Continuous Processing: Is The Pharma Industry Finally Coming Round To The Idea?

Continuous processing is not a new concept. Outside of the pharmaceutical industry, in the petrochemical, chemical and food industries, for example, companies have been steadily switching their manufacturing operations to continuous processes, primarily for cost and quality purposes. The pharmaceutical industry has, however, been slower off the mark. Although there is a rising interest in the continuous processing concept, the industry, which is synonymous with batch manufacturing procedures, has been reluctant to take the leap. The typical 'watch and wait' approach that is often seen in the pharmaceutical industry, coupled with the reluctance to invest in new technologies, processes and personnel training are primary reasons for this lethargy. With manufacturers coming under increasing and continuing pressure to reduce costs and increase efficiencies, however, the appeal of continuous processing technologies is most certainly on the up.

(JOHN-FOXX/GETTY IMAGES)

To gain some insights into the industry's current view of continuous processing, to understand the challenges and the rewards of implementing continuous processing technology, and to gauge some opinion on its future role in pharmaceutical manufacturing, Pharmaceutical Technology Europe conducted a roundtable meeting of experts in the field.

Q. PTE: In your opinion, has continuous processing been sufficiently proven to improve manufacturing efficiency and reduce costs? If so, why is the pharmaceutical industry being so slow to adopt the technology?

Nepveux (Pfizer): Continuous processing has been proven in high volume applications where capital investment avoidance and/or incremental productivity improvements carry significant value. In the drug product arena, there have been fewer examples where continuous processing was employed because it affords improved quality or functionality to the product or process. In the drug substance arena, there are more examples where continuous processing supports chemistries that are more effective than in batch mode.

Kevin Nepveux

Schoeters (GEA): Continuous processing techniques are not so uncommon in the pharmaceutical industry as one seems to think. Certain unit operations, such as tabletting or roller compaction, are in fact continuous operations, which are handled in a batch fashion. Similarly, we believe that certain technologies have been successfully proven to manufacture more efficiently and reduce costs compared with traditional batch systems.

I believe there are a number of reasons why the industry has been quite slow to adopt the technology:

• General concerns about start-up and shutdown and waste related to these phases.

• Perception on limited use, for example, that it is only suitable for large volumes.

• Regulatory concerns.

• Installed base of existing (older) equipment in many companies, causing them to question why they should change.

All of the abovementioned concerns are, however, not an issue with certain continuous processing technologies. Further, switching from traditional processes in general does not lead to a big regulatory impact.

Weiler (SAFC): Continuous processing (including Simulated Moving Bed or SMB) has been shown to improve efficiency by generating less waste through solvent recycling, producing better volumetoyield ratios and, in most cases, it is more energy efficient. In addition to these economic improvements there are exciting examples of reactions that can be performed using continuous processing technology, such as fluorinations, direct oxidations, azideforming reactions, copperorganic chemistry, which have been impossible to scaleup in batch mode without dedicated expensive installations.

Further, all major pharmaceutical companies have been using classical continuous processing technologies for decades and today most of them are active in the field of multipurpose continuous flow process research. However, as the pharmaceutical industry is highly regulated, and most projects are covered by confidentiality, many applications are not immediately visible. We are convinced that in 5–10 years we will see a lot more continuous processes implemented.

Whitfield (Inprotech): Continuous processing is well established in other industries, such as food & drink, personal care & cosmetics, petrochemical, chemicals and household detergents, and is proven to significantly improve manufacturing efficiency and reduce costs, but it is much less demonstrated in the pharma sector. The theories point to similar efficiency improvement and cost reduction benefit potential, substantiated by pockets of successfully implemented continuous processing within the pharma industry, both within primary (API) and secondary (drug product) manufacturing. A greater level of adoption is still required before we can truly state that continuous processing has been sufficiently proven in our industry but the signs are nonetheless very encouraging.

There are many regulatory, technological, economical and philosophical based reasons for the slow adoption of continuous processing within the industry but fundamentally we should not forget an important fact. The key enabling technologies, which now make it possible to manufacture pharmaceutical products with the required high levels of process understudying, control and demonstrable capability, at the most optimum scale (throughput) for the majority of business needs, did not exist until relatively recently. That said the industry has undoubtedly been slow to embrace these evolving technologies and adopt continuous processing.

Q. PTE: Are there any areas where batch processing still holds advantages over continuous processes? If so, in what scenario and why is it more beneficial?

Nepveux (Pfizer): Batch processing can have advantages in smaller volume/batch size applications where the clinical and commercial manufacturing supply chain is already in place and largely depreciated. Capital investment to develop and install continuous processing technology in these situations can be a barrier. Another area where batch can have an advantage is with low-volume, high-value products where the amount of product lost while reaching steady state (and shutting down) has significant value. This can be countered with engineering solutions that minimise or recycle startup/shutdown losses.

Schoeters (GEA): The concept of a batch will still be applied for some time in the pharmaceutical industry. However, there is no reason why modern continuous granulation and drying processes cannot be used as a batch process. Our current technology, for example, has no start-up or shutdown waste, so it can produce for instance 10 kg, 200 kg or 1000 kg, whatever the product requirement. From this viewpoint, we only see advantages of the continuous process compared with the batch process, because a continuous process is a process that runs in steady state, making it much easier to monitor and control the critical quality attributes (CQA). In a batch process, the product is in a continuous state of change, making it much more difficult to rectify any deviations from the CQAs. For existing processes originally developed on a batch system, the drivers to go for continuous processing will be mainly related to cost and quality improvements.

Weiler (SAFC): With reactions that involve solid formation and long reaction times, it is more preferable to use batch processes if safety reasons allow. In addition, simple and small-scale reactions often do not justify the initial costs for microreactor technology equipment, the redevelopment of processes or personnel training and recruitment.

Pharma processes tend to be multistep, so even though it may be possible to make some of these stages continuous, batch processing will still be a part of the overall process, as with SMB, where only the enantiomeric separation is continuous.

Whitfield (Inprotech): In general terms, batch processing has long been considered to offer greater flexibility and versatility, with less perceived regulatory risk when compared with continuous processing. Within pharma, continuous processing has retained a reputation for delivering higher efficiencies, improved control but allegedly presents less flexibility, more process complexity and greater compliance risk. Hence, batch processes still prevail where there is uncertainty about products and processes, i.e., a lack of complete understanding, or indeed sensitivity that continuous processing will reduce manufacturing flexibility. There has also been a notion that continuous processes do not scaleup effectively, again highly debatable, especially when considered against the wellknown uncertainty of batch processing scaleup. I believe tremendous technology advancements have been made over the last 4 or 5 years to address all of these concerns, including the lack of flexibility and ineffective scale-up, such that for many applications continuous processing could now be the first intent process of choice.

However, for some applications there are still some technological barriers to continuous processing, whereby batch systems are still considered to be the only proven solution. In API manufacturing, for example, continuous isolation and drying technologies are not yet proven, although progress is being made in such areas as spray drying. In Oral Solid Dose (OSD) Drug Product manufacturing, where the chosen manufacturing route is high shear wet granulation with fluid bed drying, a commercially viable solution (GEA Pharma Systems' ConsiGma) has become available only in the last 2 years, at a scale (low volume) to efficiently support the majority of pharmaceutical products. Even now, a fully continuous tablet coater at this required low-volume scale, is not available on the open market place, although the launch of such a system (O'Hara Technologies) is slated for later this year. At higher volumes, more typical for OTC medicine brands and some generics, all the required unit operations are available in a continuous processing format and have been for many years.

Q. PTE: What challenges does implementing continuous processing technologies present? How can they be minimised or overcome?

Nepveux (Pfizer): As discussed earlier, I believe that start-up/shutdown of a process can present a challenge because of product loss at the beginning and end of these stages using continuous processing.

Kris Schoeters

Schoeters (GEA): If I call upon my personal experience with the challenges that I have witnessed with our own ConsiGma technology, when using this technology from Intermediate Bulk Container (IBC) to IBC ("batch mode") we believe — and this has been confirmed by regulatory authorities — there will be a small impact from a validation point of view. When switching to the full continuous ConsiGma tabletting line, including advanced process controls and real-time release, the challenge will be the (perceived) regulatory hurdle. This can, however, be tackled by working closely together with the authorities, such as FDA and EMA, during the development or transfer phase.

Weiler (SAFC): Solid formation in general can block the reaction channels and is difficult to overcome; this occurs in 5–10% of our new process developments. Further, although continuous processing is reliable and minimises total reaction time and work-up volume, experienced and specialised personnel are required to develop efficient flow chemistry protocols; this is not typically part of a chemist's current thinking.

Another issue that needs to be addressed is the lack of definition; if a continuous process is used in the pharmaceutical industry the definition of a batch size needs to be discussed and agreed with the regulatory authorities.

Moreover, implementing continuous processing requires a change in processes that have already been validated.

These factors present a challenge to manufacturers who are seeking to implement continuous process technologies. Long term this challenge will be overcome if the cost savings are sufficient to justify the process change and if the regulatory authorities are supportive in implementing continuous processes.

Whitfield (Inprotech): Fundamentally, I believe within many pharma companies, there is a philosophical leap of faith issue to be addressed, born principally out of regulatory and technology uncertainty. Additionally, one of the main challenges is that, after more than 20 years of megamergers and acquisitions, most of the Big Pharma companies have surplus batch-based capacity and an equipment asset base that requires compelling business cases to writeoff and replace with continuous process technologies. During these times of economic uncertainty and costcutting measures, such technology investment strategies have become even more demanding.

To reassure wouldbe company decisionmakers that these continuous processing technologies are robust and will deliver the welldocumented business benefits, there is undoubtedly a need for more evidence, probably in the form of active demonstrators. One successful, fully operational demonstrator system has been established by a UK-based consortium, called Advanced Secondary Pharmaceutical Manufacturing, which is part-funded by the UK's Technology Strategy Board. The consortium involves two key European technology vendors (GEA and Siemens), two UK universities (Newcastle and Warwick) and is led by GlaxoSmithKline. Using the continuous process operations of dispensing, blending, high shear granulation, fluid bed drying, continuous product evaluation and compression, tablets are produced from powders in tens of minutes, compared with typically tens of hours in batch-based OSD processes. The F3 Factory (EU-funded) project will deliver a modular, continuous chemical plant demonstrator at Bayer's Leverkusen facility, using advanced microreactor technologies, such as the Ehrfeld Mikrotechnik "MMRS" units.

Robust, compelling and also creative business cases, which strongly support the investment in continuous processing technology and the disposal of traditional batch-based assets, can be developed by adopting a more holistic, business-integrated approach, which considers not just manufacturing benefits but also those presented to R&D and commercial divisions. Technology value roadmapping, for example, can be utilised to enhance discounted cash flow business cases.

Q. PTE: From your experience, which areas of pharmaceutical processing have manufacturers chosen to convert to continuous processes as a priority? Why do you feel these processes have been prioritised and do you believe industry should readdress their priorities?

Nepveux (Pfizer): High volume, common unit operations — roller compaction, high-shear wet granulation, tablet coating, etc. — have been prioritised by manufacturers for continuous processing. I think the opportunity is in identifying unit operations where continuous processing is inherently better than batch in terms of product quality or functionality.

Schoeters (GEA): As we are a manufacturer of granulation, drying and tabletting equipment, we have of course seen the most activity in this field. Continuous processing technologies have proven popular for either new products or products that are suffering from batch-to-batch variability (quality issues), scale up-issues, manufacturing problems, all leading to high risks and cost implications. Having read literature and online discussions on the topic, it is clear that there are also big changes ahead in favour of continuous processing for primary pharmaceutical production.

Weiler (SAFC): Continuous flow chemistry is growing in favour amongst pharmaceutical manufacturers, particularly in more challenging manufacturing cases, such as:

• Synthesis with changing product profiles – continuous processing allows much better control of reaction parameters, such as temperature, often achieving a more consistent product profile.

• Processes with safety issues – the small reaction volume in continuous processes allows the running and scale-up of exothermic reactions that could not be run without special equipment or precautions in a batch process.

• Thermally unstable intermediates – reactions can be scaled-up where thermally unstable intermediates are formed and continuously get converted into product.

• Cryogenic reactions – Because of the excellent surface to volume ratio and the short reaction time, many continuous reactions can be performed with a better temperature control and higher reaction temperatures than in batch mode. There are several continuous reactions which can be continuously performed at 0 to 15 °C where very low temperatures (-40 to -78 °C) are required in batch mode.

Whitfield (Inprotech): Many pharma and chemical intermediates companies have seriously considered continuous processing for the manufacture of small molecule APIs and several have successfully implemented such technologies for certain unit operations, including mixing, reaction and crystallisation. However, a fully integrated continuous processing system, for all the typically required unit operations, has yet to be industrialised, as far as I am able to ascertain. More recently several pharma (ethical and generic) companies have invested in dry or wet granulation and drying continuous processing systems. However, secondary manufacturing is playing catch-up, as drug product continuous processing is not as exploited as it is for drug substance manufacturing.

There are tremendous benefits that can be realised through the adoption of continuous processing for APIs, including greatly improved mixing and chemistry; increased yields, efficiencies and process safety, which are largely born out of the vastly superior process control capabilities. Moving to micro or meso scale systems hugely impacts on the factory footprint requirements, delivering significant capital savings for new build projects but not so beneficial for retrofits, which are more common in the industry right now.

Similarly for secondary continuous processing applications, improved process control, greater utilisation of equipment, floor space and resources, delivers unquestionable operational cost benefits. There is clearly now a move more towards the application of continuous processing for drug product manufacturing and some companies are even developing a fully integrated primary and secondary manufacturing capability. I believe this is ultimately the right approach to maximise the holistic benefits of continuous processing.

Q. PTE: What continuous processing technologies does your company specialise in?

Nepveux (Pfizer): At Pfizer, we have active programmes in dry and wet granulation, tablet coating, and several API process stages.

Schoeters (GEA): We specialise in continuous dispensing, dry blending, wet granulation, melt granulation, drying, tabletting and coating.

Weiler (SAFC): At SAFC, we specialise in continuous liquid/liquid synthesis, SMB and thin film evaporation.

Whitfield (Inprotech): As a pharmaceutical engineering consultant and as a direct consequence of my previous "Big Pharma" experience, I have tended to focus on secondary manufacturing applications. However, more recently, as I aim to provide fully integrated solutions for clients, I have been concentrating on the continuous flow or microreactor technologies for small molecule API applications. There have been some exciting developments in this technology area during the last 2 or 3 years that offer the pharmaceutical industry alternative continuous processing options for API manufacturing.

Q. PTE: What process and/or cost improvements have you witnessed with these technologies so far?

Nepveux (Pfizer): On the drug product, side, the paybacks have generally been modest in terms of incremental yield improvement and productivity increases. Unfortunately for continuous processing, there is plenty of excess capacity for traditional, small-molecule processing so capital avoidance is not a powerful driver. If the situation were different, I would expect to see more successful installations.

Schoeters (GEA): We have a number of case studies, which will allow me to explain the different benefits that we have witnessed with continuous processing technologies so far:

Company 1

This company opted to install our ConsiGma technology primarily to help them reduce costs, not only initially, but also in running costs. ConsiGma is a small unit that can be easily installed in existing pharmaceutical production rooms, avoiding the need to invest in an expensive change or extension of the production. It requires only a minimal continuous amount of utilities and avoids energy consumption peaks. Finally, because of continuous on-line monitoring and feedback techniques, generation of out-of-spec materials is kept to a minimum, thereby reducing the generation of toxic waste.

The business case was made for a 1.5 billion tablets/year production. The overall investment cost (building, GMP–space) was two-thirds less than what the cost would have been with conventional technology, only 30% of the manufacturing space was needed, quality costs were drastically reduced (50%) and yield was raised by more than 0.5 %.

Company 2

This company chose to install ConsiGma because there is no need for scale-up with this technology, and thus it can produce any batch size. This attribute was particularly important to this client, who regularly switched between R&D and production batches.

Weiler (SAFC): Most continuous liquid/liquid reactions can be performed at much higher temperatures, delivering an improved product quality so that additional work-up steps, such as distillation or crystallisation, can be avoided.

Andreas Weiler

If chiral phases are used, SMB is not cheap initially but it is often the only method to separate two enantiomers and the better the solvent recovery works, the more significant the reduction in running costs.

Finally, because of the short contact time, we have seen that thin film evaporation can be a cost efficient process for continuous separation of thermally unstable mixtures.

Whitfield (Inprotech): I have worked on two separate OSD continuous processing projects, one at approximately 250 kg/h and the other at 25 kg/h, one for an OTC tablet and the other an Rx tablet, both delivered significant operational benefits when compared with the traditional batch approach. In both cases the factory footprint required was only 20% of that required for the traditional batch approach. Additionally, for the Rx tablet process, two of the dried granule Critical Quality Attributes — moisture level end point and particle size distribution — were incredibly reproducible with very low variability compared with the equivalent, existing batch process.

I have also been involved in a project that delivered a fully continuous process for the manufacture of a toothpaste product at one-tenth and full commercial scales, which again realised highly compelling business benefits versus the existing batch-based process, including a six sigma process capability.

I am also aware of a continuous process for API manufacturing that simplified an extremely complex synthesis route and delivered a reaction chemistry solution that was not achievable by conventional batch reactor technology.

Q. PTE: What are your predictions for the role of continuous processing in the future of pharmaceutical manufacturing and to what extent do you believe batch processing will be used?

Nepveux (Pfizer): Continuous processing will continue to be attractive for large-volume, high-throughput applications, although I think there will be a limited number of these targets going forward. I believe continuous processing will be successful where it offers quality and/or functional advantages over batch processing and we've only just begun to explore this area. Also, to the extent that cost-effective, modular continuous processing platforms can be developed for smaller-volume applications, I think it will compete effectively with batch processing.

Schoeters (GEA): We believe in a strong growth for continuous processing initially in the so-called IBC to IBC approach. Also, more melt granulation formulations will be produced using continuous technologies. Initially, the full continuous tabletting lines will be implemented and considered in specific business cases.

Weiler (SAFC): I do not believe that continuous processing will replace batch processes but it will serve as an additional tool to solve problematic cases in terms of safety, process reliability and yield. Cost cutting will be possible only if the manufacturer already has a wide range of equipment and skilled/experienced personnel in-house. Further, I think that using flow chemistry earlier on in the drug development process will significantly shorten the time to market for new API's.

Overall, I believe that greener processing, which is associated with less waste and more recovery, will mark the future of pharmaceutical manufacturing and continuous processing will have a key role to play in realising green processing. Although most continuous processes still use traditional batch work-up procedures, if the entire downstream process can be performed continuously, we will see even greater economic benefits.

Whitfield (Inprotech): Moving from batch-based technology to continuous processing technology is a true paradigm shift, which some companies will make quite readily as they recognise the potential benefits and advantages whilst others will take a more conservative, step-by-step approach. Undoubtedly continuous processing will be the development and manufacturing process of choice for many pharmaceutical drug substance and drug product applications but unlikely for all. I expect there will be some scientific and technological hurdles that will remain difficult to surmount for some time to come, which will necessitate a batch-based solution; although I am confident that batch processing will become the minority at some point in time.

Shawn Whitfield

For me, one of the most compelling justifications for switching to continuous processing is that proven systems are available that offer fully integrated, modular and/or scalable, easily portable capability, for a wide capacity or throughput range; equally as applicable to R&D and manufacturing requirements. As such, it will deliver superior product and process understanding, control and compliance, thus facilitating real Quality by Design aspirations.

Moderated by Fedra Pavlou Pharmaceutical Technology Europe

Roundtable participants Kevin Nepveux Vice President, Global Manufacturing Services at Pfizer.

Kris Schoeters Product Manager — Continuous Processing at GEA Pharma Systems nv.

Andreas Weiler Global Business Director at SAFC.

Shawn Whitfield Director at Inprotech Pharma Consultancy Limited.