limits define the perimeter of the operating envelope that results in the range of desired process performance, whereas the safety limits define the safe processing envelope perimeter given the identified hazards that lie beyond. For example, a distillation is to be carried out at 90–100C, whereas the high-temperature interlock that shuts off the steam is set at 125C because a signifi-cant exotherm initiates at 160C.
nitration reaction may be implemented in a reactor system that does not use aqueous coolants, or that is equipped with a suitable quenching vessel, or with a sufficient containment system, or using a continuous tubular reactor with large cooling surfaces and hold-ing a small volume of reactive in-process materials.
Similarly, a process or portions of a process with a hazard of explosion is preferably operated in a plant site that is distant from populated areas (vs. an other-wise more suitable plant site not as distant from populated areas); or a process with an identified hazard of aquatic toxicity in its untreated waste would not be operated in a plant site that normally dis-charges to an aquatic habitat. In both cases, one will take preventive measures to reduce the risk, but a risk differential will exist between the two plant sites.
From the above, and most importantly, the practice of ther-mochemical safety far transcends the evaluation or the assessment of hazards. It also demands that skillful solu-tions to the hazards be provided so as to eliminate them or reduce their risks as required. While the reader may view this statement as redundant or exceedingly tutorial, the fact is that a functional discontinuity between the assessment of thermochemical process hazards and the implementation of the process frequently exists, creating an ever present pitfall for the unwary, the sloppy, the over-whelmed, and the unqualified, and even organizations with the requisite critical mass of skills and well-documen-ted procedures need to be vigilant to the gap. As in most other aspects of bulk drug process development, the utmost integration of process development and process design is the best approach to thermochemical process safety, organizational divides notwithstanding.
Additionally, the above reflects the fact that the same hazard (e.g., a reaction mass that can decompose explo-sively upon total loss of solvent) poses different risk according to the context of implementation. Thus, for the example just given of a major hazard, a process
design based on operator’s attentiveness and simple pro-cess controls would entail a greater risk than a design based on interlocking and redundant measures to pre-vent total loss of solpre-vent as well as operator’s attentive-ness. To wit, the operational risk arising from a process hazard is very much a function of the specifics of the operational context.
There are, of course, many other aspects of processing safety that are unrelated to, or overlap with, thermochemical process safety. Among the overlapping, fire and explosion hazards due to flammables handling stand out, whereas the unrelated (e.g., falls, burns, asphyxiation in enclosed spaces, static electricity, etc.) are generally addressed through the aggregate of well-established measures of operational safety, facility design, insurance policy expectations and applicable industrial or building codes.
It seems best, even for the introductory scope of this chapter, that before approaching a more specific discussion of the fundamentals and the practice of thermochemical process safety, the presentation of a broad perspective be attempted. Hence Fig. 20, in which the field is viewed from a sufficiently high vantage and that the reader is urged to examine in earnest before going further.
Three key points arise from Fig. 20:
The chemistry defines the overall scope of the hazards:
the energy release potential of the reactants and other materials used, that of the reaction and process streams generated and the toxicity hazard that attends to all the compounds involved, whether inputs, intended, or gen-erated by aberration. Accordingly, chemical acumen is utmost in the assessment and follow-up of the hazards defined by the structures at hand.
Upon assessment, a broader set of skills is needed. Will the hazards be avoided altogether by a change in the chemistry or will its risk be sufficiently reduced by a process solution? Either approach requires engineering acumen to determine that a process solution is not advisable or probable, or to devise a suitable alternative.
Finally, the implementation of whatever process is arrived at through development, and its indispensable process design collaboration, must go through further engineering analysis, by which all the applicable consid-erations must be pursued to the requisite level of detail:
from the sizing of vessel relief and area explosion venting on the basis of thermochemical and related data to the evaluation of risk scenarios that will dictate the neces-sary margins of safety relative to overlapping safety, site specifics (e.g., weather precedents, proximity to people or valuable environments), applicable regulations, insurance policy expectations and all the way up to the probable perceptions in the neighboring communities.
Figure 20 Thermochemical process safety in bulk drug process development.
Prior to the catastrophes in Seveso in 1976 (24,25) and in Bhopal in 1984 (24), these admonitions would have seemed unwarranted and even melodramatic, but not any more.
Finally, seeking relief in the small scale of bulk drug chemical processing does not help, as both instances of chemical processing operations gone badly awry were of small scale.
1. Hazard Assessment and Methods in Thermochemical Process Safety
Thermochemical hazards are numerous and richly varied in kind, each requiring more than passing consideration and, if appropriate, an assessment by engineering design calculations, simulation, experimentation, or both. The task calls for experienced good judgment, as the possibilities are too numerous. For example, an organic synthesis of six dis-tinct steps, with up to, say, 10 disdis-tinct intermediate struc-tures generated, might also have a total of 40 different material inputs and process streams. Experimental assess-ment of each is a large burden that, invariably, can be greatly reduced by the said experienced good judgment.
Herein there is not, of course, the aim to comprehensively present this subject. Indeed, the literature is ample (not sur-prisingly, most was written after the 1976–1984 experiences), and the serious reader is earnestly referred to various refer-ences, preferably in the listed sequence (24,26–28). Clearly, this is not work for the dilettanti, but for professionals willing to invest in acquiring and applying focused know-how in a multidisciplinary environment– too much is at stake. Simi-larly, firms engaged in bulk drug processing cannot approach the work in half measures, or contract it out indiscriminately or unaware of the pitfalls of doing so.
Let us discuss another perspective, this time from a closer vantage; that of the thermochemical hazards assessment.
Firstly, as indicated above, the structures at hand provide very useful leads as to what to expect. As a good rule of thumb, organic compounds that are rich in nitrogen, oxygen, or both are high on the list of reactivity and energy release structures, followed by some specific bonds and then by the less obvious cases that exist
in organic synthesis, albeit less frequently (26, pp. 18–28; 27, pp.
28–52; 28, pp. 22–27). Once so alerted, the hazards assessor has a good number of techniques for estimation of heats of reaction, for rapid screening of exotherms and instabilities in materials, com-pounds and process streams, for accurate calorimetry work under close to actual process conditions and for very specific fol-low-up of hazardous conditions (27, pp. 1–28 and 52–88; 28, pp.
27–45). Indeed, the techniques are so numerous that care must be taken to walk the fine line between necessary and marginal testing, striving to reserve the more elaborate and exhaustive methods for the cases that merit them. For example, the thermal stability of process materials and streams can be pursued to great lengths (29) as required. Similarly, the subsequent hazards of vapor or gas release or toxicity of the released materi-als need to be pursued with similar acuity, as one may go too far as easily as not far enough. In this, the incisiveness of the screen-ing effort makes the difference.
The well-executed hazards assessment meets its three basic objectives: (a) identifying and quantifying the heat effects of the intended chemistry, (b) identifying and quantify-ing, albeit not always as precisely, the thermochemical energy hazards from aberrant conditions, and (c) identifying and quantifying those hazards associated with the handling of process materials and their instabilities. Again, it is work with a great many nuances for which chemical, physicochem-ical, and engineering acumens are indispensable.
By way of vivid illustration of these assertions, one might consider the following instance, in which a labile nitrogen-rich compound was isolated as a water-moist powdery solid and dried under vacuum at50C. These latter drying con-ditions had been set at50C away from the rapid and large exothermic decomposition of the compound, found to initi-ate at100C in the screening work. Additionally, the heat-ing medium used in the dryheat-ing step was limited to55C and an ample vacuum capacity and a suitably low terminal pressure provided for the thorough removal of water. After months of processing at the ton scale, a process change was introduced in the isolation, substituting a mineral acid for
another in the final acidification prior to filtration and washing. This seemingly innocuous change resulted in a product of slightly lesser purity that, alas, was significantly less stable. The latter fact came forward upon violent decomposition of1 ton of product during the drying step.
Subsequent investigation revealed that the process change product was somewhat less crystalline and had a signifi-cantly earlier onset of decomposition, such that at 50–
55C the self-heating process of decomposition started and rapidly took the material to its violent outcome.
Finally, thermochemical hazards assessment needs to start upon scale-up to the kilo lab, and if the structures at hand are suspect, some basic screening should be done even sooner. The effort then needs to continue as the process is developed and scaled up to the pilot plant, ensuring that significant process changes are not missed—a task of skillful vigilance, as the above example emphasizes.
2. Process Design from the Assessed Hazards and Achieving an Acceptable Risk
As indicated in Fig. 20, the hazards assessment data need to be placed in a process design context, in which scale issues arise forcibly: loss of surface to volume ratio, longer time cycles of certain batch events, more difficult mixing, larger in-process inventories, and many other. Upon up development, a reasonably specific design of the scaled-up operation needs to be challenged by the hazard and the resulting level of risk evaluated. This requires a sufficient engineering input and a deliberation commensurate with the magnitude of the hazard, and the exercise resembles the do-loops of computational code, with the effort resulting in a pro-cess design solution deemed to have an acceptable risk. Often enough this analysis leads to: (a) a significant change in the basic process (the scaled-up risk demands a lesser hazard) or (b) to a highly engineered design (the hazard is accepted, but its scaled-up risk is also accepted). Examples of these out-comes are the switch to a different reaction to get to the same structure or the use of a continuous reactor (or skipping the isolation of a dry unstable intermediate), respectively.
Beyond the above, more detailed methods of analysis exist for final plant design (e.g., HAZOPS or similar methods (30, pp. 42–178), with the objective of ferreting out the risks arising from the basic process hazards as well as all other overlapping hazards in the specific context for the process operation. In many cases, the specific risk analysis results in changes to the safe processing envelope so as to deal effec-tively with the risks. This result is depicted in Fig. 21, where a contoured envelope is adopted so as to place greater ‘‘dis-tance’’ between the permissible ranges of process variables and the risks. For example, the mixed acid concentration in a hazardous nitration may be lowered to reduce significantly the risk of catastrophic failure by corrosion of the preferred (and existing) reactor vessel in the plant.
Eventually, this continuing exercise embraces all the
Eventually, this continuing exercise embraces all the