Details in the Process Scale-Up That Are Easily Overlooked

Figure 1: Axichrom collaborates with ÄKTAprocess and Master for integrated column packing.

Many of the "surprises" encountered during the process scale-up can be anticipated. If attention is paid to certain details and simple experiments are conducted during small-scale trials, and if data is collected, it can greatly aid future scale-ups.

The glass flasks used in experiments typically don’t have corrosion issues (glass is not resistant to hydrofluoric acid or compounds that may decompose to produce fluorine, as well as hot concentrated alkalis). However, the compatibility of materials and reagents must be considered in production, which is also a requirement of GMP for equipment selection. If corrosion tests of materials are conducted during small-scale trials (by adding stainless steel or other material samples to the reaction system), it will save time when selecting equipment later.

A simple measurement of the cake density can help estimate the volume of the product cake in future production and assist in equipment selection, as the filtration speed, filtration area, and cake thickness are interrelated.

1.2 Typical Scale-Up Issues

The most common issue during process scale-up is a change in reaction selectivity, which can affect product yield and purity. This primarily stems from inconsistencies in mixing during small-scale trials and production. If the influence of stirring speed has already been assessed in small-scale trials, it will be easier to identify problems when they arise. The pilot plant’s reaction vessels are equipped with variable frequency drives to adjust stirring speeds as needed.

The emergence of new crystal forms during scale-up is also common. Additionally, problems can arise with product separation; the washing of the cake in production may not achieve the same effectiveness as in small-scale trials, leading to impurities not being fully removed. Equipment that integrates stirring, filtering, washing, and drying can sometimes replace centrifuges and can improve washing effectiveness.

Another reason for issues in scale-up is the impact of production operation times. It is crucial to conduct experiments during small-scale trials to assess the effects of prolonged times on products. In actual production, prolonged distillation times have frequently led to product decomposition and unwanted side reactions.

The causes of scale-up issues often stem from a lack of understanding of reaction mechanisms, crystallization, and mixing. As discussed, many problems relate to mixing and heat transfer; however, a fundamental understanding of chemistry is necessary: besides the main reaction, what side reactions might occur? Under what conditions could side reactions be promoted? What changes might occur during scale-up, and how will these changes affect reaction selectivity? In practice, the heat transfer conditions in current reaction vessels cannot be significantly altered (though controlling the heating/cooling media and temperature differentials within the vessel can help reduce localized overheating/cooling), while mixing can be improved through careful selection of stirring speed and blade design.

2.1 What to Do During Scale-Up

Team Collaboration: Close cooperation among professionals from different fields is essential for obtaining stable, scalable processes. Chemists possess deep insights into how various variables affect product quality, while process engineers have a better understanding of feasible and safe operations in production.
Principles of Process Development and Operation: Regardless of company size, basic rules must be established to ensure safe transfer of small-scale processes to kilogram laboratories and pilot plants. Clear and strict procedures must be established, and documentation must withstand pressure, even under time constraints.
Equipment Logbooks: Maintain operational and maintenance logs for major equipment (reactors, filters, dryers, pumps, etc.) in kilogram laboratories and pilot plants. Include batch records, cleaning logs, validation records, and other maintenance documentation.
Sample Database: Create a database to collect and organize data on each sample (products, wet cakes, distillates, process by-products), including production batch numbers, collection times, and analysis results. These data are of significant reference value.
Sample Preservation: As the sample database is established, a dedicated sample room should be set up to store samples, with attention to dryness, light exposure, and low temperatures.
Fixed Process: Identify and resolve related issues before trial production. Changing processes at the last minute before scale-up can be dangerous, leading to unexpected incidents and safety concerns.
Process Risk Assessment: Conduct a risk assessment prior to trial production of new processes, involving personnel from different departments to review process safety and preventive measures in detail.
Recognize Reaction Energy Risks: Insufficient awareness or failure to identify the hazards of exothermic reactions can lead to significant injuries and accidents. The heat transfer area per unit volume in production reactors is much smaller than in small-scale flasks. For example, a 500 ml flask has a heat transfer area of about 0.02 m², while a 4000 L reactor has only 10.7 m².
Establish Production Operating Procedures: The importance of production operating procedures cannot be overstated; maintaining the timeliness of these procedures and minimizing typographical errors is crucial.
Raw Material Experiments: Use industrial-grade raw materials and conduct small-scale experiments on all materials before scaling up. This helps eliminate raw materials as a potential cause of scale-up failures.
Seize Opportunities: Preparing for pilot production requires substantial labor, time, and money. However, limited data is often collected, which is why it is essential to maximize learning opportunities from every production batch. A detailed sampling and analysis plan can help complete mass balance calculations, identify unexpected by-products, and address other potential scale-up issues.

During the transfer of production, validation is needed. Prior trial production should familiarize the process, establishing operating procedures; if trial production goes smoothly, the validation time can also be shortened. The success of trial production relies heavily on the depth of investigation into process issues during small-scale and pilot phases.

2.2 What to Avoid During Scale-Up

Avoid Complexity: Strive for simplicity in process development and scale-up. The simpler the process, the fewer opportunities for errors. Simplification reduces production cycles and waste.
Avoid Heating All Raw Materials at Once: One of the most dangerous operations is adding all reactants at once and then heating. Similarly, avoid adding the catalyst after all the raw materials have been added.
Avoid Heating Without Stirring: The heat transfer within the reactor mainly relies on stirring. Good stirring reduces temperature gradients within the reactor and ensures accurate temperature readings.
Do Not Ignore Potential Decomposition Reactions: Avoid conducting reactions within 50°C of known decomposition temperatures of reactants to prevent runaway reactions.
Avoid Adding Solids to Hot Reaction Mixtures: Adding solids to a boiling or heated reaction mixture can be hazardous. Instead, consider dissolving solids before adding them to the reactor.
Avoid Evaporating to Dry: Using a rotary evaporator to concentrate to dryness is common in small-scale trials, but it poses risks in production due to potential overheating without proper stirring.
Avoid Underestimating Process Timing: Understanding that all operations will take considerable time is crucial. Stability assessments for raw materials, intermediates, and products should be conducted before scale-up.
Avoid Ignoring Solvent Issues: While solvents with good solubility and ease of recovery may be used in small-scale trials, some should be avoided in production, especially those with low flash points.
Avoid Neglecting Quenching and Extraction: Many scale-up issues arise from post-processing, so it deserves as much attention as the reaction process itself.
Safety First: Never risk completing the reaction with all raw materials at once. Prepare for potential failures, especially with new processes.

Conclusion

Experience is critical for timely and successful scale-up. Many excellent references are available for study and adoption. Although it's impossible to predict all surprises during the first scale-up, the considerations listed above will guide further thoughts on process development and scale-up, while recognizing the importance of collaboration will enhance the chances of success.