February 2024 From the original article at Speciality Chemicals Magazine 

Landon Mertz of Cerion Nanomaterials looks at why batch still prevails in one area of the industry

At first glance, continuous manufacturing seems a modern-day marvel: a seamless and constant production method that, on paper, seems to promise efficiency, consistency, and reduced waste. And yet, the vast majority of industries remain anchored to batch processes, including nanomaterials.

Is this indicative of industries being mired in outdated practices? Or do underlying practical challenges cast shadows over the premise of continuous manufacturing? This article delves into the intricate factors guiding this choice, revealing a landscape far more nuanced than it might initially appear.

Nano & pharma

Nanomaterials and pharmaceuticals are tailored for different end products and have widely divergent price points, but they have remarkable parallels in their production methodologies. At the heart of both is a demand for absolute precision and control. Minor shifts in composition or structure can drastically alter the functionality and/or efficacy of the resulting product.

This underscores the importance of unwavering attention to detail in every production phase. Equally crucial is the commitment to rigorous quality standards. This is a pledge to drug safety and effectiveness for pharmaceuticals, while nanomaterials focus on attaining specific material properties.

As of 2022, 13 drugs were made by continuous manufacturing, a mere 0.03% of the over 19,000 prescription drugs approved in the US market. The statistics are similar across Europe and Japan.1,2 As a recent example, Pfizer transitioned Lipitor to a continuous process, but the experience was unsatisfactory. The CEO later said that to realise the full benefits from investments in continuous manufacturing, high-volume production was needed.3

Where continuous shines

Continuous manufacturing’s utility emerges in high-tonnage, single-product scenarios, such as ammonia, chlorine and various high-volume chemicals s. Its essence lies in the unbroken flow of raw materials through meticulously designed processes that consistently produce a finished product.

From an engineering standpoint, this is a marvel of design and efficiency. Economically, it demands high initial investment but promises reduced marginal costs over an extended timeframe. Establishing a continuous process requires an environment where the process can run undisturbed for prolonged periods, for multiple reasons.

Economies of scale are often driven not by improvements in raw material costs but decreased labour and energy usage. The method demands high capital expenditure for the design, engineering, installation, shakedown and accreditation of specialised equipment. The return on this investment is maximised only when the plant operates at a high capacity

Once a continuous process reaches its steady state, it can run optimally with minimal disturbances. However, reaching this state requires time and often consumes a lot of raw material. Thus, short operating times undercut the benefits of continuous processes. In a massive tonnage setting where the plant operates continuously, these start-up inefficiencies are diminished over the long run

Continuous processes can sometimes exhibit better energy-efficiency due to consistent operating conditions, especially where there would otherwise be high temperature ramp-up and ramp-down in a comparable batch process. This factor becomes significant in industries where plants run 24/7, leading to substantial energy savings

Lastly there is process control and consistency. A continuous plant offers consistent product quality due to the homogeneity of the process conditions. In single-product scenarios, this becomes crucial, as there is no room for variation in product specifications

Continuous manufacturing, despite its merits, has its challenges, especially when viewed through the lens of diverse product lines. Engineering a continuous plant is a precise endeavour tailored to a specific product. Altering this for another product can be capital- and time-intensive. Economically, this diminishes returns and challenges the feasibility of diversifying products in such set-ups

In addition, every hour a continuous process is not running is a significant economic loss. Engineering solutions can minimise downtimes, but the economic implications of operational disruptions are far more pronounced in continuous than batch processes

Why batch dominates

The transition from base chemicals to fine and speciality chemicals presents unique challenges and requirements. Base chemicals, often produced in massive quantities, are the building blocks, while fine and speciality chemicals are tailored for specific applications and hence demand a nuanced approach to production. Nanomaterials, a smaller subset of speciality chemicals, fall into this category.

Speciality chemicals amount to nearly 300,000 compounds, each with its unique properties, applications and production needs.4 According to EU data, a significant 86% of chemical compounds are produced in volumes of <10,000 tonnes/year, with 74% at less than <1,000.5

By most estimates, 85% of manufacturing in the speciality and fine chemicals market is done via batch processing. The very nature of these chemicals and the markets they cater to make batch processing an optimal choice, for many reasons.

Speciality chemicals often require intricate and multi-faceted synthesis processes, involving many different steps with dissimilar task times and processing conditions. Batch processing allows for this level of variability, enabling manufacturers to adjust for each stage of the process.

Speciality chemicals are also usually produced in small volumes tailored to specific demands. Batch processing is better suited here, allowing for efficient production without the need for continuous operation.

The speciality chemicals market can be dynamic, with fluctuating demands and new application areas emerging. Batch processing provides the flexibility to switch between different products quickly while avoiding extensive downtime.

Given the specialised applications of speciality chemicals, quality and purity are paramount. Batch processing allows rigorous quality control at the end of each production cycle, ensuring the product meets stringent standards. If an issue arises in one batch, it does not compromise the entire production run.

Many speciality chemicals are produced to specific client requirements. Batch processes can easily be customised to produce unique formulations or variants of a product, catering to each client’s specific needs.

Given the smaller production volumes and the diverse range of products in the speciality chemicals sector, the return on investment for continuous systems are often unjustifiable. Batch processes, often requiring lower initial investment, can be more economically viable

Unlike a continuous system, a batch process does not have to be designed for a specific capacity at inception. It is common to scale up a system to meet current and near-future market demand. If market demand accelerates, one can quickly scale out by duplicating production lines. This approach is often significantly more capital-efficient, especially when future demand is uncertain.

Finally, some speciality chemical reactions might be hazardous if scaled up for continuous processes. Batch processing can sometimes offer a safer environment by limiting the quantity of reactive chemicals in the system at any given time.

In essence, the unique challenges, and requirements of the speciality chemicals sector, ranging from the intricacies of the synthesis processes to market dynamics, make batch processing a fitting and often preferred choice for manufacturers.

Batch for nanomaterials

Nanomaterials are driving breakthroughs across diverse fields due to their inherent behavioural properties. The very features that make them unique – their minute size, enhanced surface area, and quantum effects – also make their synthesis complex. Not surprisingly, their manufacture has a strong predilection for batch processing, for multiple reasons.

Nanomaterials, by virtue of their size, exhibit extreme sensitivity to the conditions in which they are formed. The initiation of nanoparticle formation (nucleation) and their subsequent growth are critically dependent on parameters like temperature, concentration gradients and pH levels. Batch processing offers an environment where these conditions can be defined, controlled and replicated with high precision, ensuring the consistent nucleation and growth dynamics unique to specific nanomaterials

Many nanomaterials also require intricate processes where each stage demands distinct conditions. In continuous processing, maintaining the dynamic changes needed for each stage can be challenging. Conversely, batch processing allows for the isolation, purification and validation of intermediates at each juncture, ensuring successful transitions between synthesis stages tailored for nanoscale materials.

Given their heightened reactivity due to increased surface area-to-volume ratios, nanoparticles can in some instances pose specific safety concerns. Batch processes, in their enclosed design, significantly mitigate risks associated with nanoparticle exposure or unintended releases.

Techniques such as transmission electron microscopy, X-ray diffraction or spectroscopy are used to ensure the desired size, shape and properties are achieved in nanomaterials. Batch processing facilitates this by allowing a complete analysis of each batch, serving as a quality checkpoint and ensuring the unique attributes of nanomaterials are preserved and consistent.

The synthesis of certain nanomaterials involves precursors or reagents that can be extremely sensitive to external conditions like light, air or temperature fluctuations. The confined environment of batch reactors ensures the stability and efficacy of these precursors throughout the synthesis process, crucial for the desired nano-properties.

While the use of nanomaterials by industry is growing exponentially, many applications are still in nascent stages or cater to niche markets. The investment required for continuous production systems often is not justified by the demand or volume. Batch processes, on the other hand, offer modularity, scalability and adaptability tailored to the ever-evolving world of nanomaterials

While batch processing’s dominance in nanomaterial manufacturing arises from a confluence of factors, the unique challenges and requirements presented by the nanoscale play a central role. As the science of nanomaterials advances and as we continually push the boundaries of what is possible, the adaptability and precision of batch processing will remain invaluable.

Hybrid approach

However, there is always room for improvement. Hybrid batch manufacturing integrates both batch and continuous processing techniques, aiming to harness the strengths of each while mitigating their limitations.

By strategically employing each method at specific stages, manufacturers can achieve optimised results. Cerion Nanomaterials exemplifies this approach, adopting it in response to its customer base, which increasingly seeks enhanced processing capabilities and larger production volumes. The key advantages are integrating stages, flexibility, scalability, quality and control, and safety and environmental factors.

In hybrid systems, specific stages of a process might be continuous, while others remain batch-oriented. For example, a raw material could be processed continuously until a particular intermediate is formed, after which the material might be subjected to batch processes for final modifications and purification.

Hybrid systems offer operational flexibility. For instance, in chemical synthesis, the initial reaction stages are often more suitable for batch processing where the reaction conditions can be precisely controlled and adjusted in real-time, whereas subsequent post-processing of the nanomaterial, such as calcination, might be more suitable for continuous processing due to steady-state conditions, better heat management and improved yield.

Combining continuous and batch modes can also make scale-up more straightforward. The continuous stages can be scaled by extending operating times, while batch stages can be scaled by volume or through parallel batch units.

The continuous segments of hybrid systems can provide consistent quality due to steady-state operations. Batch segments, meanwhile, allow for tighter control over specific stages, accommodating processes that might be difficult to maintain continuously.

By integrating continuous processes where they are most advantageous, one can achieve reduced operational costs, better resource utilisation and potentially higher throughput. The batch stages can cater to processes that may not be economically viable to run continuously, due to upfront engineering investments, equipment costs, set-up times or intermittent demand.

Summary

While the broader narrative in speciality chemicals and nanomaterial manufacturing has been largely dominated by batch processing, it is important to recognise that there are always exceptions that challenge the norm. There are indeed certain materials that are effectively produced through continuous processes.

However, continuous processing remains an outlier in this domain. For a majority of speciality chemicals and nanomaterials, the complexities of their synthesis, combined with the need for precise control and adaptability, often render batch processing a more suitable, pragmatic and economically appropriate choice both for the manufacturer and more importantly, their customers.

References

1. An FDA Self-Audit of Continuous Manufacturing for Drug Products. US FDA, 31 July 2023. https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/fda-self-audit-continuous-manufacturing-drug-products#:~:text=At%20the%20start%20of%202022,finished%20solid%20oral%20drug%20products.
2. R. Chen et al., Bioprocess Online, December 2022: https://www.bioprocessonline.com/doc/where-do-we-stand-on-adopting-continuous-manufacturing-for-biologics-0001
3. K. Jhamb, Continuous Manufacturing in Pharmaceuticals: Implications for the Generics Market. Drug Development & Delivery: https://drug-dev.com/continuous-manufacturing-continuous-manufacturing-in-pharmaceuticals-implications-for-the-generics-market/
4. J. Pelley, C&EN, 12 February 2022: https://cen.acs.org/policy/chemical-regulation/Number-chemicals-commerce-vastly-underestimated/98/i7
   5. OECD Environmental Outlook for the Chemicals Industry, 2001: https://www.oecd.org/env/ehs/2375538.pdf