Having spent many years working on powder metallurgy (PM) and atomisation, it is very heartening to see the current remarkable upsurge in interest in the field. The ‘classical’ PM sintered parts business did not attract much research interest in the UK in the 1980s and 1990s, but the last twenty years have seen first, the advent of MIM and HIP and, more recently, AM or three-dimensional (3D) printing (1). These have, over the last ten years or so, led to a huge upsurge in research and industrial investment in PM all around the world. These newer branches of PM make quite different demands on the metal powders that they employ. The global volumes of powder consumed are still modest compared to the ‘classical’ PM parts business which accounts for ~1 Mt yr^–1 of Fe powder (1), but they have growth rates in tonnage terms of 10–40% per annum and high powder values (typically in the range of €7–200 kg^–1 compared with Fe powder’s €1–2 kg^–1 (2). Thus there has been a major upsurge of investment in plants to produce such high value powders. However, production capacity for vacuum melted, gas atomised powders is only around 20,000–30,000 tonne yr^–1.

The newer technologies have certain features in common, so far as powder quality requirements are concerned, but also some very major differences. The MIM process (Figure 1) consists of blending powder with plastics or waxes, injection moulding oversize parts, removing the binder (debinding) and then sintering the part to full density.

Fig. 1.

This requires, above all, fine powders, in order to have the required high degree of sintering activity to allow the green part to be sintered to high density. Typical powders have (mass) median particle sizes of 5–15 μm with maximum particle sizes from 15 μm to 50 μm. The shape of the powder is not a clear-cut demand; high tap density is desirable to reduce shrinkage (typically ~15%) when sintering to full density, but excessively spherical and smooth particles can reduce ‘brown strength’ which is the strength of the components after debinding. Purity demands are moderate, for example oxygen content is not critical, as high temperature sintering allows reduction of most oxides. Alloys include low alloy steels, a lot of stainless steels (~50% of the market) and some superalloys like IN718. Water atomisation is widely used for stainless steels, but the superalloys demand vacuum inert gas atomisation (VIGA).

The HIP process (Figure 2) consists of filling shaped metallic containers (‘cans’) with powder, which, after evacuation of air and sealing, are hot isostatically pressed, typically at pressures of the order of 1000–2000 bar and temperatures of 1000–1200°C.

Fig. 2.

This demands a reproducible and high tap density to reduce shrinkage (typically ~10–15%) in pressing and excellent sphericity and smoothness are most desirable to assist in filling shaped cans. Purity is vital, as no changes in oxygen content are possible in HIP. Thus gas atomisation is almost mandatory for this. Particle size is a secondary consideration, although for critical aerospace applications, fine powder, typically <53 μm, is used to ensure no inclusions above this size are possible. Alloys used range from stainless and tool steels to superalloys.

The AM field is rather more varied in its demands, as there are several major processes in use or under very active development (5). The biggest area now is laser sintering, which has various names, but is shown in Figure 3. This demands powders with excellent flow properties, to help spreading of powder into thin layers before sintering, or more accurately welding, the shape of the part to be made. The oxygen content is of interest; while some attempts have been made to use water atomised powders (7), gas atomisation dominates this field. A very important feature is that particle size is tightly restricted to a range variously set as nominally –53 + 20 μm or –45 + 15 μm. Thus the yield in this narrow size range has a major impact on powder production costs.

Fig. 3.

There are other AM processes, which have attracted a lot of attention in the last decade. These use ‘MIM–grade’ powders. One is binder-jetting (Figure 4), where the shape is generated from layers of powder glued together by a binder printed onto each layer of powder.

Fig. 4.

Another method is a variant of the very commonly used filament deposition technology where a filament of plastic is heated and welded onto a base plate to build the part. In this case, the filament of plastic is loaded with MIM-grade metal powder to a high degree, so that the deposited part resembles a MIM part. In both these cases, the machine does not make finished parts, but feeds a sintering operation where the binder or plastic is burned out and the part sintered to high density (with high shrinkage). The main requirement of these processes of AM are very similar to MIM, although ‘spreadability’ is needed for the binder jetting process.

Atomisation is the breakup of a liquid into a fine spray. If done on a molten material, the resulting spray commonly freezes into powder. There are many ways to atomise metal (8), but for the modern manufacturing methods discussed here, the only processes widely used are water and gas atomisation. There is also a combination of these methods, in ultra-high pressure (UHP) water atomisation (7). For all atomisation techniques, the surface tension of the alloy processed is an important determinant of particle size and it is generally found that if Alloy A makes particles with size x% of Alloy B when atomising with one technique, a similar relationship will exist for another. Thus tin is very easy to make as 10 micron powder, but steel is much more difficult.

3.1 Gas Atomisation

3.2 Electrode Induction Gas Atomisation

3.3 Plasma Atomisation

3.4 Water Atomisation

3.5 Ultra-High Pressure Water Atomisation

The interaction of the demands of the different advanced manufacturing methods of MIM, HIP and AM; and the alloys to be processed, with the characteristics of the major atomising techniques described above, naturally determine the optimum choices for powder production.

For all techniques, yield of powders of the correct size is a vital economic factor. Thus for MIM, the chief concern is to have a very fine powder to promote high sintering activity. Typical specifications call for a median size of ~10 microns with a D90 of 20–30 microns. UHPWA can provide such a powder with a yield of 70–80% from the atomised powder. Gas atomisation struggles to provide more than a 50% yield. Furthermore, one of the main rationales of employing inert gas atomisation, the achievement of low oxygen content, is of less interest for many alloys, particularly stainless steels (~50% of the market), due to the possibility of reducing many oxides in the sintering stage. Thus gas atomisation is most popular for superalloys with less reducible oxides. For HIP, which does not restrict (in many cases) the minimum particle size, nor demand a very fine maximum size (perhaps 100–300 microns) yields are very high, in the range 80–98%. For AM using lasers, which demand a tight distribution typically with max/min ratio of 2.5–3, the breadth of the distribution is critical. Atomised powders generally follow log-normal statistical distributions and can have standard deviations from 1.8 to 2.5 or more. The difference in yields in a 3:1 size range is very great. For 1.8 standard deviation (theoretical, 100% efficiently screened) yield can reach 64%, while at 2.2 standard deviation it falls to ~51%.

A further important factor is flowability. This is affected by particle shape, which is greatly affected by ‘satelliting’ where smaller particles adhere to larger ones.

Figure 7 and Figure 8 show the effect of an efficient anti-satellite system in gas atomisation (10). This can greatly improve apparent density (for example from ~3.9 g ml^–1 to ~4.5 g ml^–1 for 53/20 nominal powder) and make the difference between no flow and ~13 s 50 g^–1 hall flow rate. Thus gas atomisation with efficient anti-satellite provisions is definitely preferred for all processes demanding good flow properties and high packing density, which include HIP, AM and MIM. Another feature of advanced gas (both IGA and VIGA) atomisers is the use of heated gas which, when applied to the same nozzle and melt flow rate, reduces both gas consumption per kilogram and median particle size with the square root of the absolute temperature, thus greatly improving economics and yields of fine powder (11).

Fig. 7.

Fig. 8.

The effects of alloys to be processed are also of great importance. Already mentioned is the need for vacuum melting of (Ni-based) superalloys, but for Ti, which reacts with and is degraded by ceramics, ceramic-free melting is mandatory, which has led to the deployment of EIGA and plasma atomisation which, despite their high capital and operating costs and low productivity, have not been bettered for this material.

The more recently developed processes for advanced manufacturing using metal powder, HIP, MIM and AM have different requirements from the previously dominant PM process of pressing and sintering, which is largely served by water atomisation.

For HIP gas atomisation is used, due to the need for clean powder surfaces, with vacuum melting for superalloys. The use of heated gas improves costs and anti-satellite systems can improve flow and packing density.

For MIM, both gas and ultra-high pressure water atomisation are used. The latter is preferred, on economic grounds for many alloys that can be deoxidised in sintering. For more reactive alloys, VIGA production is used. To make the very fine powder sizes needed, hot gas operation is very helpful.

For AM, gas atomisation is almost exclusively used. To improve flow properties, the use of anti-satellite systems is very helpful and hot gas also helps the economics of the process.

“Nanobiosensors” is the 8th volume of Nanotechnology in the Agri-Food Industry, a series edited by Dr Alexandru Mihai Grumezescu, at the Department of Science and Engineering of Oxide Materials and Nanomaterials, Politehnica University of Bucharest, Romania, who is an experienced and well published researcher and editor in the field of nano- and biostructures. Once again, this is a large volume comprising twenty chapters authored by researchers from fifteen countries. The book has thus gathered the multi-disciplinary effort of international scientists in research and development of sensors or biosensors for food test and analysis application. Particularly, as it is entitled, the employment of nanotechnology in sensor development is highlighted in this book.

Nanotechnology has been a driving concept and has made tangible impact in sensor development. Different nanotechnologies, from nanoscale materials, nanostructured materials to nano- and microscale processing and assembly, are intertwined and overlapping. Indeed, nanoscience and technology can be substantially felt as an enabler in biosensor development in this book. Particularly overall the following aspects are well documented by the authors of the book:

Nanoparticles are typical and fundamental nanomaterials and it’s no surprise that they are widely used as building moieties for nanobiosensors. This is presented one way or another in many chapters of the book.

Gold, platinum and silver nanoparticles including nanowires and nanorods are some of the popular nanomaterials for sensor construction due to their unique chemical, optical, electrical and mechanical properties. Optical biosensors can be developed by exploiting the optical properties of the nanoparticles in the first instance. Chapter 4, by I. E. Paul (Vellore Institute of Technology, India) et al., details the studies of using plasmonic Au and Ag nanoparticles (including nanorods) to build colorimetric sensors to detect chemical adulterants (melamine), contaminants (pesticides such as malathion) and bacteria in food, based on adsorption mechanism in an aqueous environment. Further overview of application of plasmonic Au particles for biosensors is provided in Chapter 16 by S. K. Kailasa (Sardar Vallabhbhai National Institute of Technology, India) et al. Additional important approaches to use Au nanoparticles including surface functionalisation with biomolecules for constructing other types of biosensors (for example, electrochemical) is discussed in Chapter 5 by F. Dridi (University of Lyon, France) et al.

Au nanoparticles are known to be excellent substrates for surface-enhanced Raman spectroscopy (SERS). A brief review of SERS based nanobiosensors for food is given in Chapter 14 by N. M. Kulshreshtha (Jaipur National University, India) et al. Quantum dots (QDs) have very distinctive size dependent fluorescence properties. An interesting development is a QDs based fluorescence biosensor, for example fluorescence resonance energy transfer (FRET) biosensors. Chapter 20 by B. Bhattacharya (National Institute of Food Technology Entrepreneurship and Management, India) et al., gives a concise but quite thorough theoretical background of the fluorescence and metal based QDs and describes the mechanism of QDs working as FRET probes. The use of QDs for biosensors is also mentioned in Chapter 9 by K. Rovina (University Malaysia Sabah, Malaysia) et al. And in Chapter 16, in addition to cadmium telluride nanoparticles, the burgeoning studies of the relative new member of QDs, carbon dots for biosensor development is introduced.

The use of other commonly studied nanoparticles, for example carbon nanotubes, magnetic particles as conjugative support of biomolecules are described in Chapter 5 too. In Chapter 7 by K. Mistewicz (Silesian University of Technology, Poland) et al., the gas nanosensors based on functional nanoparticles (for example, titanium dioxide, tin(IV) oxide–zinc oxide or copper) formulations are described. Particularly presented in detail are humidity sensors built on nanocrystalline antimony sulfoiodide, employing their conductive, photoconductive, impedance or capacity properties in the presence of water. Such gas nanosensors may be used for packaging, resulting in smart and intelligent packaging systems. Further, in this book, Chapter 18 by T. Caon (Federal University of Santa Catarina, Brazil) et al., is dedicated to discussing intelligent packaging systems carrying either bio- nano- gas sensors or radio frequency identification tags to monitor pathogens or contaminants in the packaged food.

Bioactive materials are often an indispensable element in many biosensors in its original sense. A notable progress in biosensor development is the use of aptamers, short oligonucleotide sequences (single-stranded DNA (ssDNA), RNA or peptide) as bioreceptors of the sensors. The development of the so-called aptasensors is reviewed in Chapter 2 by G. A. Evtugyn (Kazan Federal University, Russia) et al., and in Chapter 3 by B. Hussain (Sabanci University, Turkey) et al. Chapter 3 lists the advantages of aptamers over monoclonal antibodies such as stability, selectivity and the screening of aptamers to obtain the tightest binding sequences from random pool. The use of aptamers conjugated to nanoparticles (for example, Au, carbon nanotubes) for detecting foodborne pathogens, toxins and allergens and in some cases even multiplexed biosensors, are described in both Chapter 2, 3 as well as Chapter 19 by R. B. Dominguez (Advanced Materials Research Center, Mexico) et al., and Chapter 9, with the advantages such as reliability and efficiency shown.

The other type of biochemical-based sensor such as enzyme-based sensors and antibody-based sensors or immunosensors are also discussed in Chapters 19 and 2. In Chapter 3 conventional food contamination detection methods including immunoassay and polymerase chain reaction (PCR) based methods are described too, which may act as a comparison.

One ultimate aim and advantage of testing and analysing food is improving point of customer care at high precision, high throughput and low cost. The integration of biosensors with microfluidic components leads to lab-on-a-chip which can fulfil these combined benefits. Chapter 6 by D. S. Correa (National Nanotechnology Laboratory for Agribusiness, Brazil) et al., highlights the power of microfluidics enhanced with biosensing. Some developments in application in food analytics is summarised. Further review of micro- and nanotechnologies leading to progress of lab-on-a-chip detection of food pathogens is reviewed in Chapter 12 by N. C. Cady (SUNY Polytechnic Institute, USA) et al.

Chapter 11 by N. Adányi (National Agricultural Research and Innovation Center, Hungary) et al., presents the development of label-free optical biosensor techniques based on evanescent field effect biosensors. Various techniques, such as reflectometric interference spectroscopy, interferometry, optical waveguide lightmode spectroscopy, resonant mirrors, fibre optics, total internal reflection ellipsometry and total internal reflection fluorescence spectroscopy are discussed. It has been pointed out that these techniques are suitable for lab-on-a-chip application.

A complexity of food testing is that multi-analyte analysis is often required. Multi-microarray analysis is very helpful in meeting the requirements. Chapter 1 by J. V. Ros-Lis (Polytechnic University of Valencia, Spain) et al., demonstrates the sensor-array approach for food quality monitoring and identification that mimics a mammalian olfactory system. This is exampled by summarising the studies of optoelectronic nose based on chromogenic arrays made of dye chemicals loaded to nano- or mesoporous inorganic support materials. The sensor arrays are used to monitor the freshness of poultry products and to identify the origin of blue cheese with the aid of multivariant analysis. Reasonably good results are obtained.

Through discussing the applications of nanotechnology in biosensor development for food testing and analysis, the book presents a very full list of sensor techniques. The volume fulfils the series’ aims of bringing together the most recent and innovative applications of nanotechnology in the agri-food industry and of presenting future perspectives in the design of new or alternative foods. This is a book that will benefit not only workers in food testing and analysis but also broader areas of the chemical and biosensing community, although it could have potentially been further enriched with the comments of the commercialisation status of the biosensors discussed.

One of the historical factors that have contributed to the slower adoption of continuous manufacturing in the pharmaceutical industry has been uncertainty around the regulatory pathways for approval by the authorities. All commercialised drugs must be manufactured by a process which the regulatory authorities have approved. Recently, the tide here has begun to change. The best evidence of this are two recent US Food and Drug Administration (FDA) approvals for drugs employing continuous manufacturing processes. In 2015 Vertex Pharmaceuticals Inc received approval from the FDA for its cystic fibrosis drug Orkambi^® which employed a continuous manufacturing process. Later, in 2016, Janssen Pharmaceutica submitted and received approval for an updated process for the human immunodeficiency virus (HIV) drug Prezista^® utilising a continuous manufacturing process. At the time Lawrence Yu, PhD, the FDA’s deputy director of the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER), wrote on the FDA’s blog: “Although it is not easy for drug manufacturers to transition from batch to continuous manufacturing, there are significant rewards. FDA encourages others in the pharmaceutical industry to consider similar efforts” (1). While these words were indicative of the agency’s warming to the prospect of continuous manufacturing in the production of drugs, an official guidance document from the FDA was absent. Such guidance documents are the chapter and verse against which pharmaceutical companies are measured in regulatory approvals. In February of 2019, a Draft Guidance for Industry on the Quality Considerations for Continuous Manufacturing was issued by the FDA (2).

While lower confidence in the acceptance of continuous manufacturing processes by the regulatory authorities has historically slowed adoption by the pharmaceutical industry, there are other unique factors relating to drug manufacture that have also played a role. Primarily these are low production volumes, low contribution costs of manufacturing relative to the overall cost of developing, launching, and marketing a drug and payback periods for the investment which are truncated by patent life expiration.

This results in many different drivers for the adoption of continuous manufacturing in the pharmaceutical industry compared to bulk chemical manufacturing. In the pharmaceutical industry today the drivers to adoption of continuous manufacturing are speed, scale-flexibility, quality and safety. While efficiency is important, the tradeoff for speed and flexibility is more important. With first-to-market pressures always looming, companies have strong motivation to develop a manufacturing process as quickly as possible. One of the unique attributes of continuous manufacturing is its ability to deliver product at a variable scale with consistent quality. Increases in production scale of one, two and even three orders of magnitude can be supported by either scaling up the continuous manufacturing process or numbering‐up the continuous manufacturing production units. These sorts of production increases are becoming very common in the life of new pharmaceutical products. Often new products are developed for an initial therapeutic indication, one which has fewer treatments available for instance but may have a smaller patient population, and later the drug is expanded to other much larger indications. This can mean a drug launches with an annual volume requirement of 50 kilograms per year yet within one to two years, if the next indications are successful, the volume requirements can increase to 5 metric tonnes per year. Regulatory requirements mandate that the quality profile of the active ingredient be the same regardless. Thus, there are strong motivations to keep the manufacturing process the same and continuous manufacturing lends itself well to this.

Johnson Matthey has adopted the use of continuous manufacturing in the products it produces for the pharmaceutical and medical industry and in the services it provides to pharmaceutical companies. In addition, in September of 2017 Johnson Matthey created a partnership with a Massachusetts based company named Snapdragon Chemistry Inc which was spun out of Massachusetts Institute of Technology (MIT) to focus on the design of continuous manufacturing processes for application in the pharmaceutical industry. Through that relationship, we can combine Snapdragon’s early stage data-rich platform for chemical route scouting and design with Johnson Matthey’s expertise in process development, scale up and manufacturing according to current good manufacturing practices (cGMP).

The Snapdragon laboratories are near to Johnson Matthey’s Devens, MA facility where we have development laboratories, kilogram-scale laboratories and a GMP manufacturing plant. This is where we do most of the development work for the pharmaceutical sector. The proximity allows for optimal interaction with our staff spending time at Snapdragon’s facility and its staff spending time at our facility while we are working together on a project.

We have applied continuous manufacturing to multiple projects together and have just kicked off a new project. We also have a pipeline of the next opportunities we are discussing with customers. It’s an exciting time as the pharmaceutical market moves toward wholescale adoption of innovation in the way drugs are manufactured, including via continuous manufacturing. It is yet unclear just how different drug manufacturing in the future will look to today, but one thing seems clear: that continuous manufacturing will play an important part in the transformation. We are very excited for Johnson Matthey to be part of this evolution.