The digitisation of traditional pharmaceutical manufacturing
PROFESSIONAL SERVICES & BANKING
The pharmaceutical industry is at a critical point, facing rapidly evolving social, healthcare, technological, and regulatory landscapes, as well as more informed and demanding patient groups. In response to these pressures, leaner drug development pipelines and manufacturing processes need to be developed and implemented, with the goal of increasing product quality, process agility, and operational cost-efficiency.
In the context of chemical manufacturing technologies, there has been little de novo innovation. Instead, most new process solutions either build on existing techniques (e.g. flow chemistry and capsule filling) or repurpose know-how from other disciplines (e.g. 3D printing and hot-melt extrusion). The next generation of pharmaceutical manufacturing systems, however, will be more tightly integrated with digital technologies and process analytical technologies (PATs).
PATs range from quality and risk management tools to process monitoring tools, and are particularly relevant for improving process efficiency, adaptability, robustness, and scalability. PATs accomplish these improvements through integration with innovative manufacturing techniques and technologies, including continuous manufacturing and the expanded use of lab robots. The overwhelming amounts of data generated by PATs will require new cloud-based and intelligent data management systems, such as the Internet-of-Things (IoT) infrastructure, to be properly managed. In addition, the cybersecurity of these systems will need to be ensured, and could rely on innovations such as blockchain technologies to track and validate data generated from production processes.
The synthesis of small molecule active pharmaceutical ingredients (APIs) is usually achieved through flow chemistry. PATs will also be important in these applications, as this method depends on microreactor systems. PATs can help maintain rigorous control of reaction conditions, which is essential when performing unstable reactions or using potentially hazardous compounds.
New techniques used in the final stage of manufacturing or moulding pharmaceutical products—including 3D printing, hot-melt extrusion, injection moulding, and capsule filling—all possess certain benefits and drawbacks, but have the potential to meet the growing need for more personalised, on-demand medicines.
KEY INNOVATORS IN THE TECHNOLOGY AREAS
CONTINUOUS MANUFACTURING LEADERS
GEA Group AG (Germany) · Glatt GmbH (Germany) · Bosch Packaging Technology (Germany)
PROCESS ANALYTICAL TECHNOLOGY LEADERS
Thermo Fisher Scientific, Inc. (US) · Agilent Technologies, Inc. (US) · Danaher Corporation (US) · Bruker Corporation (US) · PerkinElmer, Inc. (US)
INTERNET-OF-THINGS (IOT) HEALTHCARE VENDORS
Medtronic Plc (US) · Royal Philips (The Netherlands) · Cisco Systems Inc. (US) · IBM Corporation (US) · GE Healthcare (US) · Microsoft Corporation (US) · SAP SE (Germany) · Qualcomm Life, Inc. (US) · Honeywell Life Care Solutions (US) · Stanley Healthcare (US)
BLOCKCHAIN SOLUTIONS DEVELOPERS
Abra (US) · AlphaPoint (US) · Amazon Web Services, Inc. (US) · Bitfury Group Limited (US) · BTL Group Ltd. (Canada) · Chain, Inc. (US) · Coinbase (US) · Digital Asset Holdings LLC. (US) · Earthport PLC (UK) · Factom (US) · IBM Corporation (US) · Microsoft Corporation (US) · Ripple (US)
PHARMACEUTICAL ROBOTICS DEVELOPERS
Kawasaki Heavy Industries Ltd. (Japan) · FANUC Corporation (Japan), KUKA AG (Germany) · Mitsubishi Electric Corporation (Japan) · ABB Ltd. (Switzerland) · Denso Corporation (Japan) · Seiko Epson Corporation (Japan) · Marchesini Group S.p.A (Italy) · Universal Robots (Denmark) · Yaskawa Electric Corporation (Japan) · Shibuya Corporation (Japan) · Atachi Systems (US) · Werum IT Solutions (Germany)
SMALL-MOLECULE API SYNTHESIS LEADERS
Pfizer (US) · Novartis International AG (Switzerland), Sanofi (France) · Boehringer Ingelheim (Germany) · Bristol-Myers Squibb (US) · Teva Pharmaceutical Industries Ltd. (Israel) · Eli Lilly and Company (US) · GlaxoSmithKline plc (UK) · Merck (US) · AbbVie Inc. (US) · Lonza (Switzerland)
FLOW CHEMISTRY LEADERS
Syrris Ltd. (UK) · ThalesNano (Hungary) · IMM (Institut für Mikrotechnik Mainz) (Germany) · Chemtrix (Netherlands) · DSM (Netherlands) · AM Tech (UK) · Uniqsis (UK) · Future Chemistry (Netherlands) · Little Things Factory (Germany) · Lonza (Switzerland)
HOT-MELT EXTRUSION MACHINERY PROVIDERS
Leistritz AG (Germany) · Xtrutech Ltd. (UK) · Milacron Holdings Corp. (US) · Gabler GmbH (Germany) · Coperion GmbH (Germany)
HOT-MELT EXTRUSION FORMULATION DEVELOPERS
Valeant (Canada) · Allergan (Ireland) · AstraZeneca (UK) · Merck (Germany) · Pfizer (US) · Reckitt Benckiser Healthcare (UK) · Novartis (Switzerland)
The Pharmaceutical Manufacturing Industry: Context and Trends
The pharmaceutical industry is undergoing major changes in response to challenges such as expiring patents, increasing healthcare costs, diversification of markets, global economic uncertainties, rapid development of emerging markets, progress in drug research, the increase in the production of generics, the high cost of medications, and aging populations. Consequently, pharmaceutical manufacturing processes must adapt to this rapidly changing landscape.
For decades, drug manufacturing was driven by a focus on strict regulatory frameworks that emphasised the safety and quality of the final product. Recently, there has been a change in mentality, with the aim of increasing the safety and quality of medications while also reducing manufacturing costs. This shift puts engineering principles and product design at the core of new developments in pharmaceutical manufacturing. Companies are moving away from batch manufacturing with its use of off-line product testing, and towards continuous manufacturing with an integrated quality by design (QbD) approach, based on a thorough understanding of the manufacturing process and its parameters.
There are two primary approaches to technological innovation in pharmaceutical manufacturing. The first involves improving on existing methods, such as hot-melt extrusion or capsule filling, and are classified as process solutions. The second approach is to introduce novel technologies or innovative solutions, or to combine novel technologies with a traditional manufacturing process to enhance its performance. This is the case of some traditional solid dosage formulation methods that can be combined with digital technologies to cut costs, increase efficiency, robustness, traceability, and safety, while also enabling the production of new types of formulations.
Drivers of Manufacturing Innovation
Continuous manufacturing (CM)
There are currently three main drivers of innovation in the pharmaceutical manufacturing industry:
Novel drug delivery systems require practical manufacturing processes. Other than the traditional solid oral dosage form, there is still a lack of scalable manufacturing solutions for novel delivery systems, such as controlled-release, nano-structured, or targeted drug delivery systems.
There is an interest in delivering more personalised and on-demand pharmaceutical products. Developments in the field of genomics during the past 15 years (e.g., sequencing a human genome now costs $1,000 instead of $100 million) and advancements in real-time diagnostic information have resulted in a shift from the traditional “one size fits all” approach to prescribing medicine. While demand for individualised medicine has grown, manufacturing methods are still not sufficiently flexible and customisable to enable the production of cost-effective personalised therapies.
In the search for high quality and cost-effective products, there is a general preference for continuous manufacturing (CM) processes. CM consists of the continuous flow of material exposed to integrated, time-invariant operations that are regularly monitored by in-line analysis tools or PATs which ensure that the finished products comply with certain required quality attributes.
CM has a number of advantages over batch manufacturing, such as versatility (faster process development using existing CM lines), response capacity (production quantities can be changed to correspond to current demand), flexibility (CM instruments are self-contained and can be shipped to wherever they are needed) and lower costs for the completed drugs. CM is also compliant with the goals of “green chemistry”; as it has because there is no need for intermediary compounds, CM processes have a smaller carbon foot print. CM processes can also reduce product waste, and lead to savings in terms of storage, transportation, and inventory costs. Moreover, the U.S. Food and Drug Administration encourages the adoption of continuous manufacturing.
The Global Market for Continuous Manufacturing
The global market size of pharmaceutical CM was $348 million in 2017 and it is projected to grow at a compound annual growth rate (CAGR) of 13.3% to $650.4 million by 2022. The continuous manufacturing market’s leaders include giants such as GEA Group AG (Germany), Glatt GmbH (Germany), and Bosch Packaging Technology (Germany). In 2017, GEA partnered with Siemens to introduce an integrated CM line for tablets which used GEA’s ConsiGma CM platform equipped with Siemens’ Sipat for PAT Data Management. Also in 2017, Bosch Packaging Technology launched a new integrated continuous manufacturing system called Xelum for the flexible and continuous production of solid pharmaceuticals.
Process Analytical Technologies (PATs)
In an ideal continuous manufacturing process, there are no intermediate products to test for quality assurance. While this is an advantage in terms of efficiency and cost reductions, it means that other monitoring systems are required to ensure that the process is operating correctly. These monitoring systems, called process analytical technologies (PATs), are commonly used as interfacing and sensor technologies to perform in-line process measurements. However, these technologies are ready to revolutionise a wider range of tasks that are critical for the design and execution of manufacturing processes:
Quality risk management (QRM) – QRM aims to identify and assess risks, in terms of the probability of a risk’s occurrence and the severity of the risk’s consequences, and to minimise and control the associated undesirable effects.
Design of experiments – Screening experiments are performed to investigate how certain parameters in the manufacturing process impact the quality of the final product. As these experiments can quickly become daunting and time-consuming tasks, it is important to reduce the number of variables considered and number of levels investigated. To make these kinds of decisions, approaches such as fractional factorial design, central composite design, and Doehlert design, are used to minimise the number of experiments required, and thus reduce testing time and cost.
Process modelling – Computational models are used to study the effect of process parameters, the variability of material characteristics, and any disturbances to the system’s behaviour. They are also useful; when optimising, scaling up, or transferring processes between equipment. Whole process simulations are rarely used, as the level of computational complexity required has only recently been achieved by software packages such as Parsival, SolidSim or gSolids. It is more common to divide the process in one of three systems:
Fluid flow is modelled through computational fluid dynamics methods such as RANS (Reynolds-Averaged Navier-Stokes), LES (large eddy simulations), DNS (direct numerical simulations) or LBM (Lattice-Boltzmann method).
Particle-based systems are relevant for many traditional manufacturing processes (e.g. blending, granulation, milling, compaction or tablet coating).
Material monitoring – The detailed characterisation of material properties is essential to understand how they will behave in a process. This usually entails thermal and rheological evaluations. Optical imaging, ultrasonography, positron emission tomography, computer tomography, solid-state nuclear magnetic resonance (NMR), synchrotron radiation, electron microscopy, X-ray computed micro-tomography, and optical coherence tomography (OCT) are among the most advanced techniques currently used to study material properties.
Process monitoring – Process measurements are performed by interfacing the materials from the process stream with a sensor or probe. Depending on where the analysis takes place, these measurements can be:
off-line, where analysis occurs on samples outside the process flow, which excludes the possibility of collecting real-time information from the manufacturing line
at-line, where a sample is removed at real-time from the stream for analysis
on-line, where material is removed from the process flow, analysed, and returned after analysis, which can pose risks to lines requiring sterile conditions
in-line, where the probe is inserted into the process stream, and the primary challenges are ensuring safe and antiseptic interfacing.
PATs can provide benefits in measuring and increasing manufacturing performance, productivity, and product quality. They also introduce new challenges into the manufacturing process, however, especially in terms of collecting, managing, analysing, storing, and visualising the vast amount of data they create. To efficiently handle the information generated by PATs, their integration with cloud-based technologies, such as the Internet-of-Things (IoT), will be necessary.
PATs Global Market
The global market size for pharmaceutical PATs was $1.77 billion in 2016, and is projected to increase at a CAGR of 13.3% to $3.3 billion by 2021. Some examples of PAT software vendors include U.S.-based company ICONICS and their Quality AnalytiX® software, which was launched in 2013. This real-time, Statistical Process Control (SPC) software provides users with a range of quality analysis tools, including those that make it possible to visualise SPC data from a broad range of sources, and others that are used to develop “signals” that can trigger corrective actions on the manufacturing lines.
Innovative Digital Technologies Applied to Pharma Manufacturing
The Digitisation of Pharmaceutical Manufacturing
The digitisation of the pharmaceutical manufacturing industry is still in the early stages. Most applications have focused on tagging samples with RFID chips, barcodes, or QR codes, to guide the sample’s flow through carrier systems, such as conveyor belts, in the production process. There are several other challenges that can be addressed with digitisation:
Globalisation – As the pharmaceutical manufacturing industry spreads internationally, it is becoming challenging for companies to track individual stock units and manage their regulatory compliance in different regions.
Supply chain complexity – Careful planning is required due to the increasing number of collaborators to the manufacturing process, including suppliers, contract manufacturers, distributors, and logistics partners.
Pricing pressures – Increasingly competitive markets demand lower prices for medicines and medical devices, and maintaining profitability while lowering prices will require more efficient manufacturing processes.
Personalised medicines – The growing demand for individualised drugs necessitates the development of cost-effective solutions for the production of small batches of drugs, and the accurate delivery of individualised treatments from the production lines to each intended user.
Transparency – With the recent increases in the number of counterfeit and black-market drugs, regulatory bodies are demanding greater scrutiny, transparency, control, and tracking of drugs after production.
In industrial and manufacturing settings, the Internet-of-Things (IoT) refers to machinery that is equipped with sensors which can collect data in real time. The data collected from all of the machines working on a particular industrial process or manufacturing line is sent to a central system. This central system then analyses the data received from the machines, and converts it into more meaningful information to display to the system’s end-users. IoT frequently involves using big data solutions, as massive amounts of information are collected and analysed during the normal operation of an industrial process like pharmaceutical manufacturing. In the pharmaceutical industry, IoT infrastructure can also help establish a company’s continuing compliance with local regulations, as all the data used to track the production of particular batches of products would be readily available in the manufacturing plant’s databases.
At the basic manufacturing level, IoT solutions can manage the processing and flow of production data between manufacturing execution systems (MES), PATs, and control automation systems. This more complex form of integration between systems could create completely automated and highly adaptable manufacturing processes. IoT could revolutionise manufacturing productivity in three distinct ways: (i) efficiency would surge as equipment downtime is practically eliminated, (ii) the near real-time analysis of process data would improve incident response times, and (iii) tight control on processing parameters and conditions result on less variability and thus higher quality product.
The Healthcare IoT Global Market
The global market size of healthcare IoT applications was $41.2 billion in 2017 and is projected to reach $158 billion by 2022, which would represent a CAGR of 30.8%. About 30% of the top twenty pharma companies—including Johnson & Johnson, Merck, and Pfizer—have adopted IoT technologies in their manufacturing processes at some level. For example, in 2013, Pfizer, GEA, and G-CON established a collaboration to develop a portable, continuous, miniature, and modular processing system, or PCMM. This self-contained and flexible modular system can cost-effectively process a range of APIs and excipients into both tablets and capsules, even for small batches, due to its integrated smart control systems.
Digital Pharma Solutions Innovators
Companies that specialise in digital solutions for enterprise resource planning (ERP) and improving the efficiency of operations include AlertEnterprise, Deacom, AX for Pharma, MAVERICK Technologies, Open Systems Inc, SYSPRO and Ultra Corporation. Two major corporations have also created digitisation initiatives; Siemens’ Digital Factory Division provides a comprehensive portfolio of hardware and software products that can integrate data gathered from product development and production systems, as well as from third-party suppliers, while Siemens’ SIMATIC IT Unilab laboratory information management system—which is compliant with US FDA and EU regulations—can be connected to existing planning, control, and execution systems to document the manufacturing and testing of drug batches. GE’s Brilliant Manufacturing suite also aims to connect digital information regarding product design, engineering, manufacturing, supply chain, distribution, and services into one global and scalable intelligent system. Plant Pulse Optimizer is part of GE’s Healthcare initiative is in use at five of its manufacturing sites. It is an intelligent solution that collects key performance indicator (KPI) data in real-time to measure production performance and efficiency.
Cybersecurity will be a significant concern for pharmaceutical manufacturers considering a greater use of automation on their production lines. For instance, if the data fed-back into a manufacturing plant’s process control systems was “hacked” (e.g., illegally accessed and altered), the consequences of such an occurrence could be disastrous. There are technologies that could prevent scenarios like this from happening, however, and one recent technology that could help secure the data from digital manufacturing processes is blockchain.
Blockchain is a technology solution originally conceived of for use with the electronic currency Bitcoin. A blockchain consists of inter-connected packages of information, and functions like a shared, regularly updated database. This blockchain database can be distributed securely, as the addition of another block of data to the chain requires the verification of authorised users. The system is also more resistant to efforts to corrupt or tamper with the data, as the blockchain’s records can be distributed, so there is no centralised version of the data to alter or destroy. If necessary, access to the blockchain’s data can also be controlled through permission protocols.
Blockchain's Future Market
The pharmaceutical manufacturing business relies heavily on compliance with regulations and industry standards. In this context, the robustness and incorruptibility of blockchain could provide a good solution for security, transparency, data integrity, and efficient data sharing between departments, collaborators, regulatory bodies, and manufacturing or supply chain partners. Blockchain could also play an important role in tracking individual product batches as personalised medicines become more mainstream. Blockchain technology is still in its early stages and its market value is projected to undergo significant growth. The global market size of blockchain (not specifically applied to the pharmaceutical industry) was estimated at $412 million in 2017, and predicted to increase at 79.6% CAGR to $7.7 billion by 2022.
Lab Robotics for Manufacturing Execution Systems (MES)
Lab robotic systems or manufacturing execution systems (MES) are used for a number of common applications in the pharmaceutical manufacturing industry, such as packaging operations (pick-and-place and labelling), transporting items between instruments (automated conveyor belts), and drug inspection and screening (often performed with Raman spectroscopy). Packaging solutions are the most widely adopted form of MES, and by 2018 robots are expected to handle 34% of primary pharmaceutical packaging operations in the US (e.g., vial-filling, syringe assembly and boxing). The global market size of pharmaceutical robots was estimated to be $64.4 million in 2016, and is predicted to grow at a CAGR of 13.2% to $119.5 million by 2021. The benefits of introducing robotic systems to drug manufacturing processes are significant:
Efficiency: robots can allow manufacturing processes to operate at greater speeds, reduce down-time, and save space on production lines.
Flexibility: robots can be programmed to perform complex tasks or several tasks in series, and can be adapted to perform various aspects of the manufacturing process.
Accuracy: automated movements can be precisely replicated, reducing a source of human error and sparing human operators from repetitive tasks.
Sterilisation: robotics that can withstand sterilisation procedures are ideal for cleanroom processes, as the risk of human contamination is eliminated.
Reliability: the elimination of sources of human error can result in more consistent levels of product quality.
Hazardous environments: robotic systems can be used to avoid exposing workers to harmful chemicals or dangerous activities.
Automated tracking and inspection: technologies are readily available to automate the evaluation of a formulation’s quality, including Raman spectroscopy, NMR, and high-performance liquid chromatography (HPLC).
Commercial scalability: readily achieved with lab robotics by expanding running times, increasing the number of execution systems, or even by reprogramming systems for faster operation.
Globalisation: robotic systems allow for new manufacturing plants to be set up around the world with minimal personnel training, validation, and little site-to-site variability.
Several types of robotic systems are becoming commonplace in the pharmaceutical manufacturing setting. Precise Automation’s SCARA (selective compliance articulated robot arm) PreciseFlex(PF) 400 allows operators to work next to the robot without barriers and even physically control the robot simply by moving the end of its arm. ST Robotics’ High Throughput Screening Cylindrical Robot is a 2-axis plate mover mounted on a track and can accurately move samples from one instrument to another in a smooth motion. EPSON Robots’ C3-V Robots reduces the costs of aseptic manufacturing and assembly by working within isolation barriers, which prevents contamination and protects operators from exposure to toxic substances. FANUC’s M-430i A uses a pair of multi-axis robot arms and a visual tracking system, and can lift 120 items per minute while moving along the conveyor belt during the manufacturing process.
Another type of robots relevant to pharmaceutical manufacturing are those that have been specially designed to operate in sterilised environments, or “cleanroom robots”. They are ideal for processes that require aseptic conditions such as vial filling and the manufacturing of biopharmaceuticals. To avoid the risk of microbial contaminations. Such robots are rated to operate in an ISO 5 atmosphere, meaning that the number of particles per cubic meter is limited to 100,000 for particles larger than 0.1 µm and 29 for particles larger than 5 µm. They are also designed to minimise particulate generation, to have minimal crevices where particles could accumulate, and are resistant to cleaning and sterilising agents. The speed and direction of the robot’s movement can even be programmed to minimise impacts on airflow and ventilation.
One example of a cleanroom robot is FANUC’s M-430iA/2PV, which can withstand hydrogen peroxide vapour sterilisation and has a waterproof rating, as all wiring is routed through the robot’s hollow arm. Promising research on cleanroom robots is being performed by Custom Automation, and Invetech that have partnered with the biopharmaceutical Argos Therapeutics to develop automated manufacturing platforms for personalised immunotherapies.
Innovative Chemical Manufacturing Technologies
Small-molecule API synthesis – flow chemistry
Small-molecule active pharmaceutical ingredient (API) synthesis or primary manufacturing consists of the chemical preparation of the API molecule itself and it is the first stage of the formulation manufacturing process. Here, the main challenges are:
Create a flexible process while avoiding cross contamination from different APIs.
Accurately documenting the preparation of raw materials (weighing, crushing, mixing, etc.) and the conditions under which the reactions took place.
Maximising the automation of the synthesis procedure for consistent and reliable production.
Optimising the manufacturing process by integrating all reactions and purification stages into a single process, from raw materials to the final API.
Most of these challenges can be addressed through the use of novel digital technologies for pharmaceutical manufacturing described in the previous section. For example, Siemens has created several systems that can be integrated to automate synthesis processes while maintaining maximum flexibility. including: SIMATIC PCS 7 DCS (a distributed control system), SIMATIC IT MES (a manufacturing execution system) and SIMATIC SIPAT PAT (process analytical technology software).
In use for more than twenty years, flow chemistry remains the most common approach for API synthesis. and involves using an array of flow reactors. Since it is a continuous process, it has high productivity and reliability at a reduced cost and a small footprint. This is an improvement over the former batch stationary reactors, which created intermediate products that had to be carefully dealt with, and posed the risk of creating batch-to-batch variations. There are four main advantages in the use of micro-reactors for flow chemistry:
Efficiency: The high surface-to-volume ratio of these systems enhances heat and mass transfer resulting in higher yields and fewer impurities. Corning Reactor Technologies has developed a series of Advanced Flow Reactor products for API synthesis that, compared to batch reactors, enable enhancements of 100 times in terms of mixing and 1000 times in terms of heat transfer, while also reducing operation costs by 30-40%.
Controllability: These systems operate under rigorous levels of control because the volume of reacting species is small and because of active process supervision provided by PATs. One of the most common types of sensors for process measurements are based on Fourier transform infrared (FTIR) spectroscopy. They can be conveniently integrated with flow systems by adding a thin layer of IR transparent material to the micro-channels. The IR spectrum of absorption and emission can determine chemical structure, product concentration, and presence of unstable species.
Unstable reactions: The high degree of controllability on mixing rate, temperature, pressure, flow rate, and residence time makes it possible to perform reactions that would otherwise be too dangerous. Some examples are highly exothermic reactions (hydrogenation, oxidation or nitration) or reactions requiring hazardous materials (halogens, cyanides or carbon monoxide). This creates opportunities for new types of molecules to be synthesised by flow chemistry. Novartis Pharma AG have created flow reactors for continuous bi-phasic liquid/liquid reactions under superheating conditions (above the boiling point of the solvent). This has far-reaching consequences, as it greatly widens the range of available solvents.
Scalability: It is simple to scale-up production by increasing the capacity of the microreactor channels or, in order to maintain flexibility, numerous micro-reactors can be set up to run in parallel.
The Small-molecule API Synthesis Market
To many, the recent rise in large molecule (biologic) therapeutics signifies a decline in the small-molecule API market, and a shift to more complex and mechanistically more advanced therapies. While the number of approved biologic drugs has increased, the small-molecule market’s growth has remained significant. For example, in the last three years, roughly two-thirds of all newly approved drugs were small-molecules.
The global market size for small-molecule API synthesis was $157.95 billion in 2016 and is predicted to grow at a CAGR of 6.3% to $213.97 billion by 2021, with the largest market segment being oncology drugs. It should be noted that 57% of pharmaceutical companies outsource clinical-scale API synthesis while 35% outsource the commercial-scale activities.
The Growing Market for Micro-reactors
The latest improvements in flow chemistry have focused on reducing the size of the pipes that control the flow within the reactors. In these systems, the chemical reactions occur as reactants are pumped and mixed continuously in the reactor’s sub-millimetre channels to yield a product. The global market size of chemical flow chemistry (not exclusively for use in the pharmaceutical industry) was $709.85 million in 2012 and is expected to grow at a moderate CAGR of 9.4% to $1.2 billion by 2018. However, the microreactor systems market is estimated to grow much faster, at a CAGR of 22.8% in the 2012-2018 period.
3D printing technology, and more precisely stereolithography, has existed for many years. It consists of creating geometric objects by fusing materials together one layer at a time, and enables the construction of a wide variety of complex shapes. Until recently, the pharmaceutical industry used 3D printing almost exclusively for the creation of custom prosthetics and dental implants. 3D printing is now finding use in the drug manufacturing sector due to its high precision, the ability to the leverage existing knowledge of the technology, and reductions in the costs of 3D printing equipment.
Complex architectural formulations can be designed for medical products with 3D printing, due to the great degree of control that the technology provides. Innovative drug delivery systems, more elaborate than the traditional dosage forms, could be accomplished with 3D printing. For example, solid oral pills could be printed in a sophisticated construct of layers with tightly controlled release profiles, or with a combination of APIs to treat multiple diseases simultaneously. The flexibility of this technology also opens new paths for on-demand, individualised treatments, and for orphan drugs. The ability to print various APIs in a single pill, the precise control obtained over the loading of specific drugs, and the relatively low production costs for small batches means that 3D printing holds great potential for the creation of personalised dosages. This opens the door for on-demand release profiles that vary according to the age and weight of each specific patient and the severity of their condition, or even the incorporation of all the drugs needed to treat a patient with multiple conditions in a single tablet. Another advantage over other formulation manufacturing methods is that the amount of stress or compressive forces applied during the process is extremely low, which can be important when working with delicate APIs.
The greatest drawback for 3D printing drugs is the slow speed of the printing process. A 3D printer can only print one tablet at a time, and the printing procedure can take several hours. To implement 3D printing on a commercial scale would require major investments (e.g., assembling a large “fleet” of 3D printers), and it may still take too much time to be cost-effective. There are also concerns about reliability; as each formulation is produced one-by-one in a non-steady state process, there could be significant variability in pills from the same batch, or even in the spatial distribution of API within a tablet. Another risk associated with normalising the 3D printing of drugs is that it could potentially exacerbate issues relating to counterfeit medicines. However, if it was paired with the digital technologies mentioned in the previous section, authenticity and traceability could be better assured.
The 3D Printing Market
The global 3D printing in medical applications market is predicted to reach $965.5 million by 2019, expanding at an extraordinary CAGR of 15.4%. In contrast, it was estimated to be one-third of that value ($354.5 million) in 2012. As of December 2015, the U.S. FDA has authorised more than 85 3D-printed medical devices. The first 3D printed drug approval did not take place until August 2015, however, when Aprecia Pharmaceuticals released spritam levetiracetam, a tablet to treat epilepsy. Aprecia used its proprietary ZipDose® Technology to produce a rapidly disintegrating, easier-to-swallow formulation.
Hot-melt extrusion (HME) has been in use in the polymers industry as an established manufacturing process for decades, but its use in pharmaceutical manufacturing is still quite novel. HME is the process of applying heat and pressure to melt raw materials and then force them in a mixture through an orifice in a continuous process, usually driven by one or two rotating screws. Sections of screws can be designed to perform different functions such as mixing, particle-size reduction, or conveying.
One of the main advantages of pharmaceutical HME is that enhanced bioavailability of poorly soluble drugs can be achieved by producing amorphous solid dispersions (ASDs) of the API in water-soluble polymers. Discovery of APIs with low crystalline solubility is a growing challenge in formulation development. Although there are other processes that yield ASDs, HME is particularly suitable because no solvents are required, avoiding the possibility of residual amounts of solvents occurring in the final formulation. HME can also be used to produce controlled release systems (through careful selection of the polymer), nano-formulations (by incorporating nanoparticles in the polymer matrix) or multi-API tablets through co-extrusion (simultaneous extrusion of several materials).
HME is a continuous manufacturing process with high levels of productivity and low levels of product variability, but should still be closely monitored by PATs to ensure the quality of the final products. HME is also a flexible and adaptable method that can be used to formulate a range of dosages or combinations of drugs in a cost-efficient manner.
For this application specifically, it would be valuable to introduce an IoT-based data management system for accurately tagging and tracking the different variants of a product produced together with a detailed account of the manufacturing processes that each batch went through.
As well as investment, research efforts are being dedicated to better understand the HME process and its parameters, including using simulations and experimental analysis by NMR, Raman, and IR spectroscopy, and to innovate around current techniques. For example, Baumgartner et al. produced solid nanoparticle formulations by combining HME with nano-technologies and Patil, et al. combined HME with high pressure homogenisation to produce solid lipid nanoparticles.
The Challenging Market for Hot-melt Extrusion
The global pharmaceutical HME market was valued at $26.6 million in 2015 and with a slow CAGR of 3.9%, it is predicted to reach $36.4 million by 2024. The reasons behind the slow adoption of this technology could include barriers to entry, as HME equipment is expensive and the market is already dominated by a few major players. There are a range of HME formulations currently approved and marketed, such as Lacrisert® (by Valeant, an implant for dry eye syndrome), Ozurdex® (by Allergan, for macular oedema), Zoladex® (by AstraZeneca, for prostate cancer), Implanon® and NuvaRing® (by Merck, a contraceptive), Norvir® and Kaletra® (by Abbott, for HIV), Onmel® (by Merz, for onychomycosis), Covera-HS® (by Pfizer, for hypertension and angina), Nurofen® (by Reckitt Benckiser Healthcare, an analgesic), Eucreas® (by Novartis, for type II diabetes) or Zithromax® (by Pfizer, for bacterial infections). Other companies, like Molecular Profiles Ltd (U.K.) have recently made significant investments into HME technology to promote formulation development.
Injection moulding (IM) is a similar process to HME, but mixing of the packaged materials is performed beforehand. Additionally, instead of a continuous process of extrusion, the mixed, molten feed is injected intermittently into shaping moulds under high pressure. IM is a common process in the polymer industry, and numerous parts of drug delivery devices and containers such as caps, seals, valves, syringes, and inhalers are made this way. It is common for a formulation to be prepared through HME, pelletised, and then fed into an injection moulder.
IM is advantageous because of its cost-efficiency and the fact that the number of products created per cycle, as well as their size, can be easily modified. This offers the flexibility necessary to personalise dosages easily by using moulds of different sizes, or by formulating combinations of APIs by feeding multiple drugs into the injection moulder. Well-defined and complex shapes can be accurately and efficiently generated, showing the process’s value for manufacturing new types of drug delivery systems.
IM is a semi-continuous process with high levels of productivity and low levels of variability product, but as with HME, IE production lines should be closely monitored by PATs to ensure the quality of the final products. PAT monitoring can also guarantee compliance with the Good Manufacturing Practices (GMP), allowing integration with an intelligent data management system to record the details of each product’s manufacturing process, and be able to track each batch on its path through the supply chain.
The Injection Moulding Market
The global market size for IM (not exclusively for pharmaceutical applications) was estimated at $168 billion in 2013 and predicted to increase at 5.3% CAGR to $252 billion by 2018. GSK developed a FlexTab technology based on IM to formulate unique capsule-shaped dosage forms that can be filled with a variety of materials including pellets, liquids, powders, and even separate liquid and powder APIs in the same tablet. This technology was acquired by Capsugel (Lonza) in 2011. Some companies such as Thermo Haake and Alba make lab-scale units, while Nissei and Arburg have made pilot-scale IM systems.
Capsule filling is an established process in the pharmaceutical manufacturing industry, but recently, it has been adapted to produce individualised, low-dosage drugs for oral delivery. Accurate low-dosage capsule filling is an intricate process, and only a few systems that can perform this task have reached technical maturity. The demand for capsules is expected to grow, as their outer coating prevents them from disintegrating in the gastric acids of the stomach, allowing them to release their contents in the small intestine, where the APIs can dissolve and permeate directly into the bloodstream. Capsule filling also has the potential to be used as an on-demand manufacturing method for personalised drug dosages and mixes.
As with any manufacturing process for personalised medicines, the ability to track individual batches or products is essential. This can be achieved through the use of PATs integrated with an IoT-based data management system that would tag each capsule and associate it (through an RFID tag, barcode, or QR code, for instance) with a data file that holds an accurate account of its contents, manufacturing details, authenticates its source, and ensures its delivery to the intended patient. Companies in the capsule filling market are devising new systems to improve this technology. Juniper Pharma Services provide a wide range of capsule filling solutions, such as drug-alone encapsulations, powder blend or granule formulations, controlled-release with multi-particulates, liquid or semi-solid formulations, and over-encapsulations, which enclose a solid dosage form in a capsule shell. MG2 has designed a micro-dosing system for low-dosage capsule filling that is ideal for API dosages from 0.5 mg to 20 mg, eliminating the need for excipients or bulking agents. The novelty of this system is that API quantity is determined by capacitance sensors as the electric field across a capsule varies while it is being filled. Capsugel (part of Lonza) created the Xcelodose® micro-dosing technology, adopted by major pharmaceutical companies. This fully automated system can quantify dosages down to 100 mg of powder accurately and with high reproducibility by continuously monitoring the weight being dispensed to fill gelatine and HPMC (hydroxypropylmethyl cellulose) capsules.
As pharmaceutical companies search for higher-quality products and reductions in the manufacturing costs for drugs, they are under constant pressure to innovate. Recent progress is due to the industry’s improved understanding of the underlying components and mechanisms in their manufacturing processes, and particularly due to the application of PATs to production lines. Another substantial source of innovation is the integration of emerging technologies into the industry’s well-established manufacturing infrastructure. This is true of five well-known and widely used manufacturing methods: flow chemistry, hot-melt extrusion, injection moulding, capsule filling, and, more recently, 3D printing. These technologies have been continuously optimised to increase robustness, accuracy, and cost-efficiency, allowing for the creation of more complex and better-performing drug formulations. However, if these methods were combined with novel digital technologies (such as the IoT, blockchain, and lab robotics), the impacts would be dramatic and wide ranging. Such integrated manufacturing systems could create safe, fully automatised, and cybersecure CM workflows, with minimal need for operator supervision or intervention. All the data pertaining each dosage unit produced would be associated with it throughout the manufacturing process, making it easy to comply with necessary GMP regulations, to avoid counterfeit products and, in the case of personalised medicines, to reliably track each dose from the production line to the intended patient.