Chemical Industry Digest. July 2015

Continuous Manufacturing

In stark contrast to most chemical process industries, where contin-uous manufacturing is the perennial standard, the pharmaceutical industry has traditionally relied on batch processing for producing innovative products of extreme added value and societal impor-tance. For most other production supply chains, the low added value between raw material and product prices and the increasing cost of energy and labour necessitated high process efficiencies early on. The vanishing comfort of high profits in pharmaceutical markets has historically deterred the investment of effort in altering organic products syntheses and the switch from batch to continu-ous processes. Pharmaceutical industry profit margins, however, consistently diminish: R&D from initial discovery to product launch is far more expensive and time-consuming, and further pressure is induced by intense competition from generic manufacturers. A re-evaluation of pharmaceutical process synthesis is thus essential, and Continuous Pharmaceuticals Manufacturing emerges as a vi-able opportunity to streamline product development and simultane-ously improve process economicst.

Benefits of converting Batch to Continuous Processes

Dr Dimitrios I. Gerogiorgis

Dr. Dimitrios Gerogiorgis is a lecturer (Assistant Professor) in Chemical Engineering at the Institute for Materials and Processes of the University of Edinburgh, focusing on process systems modeling, design and optimisation. As a Postdoctoral Fellow at the Novartis-MIT Center for Continuous Manufacturing (MA, USA) he pioneered the model-based development and systematic evaluation of candidate continuous pharmaceutical flowsheets, and co-authored the first compara-tive economic evaluation of batch vs. continuous pharmaceutical manufacturing strategies. He has published over 30 peer-reviewed articles in journals and book series.

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Continuous Manufacturing

Chemical Industry Digest. July 2015

Continuous Pharmaceutical Manufacturing (CPM) has a very strong potential to address pressing profitability challenges but also ensure affordable

healthcare for growing populations. Continuous produc-tion methods can be scaled up faster and designed more efficiently in terms of both solvent and energy use, thus justifying the intense corporate interest demonstrated by several recent investments in production-scale fa-cilities. Exploring the constantly expanding limits of this emerging technology is a high research priority: the lit-erature abounds with candidate Active Pharmaceutical Ingredients (API) whose continuous flow synthesis and production-scale optimisation hold the key to success for CPM.

Current Pharmaceutical ManufacturingPharmaceutical processes can be split into two major

stages, known as the primary (upstream) and secondary (downstream) manufacturing: the former addresses pro-duction of the key molecule, known as the Drug Substance (DS), while the latter focuses on delivering the final for-mulation, known as the Drug Product (DP). The Active Pharmaceutical Ingredient (API) is the molecule with the desired pharmacological effects: it is produced in bulk through chemical or biological synthesis and purified via physical unit operations (crystallisation, drying, milling) and subsequently transferred to a secondary manufactur-ing facility, in which mixing one (or more) APIs with one (or more) excipients yields the final product formulation. Further physical processing (e.g. drying, size reduction/enlargement, filtration, sterilisation) may be performed. This final bulk product is then transformed into the final marketable dosage form (most frequently tablets, but also capsules, vials, tube/jar creams, aerosols) toward delivery to the supply chain.

Successful CPM of organic intermediates and/or APIs critically depends on technical advances in continuous flow synthesis, flow chemistry understanding and equip-ment development. Cost issues which affect economic viability are equally important though, governing how CPM is evaluated with respect to potential change in the industry (Behr, 2004).The economic viability of a drug product is determined using a number of factors, e.g. the total manufacturing cost, the selling price of the product, the marketing costs, and in some cases, the product and/or technology licensing costs. The key competitive edge of pharmaceutical corporations has been R&D and inno-vation: as drug discoveries steadily decrease and the mar-ket share of generics increases constantly over the past 40 years, companies now strive to improve process econom-ics in order to address a wide spectrum of threats and survive such relentless globalised competition.

Batch synthesis of complex molecules at both labo-ratory and production scale is an arduous procedure, in which long sequences of separate reactions are per-formed in large reactors, with purification steps conduct-ed between successive stages. This normally effective procedure is also extremely wasteful: the E-factor (waste-to-product ration) is as high as 25-100 for APIs, indicating that 25-100 kg of waste are generated for every 1 kg of complex molecule synthesised: the objective is thus not only to reduce the total number of chemical synthesis steps (reaction telescoping) but also improve individual yields, if possible.

The overall yield achieved in product synthesis is a key consideration in manufacturing economics. Traditionally, the yield from batch processes is poor, due to non-uni-form momentum, heat and mass transfer. A multi-stage process comprising 10 stages (each with a yield of 50%) is characterised by a very low overall yield of 0.1%. Raising the yield of each stage to 80% would only result in an overall yield of over 10%: the throughput is thus 100 times greater, necessitating smaller, less expensive equip-ment and reducing both capital (CapEx) and operating expenditure (OpEx). Additionally, higher yields will re-sult in lower solvent requirements and waste generation, thereby ensuring further cost-savings.

Manufacturing cost is a function of the number of synthesis steps: reducing the latter with more selective reaction alternative simplies fewer purification steps and more economical processes. Disruptive microreactor technology enables previously unattainable syntheses, which can now be implemented by employing novel pro-cess windows: allowing intensified process parameters (concentration, pressure, temperature) flash chemistry, in which hazardous reactions can be safely performed and highly unstable intermediates can be used in flow (Yoshida et al., 2008). Precise control of reaction residence time (< 1 s) can induce higher selectivity, which in turn has a direct bearing on production manufacturing cost: fewer purification stages and less equipment expenditure are required (lower CapEx), and less feedstock is wasted to by-product (lower OpEx).

Process control and Process Analytical Technology

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The gradual adoption of CPM concepts can result in process economic gain: CapEx sav-ings are attainable via fewer, smaller, cheap-er equipment and reduced footprint, which

are direct effects of reaction telescoping and novel process windows.

Chemical Industry Digest. July 2015

Continuous Manufacturing

(PAT) are of high importance: continuous flow reac-tors exhibit high interfacial areas due to the formation of liquid layers that are only a few tens of micrometers thick, with surface-to-volume ratios as high as 40,000 m/m(considerably higher than the traditional 100-300 m/m achieved in conventional stirred reactors). Very ac-curate temperature control is thus attainable, and exother-mic heat generated within the reactor can be dissipated quickly. The conventional, off-line qualitative/quantita-tive analysis (QA)relies on time-consuming sequences of neutralisation, phase separation and laborious chromato-graphic/spectrometric analyses.

Batch processes are inherently labour-intensive due to manual transportation of reactants to vessels for charging, discharging of products, and cleaning of process equip-ment. Replacing a batch with a continuous process results in very limited operator involvement, because only half of the labour resources are required in the new paradigm (Roberge et al., 2008).

Continuous Flow SynthesisCommon pharmaceutical syntheses include hydro-

genations, nitrations, fluorinations, oxidations and or-ganometallic reactions. Batch processes are hampered by several disadvantages: limited heat removal, high resi-dence times and vast solvent amounts used as heat sinks.

Continuous flow microreac-tors provide process inten-sification advantages (Losey et al., 2001): high mixing effi-ciency, effective heat removal and low process inventories are key for very fast, exother-mic and hazardous reactions. Several continuous flow (tube-in-tube, packed bed, microwave)microreactor types are available, accomo-

dating biphasic and triphasic reactions. Nevertheless, not all reactions can be conducted continuously: feedstocks, intermediates, by-products and products must all be soluble within the solvent, and well away from the likely precipitation range– otherwise, reaction channels will be blocked, with catastrophic reults. Hydrogenations are ex-tremely common in the pharmaceutical industry: these gas-phase reactions can benefit enormously from process intensification and the improved safety which is provid-ed by microreactor technology (Johnson et al., 2012).

Nitrations depend on corrosive and explosive nitrat-ing agents, being also prone to side reactions and waste generation: continuous-flow microreactor technology holds the promise of effective temperature control and small reaction inventories. Minimisation of reaction run-away risks allows the reaction to propagate at higher tem-peratures (Burns & Ramshaw, 2002).

Halogenations are ideal candidates for implemen-tation in continuous-flow microreactors (de Mas et al., 2003): contacting gas and liquid phases can occur in tube-in-tube microreactors, falling film microreactor and mi-cro-bubble columns: in all cases, large surface areas maxi-mise the contact between the two phases, thus increasing mixing efficiency. Organometallic reactions entail the use of highly unstable reagents: hence, theyare traditionally conducted at extremely low temperatures, with slow ad-dition of reagents to avoid temperature gradients and

possible thermal run-away within the reactor. Time-consuming, labori-ous and expensive pro-cedures threaten product uniformity due to unac-ceptable variability; nev-ertheless, microreactors can prevent off-spec pro-duction in quality-driven industry (Loh et al., 2012; Pedersen et al., 2013).

A significant body of

Figure 1. Comparison of batch and continuous pharmaceutical manufacturing stage/resi-dence times for an API.

Figure 2. Comparison of solvent use and waste generation in batch and continuous pharmaceuti-cal manufacturing.

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Chemical Industry Digest. July 2015

literature details the quest for continuous production of APIs and intermediates in order to replace batch with re-liable, superior CPM processes. Several continuous flow chemistry studies have been published, detailing the production of molecules such as ibuprofen (Bogdan et al., 2009), artemisinin (Lévesque & Seeberger, 2012) and 6-quinolone (Qian et al., 2010). A very extensive review article illustrates CPM for a wide range of other APIs (Malet-Sanz & Susanne, 2012).

Reaction KineticsMicroreactors do not perform new chemistry, but en-

able better, reliable reaction control chemistry. Hence, they are powerful tools for studying the intrinsic kinetics of highly exothermic and mass-transfer controlled reac-tions: plug flow and high interfacial are aeliminate mass transfer limitations, hot spots and concentration gradients (routinely encountered in conventional reactors) which that lead to suboptimal kinetic analyses. Zaborenko et al. (2011) conducted a kinetic study of a model amino-alcohol formation by epoxide aminolysis, reporting that a high pressure, high temperature microreactor enabled rapid and efficient kine, which reduced the time needed drastically for screening in comparison to carrying out the kinetic study in a batch reactor. The reagent amount required is drastically reduced, thus resulting in consid-erable savings. Due to the small reactor volumes, and the rapid thermal control, many different experiments can be run in quick succession in a wide range of concentrations, residence times, and temperatures: the repercussions for rapid process development and quicker release of a drug to market are obvious. McMullen and Jensen (2011) used an automated system for determining reaction kinetics, consisting of a Si microreactor embedded in a computer-aided experimentation framework for online kinetic pa-rameter estimation via model-based optimisation.

Economic AnalysisNumerous research studies highlight the incontrovert-

ible technical advantages of CPM over batch processes, but to this day very few peer-reviewed publications have quantitatively evaluated the projected economic perfor-mance benefits. Envisaging that the promise of higher yields and selectivities will result in lower operating (OpEx) and capital(CapEx) costs as a result of continu-ous operation is plausible, but a comparative evaluation of options is not a trivial task.

Roberge et al. (2008) conducted an analysis of two dif-ferent economic cases for a scaled-up reaction with an organolithium intermediate, producing up to 700 kg of product. The economic analysis did not address the pro-cess in its entirety (from raw materials to final product

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Continuous Manufacturing

Chemical Industry Digest. July 2015

Continuous Manufacturing

formulation). The first case studied represented the situ-ation where an intermediate is produced in close prox-imity to raw materials, at the beginning of the synthetic route. The second case studied a situation where the in-termediate is produced further down, much closer to the API, and economic benefits were identified by comparing three process routes.

Schaber et al. (2011) investigated the economic impact of operating a dedicated CPM plant using an organic key intermediate (KI) and three organic reactions to derive the API, toward subsequent tablet formation, at an annu-al blockbuster drug production scale (2000 tons) and sev-eral design parameters. The batch process was evaluated against four different variations of the CPM process (with and without recycle, and subsequent roller compaction/RC or direct tablet formation/DTF). The economic evalu-ation was conducted with varying KI cost (100-3000 USD/kg) and varying production yield (±10% vs. the batch pro-cess), and varying API loading of the tablet DP (10 and 50 wt%). Process flow diagrams for batch and continuous

API manufacturing are presented in Figures 3 and 4, re-spectively.

The highest production cost reduction is obtained for a switch from batch to CPM with recycle and DTF options. Depending on KI production cost, total (CapEx+OpEx) cost savings range between 9-40% when batch and CPM yields coincide, but increase considerably (19-44%) if the latter exceeds the former. Remarkably, total cost savings are still achievable even for CPM yield which is lower to that of the corresponding batch process, due to spec-tacular CapEx savings resulting from much smaller and cheaper equipment. The OpEx savings result from de-creased labour costs and lower water/solvent usage (61% and 21%, respectively), the decreased time-to-market, resulting from the ease of scale-up from laboratory-scale to full manufacturing that results from the use of contin-uous-flow equipment.

Seifert et al. (2012) conducted an economic analysis of modular CPM in comparison to multi-product batch manufacturing plants, identifying that the former results

Figure 3. Process flow diagram for batch pharmaceutical manufacturing of an API (Schaber et al., 2011).

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Chemical Industry Digest. July 2015

in a 30% Net Present Value (NPV) increase over the lat-ter: a further 35% NPV increase was obtained under the plausible assumption that construction can be completed within one year.

Scale-UpDue to slow product and process development, more

than half of the patent life can be lost before the drug makes it to the market. Once the patent protection ex-pires, the developer may lose up to 90% of market share to generic manufacturers within 12 months (Plumb, 2005): increasing the speed of delivery by decreasing R&D du-ration is hence paramount. Scale-up acceleration is thus critical toward increasing profitability. There are signifi-cant problems in the scale-up of traditional batch vessels, due to transport limitations in mixing, heat and mass transfer. Microreactors escape many pitfalls, hence rapid and efficient scaling up of novel pharmaceutical process-es can benefit tremendously from their implementation (Kockmann, 2011).

The production of pharmaceutical intermediates or APIs can vary from a few mg(initial testing, pharmacoki-netic studies), to hundreds of tons per year for a success-ful pharmaceutical blockbuster drug, Microreactors need to flexible in terms of product output. The most probable solution to dealing with such a large production range

Figure 4. Process flow diagram for continuous pharmaceutical manufacturing of an API (Schaber et al., 2011).

lies within a modular design of reactor, where the mass throughput can be increased by increasing the number of parallel channels within the multi-channel microreactor, or by using multiple microreactors. Poor material (esp. solid) flow distribution over parallel channels is a seri-ous problem, which can result in poor mixing, uneven stoichiometry, localised heat loads, fouling and reaction channel plugging. Symmetry-based hierarchical reactor design (single-channel reactor, multi-channel plate reac-tor, microreactor stack, multiplestacks) offers a conceptu-al, highly efficient scale-up procedure which retains high production-scale flexibility.

Microreactor scale-up must always consider operation (residence) time. Increasing the inlet pressure allows for greater pressure drop and higher flow rates along the mi-croreactor, while increasing the cross-sectional area of re-action micro-channels can also accommodate higher flow rates. Microreactor design optimisation is thus critical in order to ensure that momentum, mass and heattransfer processes serve simultaneously well the chemical reac-tion conducted. Mixing difficulties can be overcome by increasing the pressure drop along the microreactor and/or employing multiple reagent injection nodes, in order to prevent hot spots by spreading reaction heat genera-tion over a larger surface area. For higher capacity, in-creasing the channel size is favoured before resorting to

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Chemical Industry Digest. July 2015

Continuous Manufacturing

parallel operation of multiple reactor devices, due to the technical issues at flow splitting and merging nodes, and the expected impact on higher CapEx.

ConclusionThe benefits of continuous CPM over traditional batch

methods for manufacturing APIs and organic intermedi-ates have been presented by examining in detail the eco-nomic impact, chemical synthesis, and available reactor technology. Clearly, the gradual adoption of CPM con-cepts can result in process economic gain: CapEx savings are attainable via fewer, smaller, cheaper equipment and reduced footprint, which are direct effects of reaction telescoping and novel process windows. Concurrently, OpEx savings emerge due to increased productivity (higher yield-selectivity), reduced manpower, utilities and waste Microreactor use in CPM flowsheets enhances heat, mass and momentum transfer efficiency, and en-ables the employment of intrinsically fast, exothermic, and hazardous (e.g. Grignard, Reformatsky) reactions in an inherently safe manner, so that reaction conditions are reliably controlled, by-product formation is minimised, and higher product quality is consistently achieved. By using flash chemistry and novel process windows, pro-cess intensification can be achieved with high reliability and versatility:synthetic routes for CPM of key interme-diates and APIs can be telescoped, resulting in fewer reaction and separation steps, and more profitable pro-cesses. Kinetic analyses, process modelling and simula-tion (Jolliffe & Gerogiorgis, 2015), scale-up and plant op-timisation (Gerogiorgis & Barton, 2009) can be conducted rapidly to accelerate R&D, reduce critical time-to-market, and ensure the overall economic viability of the CPM pro-cess.

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