*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
*Naresh Jariwala*
CDMOs: Endless summer? Pharmaceutical CDMOs are still extremely bullish about the state of business now and for the foreseeable future. Andrew Warmington spoke with industry leaders at CPhI Worldwide 2019 Business leaders are not known *Naresh Jariwala*developed by small and medium- The process has accelerated for talking down the state of sized pharma companies. These immeasurably now that China has business but when everyone is trends will continue, creating further started closing down vast swathes overwhelmingly positive for years opportunities in the short term, of its coastal chemicals industry for on end, it has to be true. For at least Bradbury said. environmental reasons. six years, pharmaceutical CDMOs with a base in Europe and North Meanwhile, Big Pharma is Even the best facilities are not America have thrived. Their outlook outsourcing ever more of its safe, should they be located in a at CPhI Worldwide in Frankfurt on manufacturing needs as it focuses chemical park that closes because 5-7 November was no different. on R&D at one end of the chain of a single ‘bad apple’. Pharma and sales and marketing at the companies in particular cannot risk The main reason is the bulging other. This partly reflects a choice to being left with only a single supplier drug pipeline. Last year saw a invest in biological manufacturing, and some who thought they had record 59 FDA approvals – 42 new even though growth rates for large two have found that they did not. molecule entities (NMEs) and 17 molecules are not much faster than They increasingly want starting biologics. A growing proportion of those of small molecules. materials and intermediates from this coming from small companies, Western suppliers who can offer – who do not have – and never will As Stuart Needleman, chief and document – long-term security have – manufacturing capabilities commercial officer at Piramal of supply. and who therefore look to CDMOs. Pharma Solutions, remarked in These companies continue to find Frankfurt: “I’ve been hearing about Add to this the increasing venture capital and IPO funding how biologics are the future for complexity of molecules – by some reasonably easy to access. 25 of the 38 years I have been in estimates, the average number of this industry but I still think small steps has doubled from eight to 16 According to FDA and GlobalData molecules are going to be big. The in the past decade – the compressed industry analyst Adam Bradbury, a future is still small molecules in our timelines for low volumes and record 43 drugs in 2018 had one space, particularly in orphan drugs.” accelerated approvals, and it all or more expedited reviews, while adds up to a rosy picture, albeit 34 orphan-designated drug NMEs Back from China were approved and 65% of these Another major driver has been the were outsourced. This was a record ‘China effect’. This began years high. Of the NMEs, 23 had fast ago as customers who took their track status, significantly more than business to Asia learned that low in 2017. And 70% were outsourced, prices did not always mean low partly because so many were costs, leading to a ‘flight to quality’.
not without challenges of its own. *Naresh Jariwala* The shell is in place for a bespoke Last year, Evonik invested 36 To address this – and the capacity chemical development facility, million in special capabilities of all constraints they face – almost all which is due onstream next year. kinds. One notable development CDMOs have been investing. Additionally, a new GMP API plant is is a modular continuous pilot at the foundation stage and will be plant at Hanau, Germany, which Strictly speaking, a CDMO, completed at the end of 2021. To is now being tested. In the past, as opposed to a CMO, means address current shortfalls, Almac is Meudt said, the company lacked one who offers integrated drug adding two 1,000L, one 300L and pilot capacity in this field and substance and drug product supply 100L reactors in its existing facility. every project involved investment. from early stage discovery to With this facility, it can run many commercial supply. The $1 billion+/ Key areas of technology expansion different chemistries in parallel, and year, publicly owned players, like include flow chemistry. Almac has a implement new ones quite rapidly. Lonza and Thermo Fisher Scientific, partnership with Queen’s University do cover both bases but some Belfast to test very hazardous and/ New CEO Dr Michael Quirmbach giants, like Catalent and Aenova, or very large volume reactions for said that CordenPharma has are only present in drug product flow and it hopes for commercial avoided the problems that have and the balance naturally varies. developments in 2020. “We’re plagued some other CDMOs with doing it the Almac way, building it similar business models based on The companies featured here are ourselves locally,” Geffroy said. acquiring ex-Big Pharma sites. “Five all major players in drug substance. years ago, we had an 80% legacy Many of them are also active in high About 20% of Almac’s business business. Today it is only 30%. This potency APIs (HPAPIs), which will be is in GMP peptides, notably year, we have had organic growth of the subject of a separate article in ‘Neopeptides’ for ultra-personalised 20% in sales and we expect at least the next issue. cancer vaccines targeting a single 15% next year.” patient and made in time frames as Invest in the West short as four weeks. The company R Quirmbach – CordenPharma expects 20% Almac was pretty much a CDMO believes it is the market leader organic growth this year before the concept existed, in this field and is organising its according to Denis Geffroy, VP of manufacturing trains at Edinburgh, This reflects the strong pipeline business development for Almac where it has added 30 staff to the Sciences. It was the vision of the previous 40 in the past 12 months. but also strong demand in key founder, Sir Allen McClay, to offer integrated development services Evonik was also seeing strong areas. The company has just across the board, at all stages, even business and positive feedback when CMC services seemed to be during CPhI about forthcoming completed a facility at Plankstadt, moving east. projects, said Dr Andreas Meudt, VP of exclusive synthesis within the Germany, for an animal health Business is currently buoyant in Health Care business line. This is all areas of business, including mainly Phase II/III and commercial- blockbuster. Another major small molecules, high potency, phase projects that require a peptides, biocatalysis and flow differentiated mix of advanced investment has led to 60 new chemistry. “It is the highest level of technologies, and where Evonik’s interest we have ever seen on the financial clout and engineering people being taken on there. There market,” Geffroy said. resources are valued. is also good demand for sterile The acquisition of Arran Growing molecule complexity Chemical in the Irish Republic in plays to the company’s strengths, injectable fill-and finish for peptides, 2015 fortuitously enabled Almac to because Evonik has many different offer non-GMP starting materials advanced technologies for exclusive antibodies, oligonucleotides and to the clients who have come synthesis – notably PEGs and back from China in the past two mPEGs, carbohydrate chemistry, others based on new technology years. Some non-GMP steps of polymer APIs, fermentation, catalysis API manufacture has also been and biocatalysis, chiral chemistry recently installed at Caponago, moved there from the main site at and cryogenic chemistry. It also Craigavon in Northern Ireland. has some of the largest CDMO Italy. P capacities for APIs and HPAPIs. Facing a looming crunch in large- scale API capacity, Almac looked at “Almost every meeting we have acquisitions. Plenty of ex-Big Pharma seems to start with ‘Can we talk sites, not least in Ireland, offered a about China?’,” Meudt said. “In quick solution, “but having another the last ten to 15 years, a lot of remote site was a problem, and the chemistries have gone East and now sites did not have the same culture,” customers are desperately looking Geffroy said. Instead, a year ago, it for Western suppliers for reactions decided to follow its traditional path that seemed gone for good. of organic growth. Nitrations are a good example.” www.specchemonline.com
P Future investment plans *Naresh Jariwala*at Swords and the ex-Boehringer DeYoung said that the company “is include highly potent solid dosage Ingelheim site in Virginia. The seeing really robust demand for our forms at Plankstadt, continuous firm is also adapting its heritage services and offerings”. It is investing manufacturing at Chenôve, France, in continuous processing from the particularly in four differentiated and large-scale solid phase peptide aerospace and oil and gas markets areas, all anchored in Western synthesis capacity in Colorado, to the smaller volumes and shorter facilities: ADCs, sterile fill-finish, as well as HPAPI development timelines of pharma. HPAPIs and APIs for emerging capabilities. The company will pharma in the early stages. look to further expand its network, Based in China and the US acquiring new sites that fit with its is WuXi AppTec subsidiary STA Investment will soon take place needs in technology terms. Pharmaceutical. Dr Xiaoyong Fu, at Aurora, Ontario, for a major senior VP for API development and expansion. This is particularly Asia to US commercialisation, said that the targeted at customers moving In the past year, Korea’s SK company’s business is being driven compounds into Phase III and acquired Ampac Fine Chemicals by the same tailwinds as the market seeking certainty of supply. The and incorporated all of its pharma- in general. engineering work is done and it facing businesses into a new entity should progress early next year at called SK Pharmteco. The former Strong demand from customers, the latest. BMS launch site for new molecules notably in oncology and orphan at Swords, Ireland, is part of this, as drugs, is a more specific “We are seeing exponential SK Biotek Ireland. Existing identities driver, as are new modalities, growth in integrated projects and cultures are being maintained. such as oligonucleotides and across these sites,” said DeYoung. peptides. STA has greatly “A lot of that is about reducing “We hosted a lot of meetings here expanded its peptides and complexity and improving speed, at CPhI and they have been very oligonucleotides capacity lately and it comes from both emerging productive with regards to customer and can handle both solid and and large companies. It’s really commitment to sending projects to solution phase manufacture, unlike about speed to market more than us”, said CEO Dr Aslam Malik. “We most specialised oligonucleotide or accelerated approvals as such. The also had a lot of customer-based peptide CDMOs. other advantage we can offer is production meetings and a lot of back-integration into our facilities people showing up at our customer- The company is also expanding in India.” only event.” its API capacity in China. “Every year we add one or two plants S Kantipudi – China effect also helping India As with most CDMOs, the into our operations, so we have company was seeing Big Pharma, very big expansion plans,” said biotechs and virtual pharma about Fu. “We are also adding to our all kinds of projects. “Things have capabilities, such as various delivery really picked up a lot. Some projects technologies in oral solid dosage that we used to consider small or form. We are a true CDMO, early phase are now moving so fast active the whole way through through the FDA approval process, the development chain to the they are leaving rubber marks on commercialisation stage.” the road,” said Malik. STA, he added, is also investing Molecules are becoming more in technology capabilities, notably complex, with more steps, and HPAPIs, biocatalysis and flow thus more likely to need services chemistry. The focus is mainly like chiral chemistry or Ampac’s on using flow to solve technical, specialities, like simulated moving chemistry and safety challenges bed chromatography and energetic that arise in batch, rather than chemistry. The FDA now increasingly trying fit particular reactions into demands validation earlier in the flow. process: seven to eight steps might be done under cGMP, driving Since the show, STA has been customers to CDMOs for their R&D named as the preferred CDMO and engineering capabilities as well partner for Impact Therapeutics, as manufacturing. a Chinese clinical-stage biopharmaceutical company. In addition, added Patrick Park, VP This will cover the entire product of business development, starting development process for Impact’s materials are becoming more pipeline of oncology drugs. complex and have to be custom- made. Ampac and other CDMOs Indian summer are thus having to back-integrate. Also rooted in Asia but with Additional capacity has been added extensive Western assets is Piramal Global Pharma. New CEO Peter www.specchemonline.com
GVK Biosciences, despite the *Naresh Jariwala*emblematic of how it has evolved Rapid growth name, is heavily invested in small over the last six years, significantly molecule CDMO services too. CEO increasing its turnover and Sterling Pharma Solutions, said Manni Kantipudi has noted ever becoming much more than a large Dr Andrew Henderson, sales and more Big Pharma outsourcing as manufacturer of small molecules. marketing director, has trebled its this goes from a ‘nice-to-have’ to an revenues since the brand came essential part of every company’s In the past 12 months, noted Dr together in 2016 and expects to strategy. The India- and US-based Matthew Moorcroft, VP of global quadruple them in 2020, based firm is also seeing three new marketing, Cambrex acquired on pre-booked projects. It has also biotechs every week, he added. first drug product manufacturer diversified the customer portfolio. Halo Pharma, bringing in two None accounts for more than 15% The third factor in its strong North American sites, then Avista of sales. recent growth is the ‘China effect’ Pharma Solutions, bringing it into and a rebalancing of materials early stage services. The company In February, healthcare-focused sourcing and of chemistry and itself is poised to be acquired by private equity buyer GHO acquired biology services to India. “India has private equity firm Permira, giving Sterling. This has given the firm lots of scientists, English speaking it access to capital that will take it both resources to buy and industry and cheaper than China. On from medium-sized to big through knowledge to drive its strategy labour rates, India costs 25-30% acquisition and investment. forward. Soon after, it acquired less than China,” Kantipudi said. CiVentiChem in the US, expanding Cambrex’s business growth its offer back from the UK asset Indian service-based CDMOs are has been driven by “everything”, base in Phases II-III into pre-clinical exactly as compliant as Western Moorcroft added. “I think we are and Phase I, and, even more ones, he added. They have to be: at the point now where more small importantly, took it into the US small last year GVK Bio had 67 audits, molecules are made by CDMOs. pharma market. all but one from customers. Unlike The business model never used to product companies, some of whom work for small volume products – R Henderson – Sterling investing in US and early have had FDA issues in India, they now we are getting drugs approved phase are inspected as much for how they that are only manufactured for a few operate as what they produce. thousand patients.” Key recent investments have Due to strong demand, last year Portuguese CDMO and generic included a £12 million milling and the company put up a facility in API manufacturer Hovione was Vizag with 100,000L capacity and highly commended in the same micronisation plant, a SAP platform the utilities are in place to expand award category at CPhI. The fourfold. It also started a new company “has enjoyed a very and a combined heat and power HPAPI block and will install its first good ride”, according to Fredric flow chemistry reactor in 2021, Kahn, VP of marketing and sales. unit for the main site at Dudley, mostly for process optimisation Being privately owned, it has been work in medchem. able to reinvest for long-term near Newcastle-upon-Tyne, UK. In growth. GVK is the largest player in 2020, the second of three phases discovery in India, with about A major three-year investment 1,500 people in the field. For that plan is now in progress, covering in the capex programme will begin, reason, Kantipudi has coined the drug substance, drug product, term ‘CRDO’ to describe it and formulation and new technology including four new large-scale emphasise science, even though it capabilities. By 2025, Hovione will is very active in the ‘M’ as well. The have installed about 11 spray reactor streams. CDMO market is growing by 8-9% drying units, ready to address the this year, he estimates, but over the challenge of larger molecules that “We mean to be ahead of last four years, GVK has outpaced bring bioavailability and solubility even that by three times. issues. the curve in capacity, so that we Award-winning services Other investments include further never run out of it after winning At Frankfurt, Cambrex was development at the main site in celebrating winning the CPhI Award Loures, employing some 200 the business,” Henderson said. for Excellence in API Development scientists, and another in Lisbon, for its crystallisation screening where a new facility housing 200 “We have several possible P and process development, more scientists was opened last year. particularly highlighting a peptide crystallisation project that bridged Finally, Hovione has acquired the gap between the laboratory a piece of land near Lisbon that and manufacturing plant. This was is ten times larger than Loures. the company’s fourth win in the Announcements can be expected in category in four years and perhaps the near future about investments there in multiple fields, depending on priorities. www.specchemonline.com
P acquisitions in the pipeline for *Naresh Jariwala*testing created a lot of pressure inas technology. The QC and QA commercial-scale API manufacture our QC system, so we expanded. groups will be expanded next. in Europe.” Sterling’s portfolio is We thought this would be enough Other key investments have been about 30% pre-launched products for many years to come but we are in HPAPIs, an aseptic crystallisation and 70% launched, to ensure that already at nearly 88% unit in France and a Hastelloy it is protected against any funding- capacity utilisation.” spray-dryer that was installed for a related downturns. customer who had a problem with The older QC laboratories his original CMO. Technology-wise, the firm is will now expand their process getting into flow. It has developed development capabilities as “We are also seeing a lot of a continuous biocatalytic reaction more and more customers come business coming back from Asia. on a fixed bed and is looking to Fareva earlier, and with less We still see some resistance when at treating the waste stream robust processes. This reflects both it comes to interpretations of price, from large-scale thiophosgene the loss of internal capabilities because come customers still have production in flow. In Henderson’s at pharma companies and the a mindset from working there or view, the move is less about the increasing trend for CDMOs, are still spend-focused, looking at economics than safety; flow is whose staff to tend to stay with jobs upfront costs without looking to the best used where it can make and projects longer, to “hold the longer term,” added Faust. hazardous reactions safer or offers knowledge”. better temperature and pressure Particularly when dealing with control. “It is difficult for a CDMO to orphan drugs and accelerated have the time to become a subject approvals, he said, “if you start Chad Telgenhof, interim COO matter expert and go through all with a weak supply chain, you’re at Alcami, another private the information their customers going to end with one – there’s equity-owned CDMO, said that dump on them, but increasingly no time to move it”. Companies the company is “seeing a lot of they have to,” Faust continued. would do better to set a decisive, favourable and positive trends” “On the other side, we can now strategic development of their end and is positioning itself to focus on produce so much data that goals and work back from there, its strengths in science. The sector customers don’t have the personnel especially when the cost savings has been through some large-scale to review all the documents and available in Asia are shrinking consolidations and the – relatively give us the OK in good time.” rapidly and especially if they have – small players like Alcami are now any weaknesses in their knowledge sorting out their positions. True collaboration and trust and rely on a CDMO. are thus essential to making the A major investment in partnership process work. Fareva, as a result, Pharma firm Servier launched with a client is planned at the firm’s is investing in people as much Servier CDMO in 2015, catching sterile facility at Charleston, South Carolina. On the technology side, S Franguelli – Repurposing the company sees working with old APIs for niche uses customers on their second or third generation products after initial patent expiry as a key capability. There is a growing trend this way, Telgenhof said, particularly in small- volume therapies and animal health. Substance & product Fareva is a giant in drug products but also has three API sites in Europe. Recently, said James Faust, director of API business development in North America. The Excella operation in Germany completed a 8 million capacity expansion of its QC labs to address the regulatory authorities’ increasing demand for testing of starting materials and intermediates, as well as APIs. “The idea of simply doing ID testing and accepting a C of A are falling out of favour,” said Faust. “All of these analytical method developments for validation and
the wave at the right moment when S Blocher – Big Pharma monoplants not always the answer pharma companies were bringing production back to Europe, according to business development manager Eric Bourdais. It has been “overwhelmed” by demand at the API site at Bolbec, France, and has moved some to another in Toledo, Spain. The two sites combined have 545 m3 of capacity. To address the demand, Servier invested heavily at Bolbec last year, with a new workshop for its InnoPrep industrial chromatography services. This year, it has focused more on drug product, with a workshop in Ireland dedicated to its InnoOne brand of high potency formulations. These are both quite unusual, Bourdais claimed. *Naresh Jariwala* Covering the chain Recipharm has been investing complementing the existing Ru-SNS in updating its plants with key catalyst. Both offer environmentally Recipharm is also based mainly technologies for finishing part in preferable and all-round easier in drug product but since 2014 particular, and in new technologies options to the use of hydrides in has been a CMO in early-stage like hydrogenation and flow the reduction of esters and other discovery and small molecule chemistry for hazardous reactions. carbonyl compounds, it is claimed. APIs, based on acquisitions in Italy, At present, it is active here at lab Sweden and Israel. These have scale and on an opportunistic China as a market been put together in one business basis. Electrochemistry and unit and have grown with the hydrogenation are particular areas Switzerland’s Dottikon Exclusive trend towards integration in early of interest for transfer to flow, chemistry, according to Gianluca Franguelli said. Synthesis, a more traditional, single- Franguelli, VP of drug substance development. “We’re keeping busy, that’s for site API supplier, has also been busy sure,” said Tom Sturgeon, assistant “Eighteen months ago, we fixed director of business development behind the scenes. Investments these units in drug substance within at Johnson Matthey, “and we’re our development unit, which now looking at investments and this year have totalled CHF 60-70 includes seven different sites and expanding our capacities and covers the whole supply chain from capabilities.” Much of this has been million and there will be more still early chemistry,” Franguelli said. in high potency and technologies “Every time we develop something related to it, but also in the general in the coming years, including a in the medchem units, it is done in CDMO business. co-ordination with the GMP sites, new building with 150 work stations which helps smooth the next steps Indeed, Sturgeon said, a recent through the clinical phases.” piece of research established that for process development, process JM technologies have had an Business, he added, is going impact on over one third of all design and QA. very well in 2019, including in small molecule launches in the old, often large-volume molecules last five years. Often this has been A new API drying facility has that are being repurposed for connected to its particle design and niche applications through process catalysis expertise. also been commissioned. Several redesign. At Frankfurt, JM announced engineering activities are ongoing, “Customers want us to keep that it had licensed in Ru-PNN control of any potential issues that homogeneous ester hydrogenation including a new large-scale multi- can arise from the molecule – this catalysts from Green Centre demand comes from them and Canada on an exclusive basis purpose plant and a new pilot it has sometimes been a surprise and at commercial scale, when the molecule is already plant, as well as debottlenecking to known. They sometimes also come to us for the formulation boost existing large-scale plants. stage.” Up to date this has been self- funded, according to Dr Markus Blocher, CEO, chairman and majority shareholder. “I think the key pharma industry challenges will be limited high- quality manufacturing capacity, as more projects are on the market, back-integration of raw materials is increasing, with all the interruptions in supply chain from China, P www.specchemonline.com
PATIENTS AT THE HEART OF IT Piramal Pharma Solutions has become the first CDMO to appoint a chief patient-centricity officer, in the form of industry veteran Stuart Needleman. Speaking at the launch of the CPhI Annual Industry Report, Needleman noted that this trend began in Big Pharma, with AstraZeneca and a few others creating positions *Naresh Jariwala* like his. Hopefully, the rest of the CDMO space will also move in this direction. The concept, he said, is “about putting the patient first in an open and sustained R Needleman – The patient engagement”. It is linked to the development of is also the CDMO’s customer personalised medicine but more about the fact that, ultimately, the customer is the patient. “The patient is who pays the pharma company, but is also the one who pays us.” “If you put the patient at the centre of the universe from a CDMO perspective, it changes the way you behave internally,” Needleman continued. “It changes the mindset of an operator on the shop floor who goes home at 5.00 p.m. and therefore the drug doesn’t get shipped and someone didn’t get a vital medicine.” Traditionally the CDMO business is one step removed from the patient. If it can develop a new mindset of not going home until the job is done, said Needleman, “this should resonate with our customers and enhances our common purpose.” To achieve this, Piramal has begun inviting patients to talk to workers at its plants so that they can appreciate what their work means. It is also appointing patient awareness councils, made up of a cross- section of people at each site, to discuss what the company can do better and the metrics to measure this. CEO Peter DeYoung added in a separate interview: “We regard patient-centricity as the logical extension to our customer-centricity. W Cleaning of a nutsch filter at Saltigo’s Leverkusen site Put simply, it’s sharing the same mission with our customers and understanding what motivates them, which is the patient, so we can better partner with them.” P and consequent repatriation of with price pressure on branded “Nobody really thinks things will projects is filling up capacity in the generic drugs and uncertainties go back to normal next year,” Klein West,” Blocher said. on how pricing is handled for remarked. “Everyone is preparing innovators. In the longer term, for this situation to continue for “There are some Big Pharma Chinese pharma companies may three to five years or even longer, mono-plants out there for sale, but become a customer for Western because the consolidation in China they are not always useful for multi- CDMOs, Blocher said. will continue and China will move purpose contract manufacturing. to a different quality, safety and In addition, not having R&D at Saltigo is also performing environmental standard level.” the same site as manufacturing is well, said Andreas Klein, head a disadvantage when processes of marketing and sales. Many For now, it is not always easy are being squeezed so fast due to customers are building Western- to change from one day to the accelerated approvals,” he added. centred supply chains for starting next, particularly for complex and materials, intermediates and heavily regulated products, when Meanwhile, oncology is an APIs, and CDMO capacity is customers are looking for rapid increasingly dominant part of the heavily booked. Some customers, implementation and long-term pipeline and China is becoming a he said, expect to see this and solutions. Saltigo is thus asking for fast-growing market for oncology consequent cost pressures lead to a four- to five-year commitment from drugs, albeit an unpredictable one consolidation in the CDMO sector. customers to campaigns. at times of trade wars and tariffs, www.specchemonline.com
*Naresh Jariwala* Ongoing challenges enquiries for intermediates Brexit. The continued uncertainty with a Chinese supply chain, has driven some business booms One challenge arising in the past particularly for hazardous, through pre-emptive ordering but six to nine months, said Klein, had complex molecules where there it is also a major problem – and been molecule availability. “This have been safety issues in China. not just because JM is largely UK- was part of every second discussion CordenPharma and Almac both based. here. Do we, as a society, know work internally with non-GMP how often we are standing on just operations to source materials. A second challenge comes from one leg for crucial molecules in However, noted Quirmbach, a boom market, said Dottikon’s day-to-day demand?” “There is a problem in that some Blocher. “As cGMP manufacturing want to order in the West and pay capacity gets short, people are Some customers are moving the Eastern price.” making opportunistic moves. proactively now that they realise That’s dangerous in this business. that they may be single-sourced, JM’s Sturgeon also cited China, If you deceive your pharma and are asking CDMOs for in terms of the tariffs and problems customer and he has a problem support. The issue, Klein said, in moving materials, as a top with his supply, he won’t forget is less about urgent needs, but three concern. More pressing, for the next ten years. There working to develop a solution over however, are the media-driven are people now playing with the next two to three years. crisis in opiates, where the price increases for short-term company is a major supplier, and gain.” £ Henderson agreed that Sterling has seen a growing number of www.specchemonline.com
! \" Glyphosate: A poisoned legacy? Glyphosate litigation is having a visible impact on Bayer, but the company believes that the herbicide is still essential. Gregory Morris reports the latest *Naresh Jariwala* BAYER’S Q3 FINANCIAL report clearly shows the Cases pending in US federal courts have been effects of growing litigation in the US against consolidated into a multi-district litigation in the glyphosate. This is the active ingredient contained Northern District of California for common pre-trial in several herbicides of the company’s Monsanto management. In the first, in March, a jury awarded subsidiary, including the ubiquitous Roundup brand. around $5 million in compensatory and $75 million in punitive damages – later reduced by the trial court Buying Monsanto was part of a sweeping to $20 million – to a plaintiff who claimed that a consolidation in agrochemicals that also saw the Monsanto product caused his NHL. emergence of Corteva and the acquisition of Syngenta by ChemChina. Monsanto’s original patent on In the third trial, in May, a California state court glyphosate had expired in 1991, though it gained jury in Alameda county in the San Francisco Bay area extensions until 2000 on some formulations and as awarded the two plaintiffs a total of $55 million in recently as 2014 on some GMO seeds. compensatory and $2 billion in punitive damages. The latter was again, subsequently reduced by the trial For the first nine months of 2019, Bayer’s EBIT court to $86.7 million. In both cases, Bayer stated that decreased by 74.6% on the same period of 2018 to it disagreed with the verdict and would appeal, vowing €1,035 million, after net special charges of €827 “to defend ourselves vigorously in all of these lawsuits”. million. Of this, €683 million was connected to the integration of Monsanto, which it acquired in 2018 More trials to come for $63 billion, divestments to BASF and legal fees in Three more trials that were originally scheduled for connection with the glyphosate litigation. 2019 have been postponed. The next are scheduled to begin in January 2020 in California and Missouri The vertiginous changes in Bayer’s enterprise state courts, although the dates remain subject to value (EV) since then mark the radical shifts that change. As of 11 October, nine Canadian lawsuits the glyphosate litigation has wrought. It had slid relating to Roundup and seeking class action to a multi-year low of $96 billion on 2 April 2018, certification had also been served on Bayer. recovered to $107 billion by 26 June and soared to $157 billion with Monsanto in the fold. By the end of So far, Bayer’s legal defence has been based on the 2018, however, it had plunged back to $108 billion. assertion that multiple regulatory reviews in multiple The recent low was $98 billion on 18 June, though it countries have declared glyphosate safe. Another inched back to $113 billion on 29 October. relevant point, one that the company is not likely to trumpet, is that it has become irreplaceable. Vast As of 11 October, lawsuits had been served in the US by some 42,700 plaintiffs, claiming to have been exposed to glyphosate-based formulations manufactured by Monsanto, and seeking both compensatory and punitive damages. The resulting injuries claimed include non-Hodgkin lymphoma (NHL) and multiple myeloma. # # Find more at www.specchemonline.com
*Naresh Jariwala* areas of North America and worldwide are planted Roundup has been the subject of intense debate and lawsuits in monoculture crops genetically modified to enable them to survive glyphosate treatment. agricultural history … [It] became a chemical titan in the mid-90s with the advent of glyphosate-tolerant “From the standpoint of the whole process of weed crops. As of 2018, it’s difficult to overstate the ubiquity control, the drastic commitment has been made to of Roundup and its generic copycats.” GMO Roundup-resistant seeds and crops,” says Mick Lewis, president of the American Society of Agricultural For all the excitement over the pairing of weed Consultants. “I doubt we would have corn or soybeans killer and custom-made seeds, glyphosate and GMO to plant” if glyphosate were banned or withdrawn, he crops are clearly just another stage in the cycle of adds; it would be “extremely disruptive.” agrochemicals, and not the permanent solution they were once taken to be. “Yes there is a problem Despite the few early verdicts and the growing with glyphosate-resistant pigweed,” says Lewis. “So number of suits filed, Lewis adds that the general growers take a hoe and chop a few weeds for now, attitude of the farm community in North America, but the problem is getting worse.” especially the big commercial growers, “is that they have not seen any proof of health dangers. Also, they Perhaps aiming to kill two birds with one stone are not enthusiastic about changes being imposed on Bayer announced plans in June to invest €5 billion to their way of doing things.” develop alternatives over ten years. The company P Hard to replace In addition, the industrial and retail herbicides displaced by glyphosate formulations were worse. “Roundup-ready genetics have eliminated a lot of other herbicides that may be more dangerous. That is an important issue. Overall the use of herbicides and insecticides [in commercial agriculture] has been reduced,” Lewis says. A report by Farm Journal’s business publication AgPro late in 2018, called glyphosate “the world’s most common herbicide, often considered as one of the most benchmark technological advances in Find more at www.specchemonline.com
*Naresh Jariwala*
*Naresh Jariwala*
\" # \"!\" ! The science of beautiful hair Christian Allan of CrossChem and Dr Sabilla Digel of Berg + Schmidt look at the chemical and mechanical effects of glycolic acid on human hair keratin* GLYCOLIC ACID IS is a proven keratin cross-linkages and repair active ingredient in skincare disrupted H-bonds. products. In recent years, it Evans et al. have demonstrated has also attracted attention that treatment with glycolic for its potential in hair care. acid significantly decreased the *Naresh Jariwala* Qualitative testing has shown Young’s modulus of hair samples that, when compared with and how this behaviour could be untreated human hair, hair reversed using deionised water. samples treated with glycolic acid This indicates that treatment did demonstrate decreased elastic not permanently alter the hair modulus, increased denaturation Second structure, but instead induced coil temporary plasticisation.3 temperature (TD) and greater lubricity. Glycolic acid, a small and highly permeable -hydroxy acid, is While such results signal an exciting new option in the world perfectly suited to rebuild stability of hair care, the chemical and First in damaged hair. Following many biological mechanisms by which coil cosmetic chemical hair treatments, glycolic acid improves hair health Young’s modulus often increases are not well understood. This article significantly.3 reviews past and present research The small molecular size and to develop a comprehensive structure of glycolic acid make it explanation for the molecular an ideal addition to restore the interactions between glycolic acid broken H-bonds by penetrating and human hair. deep into hair strands and instigating cross-link repair. Decreased elastic modulus Glycolic-acid treated and Keratin comprises over 90% of Figure 1 – Coiled coil of two -helices untreated hair samples were the dry weight of hair. In keratin, treated with a 5% glycolic polypeptide chains are wound into acid solution and were tested ‘coiled coils’ bunched together in microfibrils (Figure to generate stress-strain relations. Test results 1). The ability of these coils to unwind and temporarily demonstrated a quantifiable relationship that break internal H-bonds allows these -helical treatment with glycolic acid resulted in a decreased structures to both stretch and recover. Young’s modulus of hair samples when all other Normally, shape is restored when tension is released conditions were held constant.3 and H-bonds reform. When internal hair bonds are A separate tensile strength experiment also disrupted, however, flexibility in hair strands is lost and demonstrated improved tensile properties in glycolic hair becomes weaker. acid-treated samples compared to untreated controls The elastic (Young’s) modulus is a numerical ratio and strands treated with a variety of other hair used to quantify the resistance of a material to elastic product components.4 deformation. In human hair, a smaller elastic modulus signifies a greater ability to withstand damage. In Increased TD damaged hair, the disruption of the H-bonds leads Keratin is a structural protein that forms stable fibres, to a diminished ability for self-repair and in turn which are key in many biological structures like hair, increases the elastic modulus.1 nails and the outer layer of skin. If subjected to heat Carboxylic acids have been shown to assist in the or chemical conditions beyond a certain threshold, formation of molecular cross-linkages within -keratin. however, keratin will suffer denaturation, in which As Song et al. stated, “Cross-linking … could build internal bonds are broken down and the molecular bonds between the carboxyl groups in the [acids] … structure is compromised. and thus help hair partially regain intermolecular force Wortmann et al. have discussed how denaturation and restore its mechanical properties”.2 They also takes place in specific sets of cells within the cortex showed that the addition of carboxylic acids, such as of keratin fibres.5 TD decreases significantly with -hydroxy acids, into keratin structures can help restore the increasing presence of water as a volatile $ $ Find more at www.specchemonline.com
Figure 2 – Glycolic acid cross-linking effect in hair Decreased lubricity occurs when the cuticle layers ‘catch’ and rub together, creating tangles or static Healthy hair keratin electricity.6 Cuticle disorder can also lead to water Broken hydrogen & disulfide bonds penetration into hair strands, while consumers *Naresh Jariwala* “overwhelmingly prefer the feel and properties of Glycolic acid cross-link hair that is equilibrated at low humidity, i.e. that possesses low water content”.4 plasticiser. The increased presence of water in In research conducted by Berg + Schmidt, damaged hair also leads to hair frailty, linking denaturation human hair samples were concurrently subjected to 7% citric acid & 7% glycolic acid solution at pH 3.8 temperature to the chemical characteristics of the for one hour. It took longer for water to penetrate into the glycolic acid-treated hair sample, with droplets keratin matrix.3,5 remaining on the surface of the hair for a longer time span (Figure 3).7 The straightening and smoothing of Glycolic acid, unlike water, is a non-volatile the cuticle’s shingle structure by glycolic acid results in a more hydrophobic, ordered and healthy hair strand. plasticiser. Evans et al. noted that the loss of strength Flexible H-bonding and cross-chain linkage in in keratin structures correlates with the strength of -keratin structures give healthy hair molecular order and characteristic versatility.8 The effects of lateral links between keratin strands (Figure 2).2 the chemical structures of polycarboxylic acids on molecular and performance manipulation of hair They performed an experiment that showed that the keratin also shows carboxylic acids like glycolic acid to be effective in strengthening and maintaining tendency for hair breakage is dramatically increased polymeric chemical linkages in keratin. Further testing performed by Berg + Schmidt revealed that hair samples treated with glycolic acid conditioners required less force to pass a comb through the hair sample. These tests show that glycolic acid increases lubricity by reordering and rebinding the keratin scales of the hair shaft cuticle, thus aligning the cuticle and preventing penetration of the hair strand by foreign molecules. at high humidity. By stripping away water, glycolic acid decreases volatility in the hair structure and creates a Conclusion more stable keratin matrix, leading to an increased iTtD. Previous articles have delivered a limited explanation In a dynamic vapour sorption (DVS) experiment, of the glycolic acid benefits in hair care. This study was shown that treatment with glycolic acid produced has shown the polymeric nature of human hair keratin, formed into -helical structures, gives rise to a significant reduction in the water content of hair, where hair treated with glycolic acid showed a greater molecular geometry well-suited to beneficial chemical resistance to water adsorption as opposed interactions with glycolic acid. The helical nature of to baseline.2 keratin also gives rise to brittleness, dullness and A differential scanning calorimetry (DSC) test general unhealthiness when cross-linkages between was also performed to determine the gTlDycoof lhiceaacltihdy hair strand keratins become disrupted. hair. This showed that treatment with Glycolic acid’s effectiveness in repairing such coFnusritshteenrtDlySgCenmeeraatseudreinmcerenatsseddemhaoinrsTtrDa.3t,e5d a ~6.5˚C breakages derives from being a carboxylic acid and the smallest, simplest member of the of -hydroxy winhcrileeadseaminaTgDedfo(rbtlreeaactehdedh)esaalmthpy lheas itrresaatmedplwesit,h acid family. Its small size allows it to more effectively penetrate hair strands, leading to more effective glycolic acid showed a ~2.5˚C increase in TtrDe.4aTteadken distribution of glycolic acid compounds throughout the together, these tests show that hair samples entirety of treated hair and the elimination of water. with glycolic acid demonstrated a greater resistance Overall, improvements in hair characteristics such to water adsorption and a corresponding increase in as denaturation temperature, elastic modulus, and denaturation temperature. lubricity can all be obtained through the use of glycolic acid. This review shows that both healthy Increased lubricity and damaged hair can benefit from the addition Hair lubricity is largely the result of physical of glycolic acid in order to repair broken molecular properties affecting the outer cuticle of a strand of hair, a fibrous, cable-like structure of the cortex linkages within hair strands and prevent penetration enveloped by an array of scale-like cuticle cells that surround and protect the hair cortex, overlapping of hair by unwanted foreign molecules. P much like shingle roofing. * – Also contributing to this article were Jeffrey Weeks of CrossChem and Florence Olechowski of Berg + Schmidt Find more at www.specchemonline.com
\" # \"!\" ! 0 hours 2 hours *Naresh Jariwala* 4 hours 6 hours 8 hours 10 hours Figure 3 – Absorption of water droplets into hair Note – Left: hair treated with 7% glycolic acid solution. Right: hair treated with 7% citric acid solution P References: 5. F.J. Wortmann, G. Wortmann, J. Marsh & Knut 1. J McKittrick, P.-Y. Chen, S.G. Bodde, W. Yang. E.E. Meinert, Thermal Denaturation & Structural Changes Novitskaya & M.A. Meyers, JOM, 2012, 64(4) of -Helical Proteins in Keratins, School of Materials, University of Manchester & Procter & Gamble Service 2. K. Song, H. Xu, K. Xiea & Y. Yang, RSC Adv., 2016, 6, 58594 6. P. Jarreau & B. Clark, The Pursuit: LSU College of Science Blog, 16 May 2017 3. T.A. Evans, J.M. Altland, R. Burch & Jeff Horsager, Glycolic Acid No Longer Just For Skin – Changing the 7. F. Olechowski & S. Zhong, Glycolic Acid & its Internal Properties of Hair, T.A. Evans & DuPont Beneficial Effects on Hair: Claim Substantiation, In- House Testing, Berg + Schmidt 2018 4. J.M. Stasko, Determining the Effect of Using Glycolic Acid in Hair Care Products, DuPont Glypure 8. D.R. Goddard & L. Michaelis, A Study on Keratin, White Paper, 2009 Laboratories of The Rockefeller Institute for Medical Research, New York. Received for Publication, 16 May 1934 $ $ Find more at www.specchemonline.com
Don’t sweat it Rey Ordiales of Elementis looks at the key drivers in the choice of antiperspirant and deodorant actives MANUFACTURERS OF *Naresh Jariwala*Figure 1 – How sweat is formed (left) & how antiperspirants act against it (right) ANTIPERSPIRANTS are striving Claims & markets different claims varies from one to deliver products that meet market to another (Figure 2). consumers’ expectations for high Consumers commonly make their performance and varied forms, purchase decisions based on the Antiperspirant market trends while also addressing regional and manufacturer’s claims, most of are regionally driven by cultural, cultural attitudes and behaviours which are promoted in product geographic, temperature and that affect their personal hygiene marketing materials and on the demographic factors. The US habits and purchasing decisions. packaging. Typical claims may remains a large market but Latin In today’s market, end users want include: America is very significant too, access to traditional roll-ons, stick as Brazilians in particular include products, aerosols and individual •Sweat reduction antiperspirant and deodorant disposable wipes that perform as •Extra effectiveness products into their daily grooming per product claims. •Clinical or professional strength routines (Figure 3). In emerging •Reducing stress sweating countries with young populations, Key drivers include health and •Most advanced active technology such as India, changing lifestyles wellness, a growing middle class •Body-responsive or heat-activated and increases in product availability in developing regions, the desire •Protection for 48 or 72 hours are driving market growth. for multifunctional products that deliver skin care benefits and Other common product claims Product safety P meet the demand for effective, relate to aesthetic benefits. long-lasting performance. No These include low residue, skin An important trend in today’s matter what the product format, conditioning, moisturisation, market is increased consumer formulating with effective actives inhibiting hair re-growth, smoother awareness and preference for is the only way to meet wetness shaving, no irritation and low products formulated with protection claims. fabric staining. The prevalence of Antiperspirants v. deodorants Figure 2 – Regional variations in claims Source – Mintel GNPD 2019 Whether a consumer uses antiperspirant or deodorant depends on his or her activity level and personal preferences. Antiperspirants are deodorants, but deodorants are not antiperspirants. Put simply, deodorants are designed to mask or eliminate the body odour caused by the bacterial breakdown of sweat (or perspiration). They are typically considered to be cosmetic products. Antiperspirants combat odours by attacking their root cause, which is perspiration. They temporarily and superficially clog the pores of the skin to prevent sweat and the formation of body odour (Figure 1). Antiperspirants are considered to be an over-the-counter drug in the US and must meet the strict provisions of the FDA Antiperspirant Monograph (21 CFR Part 350). Find more at www.specchemonline.com
P natural ingredients. The vast majority of today’s antiperspirant products use aluminium salts as an active ingredient. These naturally derived and highly effective active ingredients have been used safely since 1952, when the first roll-on applicator was launched. They have undergone rigorous review by the US FDA, the EU Scientific Committee on Consumer Safety and the Japanese Ministry of Health Figure 3 – Regional retail market sizes & trends for antiperspirants & deodorants, 2018 & Welfare, and found to be safe for Note. Source – Euromonitor *Naresh Jariwala* use in antiperspirants, cosmetics, pharmaceuticals and antacids. Roll-ons are the most common residue on skin and clothing. Their In recent years, concerns have product form in cost-sensitive advantages include dry, non-tacky been raised in the press and markets. Liquid antiperspirant actives application, good product adhesion online about the potential for such as aluminium chlorohydrate to the skin and clinical strength. aluminium-based antiperspirant and the more effective aluminium active ingredients to cause harm. zirconium glycine actives are typically Conclusion However, these concerns have been used in this application form. Roll- For all product forms except aerosol, critically reviewed by prestigious on types include emulsion, hydro- the best performing products are scientific and governmental alcoholic, anhydrous suspension and aluminium zirconium glycine type bodies, who have determined thickened aqueous formulations. actives. For aerosol formulae, that aluminium does not pose a Application advantages include specialised enhanced-efficacy health risk when used as intended high efficacy in delivery (resulting aluminium chlorohydrate actives in cosmetic and pharmaceutical in no waste), even distribution provide the maximum wetness applications. of the active in solution and protection available. To achieve low residue (resulting in a clear clinical strength claims, formulators Product format & actives product). Some of the application would need to use concentrations Aerosols represent the fastest challenges include wet application approaching the 20% maximum growing antiperspirant product form. to the skin, which can be slow level on an anhydrous solids basis for Aluminium sesquichlorohydrate and drying or tacky while drying. aluminium zirconium active and 25% aluminium chlorohydrate, both in A mixture of cyclopentasiloxane, for aluminium chlorohydrate-based powder form, are the actives most isododecane and PEG-10 products, as allowed by the US FDA. used in these spray applications. They dimethicone disteardimonium Aluminium and aluminium are typically formulated as anhydrous hectorite for emulsion stability will zirconium salts are time-proven, powder-in-oil suspensions, with a dry, yield benefits like thixotropic flow effective personal care actives non-tacky application. for ease of pouring when needed, that provide antiperspirant and Easy, quick and clean application more uniform coverage, enhanced deodorising effects. A large make this an increasingly popular stability, sensory attributes for selection of actives is available to form among consumers globally. consumers, such as ease of the formulator to design tailored Consumers appreciate application application and a silky after-feel. products to serve specific market advantages like spraying on dry, A trihydroxystearin thickener will needs. Product formulators can turn being convenient and hygienic, deliver an outstanding sensory to speciality chemicals experts for ready application – for example, profile, pH and electrolyte stability, consultations on active selection and on a hot day or after exercising – plus easy incorporation. formulation development as well as and enhanced fragrance effect. Stick products are an efficacious samples of high-performance actives Product bounce-off remains an product form, popular for clinical to allow them to meet the demands application challenge that reduces strength performance. They of consumers around the world. £ the product form’s overall cost- comprise complex gelled wax effectiveness. Including a suspending systems with powder active and CONTACT and anti-caking agent, like an aesthetic modifiers suspended in optimised organoclay dispersion, will an emollient oil carrier system. Rey Ordiales provide such benefits as suspension High performance aluminium Technical Service Manager - and uniform dosage of actives, zirconium complex actives with fine Antiperspirant Technology better re-dispersal of settled actives, particle sizes are typically used to Elementis prevention of nozzle blocking, and optimise appearance and efficacy, +1 609 443 2291 fewer staining and whitening effects along with high refractive index [email protected] on clothing and skin. fluids to minimise visible white www.elementis.com
$ # ! ! \" *Naresh Jariwala* Risk evaluations under TSCA: The state of play Lynn L. Bergeson of Bergeson & Campbell summarises how the EPA is going about implementing Congress’s risk evaluation mandate AMONG THE CHANGES when Risk evaluation process The processes Congress mandated the Toxic Substances Control are fairly straightforward. The EPA Act (TSCA) was amended by the Under TSCA, the EPA was not is to: Frank R. Lautenberg Chemical required to assess the potential Safety Act for the 21st Century, risks posed by existing chemical •Prioritise active, existing also known as Lautenberg or ‘new substances to any discernible TSCA’, none is more consequential schedule. This glaring omission chemical substances into ‘high’ than the requirement that the US was the subject of chronic, Environmental Protection Agency withering criticism and a key and ‘low’ priority categories (EPA) conduct risk evaluations for rallying cry for reform. ‘high priority’ chemical substances. •Assess the potential risks of high We are now three years into new New TSCA included specific TSCA and this is being done, amid requirements for the agency to priority substances spirited debate and, inevitably, develop and implement chemical litigation. prioritisation and risk evaluation •Publish the intended scope processes by June 2017, a deadline it met. of the risk evaluation to aggressive timelines •Complete the risk evaluation no later than 42 months after its initiation P Find more at www.specchemonline.com % %
$ # ! ! \" The EPA is overseeing the administration of reformed TSCA P Chemical uses found to pose *Naresh Jariwala*peer-review two in 2019 and thecertain conditions of use, and unreasonable risks must be remaining four in 2020. any resulting exposures deriving mitigated until the risk is abated. from the risk evaluations, violates Since the EPA has identified The EPA is also required to ensure TSCA. They argue that the law’s more than 40,000 active existing that risk evaluations are under mandate to determine whether chemical substances, the process way for a least 20 high priority a chemical substance presents will continue for decades. substances and to designate at an unreasonable risk requires an least 20 chemicals as low priority evaluation of its total risk and the To get things started, the EPA was substances by the end of 2019. On phrase ‘under the conditions of required to initiate risk evaluations 20 March, the agency published a use’ “unambiguously means all of on ten chemicals drawn from the list of 40 chemicals, 20 of each, for the chemical’s conditions of use”. 2014 update of the TSCA Work prioritisation purposes. It intends to Plan for Chemical Assessments. issue timely final designations. The petitioners also argue that The agency released its first the EPA unlawfully rewrote the draft risk evaluation of the ten The inevitable: Litigation definition of conditions of use to substances in November 2018 Unsurprisingly, not everyone is omit a chemical’s current and future concerning the chemical Colour pleased with the EPA’s efforts. Since use and disposal if its manufacture, Index (CI) Pigment Violet 29. Lautenberg was passed, more processing, and distribution for The Science Advisory Committee than 20 lawsuits have been filed that specific use are not ongoing – on Chemicals (SACC) has since against, challenging regulatory so-called ‘legacy uses’. Congress’s conducted a peer review on this. actions, including the chemical risk inclusion of ‘use’ and ‘disposal’ evaluation process. Several NGOs as ‘conditions of use’ rule out this Three other risk evaluations for challenged the rules in two different construction, they assert. substances included in the first ten federal appellate courts. The cases have been released for comment were consolidated in the US Court On 16 May, the court heard oral and peer-reviewed by the SACC, of Appeals for the Ninth Circuit, arguments. It questioned whether including 1-bromopropane, with Safer Chemicals, Healthy petitioners had standing to be 1,4-dioxane and cyclic aliphatic Families as the lead petitioner. before the court and suggested bromide cluster. The EPA intends that they could wait to see whether to release four of the remaining At the litigation’s heart is the the EPA will ignore certain uses of draft risk evaluations for public EPA’s interpretation of chemical use chemicals in its risk evaluations. comment by the end of 2019 conditions that must be considered Next, the court ordered the and the other two in January in a risk evaluation. The petitioners petitioners to file a supplemental 2020, while the SACC intends to argue that its decision to exclude brief addressing why they should be % % Find more at www.specchemonline.com
allowed to bring a lawsuit against *Naresh Jariwala*developed by the EPA and developThe implications of this decision the EPA, potentially foreshadowing that record. are considerable. If citizen plaintiffs a determination that the case is not are able to obtain de novo review yet ripe for review. In late 2016, Food & Water of EPA decisions in response to Watch and others filed a Section 21 administrative petitions, reviews Administrative challenges petition under new TSCA seeking to unbounded by the agency’s Before we move off judicial prohibit the addition of fluoridation administrative record and challenges, we should reflect briefly chemicals to drinking water. The supplemented by new evidence on another area in hot dispute. EPA denied the petition. The citizen elicited by trial court discovery TSCA Section 21 authorises ‘citizens’ petitioners appealed the decision rules, they may be inclined to to file petitions with the EPA urging to the US District Court for the do this as a convenient work- it to issue, amend, or repeal a rule Northern District of California, around to unfavourable TSCA risk or order issued under, among other asking the court to declare that they evaluations. TSCA provisions, Section 6. This is had properly shown that this poses an administrative procedure that unreasonable risks under TSCA. Litigation is expected to requires the agency to respond continue. And the chances are not within 90 days of submission. The EPA sought to dismiss the motivated stakeholders will pursue action, which the court denied. administrative remedies under Petitioners may seek judicial The agency then sought to Section 21. £ review by a federal district court limit the record on review to its of a petition denial or may administrative record and to CONTACT appeal if the EPA fails to respond bar the petitioners from seeking in time. Under the rules, the discovery. The court denied that Lynn Bergeson reviewing federal district court is motion too, ruling that the scope Bergeson & Campbell granted de novo review, which of its review is not limited to the has traditionally meant that administrative record, that a de + 1 202 557 3801 the reviewing court would be novo ‘proceeding’, to quote the [email protected] authorised to review the entirety statute, reflected Congress’s desire www.lawbc.com of the administrative record to allow the reviewing court to consider additional evidence. Find more at www.specchemonline.com
$ # ! ! \" Brexit for EU-27 companies *Naresh Jariwala* The UK authorities are trying to keep EU-27 companies informed about how to handle the post-Brexit transition. We report from a recent event THE UK WAS due to leave the EU over the functions of the European paying any applicable fees to the on 31 October, so an information Chemicals Agency (ECHA) in the HSE; or, to register the substance event about what this would mean planned UK version of REACH. themselves using a UK-based for companies in the chemical entity, i.e. an Only Representative industry when CPhI Worldwide Most of the official planning (OR). UK downstream users can came to Frankfurt the week went into the ‘no deal’ scenarios. use the notification process to after seemed logical enough. Regulators, the speakers said, ensure compliance in the interim One was duly organised at the would have been ready had this between the date of exit and British Consulate-General on 4 happened on any of the days acceptance of the registration. November. In the event, of course, in 2019 where it might have Detailed guidance is available on there was no exit on Hallowe’en. happened. About 150 additional the HSE website, covering multiple staff had been recruited to man different scenarios. ECHA has also Instead, Brexit was extended to helpdesks and prepare for a future published guidance. 31 January 2020 and the UK was trade agreement. Work went into preparing for a general election on implementing the planned ‘lift Because the discussions were 12 December and every possibility and shift’ of EU regulations into conducted under ‘Chatham House was still open: the revocation of UK ones and to build capacity rules’, no quotes could be attributed Article 50; a managed exit with generally. The UK REACH-IT system to individual speakers. They have a free trade agreement after a has been built out and exercises therefore been anonymised and transition period to the end of carried out to test it in as close to the rest of this article is presented 2020; a no-deal exit at the end of real-life scenarios as possible. in a Q&A format, as voiced by 2020; or an immediate no-deal attendees at the event and the HSE exit on WTO terms. As one speaker A statutory instrument has been and DEFRA speakers. quipped: “Brexit has had more put in place setting out transitional twists and turns than polymethyl measures on what businesses Importers to the UK will have disiloxane”. should do to retain access to the to notify every product they UK market. All existing UK-held import there, but no supplier Although there were other registrations and authorisations will supply their full recipe speakers, the audience mostly under REACH for substances and the need to resubmit a wanted to hear from officials imported from the EU will remain dossier within two years will at the two bodies that will take valid on and immediately after make doing business very over responsibility for chemical exit day. difficult. What to do? regulation if and when the UK leaves: the Department for the EU exporters have two options: It is beyond our control to be Environment, Food & Rural Affairs to have a UK customer notify the involved in those commercial (DEFRA) and the Health & Safety substance as an importer within Executive (HSE), which will take 180 days and register it within two years, with a full data package, % % Find more at www.specchemonline.com
negotiations. We support trade *Naresh Jariwala*that’s a different matter. In ECHA has with Canada speaks of associations in encouraging addition, the government has ongoing cooperation and exchange companies to be pragmatic made a political declaration about of staff. If we have something like about sharing data but we also the future relationship with the EU that, we at least have an idea of recognise that it is quite possible and that talks about cooperation what the EU approach is and what that some companies holding the with ECHA. This remains subject is coming down the system. The UK rights to data will believe that it is to negotiation, which is a big government will need to take some not in their commercial interests caveat, but there may be scope in quite strategic policy decisions. On to make it available. We cannot the future for the UK to negotiate a more practical level, there may know before leaving quite what access to the data. be divergence for a short time if the will happen when we do. There government takes political decisions will be pragmatic solutions and We are in the easy phase about what is in the UK’s best the problem will not be as bad as right now – it has essentially interests. In taking them, we would it could be. It would be interesting been ‘copy and paste’ with not be replicating the procedures to hear what the ‘mood music’ is some nice thoughts about the of REACH and ECHA but we would on this. Some companies seem transition period. In five to be following the same principles of to be waiting on what everyone ten years from now, how far scientific advice and transparency else does! The two-year period is will UK REACH diverge from in decision-making. We would about striking a balance between EU REACH in terms of say, probably take the view that the giving a reasonable amount of rules and IT systems, or if the science and the hazard are what the time to obtain the information EU makes major reforms to EU assesses them to be, but might and recognising that the HSE REACH? And what is Britain’s not want to go down the route of will need it within a reasonable business model after Brexit? restrictions and authorisations. The time. We will keep the timeline post-Brexit model will depend on under review – though of course Alignment with the EU does have the outcome of the election: Prime if a company does not want to some impact on the UK’s ability Minister Boris Johnson’s vision make that information available, to strike trade deals with other is of a Canada-style free trade it does not matter how much time countries, in chemical regulation agreement and looser alignment, is given. Our regulatory approach and other fields. If we want our own while Labour has promised to is based on looking at the areas independent regulatory regime, renegotiate the exit deal with the of major risk and these are about that makes it difficult to simply EU and take a new deal back to use, not supply. So, if you have rubberstamp whatever the EU does a second referendum, including not got a registration or the full – and, as a third country, we would closer alignment on regulation and data package in that two-year no longer have the same shared workers’ rights. period, you are not going to feel resource and would not be in the the full wrath of the regulator on same work programme. The issue is What information will have Day One. The key question for us about where the government wants to be put into a UK-REACH IT is whether or not you are trying to strike that balance. A lot depends system? to come into compliance. If you on the agreement we make with the are trying but are struggling to get EU, both in terms of trade with the Based on the discussion we have the data, we will take a pragmatic EU and on cooperation with ECHA. had, it should be the simple approach. If you are freeloading, A memorandum of understanding information you already have, P Find more at www.specchemonline.com
$ # ! ! \" P such as the names and addresses of the business – the data fields will be the same as in REACH, with the only difference being that it must be a UK-based company. You will not have to provide any other new information. It will be a Iuclid-based system, so if you have the data you can input it in the same way as in EU REACH. How will polymers and Annex IV and V substances be treated under UK REACH? *Naresh Jariwala* In the initial stage, everything on Annex IV and V at the time of leaving will have exactly the same status in UK law as in EU law. Going forward, the UK will have to have some discussion about whether it adopts the same approach. Will it be easier and cheaper commercial. We need to distinguish to access the UK market. From to register chemicals in the UK between registration and the that point of view, the advice to if they are only intermediates regulatory part. The latter, such companies based in the EU-27 being processed there via as Annex IV and V, will stay the is to find someone based in the multi-step synthesis and are same when we leave unless the UK UK to handle the registrations not destined for export to makes a conscious decision to do under REACH, the CLP or the BPR, the EU-27 as part of the final something differently. Registration because EU-based registrations product? is about market access. will no longer apply in the UK. It is the same in reverse for UK It will certainly be an easier and What should companies do companies who want to export cheaper procedure if they stay to handle the short-term to the EU. Under REACH, there is in the UK. Ultimately, if they go implications of a no-deal the option of another company abroad, somebody will have to situation? How should we or an OR to do the registration, take the decision about who is organise our supply chains, but the other regulations require exporting this and then find an for example? Can we continue an importer to place your product importer willing to place it on the to supply products to the UK on the market. You need to know market in the EU. in the aftermath? your supply chain and who, in the UK, receives your product, then If the systems are basically We recommended, in advance of begin a dialogue with them to going to be the same, would a no-deal exit, having a look at see if they are ready to accept the it not be sensible if companies the guidance and the transitional responsibility of placing it on the could ‘grandfather’ EU provisions we put in place. These UK market. If materials are on the registrations in the UK? are intended to ensure a transition UK market ahead of a no-deal period so companies can maintain exit, they will be allowed to remain In a way, the difficulty arises access to the UK market. The dates on the market, but at some point, because we have ‘lifted and for providing the basic information you will have to find someone shifted’ REACH into UK law, so we and the two-year limit to supply the registered in the UK to do it. £ are also lifting the ‘no data, no detailed information were created market’ principle. We have to have to make it as easy as possible to CONTACT that data within the two years in continue to supply the UK after a order to validate the registration no-deal exit. If we leave, then the Health & Safety Executive and allow access to the UK market. UK regulatory regime will come The bottom line is that we will into play and companies will www.hse.gov.uk/brexit shift the regulation but the EU will need to be established in the UK retain the data and won’t release this to a third country, because it’s % %
*Naresh Jariwala*
! Biocatalytic oxidations using oxygen at pilot plant-scale *Naresh Jariwala* Martin Schürmann of InnoSyn reviews some recent case studies from the RoBOx project* BECAUSE MOST FINE and available and demonstrating Target biooxidation enzymes speciality chemical compounds their applicability at pilot plant are oxygen-functionalised organic scale should close the gap & reactions molecules, the efficient introduction between academic and industrial of hydroxy functionalities and biooxidations, at least partially. To ensure the development and their further oxidation represent demonstration of a broadly key transformations in chemical We further reasoned that the applicable technology platform synthesis. Especially with regio-, oxygen supply in standard stirred- we selected four enzyme classes chemo- or enantioselective tank-reactors could also limit directly or indirectly relying on reactions, biocatalytic efficient biooxidation processes. molecular oxygen as oxidant: transformations catalysed by Therefore, we began a project to cytochrome P450 and Baeyer- isolated enzymes or whole demonstrate the applicability of Villiger monooxygenases (P450s cells are often superior to biocatalytic oxidations with oxygen and BVMOs) and alcohol oxidases chemocatalytic approaches. as terminal oxidant, as part of and dehydrogenases (AOXs and the EU Horizon 2020 project, ADHs, Figure 1). On the other hand, few such RoBOx (Robust Biocatalytic processes have been implemented, Oxidations). This article discusses P450s and BVMOs selectively mainly due to low productivity and some demonstration campaigns introduce an oxygen atom into high enzyme consumption. Making performed in InnoSyn’s pilot (non-activated) C-H bonds and more stable and active enzymes plant facilities. C-C bonds next to a carbonyl, respectively. These reactions require the biological reduction equivalent Gluconic acid D-glucose Gluconic acid D-glucose Glucose Glucose dehydrogenase dehydrogenase NADH Catalase oxidase Figure 1 – Enzymatic oxidations using molecular oxygen as terminal oxidant \" \" Find more at www.specchemonline.com
bottle and measuring the oxygen concentrations dissolved in the reaction mix and in the off gas, were both essential. For each of the demonstration cases, we performed thorough safety and Hazop studies to determine the windows of safe operation. As we wanted to apply pure oxygen, a key aspect was to avoid forming combustible mixtures of organics and oxygen during the reaction, especially in *Naresh Jariwala* the reactor headspace. Based on the initial reaction characterisation and optimisation at small scale and the Hazop studies, we identified sufficiently wide windows of safe operation to transfer all processes to our pilot plant, which allowed high reaction productivities without compromising safety. Figure 2 – Enzymatic oxidation reactions using four different redox enzyme classes One safety measure was to cmoonntiintourotuhselyOin2 concentration the liquid phase nicotinamide adenine dinucleotide finally optimised and scaled up to and in the gas outlet at 1L scale. in its phosphorylated and reduced 100L pilot-scale demonstrations form (NADPH) to reduce the second at InnoSyn. Four – one for each The oxygen concentration in the oxygen atom to water. enzyme class – will be discussed here, one briefly because it has reactor headspace was kept below While both AOXs and ADHs, been published before, highlighting can selectively oxidise one of the scale-up and oxygen supply 8% (v/v) using a nitrogen sweep. In the hydroxyl-groups in a target strategy aspects (Figure 2): molecule to a carbonyl, AOXs use addition, the oxygen measurements oxygen directly in an irreversible • Allylic hydroxylation of breya-pctrioodnu, cptr.oAdDuHcisngusHe2NOA2 Da+s or enabled the operator to ensure NADP+ as a direct oxidant, which -isophorone to 4-hydroxy- needs to be recycled back to the isophorone by a P450 that sufficient oxygen was always oxidised form to make material costs viable. This can be achieved • Baeyer-Villiger oxidation available in the reactor. elegantly by coupling the oxidative ADH reaction with an NAD(P) of cyclopentadecanone to Regioselective P450 H oxidase (NOX) that consumes pentadecalactone by a BVMO hydroxylation of -isophorone molecular oxygen and forms only -isophorone is a readily water as by-product. • ADH oxidation of a lactol to a available precursor to many fine chemicals, including monomers As P450s and BVMOs consume hydroxy-lactone for speciality polymers and the reduced form NADPH, the vitamin intermediates. It has to oxidised NAD(P)+ has to be recycled • Oxidation of vanillyl alcohol to be hydroxylated and oxidised using a different enzyme. Most often, when used to make the vitamin E glucose dehydrogenase (GDH) vanillin by an AOX precursor keto-isophorone. is used, with cheap D-glucose as sacrificial substrate. This is oxidised Oxygen supply & safety While chemical oxidation to D-gluconolactone, spontaneously The systematic characterisation occurs via the thermodynamically hydrolysing to D-gluconate at neutral and optimisation of the reactions unfavourable, energy-intensive pH. Finally, the H2O2 produced by occurred in parallelised 50 ml isomerisation to-isophorone, AOXs has to be scavenged. auto-titration reactors, controllable P450 enzymes can directly in stirring and temperature and perform allylic hydroxylations Among the 11 demonstration equipped with adjustable aeration of substrates like-isophorone cases selected from various by pre-wetted environmental air. to 4-hydroxy-isophorone. The chemical segments, seven were For process development from 1L subsequent oxidation of the latter scale onwards, a controlled oxygen can be performed chemically or supply with pure O2 from a gas enzymatically. We succeeded in performing an in principle redox-neutral enzymatic cascade of P450 and ADH, as discussed in previous P Find more at www.specchemonline.com
! P publications.1,2 However, the productivity of this cascade was one order of magnitude lower than the space-time yields of 1.0 g/L-1/h-1 we obtained earlier using the GDH/ glucose system producing >1 kg of product in two 100L batches.1,3 BVMO-catalysed Baeyer- *Naresh Jariwala* Figure 3 – BVMO-catalysed oxidation of cyclopentadecanone to pentadecanolide using O2 as oxidant. Villiger oxidation of Note: NADPH recycled using GDH & D-glucose. Conditions: V = 100 L, T = 30°C, pH 7.5, 2 - 1 L/min O2, addition of CPD cyclopentadecanone portions in methanol, finally about 20% (v/v) methanol, 10% (w/w) D-glucose, 0.5 mM NADP+, 0.2% (v/v) GDH-01 and 17% (w/w) RrCDMO liquid enzyme formulations The biocatalytic Baeyer-Villiger oxidation of (cyclic) ketones to reaction did not cause combustible trees, but can also be produced by esters or lactones is of interest mixtures in the reactor headspace, biocatalysis, with natural aldehydes because of the usually high wbehleonwth8e%O(v2/vc)o. nTcheisntwraatsioancwhiaesvekdept as starting materials. enantio- and regioselectivity of sbuypmpleyatsoutrhinegreOa2c,tiaodnapprtoinggreitsss, and BVMOs.4 Even BVMO oxidations safeguarded with a N2 sweep. The most efficient and selective of unsubstituted cyclic ketones to ADH in the oxidation of this lactones can be attractive as they Chemo-/regioselective lactol massoialactone analogue was avoid using harmful chemical oxidation with ADH C-Lecta’s ADH-99. No oxidation of oxidants in chemical BV-oxidations. As target reaction for regio- or the secondary alcohol functionality chemo-selective oxidations of was detected, indicating a We used unsubstituted hydroxyl groups we selected complete selectivity of this enzyme cyclopentadecanone (CPD) as the oxidation of a lactol OH in for the lactol-OH group. model substrate for the BVMO a molecule, also containing a oxidation of hydrophobic and secondary alcohol function (Figure This enzyme was produced via poorly soluble macrocyclic ketones, 4). The hydroxy-lactol was derived E. coli fermentation and applied knowing that these enzymes can from a DERA aldolase reaction as freeze-dried enzyme together be regio- and enantioselective with based on a previously described with InnoSyn’s commercial NOX- similar, substituted ketones.5,6 procedure.8 01 liquid enzyme formulation. While ADH-99 tolerated high We applied CPD monooxygenase Such hydroxy-lactols and their lactol substrate loadings of from Rhodococcus ruber (RrCDMO) hydroxy-lactone oxidation products >50 g/L very well, the NOX with our thermo- and solvent-stable are useful intermediates towards enzyme was inactivated by lactol GDH-01 for NADPH regeneration flavour lactones. Natural -lactones concentrations above its water- (Figure 3).7 We produced both like massoialactone are currently solubility of about 35 g/L. enzymes in high cell-density, obtained by extraction from tropical E. coli fed-batch fermentations Applying polar but water- and used them as liquid enzyme immiscible solvents like 2-ethyl- formulations. hexanol, which form a second phase acting as a substrate For optimisation and scale- up, it was essential to identify methanol as a co-solvent which could effectively dose the substrate and improve its mass transfer into the aqueous phase where the enzymatic reactions occur. Eventually, we could apply up to 25% (v/v) methanol as RrCDMO was also very stable under this condition (95% residual activity after seven days). Finally, >4 kg of pentadecanolide (PDL) were produced using pure O2 in 100L reaction volume within ten hours and with 96% yield. Subsequently, PDL was isolated as a clear oil after extraction, filtration and distillation. Safety and Hazop studies before scale-up revealed that even the total of 25% (w/w) organics in the \" \" Find more at www.specchemonline.com
biocatalytic oxidation to vanillin by an isolated enzyme could thus be an overall efficient process, while preserving the natural grade of the vanillin product. Therefore, we embarked on demonstrating the technical feasibility and scalability of this reaction. The fundamental differences to the previous cases are that no cofactor has to be recycled and the by-product of the oxidation (wFiitghuorexy5g)e. nThiserneoftowrea,ttehrebauut xHil2iaOr2y *Naresh Jariwala* escnazvyemnegirnegqueinrezydmwealsikaencHat2aOla2-se, to protect oxidase and reactants from chemical oxidation. In the reaction characterisation and optimisation on 50 mL to 1L scale, we added a commercial catalase. EUGO from Rhodococcus jostii has a high activity and affinity for vanillyl alcohol and was efficiently produced in high cell- density E. coli fermentation in our labs.9 Base titration was required Figure 4 – ADH-catalysed oxidation of a hydroxy-lactol to the corresponding hydroxy-lactone to compensate for the formation using O2 as terminal oxidant. of the more acidic vanillin product Note: NADP+ recycled using NOX & O2, forming H2O as by-product. Conditions: V = 75 L, T = 28°C, pH 7.0; Ratio of 2-ethyl-heaxanol plus lactol to water phase 1:1. 5% (w/w) hydroxy-lactol, 0.5 mM NADP+, 1 g/L ADH-99, 4% (v/v) NOX- and keep the pH at 9.5. 01 liquid enzyme formulation Dark colour formation and incomplete mass balances – especially at basic pH values – indicated that significant amounts reservoir, protected the NOX from at a productivity of 6.3 g/L-1/h-1. roefaHc2tiOon2sw, edrueesttoill present in the inactivation and facilitated the In the pilot plant reaction, the the low affinity fast and quantitative oxidation of product yield calculated on the the hydroxy-lactol at 50 g/L. With oxygen consumption fitted well with of catalases for it. Consequently, 50% 2-ethyl-hexanol and 50% the yield based on GC analysis, buffered aqueous phase 50 g/L of despite a certain deviation or delay. higher activity loadings of catalase hydroxy-lactol were quantitatively oxidised at 1L scale within four Chemo-selective oxidation did not solve this issue, while the hours, using pure oxygen for the of vanillyl alcohol by AOX NADPH re-oxidation through the to vanillin chemical quenching of Hto2Ob2e with NOX enzyme. The pilot plant campaign with the sodium sulphite proved fourth enzyme class of alcohol The safety studies again revealed oxidases was carried out with effective.10 that no combustible mixtures eugenol oxidase (EUGO) and could form when using pure vanillyl alcohol as substrate. While Remarkably, the oxygen supplied oxygen, even when 50% of the the chemical synthesis of vanillin reactor content was organic can be regarded as efficient to the reaction was mainly components. Therefore, we scaled and cheap, the biotechnological up the reaction linearly from the production of natural vanillin is consumed by EUGO for vanillyl lab to our 200L pilot plant reactor, hampered by the toxicity of vanillin again taking care that oxygen to recombinant production hosts. alcohol oxidation, while the sodium concentrations in the headspace did not exceed 8% (v/v). Vanillyl alcohol production does sulphite was preferentially oxidised not have this toxicity issue and can In 75L of total reaction volume, achieve higher product titres. The bsoydHiu2mO2s.uAlp3h3it%e molar excess of 3.5 kg of hydroxy-lactone were combination of vanillyl alcohol with respect to produced at >95% assay yield production by fermentation and its within eight hours reaction time vanillyl alcohol was sufficient for almost quantitative vanillin yields. We therefore performed the EUGO oxidation of 5 kg vanillyl alcohol to vanillin in 100L reaction volume with sodium sulphite instead of catalase. Within nine hours, more than 4 kg of vanillin were produced, which relates to a high space-time yield of about 4.2 g/L-1/h-1. P Find more at www.specchemonline.com
! P Sodium sulphite consumption in the pilot plant was higher than at lab scale: after five hours the mass balance decreased and the base titration increased, probably due to the formation of Dakin oxidation side-products from vanillin. Dosing an additional 0.2 equivalents of sodium sulphite brought the reaction back on course until it was terminated after nine hours at 95% conversion. The enzyme material was filtered off and vanillin was extracted with isopropyl acetate. No overoxidation to vanillic acid could be detected at any EUGO reaction scale, underlining the exquisite chemoselectivity of this biocatalytic oxidation. *Naresh Jariwala* Conclusions Figure 5 – AOX-catalysed oxidation of vanillyl alcohol to vanillin with O2 as oxidant & H2O2 as by-product. We have successfully scaled up four different oxidative Conditions: V = 100 L, T = 25°C, pH 9.5; 5% (w/w) vanillyl alcohol, 5.5% (w/w) sodium sulphite (initially), aeration: 4 - 1 L/ enzyme classes in our pilot plant min pure O2, 5% (w/w) EUGO liquid enzyme formulation facilities. In all cases, oxygen had to be applied in form of References 6. J. Brummund, H. Straatman, tphuereh,igchomprpordesuscetidviOtie2storeaqcuhirieedve 1. M. Tavanti, F. Parmeggiani, N. Smeets, C. Kleist, W. Peeters, for the non-pharma products J.R. Gómez Castellanos, A. Mattevi M. Müller & M. Schürmann, selected for the demonstration & N.J. Turner, ChemCatChem unpublished results campaigns. 2017, 9, 3338-3348 7. J. Brummund, C. Kleist, High oxygen-transfer rates 2. W. Bonrath, J.R. Gómez M.P. Meissner, G.D. Rane, required for high volumetric Castellanos, A. Mattevi, J.M. Woodley & M. Schürmann, productivities of up to 14 g/ F. Parmeggiani, M. Schürmann, in preparation L-1/h-1 could be achieved in a M. Tavanti & N.J. Turner, standard 200L stirred-tank- International Patent Application 8. D. Mink, M. Wolberg, reactor of our pilot plant with only 2018, WO2018/185304A1 M. Schürmann & I. Hilker, slight adaptations to the reactor. International Patent Application Based on all these findings we 3. I. Kaluzna, T. Schmitges, 2007, WO2007/068498A1 foresee a good predictability and H. Straatman, D. van Tegelen, scalability to full-scale industrial M. Müller, M. Schürmann & 9. J. Jin, H. Mazon, R.H. van den processes with all four enzyme D. Mink, Org. Process Res. Dev. Heuvel, D.B. Janssen & M.W Fraaije, classes, especially ADH, AOX and 2016, 204, 814-819 FEBS J. 2007, 274, 2311-2321 BVMO biocatalysts. 4. N.M. Kamerbeek, D.B. Janssen, 10. H. Straatman, J. Brummund & On the way to these pilot plant W.J.H. van Berkel & M.W. Fraaije, M. Schürmann, submitted. demonstrations, we and the other Advanced Synthesis & Catalysis RoBOx project partners developed 2005, 345 (67), 667–78 CONTACT platforms for new, more robust BVMO, P450, ADH and AOX 5. H. Iwaki, S. Wang, S. Grosse, Martin Schürmann enzymes, as well as GDH and H. Bergeron, A. Nagahashi, InnoSyn BV NOX enzymes for cofactor J. Lertvorachon, J. Yang, Y. Konishi, regeneration. Scalable protocols Y. Hasegawa & P.C. Lau, Applied & [email protected] and processes to produce them Environmental Microbiology 2006, www.innosyn.com by fermentation were established. 72 (4), 2707-2720 Altogether, we have taken significant steps to bring the successful industrial application of oxidative enzymes using oxygen from the exception to the rule. £ \" \" Find more at www.specchemonline.com
*Naresh Jariwala*
Having its own fleet of trucks is integral to Airedale *Naresh Jariwala* Keeping it in the family Airedale Chemical has changed its Marr – Airedale perfectly suited to contract emphasis under a third generation manufacturing managing director. We went to pay the company a visit AIREDALE CHEMICAL IS something The single most important now five qualified chemists in of a throwback in the days driver of Airedale’s growth, says the labs, three on the chemicals of rebrands and M&A-driven commercial director Daniel Marr, side and two on dyes, and the change. Not only is it named after who oversees sales, marketing company now has all the facilities something tangible – the area of the and the technical side, has been needed to do QC, sampling and UK where it is located, quite close to phosphoric acid. In 2008, Airedale new product development. Money Haworth, the world famous home concluded a distribution agreement also went into new departments of the Brontë sisters – it is entirely with China’s Chengxing Group. including marketing and owned by the Chadwick family, with This injected about £15 million/ procurement, then, in 2015, the no external shareholders. year of additional turnover into it. acquisition of Rigest, a distributor The company has now been The money was reinvested in a in operation for 45 years. When way that changed the landscape, Brian Chadwick founded it in notably in new mixology for the 1973, the company consisted of site, allowing it to become a him formulating dyes in a cement manufacturer for the first time. The mixer for the local textile industry. site has been extended, with four In that first year, it turned over new warehouses, and a new tank about £56,000. Since then, it farm is also nearing completion. has had four different sites but This is the direct result of the has been at its current one at growth of manufacturing and an Cross Hills, near Keighley in West expanded customer base. Yorkshire since 1994. Chemical trading began in 1997. Other investment has gone into the R&D laboratories – there are ! ! Find more at www.specchemonline.com
of food ingredients turning over *Naresh Jariwala* “We want to use peracetic “Relationships are in our culture about £3.5 million/year. acid, one of our manufactured and in the staff philosophy,” products, as the basis for how says Marr. ‘Out staff have good The biggest end use market we take it forward and do more relationships with each other, at present is water treatment, as manufacturing here,” Marr which is why they rarely leave the Airedale supplies phosphoric acid says. Now that the site has been company. Our sales team has a to all the major utilities. Others expanded with more and larger relationship-focused strategy with include cleaning and detergents, vessels, Airedale wants to sweat our customers. We have built some into which it sells peracetic acid those assets more. great relationships with suppliers and commodity surfactants. The too, to get the best raw materials company also sells farm chemicals, Four key values at the best prices. And we have such as manganese nitrate, which “One thing I have been adamant good distribution agreements on is used in fertilisers. As yet, it is not about is having a set of values for these with multiple suppliers.” very strong in this market and the company that really highlight Marr recognises that it needs the attributes of Airedale, including Coping with Brexit to partner up with others with being [an] independent, family The latter, adds Marr, “is good for more knowledge of the relevant business,” says Marr. He cites us in terms of Brexit-proofing” – chemistry. four in particular: quality, trust, and Brexit preparation has been innovation and relationships. another of his responsibilities. The In 2016, Chris Chadwick company has drawn up a priority succeeded his uncle Richard, Quality is mainly delivered list of the top 16 products that who is now the chairman, to through customer service, by account for most of its sales, within become the firm’s third generation means of a dedicated account which the procurement department managing director. This led to management service and next-day has worked with manufacturers to a series of new appointments. delivery in most instances – in some establish their REACH position and Marr himself, formerly head of it is same-day, though Airedale’s secure the supply chain, much of marketing, joined the board recent growth makes that harder to which comes from the EU. in January 2019. It also led to do – all based on speed, tracking a change in philosophy, from services and punctuality. Having most of its sales in the aggressive growth in commodity UK, recruiting locally and owning chemicals to evolving into new “Richard Chadwick’s ethos was its own fleet of 20 trucks give some product areas as well. always that the customer gets what protection against the potential he wants as quickly as we can get negative impacts of Brexit, it to him. Without that, we are not whatever those might turn out to an important company,” adds be, Marr says. In addition, Rigest Marr. For this reason, the company brought with it an Irish subsidiary, does not run on a just-in-time which has enabled Airedale to basis; it keeps stock levels high in move its BPR registration for P order to be able to supply at short notice. A small pack line is a recent investment The second factor, trust, emanates from being a family business. “Our sales team builds relationships with customers and our scale is much smaller than that of some of our competitors,” Marr says. These vary from field to field: from the large distributors like Brenntag in many arenas, to others on a product-by-product basis in key products. “Innovation is something we are working at all the time. We do it by looking at new product categories and we are spending a lot more time in R&D.” Among these are phosphonates, where Airedale is developing new products and signing distribution agreements in new areas to broaden its range, acquire more technical expertise and generally boost its market credibility. Find more at www.specchemonline.com
Storage tanks outside P peracetic acid to them and *Naresh Jariwala*flocculants in industrial waste water“This is right up our street and it’s continue trading with the EU. treatment processes. how the Chadwick family wanted the company to be built and to look There have been questions from The company also makes in contract manufacturing,” Marr customers about Brexit, but none surfactants and has a heritage says. “These are the kind of things has stopped working with Airedale business in dyes and auxiliaries for large players would often tend to because of it. “It’s been a headache the carpet industry, mainly in Eastern pass on but we are finding angles but I feel we are in a comfortable Europe, that is still profitable. Over in this market and seeing some real position and have done everything the next three years, the aim is to value in it as well.” we can to address it,” Marr says. develop an expanded, higher value Despite all the uncertainties, 2019 range of products. The contract manufacturing has been a very good year overall. business, he adds, is going very The company is fully on budget and Push to CMO well. The customer base has the top 16 products are all poised to Another thing Marr will grown by about 30% over the deliver the results expected of them. particularly push is the contract last three years and there are manufacturing side. Airedale, he some exciting projects going on Airedale does not see itself as a says, is a “perfect company” for at present. “Brexit doesn’t seem speciality chemicals company – at this. “Because of our scale and to be having an impact on these least not yet. “I’d like to think that structure, we can make decisions opportunities either: we are still in the next five years it is something quickly about whether a particular getting a lot of enquiries about we could call ourselves, but we chemistry can fit or not. We can it, as a UK company, despite the can’t shy away from the fact that adjust things on our site and invest unknowns.” we were built on commodities and quite quickly as well and, although they will remain important. What we have a modestly sized site, we Because it can take a long time we want now is to develop more have scalability.” from lead to reality in contract strings to our bow,” says Marr. manufacturing, Airedale still needs The company is currently working to grow its off-the-shelf product The range includes multiple on a number of products on this sales that deliver from day to day REACH-registered phosphonates, side of the business and has seen “but the contract manufacturing including reactive grades. In a lot of interest. The applications opportunities are the future of the April, Airedale launched two new are all industrial, including a company. There is a high degree of distributed products in Airfoam, a demulsifier for the oil market, and security – you are working with the range of four silicone and non- niche – so much so, in some cases, customer to get from A to B and silicone products to control foam that the markets for them cannot there is trust involved in working once it has formed, and Airpol, even be identified as such. with a customer’s formulation.” a range of ten polymers used as ! ! Find more at www.specchemonline.com
In early 2018, a small-pack *Naresh Jariwala*on the business,” Marr says. Thefrom 2017 to 2018 and a second chemical filling line was acquired. philosophy has now changed borehole is being sunk on site so Airedale supplies industrial totally. Three years ago, the that the company can source all customers with 25L packs and Airedale Foundation was set up of its water needs on-site. A new has its roots in bulk packaging to build a relationship with the building, which is going up now, will but has seen a growth in interest local community, largely through have solar panelling on the roof. for small pack options, including partnerships with local primary dilution, among customers. and secondary schools, as well Finally, the routing of the fleet is Hazardous waste management as sponsoring defibrillators and organised to reduce the company’s has been another recent addition, maintaining public toilets. carbon footprint much as possible. starting with taking in phosphoric “Having them is an expensive acid waste from a carbon The initiative has included regular pleasure for the company but black-producing customer for work placement schemes and taking ultimately it’s intrinsically linked to regeneration and resale. part in Bradford Manufacturing our values, enabling us to deliver Weeks, a series of events organised next day,” says Marr. “Without In the community by the West & North Yorkshire them, we would be just another The site, which is hemmed in Chamber and led by Bradford chemical company using external by residential housing and Chamber of Commerce, to haulage.” £ commercial development, now encourage young people to consider has limited options for further careers in manufacturing. As a result CONTACT growth. Indeed, Airedale has of all this, Marr says, the community expanded more than would ever has become more receptive to Daniel Marr have been expected when it came Airedale, which won this year’s CIA Commercial Director to Cross Hills. This has created Reputation Award. Airedale Chemical its own challenges in terms of the Company Ltd. local community, which has a say Over the last three years, the whenever the company applies for company has also spent on +44 (0)1535 637876 planning permission. improving the site’s environmental daniel.marr@ and sustainability profile. In airedalechemical.co.uk “Historically we didn’t really 2017, it attained zero-to-landfill www.airdalechemical.com connect with the community at all status, winning it a Green Apple and that had a negative impact award. Water, gas and electricity consumption was reduced by 35% Find more at www.specchemonline.com Filling line at Airedale
*Naresh Jariwala*
consistently delivering manufacturing excellence are at equipment required for product development, which is the heart of meeting any customer’s needs.” precisely where CMOs can provide assistance. Demands for specialised blending and packing services Caitlin Rafferty, group marketing manager vary widely by sector. Powders can require packing in at Hydropak, part of the Rakem Group, says: weights from 50 gm up to 1,500 kgs in a variety of “Historically we have grown from a chemical formats, such as pouches, bags, foil packs, tubs or distribution company to now providing customers pails. Similarly, liquids can be blended and packed in a with a complete toll manufacturing service. We are combination of containers from 50 ml to 1,000L. increasingly supplying a mix of ready-made and packaged products prepared for shop shelves and Technology and investment therefore play an online retailers.” important part in the service CMOs deliver to clients. Specialised production, such as vacuum drying Sustainability key and sieving, milling, grinding and micronising, are Another significant development in the outsourcing available alongside flexible packing lines, all of which of filling and blending requirements is the need to can offer a capability or capacity that companies often demonstrate sustainability throughout the supply chain. do not have themselves. “We have seen noticeable market pressure for Needs of start-ups environmentally sensitive materials and packaging,” Recent years have seen the growing presence of start- confirms Martin Usher, managing director at up businesses in the chemical industry, with creating a Grotech Production. “In response, we have made a business online and selling via channels like Amazon conscious effort to reduce our use of plastic, as well heavily encouraging this growth. Routes to market are as cutting our overall carbon footprint and energy a lot wider now and many CMOs are noticing that consumption.” customers therefore need help with their manufacturing. Linked to this is the challenge of using For these new businesses, CMOs are able to provide environmentally friendly resources, with CMOs now vital support when launching a product. Start-ups often looking at finding ways to lower their dependence have new products and developments at more irregular on non-renewable resources. As oil and natural gas intervals in comparison to larger, established companies. supplies decrease, some in the sector are now using They also tend to lack the in-depth skills and range of technologies such as those based on biomass to P *Naresh Jariwala* Find more at www.specchemonline.com P
*Naresh Jariwala*
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