Process chemistry
Process chemistry is the arm of pharmaceutical chemistry concerned with the development and optimization of a synthetic scheme and pilot plant procedure to manufacture compounds for the drug development phase. Process chemistry is distinguished from medicinal chemistry, which is the arm of pharmaceutical chemistry tasked with designing and synthesizing molecules on small scale in the early drug discovery phase.
Medicinal chemists are largely concerned with synthesizing a large number of compounds as quickly as possible from easily tunable chemical building blocks. In general, the repertoire of reactions utilized in discovery chemistry is somewhat narrow. In contrast, process chemists are tasked with identifying a chemical process that is safe, cost and labor efficient, “green,” and reproducible, among other considerations. Oftentimes, in searching for the shortest, most efficient synthetic route, process chemists must devise creative synthetic solutions that eliminate costly functional group manipulations and oxidation/reduction steps.
This article focuses exclusively on the chemical and manufacturing processes associated with the production of small molecule drugs. Biological medical products represent a growing proportion of approved therapies, but the manufacturing processes of these products are beyond the scope of this article. Additionally, the many complex factors associated with chemical plant engineering and drug formulation will be treated cursorily.
Considerations in process chemistry
Cost efficiency is of paramount importance in process chemistry and, consequently, is a focus in the consideration of pilot plant synthetic routes. The drug substance that is manufactured, prior to the formulation, is commonly referred to as the active pharmaceutical ingredient and will be referred to as such herein. API production cost can be broken into two components: the “material cost” and the “conversion cost.” The ecological and environmental impact of a synthetic process should also be evaluated by an appropriate metric.An ideal process chemical route will score well in each of these metrics, but inevitably tradeoffs are to be expected. Most large pharmaceutical process chemistry and manufacturing divisions have devised weighted quantitative schemes to measure the overall attractiveness of a given synthetic route over another. As cost is a major driver, material cost and volume-time output are typically weighted heavily.
Material cost
The material cost of a chemical process is the sum of the costs of all raw materials, intermediates, reagents, solvents, and catalysts procured from external vendors. Material costs may influence the selection of one synthetic route over another or the decision to outsource production of an intermediate.Conversion cost
The conversion cost of a chemical process is a factor of that procedure's overall efficiency, both in materials and time, and its reproducibility. The efficiency of a chemical process can be quantified by its atom economy, yield, volume-time output, and environmental factor, and its reproducibility can be evaluated by the Quality Service Level and Process Excellence Index metrics.Atom economy
The atom economy of a reaction is defined as the number of atoms from the starting materials that are incorporated into the final product. Atom economy can be viewed as an indicator of the “efficiency” of a given synthetic route.For example, the Claisen rearrangement and the Diels-Alder cycloaddition are examples of reactions that are 100 percent atom economical. On the other hand, a prototypical Wittig reaction has an especially poor atom economy.
Process synthetic routes should be designed such that atom economy is maximized for the entire synthetic scheme. Consequently, “costly” reagents such as protecting groups and high molecular weight leaving groups should be avoided where possible. An atom economy value in the range of 70 to 90 percent for an API synthesis is ideal, but it may be impractical or impossible to access certain complex targets within this range. Nevertheless, atom economy is a good metric to compare two routes to the same molecule.
Yield
is defined as the amount of product obtained in a chemical reaction. The yield of practical significance in process chemistry is the isolated yield—the yield of the isolated product after all purification steps. In a final API synthesis, isolated yields of 80 percent or above for each synthetic step are expected. The definition of an acceptable yield depends entirely on the importance of the product and the ways in which available technologies come together to allow their efficient application; yields approaching 100% are termed quantitative, and yields above 90% are broadly understood as excellent.There are several strategies that are employed in the design of a process route to ensure the adequate overall yield of the pharmaceutical product. The first is the concept of convergent synthesis. Assuming a very good to excellent yield in each synthetic step, the overall yield of a multistep reaction can be maximized by combining several key intermediates at a late stage that are prepared independently from each other.
Another strategy to maximize isolated yield is the concept of telescoping synthesis. This approach describes the process of eliminating workup and purification steps from a reaction sequence, typically by simply adding reagents sequentially to a reactor. In this way, unnecessary losses from these steps can be avoided.
Finally, to minimize overall cost, synthetic steps involving expensive reagents, solvents, or catalysts should be designed into the process route as late stage as possible, to minimize the amount of reagent used.
In a pilot plant or manufacturing plant setting, yield can have a profound effect on the material cost of an API synthesis, so the careful planning of a robust route and the fine-tuning of reaction conditions are crucially important. After a synthetic route has been selected, process chemists will subject each step to exhaustive optimization in order to maximize the overall yield. Low yields are typically indicative of unwanted side product formation, which can raise red flags in the regulatory process as well as pose challenges for reactor cleaning operations.
Volume-time output
The volume-time output of a chemical process represents the cost of occupancy of a chemical reactor for a particular process or API synthesis. For example, a high VTO indicates that a particular synthetic step is costly in terms of “reactor hours” used for a given output. Mathematically, the VTO for a particular process is calculated by the total volume of all reactors that are occupied times the hours per batch divided by the output for that batch of API or intermediate.The process chemistry group at Boehringer Ingelheim, for example, targets a VTO of less than 1 for any given synthetic step or chemical process.
Additionally, the raw conversion cost of an API synthesis can be calculated from the VTO, given the operating cost and usable capacity of a particular reactor. Oftentimes, for large-volume APIs, it is economical to build a dedicated production plant rather than to use space in general pilot plants or manufacturing plants.
Environmental factor (e-factor">Green chemistry metrics">e-factor) and process mass intensity (PMI)
Both of these measures, which capture the environmental impact of a synthetic reaction, intend to capture the significant and rising cost of waste disposal in the manufacturing process. The E-factor for an entire API process is computed by the ratio of the total mass of waste generated in the synthetic scheme to the mass of product isolated.A similar measure, the process mass intensity calculates the ratio of the total mass of materials to the mass of the isolated product.
For both metrics, all materials used in all synthetic steps, including reaction and workup solvents, reagents, and catalysts, are counted, even if solvents or catalysts are recycled in practice. Inconsistencies in E-factor or PMI computations may arise when choosing to consider the waste associated with the synthesis of outsourced intermediates or common reagents. Additionally, the environmental impact of the generated waste is ignored in this calculation; therefore, the environmental quotient metric was devised, which multiplies the E-factor by an “unfriendliness quotient” associated with various waste streams. A reasonable target for the E-factor or PMI of a single synthetic step is any value between 10 and 40.
Quality service level (QSL)
The final two "conversion cost" considerations involve the reproducibility of a given reaction or API synthesis route. The quality service level is a measure of the reproducibility of the quality of the isolated intermediate or final API. While the details of computing this value are slightly nuanced and unimportant for the purposes of this article, in essence, the calculation involves the ratio of satisfactory quality batches to the total number of batches. A reasonable QSL target is 98 to 100 percent.Process excellence index (PEI)
Like the QSL, the process excellence index is a measure of process reproducibility. Here, however, the robustness of the procedure is evaluated in terms of yield and cycle time of various operations. The PEI yield is defined as follows:In practice, if a process is high-yielding and has a narrow distribution of yield outcomes, then the PEI should be very high. Processes that are not easily reproducible may have a higher aspiration level yield and a lower average yield, lowering the PEI yield.
Similarly, a PEI cycle time may be defined as follows:
For this expression, the terms are inverted to reflect the desirability of shorter cycle times. The reproducibility of cycle times for critical processes such as reaction, centrifugation, or drying may be critical if these operations are rate-limiting in the manufacturing plant setting. For example, if an isolation step is particularly difficult or slow, it could become the bottleneck for API synthesis, in which case the reproducibility and optimization of that operation become critical.
For an API manufacturing process, all PEI metrics should be targeted at 98 to 100 percent.