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Process Chemistry Goes Beyond Scale-Up

IEmployee@U2t’s a common misconception that process chemistry refers strictly to process scale-up. While it’s true that process chemistry is a crucial component of optimizing the scale up of an active pharmaceutical ingredient (API), its utility stretches far beyond. More importantly, it plays a role across the drug development & commercialization cycle.

Input at the Design Stage…

Process chemistry input at the design stage can lead to process improvements, better yields and shorter development paths. While each product tends to be distinct, they each utilize many common or related chemical processes.

The objective of process chemistry is to gain an understanding of the factors that can control the outcome of the chemical process and predict what will occur when process changes are made. Bringing process chemistry experience to bear early in development can help determine broad paths to follow, and forms the basis for a more in-depth knowledge of a compound’s characteristics.

…Can Impact Final Product Traits

Many process chemistry decisions made earlier in development have far-reaching consequences. Crystallization, for example, can impact product dissolution rates, bulk density, compressibility and flowability. Incremental improvements in crystallization directly influence the overall efficiency of the process, its reproducibility, yield, and final product quality.
3 Elements of Process Chemistry Design

Common process design procedures consist of three basic elements: input → output streams, recycle systems and separation systems.

  1. Optimizing the Input Output Stream
    Process chemistry
    design begins with a broad concept of the input and output streams. Note that each reaction leading to a drug intermediate also has input and output streams. Optimization requires building comprehensive knowledge of the role of each reactant and intermediate, and the ideal environmental conditions for their use and production.
  1. Adding Recycle Systems for Process Chemistry
    Although the aim of each reaction is complete synthesis of the input molecules into the intermediate or final product, in reality one or more of the components will likely be in slight excess to drive the reaction in most situations – especially at larger scales.After separation of the unreacted or partially-reacted input molecules from the desired intermediate or product, these unreacted or partially reacted components can be harvested and recycled. In some cases, they may form part of the input stream in the next batch of the reaction, at a “recombination point.” I’ve written before about some of the EHS implications for reducing output streams. Recycling of these partially-reacted input molecules reduces waste and can be cost effective.
  1. Separation Systems
    Separation systems depend on the distinct properties of the unreacted or partially-reacted components and the desired product or intermediate. Common techniques include distillation, absorption, adsorption, membrane processes, and Optimization of each separation step improves quality and can improve profitability.

Knowledge of Equipment, Control of Parameters a Must
Equipment can fail, and chemical reactions can proceed too slowly or in an uncontrolled manner. Process chemistry can predict the “weakest link(s)” in the synthetic process and indicate the steps most likely to benefit from extra monitoring. Experience with each piece of equipment and reaction type contributes to the preventative mind-set and the remediation process.

Since some chemical reactions require specific environmental conditions (e.g., temperature, humidity, pH), tight control of these parameters can help maintain consistent yields.

Defining the Process Chemistry Procedures

Process chemistry procedures need to be well understood and easily scalable. For each well-characterized API production project, process scientists will identify and possess a clear understanding of:

  • kinetic reaction(s) optimization
  • all critical sources of variability (critical process parameters, mechanistic insights)
  • potential variability, and methods of control
  • the design space for materials, the process parameters, the equipment for manufacturing, and the necessary environmental controls to provide  efficient large-scale manufacturing
  • potential “weak links” in the API production scheme.

Optimizing API Production with Process Chemistry Insights

Good decisions in process chemistry are founded on appropriate whole process representations, sufficient understanding of key operations, and detailed performance metrics. Decisions may require specialized techniques and data that foster comprehensive perspectives on the API production process. Broad experience in API production can provide a foundation for problem-solving and suggesting solutions.

The key to improving performance is to consider process understanding as an important value-add. While each step requires a predefined series of development tasks, most benefits accumulate from integration of process chemistry throughout the API synthesis process rather than focusing on the perceived “weak link” incidental product or intermediate.

 

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