Deep Biologic Exploration

FEBRUARY 2018 # 38

Upfront In My View Business Best Practice Does brand really matter Seeking efficacy answers Brexit: hoping for the best Join the crowdsourcing for pharma medicines? for inhalable drugs but planning for the worst revolution today!

13 18 – 19 34 – 39 42 – 45

Experts discuss analytical advances that are easing biopharma characterization.

20 – 29

www.themedicinemaker.com Kelsey Kehrli Data Review Scientist PSG

| Active ingredients Dynamic people

Meet the experts you’ll enjoy working with and discover why we’re one of the biggest names in small molecule APIs.

DCAT Week, March 19–22, Lotte NY Palace, New York CPhI North America, April 24–26, Booth 613, Philadelphia www.cambrex.com

Custom development Generic APIs Controlled substances & manufacturing Online this Month

Think Fast, Screen Faster

Combinatorial chemistry and other procedures have produced large libraries of chemical compounds – the (re)activity of which needs to be assessed. High throughput screening (HTS) is already an important component of the drug discovery toolbox in that regard, but could it be better? Graham Cooks, Henry B. Hass Distinguished Professor of Analytical Chemistry at Purdue University, Indiana, USA, certainly thinks so.

Read about Cooks’ work at http://tmm.txp.to/0218/Cooks

Dengue Vaccine 101

In November 2017, Sanofi updated the product information about its Dengvaxia vaccine based on long-term data. Differences in vaccine performance were identified based on prior dengue infection; the vaccine was found to provide “persistent protective benefit against dengue fever” in those who had prior infection. Those who had not been previously infected by dengue virus may, in the longer term, experience more cases of severe disease upon dengue infection. Over 700,000 children in the Philippines were vaccinated with Dengvaxia in 2016, but the vaccination program was suspended after Sanofi’s announcement – and there are concerns in the Philippines that a small number of children may have died because of the vaccine.

We examine the controversy on our website. Read more at http://tmm.txp.to/0218/Dengue

www.themedicinemaker.comwwwwww.themeedic ISSUE 38 - FEBRUARY 2018 Contents Editor - Stephanie Sutton [email protected] Deputy Editor - James Strachan [email protected] Deputy Editor - Roisin Mcguigan [email protected] Content Director - Rich Whitworth 13 [email protected] Editorial Director - Fedra Pavlou [email protected] Publisher - Richard Hodson [email protected] Sales Manager - Helen Conyngham [email protected] Head of Design - Marc Bird [email protected] Junior Designer - Hannah Ennis [email protected] Digital Team Lead - David Roberts [email protected] Digital Producer Web/Email - Peter Bartley [email protected] Digital Producer Web/App - Abygail Bradley [email protected] Audience Insight Manager - Tracey Nicholls [email protected] Traffic & Audience Database Coordinator- Hayley Atiz [email protected] Traffic and Audience Associate- Lindsey Vickers [email protected] Traffic and Audience Manager Jody- Fryett [email protected] Social Media / Analytics Associate - Ben Holah [email protected] Events Manager - Alice Daniels-Wright [email protected] Marketing Manager - Katy Pearson [email protected] Financial Controller - Phil Dale [email protected] Accounts Assistant - Kerri Benson [email protected] Chief Executive Officer - Andy Davies [email protected] Chief Operating Officer - Tracey Peers [email protected] Change of address: [email protected] Hayley Atiz, The Medicine Maker, Texere Publishing Ltd, Haig House, Haig Road, Knutsford, Cheshire, WA16 8DX, UK General enquiries: www.texerepublishing.com [email protected] +44 (0) 1565 745200 03 Online This Month Upfront [email protected] Distribution: The Medicine Maker (ISSN 2055-8201), 10 A Goal in MiNDS and The Medicine Maker North America (ISSN 2514-7536), is published monthly by 09 Editorial Texere Publishing Ltd and is distributed in Are You Ready? 11 Trials of a Medicine Maker the US by UKP Worldwide, 3390 Rand Road, South Plainfield, NJ 07080 by James Strachan Periodicals postage paid at South Plainfield, NJ POSTMASTER: Send US address changes to 12 Business-in-Brief The Medicine Maker C/O 3390 Rand Road, South Plainfield NJ 07080. Single copy sales £15 (plus postage, cost available On The Cover Cover 13 What's in a (Brand) Name? on request [email protected]) Annual subscription for non-qualified recipients £110 FEBRUARY 2018 # 38

Upfront In My View Business Best Practice Diving deep below the 14 Cherchez la Femme? Does brand really matter Seeking efficacy answers Brexit: hoping for the best Join the crowdsourcing for pharma medicines? for inhalable drugs but planning for the worst revolution today! Reprints & Permissions – [email protected]

13 18 – 19 34 – 39 42 – 45

Deep Biologic Exploration The opinions presented within this publication are those of the authors

Experts discuss analytical advances that are easing biopharma characterization. 20 – 29 surface of biomolecules with and do not reflect the opinions of The Medicine Maker or its publishers, Texere Publishing. Authors are required to disclose any relevant financial analytical technologies. 15 Innovation: Your Way arrangements, which are presented at the end of each article, where relevant. © 2018 Texere Publishing Limited. All rights reserved. www.themedicinemaker.com Reproduction in whole or in parts is prohibited. Our Commitment, The Industry Leading Experience

PCI Pharma Services – a market leader for integrated drug development and commercialization

The foundation of a successful partnership is trust. At PCI, we dedicate our unwavering commitment to provide the industry leading customer experience. This focus enables us to be a trusted partner to 19 of the top 20 pharmaceutical companies in the world. We earn trust by providing our clients flexibility and responsiveness, outstanding operational performance, and the support of uncompromising quality and regulatory standards. By this commitment we deliver our clients an end-to-end development and commercialization solution including drug development and scalable drug manufacturing, integrated clinical trial services, and commercial packaging services. We are trusted to support lifesaving medicines destined to over 100 countries around the world.

We invite you to learn more about what the PCI commitment can do for the success of your business.

pciservices.com

Why you must attend CPhI Japan 2018

1 2 3

Meet the Japanese pharma %XVLQHVV0DWFKPDNLQJ &RQIHUHQFHUXQQLQJ industry under one roof and Programme throughout the exhibition ÀQGWKHODWHVWWHFKQRORJLHV DQGLQQRYDWLYHSURGXFWV Build partnerships and Unrivalled, free of charge understand the access to insight and Connect, network & interact market - the crucial VXFFHVV LQIRUPDWLRQRQWKHORFDOPDUNHW with 500+ exhibitors IDFWRUVLQWKH-DSDQHVH and its regulations via from 26 countries market government workshops held at the event.

Organised by: Japan’s most comprehensive pharmaceutical exhibition gotocphi.com/jp2018 34

In My View Report

16 Pharma companies have 30 Getting on the Fast Track: many priorities to balance and Manufacturing Training for are increasingly looking for Cell Therapies innovation in software to help, says David Harty.

18 According to David Lewis, if we Business are to reach new highs with inhaled drugs then questions 34 Hold me Closer, UK Pharma around efficacy must be answered. Brexit negations are ongoing, but pharma companies remain concerned about supply chains.

Feature

20 Deep Dive into Best Practice Biopharmaceutical Analysis Where would the industry be 42 A Problem Shared… without analytical science? Open innovation can secure a Experts give their view on better future for R&D because the challenges of biopharma strength is found in numbers. characterization and the opportunities for further 46 Fumigation: Choose Sitting Down With innovation. Your Weapon! A former site fumigation lead offers 50 Nigel Darby, Advisor, his tips and tricks for overhauling GE Healthcare Life your fumigation system. Sciences, Sweden.

www.themedicinemaker.com CELEBRATING THREE YEARS OF HUMANITY IN SCIENCE

The Humanity in Science Award recognizes and rewards scientific breakthroughs that aim to have a real impact on humankind’s health and wellbeing.

2015 2016 2017

Peter Seeberger & Andreas Seidel- Waseem Asghar, Assistant Professor Richard Jähnke, Global Pharma Morgenstern, Directors at two at Florida Atlantic University, Health Fund (GPHF), developed and collaborating Max Planck institutes developed flexible sensors for the rapid continuously improved GPHF Minilab in Germany, developed an innovative and cost-effective diagnosis of HIV – and – a “lab in a suitcase,” enabling resource process to manufacture the most effective other infectious diseases – in point-of- poor countries to rapidly identify drugs to treat malaria from plant waste care settings. substandard and falsified medicines. material, air and light.

Nominations will open soon for the 2018/2019 Humanity in Science Award www.humanityinscience.com Are You Ready? Brexit could cause chaos for pharma’s fragile supply Editorial chains – especially if companies are unprepared.

n January, the EMA launched a survey to learn how (or if!) pharma companies were preparing for Brexit (1). And towards the back end of last year, I spent the Ibest part of an afternoon at CPhI conducting my own straw poll on people’s thoughts about Brexit and its potential impact. (No, I’m not a masochist). A number of delegates told me they had plans in place, but a considerable proportion of companies weren’t particularly prepared. And some even refused to believe Brexit would happen. At the show, I also chatted with Sascha Sonnenberg, VP Commercial Operations Americas and EMEA at Marken – a company that specializes in supply chain solutions for clinical trials. Sascha spends much of his time explaining what Brexit might mean for his clients – and what they should be doing about it. Bigger firms tend to be prepared, he says, but smaller companies, particularly those outside of Europe, “do not have Brexit on their radar.” (Read more of his views on page 20). The EMA has been pretty explicit in explaining what Brexit will look like in the absence of an agreement. Although, industry is hoping for mutual recognition agreements, for now, the EMA is assuming the UK will be treated as any other third country – with MAs, orphan designations, batch release, Qualified Person Responsible for Pharmacovigilance, and Pharmacovigilance System Master Files, all needing to Reference be transferred to the European Economic Area before March 1. EMA, “EMA surveys pharma companies 30, 2019. Sascha shared his concerns about a bottleneck on the on their preparedness for Brexit”, (2018). EU side as companies rush to make sure they’re ready to carry Available: http://bit.ly/2BsKPX2. out batch release, as it could delay or endanger ongoing trials. Accessed 24 January, 2018. But even if the industry gets everything it wants in terms of regulatory equivalence and mutual recognition, pharma companies will be using the same ports and roads as exporters from other industries. Unless there’s an agreement that effectively eliminates the need for customs checks across all sectors, pharma companies will inevitably face delays at the border... Who knows what shape Britain’s relationship with the EU will take after Brexit or what the costs/benefits might be in long term? But are you really willing to wager that things won’t be any different on Brexit? I feel it’s appropriate to quote my countryman, Roger Moore: “It is better to be prepared for illness than to wait for a cure.”

James Strachan Deputy Editor

www.themedicinemaker.com 10 Upfront

Dagdeviren took A Goal in MiNDS her inspiration from Upfront an unusual source: An implantable neural device Turk ish coffee – Reporting on research, can deliver drugs to the brain specifically the fine with pinpoint accuracy porcelain cups and personalities, policies and plates that are served partnerships that are A team of researchers from MIT on a tray in Dagdeviren’s shaping pharmaceutical have taken the first steps towards the home country. development and development of a needle that can deliver The miniaturized neural drugs to specific parts of the brain (1) drug delivery system has multiple manufacture. – potentially reducing the off-target tiny components, including two effects that come with drugs used to fluidic channels connected to wireless We welcome information treat neurodegenerative conditions. micropumps for delivering nanoliters on any developments in The researchers tested the device – of drugs on demand, and an electrode which they call MiNDS – in mice and to record neural activity for potential the industry that have a rhesus macaque monkey. The results feedback control. “These components really caught your eye, showed that the device could deliver are all thinner than a hair fiber and in a good or bad way. drugs selectively to small deep-brain can’t be handled with bare hands,” Email: stephanie.sutton@ structures in a controlled manner. says Dagdeviren. Positron emission tomography imaging Much like a Turkish coffee tray texerepublishing.com showed localized drug delivery with a provides stability to the tiny, fine- volume of ~1-mm^3. “This is essential, featured coffee cups and plates, given that many key neural circuit nodes Dagdeviren microfabricated a polymer have such small volumes,” says Canan tray on a plannar silicon substrate in Dagdeviren, assistant professor at MIT 2D to support the delicate components. and lead author of the study. “While the mechanical stability is provided by the polymer tray, I used microfabrication tricks to lift-off the entire device platform from the planar, rigid substrate and encase it in a round, flexible stainless steel needle,” she says. The result is a 3D platform able to reach deep brain structures without the need of an extraneous guide tube to implant in the brain. MiNDS has a diameter of 200 μm – slightly thicker than a hair fiber – and can be scaled: for small animals the team used a small MiNDS with a length of 1 cm, whereas for non-human primates they used a 10 cm one. Upfront 11

31-gauge needle,” toxicity.” She also believes MiNDS she says. “Our could be used to deliver growth factors experimental and stem cells to regions of significant findings show no cellular necrosis. “For neurological and infusion past the cardiovascular diseases, combining programmed end growth factor therapy with electrical of pumping with the stimuli might help regenerate micropumps, indicating electroactive cells. The customizable that there is negligible passive features of MiNDS could open new leakage of fluid out of the drug routes to deliver not only light but Although previous infusion channels.” also chemicals and electricity to other studies have reported on Dagdeviren envisages additional organs with pinpoint spatiotemporal devices with various sizes, down uses for the device beyond the brain. resolution,” says Dagdeviren. to 70 μm and infusion volumes as small “Another potential use of MiNDS as 10 nl, Dagdeviren says they suffer could be for targeted delivery of Reference from diffusion and leakage problems. chemotherapeutics to tumors in the 1. Canan Dagdeviren et al., “Miniaturized “Our infusion micropumps can be body,” she says. “Such a technique neural system for chronic, local intracerebral refilled, even while implanted, via a would provide delivery of higher drug delivery”, Sci Trans Med, 10, 425 septum that can be penetrated using a doses without the associated systemic (2018). PMID: 29367347.

Brought to you by GE Healthcare 12 Upfront

drug compounding pharmacy Business-in-Brief operation, AmerisourceBergen has run into regulatory problems with Ongoing bribery its PharMEDium lab in Memphis, investigations, sitting out the USA. In January the company Super Bowl, and achieving had to recall compounded sterile excellence online… What’s products due to lack of sterility new for pharma in business? assurance, and in February it received a Grand Jury subpoena Regulation for testing documents on a certain type of syringe. • The management board of the • In an ongoing bribery probe, EMA recently met to discuss their GlaxoSmithKline is facing new new premises in Amsterdam. A questions from the UK Serious new, tailor-made facility will be Fraud Office. GSK has been asked Rare diseases & Orphan drugs built for the EMA in the business to provide information regarding district Zuidas, but this will not be “third-party advisers engaged by • Rare Disease Day will take place ready before the UK leaves the EU the company in the course of the on February 28, with the aim at the end of March 2019 (expected China Investigations”. of raising awareness about rare completion is November 2019). diseases and the impact on patients’ Temporary premises for the agency Marketing lives. It is believed that 1 in 20 are being prepared in the Sloterdijk people will live with a rare disease area of Amsterdam and will be • Pharma companies sat out the at some point in their life. ready by January 1, 2019. Super Bowl for the second year • In his first State of the Union • The UK and China have signed a in a row, despite it being the address, Donald Trump urged memorandum of understanding largest (albeit most expensive) Congress to pass the “Right to on medicine and device regulation, US advertising opportunity of Try” Bill, which aims to make it and expanded on the previous the year. The decision may have easier to give patients with terminal memorandum, with new areas of been influenced by the backlash illnesses access to promising cooperation outlined, including three pharma companies faced investigational therapies that have effective regulation of online trading. two years ago for ads than ran not yet been approved by the FDA. • The European Commission during the Super Bowl, with some Some patients, particularly those has proposed mandatory future viewers questioning the timing suffering from rare diseases, say European cooperation on Health of discussing fungus and diarrhea they would welcome the bill, but Technolog y Assessments. The during a soccer game. the National Organization for legislation, currently being discussed • GSK has rocketed from number Rare Disorders is concerned that by the European Parliament, covers five to number one in an online there may be “bad actors looking to joint clinical assessments for the excellence ranking by Bowen Craggs profit off of false hope”. innovative health technologies, joint & Co – the first pharma company • The National Institutes of Health scientific consultations whereby to do so in almost ten years. The is partnering with government, developers can seek advice from company’s strong homepage, biopharmaceutical and non- HTA authorities and identification headlines, career section and it’s profit organizations to help of emerging health technologies to transparency in its online presence improve drug development identify promising technologies early. all contributed to it moving up successes for Parkinson’s disease. the rankings. “GSK turned what The collaboration will focus on Controversies was a good site into an excellent identifying and validating disease one through relentless polish and biomarkers and new biological • After paying US$2.5 billion to refinement,” said Scott Payton, targets. More than $12 million has buy the PharMEDium sterile managing partner at Bowen Craggs. been invested as part of the initiative. Upfront 13

What’s in a (Brand) Name?

Do patients care about your brand? Not as much as they care about your outcomes

Pharma and healthcare companies spend billions (1) on marketing and promoting their brand – but it may not always be worth it, according to a recent patient survey. The global professional services company Accenture Life Sciences quizzed 8,000 patients from the US, UK, France and Germany on their attitudes to brand loyalty and treatment decisions. Perhaps unsurprisingly, they found that the vast majority of patients (69 percent) consider the benefits of a product more important than its brand. But on the other hand, 25 percent of patients – a significant number – did rate brand loyalty or popularity as a top factor Demonstrate that your product can provide Consider whether allocation of in their healthcare decisions. better outcomes, and consider how you can resources is optimal Other important factors for patients best communicate this to different patients The authors also question whether when considering treatment choice were – what evidence matters, and to who? some of the resources and expenditure their relationship with their doctor (66 Data-sharing and analytics are crucial to currently dedicated to brand promotion percent), the ability to maintain their understand what and how to communicate might be better used to fund things that current lifestyle (55 percent) and ease with healthcare providers and patients. really matter more to patients, such as of access to care (53 percent). Of the Also, remember that patients might not more real world evidence for your 14 factors in the survey, product brand speak your “language” – speak to patients product, or patient access programs. came in 12th. in a relevant and understandable way. “Our research makes it abundantly The Accenture survey authors, Jim clear that product launch strategies must Cleffi and Boris Bogdan, suggest Tailor your product launches to match evolve from one-size-fits-all approaches,” some key things to bear in mind when the needs, preferences and motivations says Accenture Life Sciences Managing launching a new product. of patient sub-segments, considering Director Boris Bogdan. “Understanding factors such as, geography and the how patient sub-segments behave Bring an outcome to market, specific disease differently will fundamentally shift not just a product Consider who your patient is; for example, promotional decision-making and the Begin focusing on outcomes at the clinical younger patients are generally more likely to development of supporting services.” trial stage, and focus on launching evidence- switch if they think there is a better option based solutions rather than just products. available, whereas many baby boomers References Use this mindset to inform your launch reported that their treatment decisions are 1. Kantar Media, eMarketer calculations. strategies and commercialization plans. affected by a lack of knowledge about what’s 2. Accenture, “Product launch: the patient available. The location of patients has just has spoken”, (2018). Available at: When you launch a product, lead with as much impact as their age, making local http://bit.ly/pharmabranding. the evidence launch teams are crucial. Accessed February 1, 2018.

www.themedicinemaker.com 14 Upfront

inclusion of women increases from 22 References Cherchez la percent in phase I trials to nearly 50 1. KA Liu, NA Mager, “Women’s involvement in percent for phase II – III trials (3). clinical trials: historical perspective and future Femme? “The results of this investigation show implications”, Pharm Pract, 14, 708 (2016). that drug trials are appropriately designed PMID: 27011778. A recent review of FDA regarding inclusion of men and women. 2. S Pal, “Inclusion of women in clinical trials of data suggests that women Furthermore, the underrepresentation of new drugs and devices”, US Pharm, 40, 21 are now better represented women in trials as observed in the 1980s (2015). in clinical trials and before seems to be resolved for most 3. A Chen et al., “Representation of women and drug trials that we investigated,” reports minorities in clinical trials for new molecular It is now widely accepted that biological study co-author Robert Rissmann (4). entities and original therapeutic biologics sex can affect a person’s reaction to a drug. But there is still some way to go. TheThe approved by FDA CDER from 2013 to But historically, the standard clinical authors acknowledge that the scopee ooff 2015”,2015”, J Womens Health, [Epub ahead of trial participant has been male. Is this their study is limited, and may not covercover print]print] (2017).(2017). PMID:PM 29048983. still the case, or have things improved? all the disease areas in which womenomen 4. EurekAlert!,EurekAlert!, “Are women reallyreally under- Some recent studies and reviews report may still be underrepresented. OtherOther representedrepresented in clinical trials?”, (2(2017).017). that barriers still remain, and that researchers have also reporteded that AvailableAvailable at: http://bit.ly/wmntrials. women continue to be underserved by there is still room for improvementement in Last accessed February 1, 2017.2017. clinical trials (1, 2). our understanding of sex differencesifferences However, an analysis of FDA clinical in response to some drugsgs (1) and trial registration data for frequently some racial minorities continuentinue to bebe prescribed drug classes found that the underrepresented in variouss areasareas (3).(3).

PUTTING WHAT?HAT? WHO? NUMBERS 484,896 TO new drugs approved by the FDA total participants*: Center for Drug Evaluation CLINICAL and Research between 2013 and 2015 (new molecular entities and were TRIAL original therapeutic biologics) women INCLUSION 2,455 clinical trials 77.2% were White

60 indications 12.2% were Asian were Black/ African 13 therapeutic groupings 6.4% American

*Sex was reportedted for over 99.9 percent of trial participants, race for approximately 97.597.5 percent of participants, and age for 72.2 percent of participants. were aged under 65 years of age 70.9% Upfront 15

Innovation: Your Way

The Medicine Maker ended 2017 with a celebration of innovation in industry drug development technologies by compiling a list of the 15 top technologies to hit the market in 2017. All of these winning innovations can make a mark on drug Innovation development and manufacturing activities, but which is the Awards most ground breaking? We will give one of our winners the chance to showcase the full development story behind their innovation in a future 2017 issue of The Medicine Maker. And we want you to choose!

Vote for the innovation you would like to read more about at: http://tmm.txp.to/2017/innovationwinner. Voting closes on March 1, 2018.

Winners

• AFG 5000 • Cadence Inline Diafiltration Module • Eshmuno P anti-A & Eshmuno P anti-B resins • HakoBio • H3N2 Challenge Virus • iQ • KLV 1360 • MabSelect PrismA • MicroCal PEAQ-DSC • Prodigi • Q Exactive HF-X Hybrid Quadrupole Orbitrap Mass Spectrometer • Valor Glass • VarioSys Move • VHP DC-A Decontamination Chamber Atmospheric • X500B QTOF 16  In My View

comes to pharmacovigilance. The Software: The introduction of patient involvement In My and the accompanying data can Best of Jugglers open privacy concerns both from a regulatory perspective and a consumer View As pharma companies privacy standpoint, which can have attempt to keep too many dramatic brand protection concerns. balls in the air – drug That said, changing regulations, In this opinion section, costs, regulatory demands, even more stringent ones, can have experts from across the consumer perception, return advantages. Regulatory changes force world share a single on investment – they will companies to seek out more flexible increasingly turn to software and comprehensive solutions – in strongly held view or that can harness data in new the process abandoning many of the key idea. and interesting ways. silo or stovepipe solutions previously prevalent. Ultimately, companies Submissions are welcome. have the opportunity to become more efficient and profitable. Articles should be short, The world is growing smaller as we focused, personal and become increasingly connected by passionate, and may growing mountains of data. As pharma companies attempt to balance multiple deal with any aspect markets, different geographies and of pharmaceutical increasing regulatory requirements, development or advanced software systems can be a huge help. By reducing errors and manufacture. ensuring that the correct requirements They can be up to 600 are followed, software can have a far- words in length and reaching impact from initial planning By David Harty, Head of Professional and algorithms that support sales written in the first person. Services, Adents, France efforts across the marketplace, to the most granular operational tasks needed Contact the editor at: Modern software companies rarely look to fulfill production requirements. stephanie.sutton past three-to-five-year planning cycles because of the rapid change of technology @texerepublishing.com and, of course, the immediacy of many business requirements. However, “The world is when we consider a variety of factors – including the current change in pace growing smaller as of automation, regulatory requirements, and consumer demands – it’s clear that we become the role of software in manufacturing is exponentially increasing. Exciting increasingly times lie ahead! And not just for vendors who stand to profit of course, but also connected by for pharma customers who will benefit from increasing software innovation. growing mountains Privacy is perhaps one of the biggest issues in the new era of data of data.” and software, especially when it In My View  17

I believe software’s ability to values and rights with regulatory increase quality and support “right- requirements, global marketplace “We will be able to the-first-time” production goals will competitiveness, consumer perception, only be surpassed by the power to intellectual property protection, and challenge and provide lifecycle management for all return on investment. Most research products, even immediate consumable does not yield a marketable, profitable verify those medications. Powerful management product, but there is an increasing tools will allow us to fully understand viewpoint – a false one, in my opinion medicines’ a particular medication. We will know – that big pharma is a purely profit- when and where source components driven machine. I believe that as more authenticity – the were produced for recall purposes; information is made available and as we’ll be able to witness medicines’ transparency increases – driven by crux of regulations journeys across supply chain networks software that can make better use of to ensure compliance in handling and data – consumers and patients will currently being storage conditions; and we will be able be better informed about the inner to challenge and verify those medicines’ workings of the world of pharma. In rolled out across authenticity – the crux of regulations time, the public will hopefully begin to currently being rolled out across see the complexities of producing and the globe.” the globe. delivering the medicines they need, The pharma market is under increasing shining a more positive light on the pressures to balance shareholder pharma industry. 18  In My View

The defining focus of research in The Next the inhalable drug area has, until now, been aimed at learning how to disperse “Understanding (Air)Wave of formulations efficiently enough to deliver a clinically efficacious dose – the dynamics of Inhalables and, in particular, how to create and disperse particles of a size that facilitates dose dispersion is The inhaler is an important deposition in the lung. The importance drug delivery device, but for of this work should not be overlooked, therefore a critical the technology to evolve, but there are important challenges yet questions about efﬁcacy must to be tackled. To reach new levels of first step towards be answered. performance, and to better meet patient requirements, I would argue that we better drug now need to start asking new questions. There are three key questions that the delivery control.” field must address:

i. How can we develop a better to pave the way towards increasing our understanding of aerosolization understanding. New knowledge will performance by extending be particularly valuable as the focus of By David Lewis, Director of Aerosol current research? research activity shifts to the potential Research, Chiesi Ltd, UK. ii. How can we better understand of extra-fine particles (those less than particle behavior on the way to the two microns in size), which increasingly Since they were first developed in the lung (especially the influence of appear to offer both clinical and product 1950s, advances in inhaler drug delivery humidity on particle properties)? performance benefits. technology have been substantial. But iii. How can we improve drug uptake Next, it is important to establish a better compared with tablets, the technology within the lung? understanding of the patient response it still in its infancy. Inhaled drugs are to inhaled particles (and vice versa), delivered directly to the target tissue The aerodynamic particle size ultimately allowing researchers and where they can act immediately, in distribution (APSD) of the therapeutic clinicians to understand why patients may contrast to systemic delivery methods. aerosol produced by an inhaler plays a key respond differently to the same product, This localized delivery is a widely role in the physical mechanics of particle according to their age or disease state. For recognized benefit of inhalables, deposition in the airways – which means example, during drug development and as a lower dose is generally needed it directly affects the efficacy of the manufacture, the aerodynamic particle to achieve therapeutic effect. Since treatment. Understanding the dynamics size distribution of inhaled drug particles their initial design, inhaler devices of dose dispersion is therefore a critical is usually measured in a low humidity and formulations have undergone first step towards better drug delivery environment, using the technique of rapid innovations; most notably the control. For pressurized metered dose cascade impaction. But there’s a problem: introduction of hydrofluoroalkane as inhalers (pMDIs), we require a detailed the route the drug particles follow is a propellant in metered dose inhalers, understanding of the atomization and close to a saturated water environment, which improved the degree of drug evaporation processes that determine meaning that test data may not accurately deposition in the lung. Despite this, the size of particles delivered – a major represent what is going to happen in vivo. more improvements in inhaled delivery challenge, but it potentially opens Fine particles tend to be hygroscopic, methods are required to further increase up a route to higher performance which means that when they are subject the drug dose reaching the lung by efficiency. The use of innovative to high humidity they will absorb water manipulating particle properties and imaging technology to investigate relatively rapidly because of the high therefore improving the treatment of the aerosol plume, in combination surface-area-to-volume ratio, becoming prevalent respiratory diseases, such as with the intelligent application of larger than they were when they entered chronic obstructive pulmonary disease. computational fluid dynamics, is helping the body. In the past, inhaler testing may In My View  19

not have taken this into consideration. Additionally, the composition of the needs of specific patient groups in a But now, researchers are paying more the RTLF changes depending on the more efficient way. There is potential to attention to the effects this can have on region of the lung, so when particles be explored by developing more efficient the deposition behavior of the drug, and transverse the lining, the dissolution, technologies that use formulations with the resulting dose received by the patient. cellular uptake and therapeutic efficacy reduced active pharmaceutical ingredient Oxygen levels in the lung are also all depend partly upon where the drug loading. Respiratory diseases represent known to affect the uptake and behavior particles reach. And that’s one reason a huge burden on healthcare services of inhaled particles, as shown by research why dissolution testing has become across the globe, with developing into the impact of pollutants (1). Within an important theme. Once an inhaled countries in particular struggling with the lung, the steady state concentration of drug has deposited, the absorption –and, the associated financial weight of such oxygen is significantly lower than the 21 therefore, the therapeutic effectiveness conditions. By improving inhaled drug percent used for many experiments. Once of the drug – depends on the active delivery uptake within the body, we have particles have deposited (frequently in an drug dissolving in the fluid available at the opportunity to improve the patient unpredictable manner), it is the respiratory the target site. As it stands, there are experience, and at the same time reduce tract lining fluid (RTLF) that has a no dissolution test methods specified healthcare costs. defining influence on the uptake of inhaled for inhaled products; however, FDA molecules, and particle transportation at grants have been released to investigate Reference the air-lung interface. RTLF changes with this aspect of performance. 1. I Mudway, “’Learnings’ about the lung - small age and with disease state, and therefore Improved understanding of in vivo particle interactions from environmental science”, plays a role in the variable lung response particle behavior will allow us to more Presented at the Innovation in Inhalation in different patients. closely tailor inhaled products to meet Meeting, July 9, 2016; Newport, UK.

DEEP DIVE INTO BIOPHARMACEUTICAL ANALYSIS

---

Advanced tools across a number of analytical techniques are helping medicine makers better understand their biomolecules – ensuring both safety and efficacy. And when it comes to real-time analysis to improve control over biopharma production processes, rapid and robust measurements will be crucial. Are today’s technologies up to the job? We speak with four analytical experts to gain a fresh perspective on the challenges of biopharmaceutical characterization and the opportunities for further innovation.

----

By Stephanie Sutton, Editor

www.themedicinemaker.com 22 Feature

Why is deep biopharma characterization so important for the discovery, development, and ----- manufacture of new biologic drugs? “The ability to hyphenate Anurag Rathore: The importance, as well as significance, of characterization for biopharma arises from the complexity charge-based separations, of the product. Biotherapeutics are complex nano-machines, designed to work at a specific rate, for a specific function. such as ion exchange This specificity can only be assured if all the parts of the nano-machines are intact and aligned accurately. For this, it chromatography, with MS also is important to first understand how different stresses impact the assembly. Moreover, as it is a product used in bulk (millions enables manufacturers to better of molecules per dose), the range of contaminants and their effect on product function will vary. understand protein structure Characterization helps define all of the above features in minute detail – and this understanding can then be and protein-protein interactions used in all aspects of development and manufacturing as a signature of the molecule’s behavior. In the drug discovery in the native form.” phase, anomalies identified during characterization of a biotherapeutic for a certain target might also help identify ----- treatments for other disorders. Characterization to some extent also helps understand and manage the risk involved with manufacturing, and can help alleviate the cost attached to clinical trials. In my opinion, there are very few industries has definitely been a recipient of major developments in the last where quality of the product matters so much to the consumers. decade; there are two significant advances I would highlight. Ultimately, regulation of this quality comes down to efficient The first is mass spectrometry (MS). When hyphenated with and accurate characterization. separation tools such as electrophoresis and chromatography, MS has made it possible to probe the molecular structure Koen Sandra: Anurag summed that up very nicely. of complex biomolecules in previously uncharted ways. Biopharmaceutical products come with enormous structural Combinations such as LC-MS-MS (liquid chromatography- complexity. The molecules are large (monoclonal antibodies tandem mass spectrometry) allow us to accurately identify have a molecular weight of 150,000 Da) and heterogeneous the mass of a molecule to the fifth decimal place and pin- as a result of the biosynthetic process and subsequent point not only the type but also the exact location of a range manufacturing steps and final storage. Despite the fact that of chemical and enzymatic modifications. Even modifications typically only one product is cloned, the final drug substance as complex as glycosylation are now being increasingly profiled or drug product is composed of a mixture of hundreds of using characterization tools. If there is a modification that can variants that differ in post-translational modifications and be separated via a specific mode of chromatography, it can be higher order structure. These different variants can have an identified by mass spectrometry. impact on function, stability, efficacy, as well as safety. During The second set of tools that are becoming increasingly development, these characteristics need to be determined in promising are surface plasmon resonance (SPR) and biolayer great detail using state-of-the-art methodologies and closely interferometry (BLI). These tools have made it easier to perform monitored prior to clinical or commercial release. For that, a binding assays and have significantly boosted productivity. wide range of analytical techniques and methodologies must They are gradually becoming the industry gold standard for be used. measuring drug specificity and kinetics.

What analytical advances have had the biggest Kyle D’Silva: I agree that MS is one of the biggest advances. impact in terms of developing biologics? MS has given drug manufacturers a greater level of structural insight into their products than any other technique in recent AR: The field of analytical characterization of biotherapeutics years. The ability to hyphenate charge-based separations, The Experts

Anurag S Rathore Anurag is familiar with both academic and industry perspectives such as ion exchange chromatography, with MS also enables in biopharma characterization. manufacturers to better understand protein structure and Today, he is Professor in the protein-protein interactions in the native form, delivering a Department of Chemical deeper understanding of the drug and its mode of action. Engineering at the Indian Institute of Technology in New Delhi, but he has previously KS: New mass analyzers have been introduced with improved held roles at Amgen and Pharmacia Corp. His robustness, sensitivity, resolution and mass accuracy. Today, main areas of interest include process development, you can use MS to study primary structural features, such as scale-up, technology transfer, process validation, amino acid sequence and post-translational modifications, as biosimilars, continuous processing, process analytical well as higher order structures. All of this results in enormous technology and quality by design. amounts of data for which new powerful software tools have been developed. However, it is important to point out that, despite the significant progress made in software algorithms, Kyle D’Silva data analysis still requires substantial manual intervention. Kyle offers insight from the point Interpreting all the different spectra to this day remains of view of a technology provider. somewhat of an art, and finding people with the right expertise Following a PhD in applied ultra- is very challenging. trace mass spectrometry, he held Many advances have also been made in chromatography, roles as a mass spectrometrist such as the introduction of highly efficient columns (with and applications chemist before chemistries tailored towards the analysis of biopharmaceuticals) deciding to move into product marketing at Thermo and instrumentation capable of successfully operating these Fisher Scientific. Today, he focuses on technologies columns. Separations nowadays are even performed in multiple for both pharma and biopharma applications. dimensions to gain in resolution – two-dimensional liquid chromatography (2D-LC) is a good example. Looking back to the characterization of the first Koen Sandra recombinant therapeutic protein (insulin) in the late 1970s/ Koen is currently the Scientific early 1980s, chromatography and mass spectrometry were of Director of the Research Institute modest performance compared with the current state-of-the- for Chromatography (RIC). He art. Though fast atom bombardment was used to introduce is also the co-founder and co- insulin into low resolution mass spectrometers, today the owner of anaRIC biologics and of Nobel Prize awarded technology, electrospray ionization, has Metablys, an institute performing become the standard to introduce small peptides and large metabolomics and lipidomics research. As a non- proteins into high-resolution mass spectrometers equipped academic scientist, he is the author of over 40 highly with a variety of fragmentation modes, providing sequence cited scientific papers and has presented his work at information and allowing modifications to be detected and numerous conferences as an invited speaker. localized at very low levels. HPLC separations used to be performed on columns packed with 5-10 μm porous particles Hermann Wätzig and pumps operated at 400 bar, but we now have sub 2 μm Hermann has spent his career in porous and superficially porous particles and system pressures academia and is today Professor up to 1500 bar, allowing us to resolve minor structural at the Technische Universitat differences in a short analysis time. Braunschweig in Germany. Since There was a time when scientists had to identify all peaks in 2001, he has been the chair of the a peptide map using Edman degradation – a very lengthy task pharmaceutical analysis/quality – but now we can easily acquire and process 24 peptide maps control division of the German Pharmaceutical a day thanks to the many developments in chromatography, Society. He is a scientific committee member of mass spectrometry and accompanying software tools. Germany’s Federal Institute for Drugs and Medical Devices (BfArM) and an expert of the European Hermann Wätzig: We are constantly improving our Pharmacopoeia. understanding about the quality of the biologics being

www.themedicinemaker.com 24 Feature

produced and how aspects such as charge variance and size variance play an important role. I think this is mainly because ----- of chromatography and electrophoresis – (U)HPLC ((ultra-) high-performance liquid chromatography) and capillary “When biosimilar developers electrophoresis in particular. These technologies continue to deliver better separations. MS, of course, is a much newer re-characterize blockbuster technology; many interesting things are happening there and I must admit that it continues to surprise me! Chromatography products developed 20 years and electrophoresis are older techniques that are very well understood so naturally the advances are smaller – but still ago using current state-of-the- very important. art analytical tools, many more How has biopharma characterization affected the development of biosimilars? details are revealed that pose

AR: Analytical technologies have made the cost of enormous challenges to positionp biotherapeutic production more manageable. Newer guidelines for biotherapeutics across the globe seem to be highlighting a product within the ooriginatorriginat the trend of increased reliance on detailed characterization as opposed to clinical trials, which has direct repercussions in specifications.” terms of drug costs – the reduction in cost of clinical trials allows for cost-effective pricing of the final product. -----

KD: Advances in analytical techniques enable biosimilar manufacturers to identify potential product differences compared with the reference innovator product that may affect the purity, safety, and efficacy of the biosimilar candidate. It is incumbent upon biosimilar manufacturers to exhaustively What are the biggest discussion points in characterize both the innovator molecule together with their biopharma characterization? Where are there own biosimilar version. Modern analytical technologies can clear gaps or unmet needs? provide biosimilar manufacturers with even greater knowledge about the microheterogeneity of an innovator biologic than the AR: We have come a long way in understanding protein reference product manufacturer themselves. molecules as products – but this understanding has also led us to appreciate the limitations of our knowledge. When we KS: Regulatory agencies evaluate biosimilars based on talk about “quality attributes,” there are some cases where their level of similarity to the originator. In demonstrating an understanding of the “cause and effect” is still lacking. similarity, an enormous weight is placed on analytics – and In most cases, these gaps in our understanding are because both the biosimilar and originator need to be characterized of current technical limitations, which I am certain will be and compared in extensive detail. The analytical package resolved in the near future. One example is aggregation; there for a biosimilar submission is considerably larger than that are already established immunogenic effects of the presence of an originator. During the development of an originator of this class of contaminant, making it a Critical Quality product, the major goal is to show a clinical effect, but for a Attribute (CQA), but we still need to understand, in greater biosimilar developer the goal is to demonstrate similarity. The detail, the specific effects of individual aggregate species structural differences highlighted define the amount of clinical on immune profiles. The mechanism of anti-drug antibody studies required. When biosimilar developers re-characterize formation is poorly understood; whether the response pathway blockbuster products developed 20 years ago using the current is generic to aggregates or species specific still needs to be state-of-the-art analytical tools, many more details are revealed resolved. Understanding this would greatly help in defining that pose enormous challenges to position a product within specific ranges for this class of contaminants. It would also help the originator specifications. in predicting drug behavior more accurately during storage Feature 25

conditions and, ultimately, the quality off thethe productproduucct aatt the chromatographicchhromatograph characterization tests that monitor for CQAs, time of patient-administration. into a singlesinglg e multi-attribute-monitoringmult workflow using high A similar gap exists in our mapping of the glycancan profileprp ofifilel ooff resolutionresolution accurateaccurate mmass MS in the quality control lab. Based complex biomolecules, such as monoclonal antibodies.dies.s GGiveniven on a peptide mmappingapa pip ng aapproach,p such tools enable the parallel the wide range of possible combinations of glycans thathat cancan monitoringmonitoring of seseveraleveral CQCQAs in a single run, meaning that attach to the antibody backbone, complete profiling of thesehese severalses veral orthogorthogonalonnaal methodsmethods can be replaced by biotherapeutic variants becomes a technical challenge. Moreover, given thehe qualityquality control.conttror l. acute sensitivity of biotherapeutics to their environment, it becomes even harder to ascertain how true a given profile HW:HW: I seeseee room fofor improvement in terms of the setting is and what changes have been introduced because of the of properroper spsspecificationsecifi – at the moment, I feel as if there analysis itself. are compromises.mpproom Biopharma products are incredibly sophisticated and widely available to patients in different KD: One of the key trends we see discussed is the advancement therapeutic areas – but because the product is so sophisticated, of MS from the development arena further down the product there are still byproducts. It is not completely understood pipeline into manufacturing and quality control. Here, which of these byproducts will give unwanted side effects we see a great desire for companies to consolidate several and which will not. And right now I think there is a

www.themedicinemaker.com 26 Feature

The power of advanced analytical tools. RPLC×RPLC-QTOF-MS analysis of infliximab originator and candidate biosimilar. Drawing of the mAb with annotation of the modifications. Courtesy of the Research Institute of Chromatography (www.richrom.com).

compromise on the amount of impurities that are allowed in a AR: Academia and industry research goals are mostly biopharma product. well aligned to each other with their primary focus on For example, there may be an impurity specification of eight societal welfare, but the priorities of the two are not always percent for a biologic versus one or two percent for a small superimposed. Academic research is driven by the impact it molecule drug. Gradually over time, eight percent should will have on the global research community, and the measures perhaps drop to five percent, and then three percent and so of success are largely based on publications. Industry, on the on. The need for lower levels of impurities will drive further other hand, is driven by the impact it will have on day-to-day advances in analytical and purification technologies. activities, and the measures of success are largely based on the The specifications are set via the ICH – which does a very long- and short-term value it creates for the company. Though good job – but there are a lot of mutual recognition agreements the industry aims to comply with the regulatory guidelines about which specifications are necessary versus those that are for approval, academicians constantly look to evolve any set actually obtainable. Once again: it is a compromise. One norms. For example, a decade ago, charge heterogeneity of a would really love to have tighter specifications, but everybody monoclonal antibody based therapeutic was not considered understands – myself included – that it may be too difficult to be a CQA, as the acidic and basic variants were believed at the present time. to have the a similar safety and efficacy profile as the main product. However, after numerous interesting publications Have you noted any different trends or priorities from both industry and academia, charge heterogeneities are in industry as opposed to academia? now considered significant to a product’s safety and efficacy. Feature 27

can also dwell on projects for longer than industry (where time ----- is a constant pressure) and so can more thoroughly investigate a molecule and gain a deep understanding. “While researchers and Many technological advances and new equipment manufacturers instruments offer increased sensitivity. Should sensitivity always be a priority? are continuously pushing the AR: Manufacturers have been continuously challenged to bar on improving sensitivity, develop analytical methods for timely and accurate product determination, as well as potential contaminants throughout I feel where we lack in our the manufacturing process, from raw material selection to process analysis, formulation development, and release testing. understanding is how the Analytical technology advances that offer increased sensitivity and shorter analysis time are always welcome, but this is different tools compare with application specific. For instance, MS-based methods and next-generation sequencing are addressing greater sensitivity, each other – and which of them dynamic range, resolution, mass accuracy, and user-friendliness in less time, and pharmacokinetic/pharmacodynamic are redundant.” analysis requires high sensitivity methods for detecting pico/nanomoles of target drug in the presence of multiple ----- interfering compounds. While researchers and equipment manufacturers are continuously pushing the bar on improving sensitivity, I feel where we lack in our understanding is how the different tools compare with each other – and which of them are redundant. KD: Industry and academia actually make very effective partners. There is certainly a trend for large bio/pharma KD: Companies need to understand their products, but manufacturers to outsource discovery to academia, which although sensitivity gives greater confidence in results, is full of new thinking, and we see greater migration of on its own it doesn’t deliver knowledge. Every step that pharma research hubs around academic sites, such as those in takes the customer from sample to knowledge must be as Cambridge, MA (USA), and Cambridge, UK, because of the simple as possible, including sample preparation, simplified availability of knowledge. To ensure success though, I think acquisition, automated data processing and interpretation, it’s important to use a bridging organization that has a keen and robust reporting of results. It is incumbent on instrument understanding of both languages and the needs of academic manufacturers to provide tools that deliver knowledge to the and industrial partners – because ultimately both parties are end user, not just performance. However, confidence in the very different! One good example is the charity LifeArc in result often comes from the foundation of high performance the UK – they act as a keystone in the bridge to spanning instrumentation and high quality data. Without this the divide between academic research and drug developers. foundation, poor data quality can lead to misinterpreted These types of organizations usually have the latest technology results, with huge time and cost implications. in drug characterization to ensure that quality is maintained as a concept moves from the academic arena to commercial KS: Better sensitivity is not necessarily what biopharma drug development. companies want, but it is a consequence of the recent advancements in analytical tools. Today, it is remarkable that HW: As Anurag says, the goals of each side are ultimately the we can detect individual host cell proteins (HCPs) at 0.1 same, but I think there is more freedom in academia to try out ppm levels and product variants at levels below 0.1 percent. new ideas and new techniques. Findings are very important in In project meetings, we often hear the comment “we don’t academia so you embrace the latest, sophisticated equipment for want to know about all these low level variants” or “we hope proper characterization to gain greater knowledge. Academia you have not found new liabilities.” As analytical scientists, we

www.themedicinemaker.com 28 Feature

feel it is our duty to reveal all ththehe dedetailstails of thetheh mmoleculesololeccules wwee KD: The complexity of biopharmaceuticals requires advancedvanced are studying. At the HPLC 2016 meetingmeetingting inin SanSan Francisco,FrF anciiscsco,o technologies to analyze them. More technologies areare nownow Reed Harris (Genentech) showed an interestingteresting graph plplottingloto tiingn being developed with greater automation for routinene process- the number of modifications revealed inn aa moleculemolecule veversusr analytical and quality control environments. Do we haveave highhigh-- popularity within the project team. When discoveringdiscoverin the resolution mass spectrometry sitting next to the bioreactoreactor first set of modifications, the popularity withinhin th the team for real-time monitoring? Not routinely. But multi-attributeute increases substantially. After having shared yet another set monitoring using high resolution accurate mass MS are of modifications, popularity declines – and at a certain point already being deployed at scale in biopharma quality control you are Doctor Doom because of the consequences that your departments, and the production environment of the near findings can have on the timeliness of a project. future will almost certainly be adopting such techniques too. In the development of new techniques and technologies, I think priority should lie in robustness. We need to obtain the KS: This has everything to do with the complexity of same results over and over again. biomolecules. Measuring oxygen levels, pH, and so on, can readily be performed using sensors, but studying the HW: Being from academia, my opinion is that sensitivity is biopharmaceutical in situ demands more sophisticated always beneficial! Sensitivity allows you to see and understand chromatographic or mass spectrometric tools – which very more – and I think scientists from commercial biopharma often include tedious sample preparation. As an extreme should share this view. Sensitivity, however, is not the only example, monitoring glycosylation requires glycan release, important feature of a system – separation efficiency and labeling and chromatographic separation (eventually also robustness are equally important, depending on what you incorporating a purification step). Various groups within the are trying to achieve. If you are looking for a certain minor biopharmaceutical industry have, nevertheless, made enormous component, you need sensitivity, but if you have a more progress in real-time monitoring of CQAs directly from complicated process that you are looking to control then the process. you perhaps need separation efficiency. System reliability is also crucial. Interestingly, I think that standard analytical HW: Most definitely it would be very valuable to have more equipment can sometimes be more reliable than newer, analytical data during processing, but this is not easy. To start sophisticated instruments. For example, I find that standard with, there is the issue of fouling of the sensors or the sampling HPLC equipment can be a little more reliable than highly in biopharma production – how do you prevent carryover from sophisticated HPLC, electrophoresis or MS systems. I am sure one analysis to another? There are many basic challenges like that all the instrument vendors are addressing this though – this that must be solved before we can begin to implement and most definitely there is considerable progress being made. analytical systems directly in production.

Could you explain the challenge of developing What emerging characterization tools have systems for real-time analysis during potential but are not yet routinely applied? biomanufacture? AR: One area that is ripe for future development is real- AR: Improvements in MS have dramatically improved our time monitoring of product attributes through all stages of ability to obtain detailed protein molecular information. In development and manufacturing. Typically, the different addition, the continued development and deployment of such manufacturers of process equipment and analytical equipment MS-based applications will enable finer control of bioprocess each use their proprietary software for equipment control. optimization, allowing for correlation of manufacturing And that creates significant challenges when one tries to process changes to both molecular structure and yield. integrate the process and analytical equipment to get real- Numerous hybrid MS-based analytical techniques, including time information during manufacturing. Another major ion mobility-MS, capillary electrophoresis-MS, hydrogen- challenge is the mismatch between the time that is available for deuterium exchange-MS (HDX-MS), and size-exclusion analysis and the decision making required during processing. chromatography coupled to native MS are yet to make their For example, typical chromatographic elution occurs in 15- way into routine use. Alternatives to conventional cell-based 30 minutes, and a typical HPLC assay takes 30-60 minutes analytical methods and continuous processing requiring to do a single analysis. process analytical technology for real-time process monitoring are in the pipeline for implementation in industry. Also, real- timetit m efficacy assessment platforms have been proposed (for example, CANScript technology), which I believe will greatly enhance effective biologic development. 11 – 15 June 2018

KD: We too see phenomenal growth in HDX-MS, especially in Frankfurt am Main areas such as biosimilarity studies from biosimilar manufacturers, but also innovator companies looking to protect their patents. Top-down or middle-down MS protein characterization is also showing great promise as a simple minimal or preparation-free method for confirmation of protein structure. Historically, the sequence coverage obtained from a top-down fragmentation experiment didn’t meet the demands for biopharmaceutical manufacturers, but with advancements in fragmentation methods we see great interest in this technique because it can achieve near-full coverage, providing confirmation of primary structure, localization of post-translational modifications and the intact or subunit mass of a biologic. Intact and subunit analysis of biologics is also becoming more information rich due to the coupling of chromatographic separations with MS, and the clarity and accuracy of intact protein mass spectra on the latest MS platforms.

KS: I think it is a very exciting time to be involved in biopharmaceutical analysis given the enormous advances in instrumentation. Mass spectrometry, the workhorse in R&D, is slowly finding its way into routine environments as a release tool. We also have high hopes for 2D-LC, where two different separation mechanisms are combined, with the aim of increasing overall resolution and thereby providing the next level of product detail. BE INFORMED. HW: I expect considerable progress to come from automation, BE INSPIRED. particularly sample preparation steps. Less error by dilution or extraction steps will certainly improve analytical precision. BE THERE. Miniaturization also has great potential to speed up analyses, and improve precision by multiple measurements and using › World Forum and Leading Show for the obtained average values as reportable results. Improved the Process Industries surface technologies can reduce the fouling of the analytical instrumentation, enabling the very much desirable process › 3,800 Exhibitors from 50 Countries analysis of biopharma products and their impurity profiles during production and clean up. › 170,000 Attendees from 100 Countries

www.achema.de 30  Sponsored Feature

Getting on the Fast Track: Manufacturing Training for Cell Therapies

Looking to advance in the exciting area of cell therapy? The new CELLT1 course is here to help bring staff up to scratch.

By Trevor Smith

Cell therapy is one of the hottest topics right now in the biopharma industry, with ambitious goals for making patients with no other treatment options well again. New developments are reported every day, and more and more companies are looking to expand into this area. My background lies in microbiology and immunology, so I’m familiar with dendritic cells, T cells and so on. Today, I focus on cell therapy at GE Healthcare – in particular, on the validation of new technologies for producing cell therapies. I also work on developing new intellectual property for future products. Recently, I was asked to help write the course for GE Healthcare’s CELLT1 training course for advanced cell therapy technology, which falls under our Fast Trak training and education services. The stakes are also very high, so challenges associated with scale up and Why does the industry need a training companies cannot afford errors or time manufacturing site expansion, with a focus course for cell therapies? Similarly to working delays. Safety is paramount, so due care SR¾I\MFMPMX]ERHIJ½GMIRG]%RHSRISJ with other biological drugs, consistency, and attention must be paid to manufacture the latest additions to our offerings is the cleanliness and a suitable background and scale up – but, at the same time, aforementioned CELLT1 training course. ORS[PIHKISJXLI½IPHEVIGVMXMGEP%R]SRI there is a push for faster turnaround Other training courses tend to be limited comfortable with traditional cell culture times and reduced costs. To achieve both, to singular components of the process for bioprocessing can learn to work with the industry needs innovation around when it comes to cell therapy – yes, there is GIPPXLIVETMIWFYXXLIVIEVIWSQIWTIGM½G process optimization. GE Healthcare’s training for individual pieces of equipment challenges that require new training – and Enterprise Solutions, which includes and individual types of operations, but we the equipment is specialized and very much equipment, integrated services and staff felt that there was a lack of cohesive, end- at the cutting edge. training, are designed to help address the to-end manufacturing training courses. Sponsored Feature  31

8LIVIMWEPWS/9&MS[LMGLMWFYMPXJSV “Ultimately, you New Ways of Thinking the customer with the whole project managed by GE Healthcare. We can help need a variety of Changes in the market demand new a company break into new markets and ways of thinking. How do you scale up XEOIE[E]XLIWXVIWWSJ½KYVMRKSYXLS[ different systems to manufacture the new treatments to get the right permits to break ground – TEXMIRXWRIIH#%RHLS[HS]SY GE Healthcare is a global company so we and you need to be satisfy regulators, while minimizing are accustomed to operating in diverse FSXL½RERGMEPERHTVSHYGXMSRVMWOW# QEVOIXW/9&MSMWEXYVROI]WSPYXMSRXLEX able to coordinate GE Healthcare’s Enterprise Solutions can be built out over different phases. It bring together a range of services and LIPTWQMRMQM^IFYWMRIWWERH½RERGIVMWOW the whole process.” products, with the aim of supporting by allowing you to adapt more readily to companies from process development GLERKIWMRTVSHYGXHIQERH8LI/Y&MS through to commercialization for design for cell therapies can produce Class is in session biopharmaceuticals and cell therapies. up to 3,000 doses a year, based on the When developing new systems and It is based on modular approaches WTIGM½GTVSGIWW technologies, you gain a unique insight designed to help manufacturers be Enterprise Solutions is all about that can be very valuable. We weren’t QSVI¾I\MFPIERHIJ½GMIRX*SVI\EQTPI WYTTSVXMRKGYWXSQIVWJVSQ%XS> WEXMW½IH[MXLWMQTP]XVEMRMRKYWIVWSR we offer process development services from process development, to training individual pieces of equipment because, that can help customers move from staff during the construction of a new ultimately, manufacturers need a variety open to closed processes that are also facility, to setting up the equipment. The of different systems and need to be scalable. Concurrently, customers can equipment does not necessarily all have able to coordinate the whole process. take advantage of our Fast Trak training to be from GE Healthcare – our goal is In general, the hardware aspect of the courses so that staff are trained while to get customers to market faster, and cell therapy process is locked down – our process development is being done. GE we can work with other suppliers to Enterprise Solutions can demonstrate the Healthcare also offers the FlexFactory make that possible. Within 22 months, full line of equipment and an optimized production platform – a closed, semi- it’s possible for us to build and qualify a ¾SSVTPER&YXMRWXVYQIRXEXMSRSRP]KIXW automated solution predominantly company’s entire manufacturing facility you so far; companies need reliable, well- using single-use and scalable technology – from closing processes, to training trained staff and cross-site alignment to – that can be set up in new or existing teams, and then handing over the keys ensure consistency and product safety. manufacturing plants. to the new facility. CELLT1 is designed for research and development scientists, process engineers, and manufacturing technicians. -XEHHVIWWIWXLIJYPPGIPPXLIVET][SVO¾S[ – from the isolation of target cells, to expansion – this is one of the longest We also discuss the idea of digitalizing LEVZIWXMRKXS½REPJSVQYPEXMSRJSVTEXMIRX process steps. Our bioreactor systems are manufacturing processes, which is administration. It includes training on ZIV]¾I\MFPIMRXIVQWSJTVSKVEQMRK[LMGL something we find companies are instruments and standard operating is useful because they can be adapted to increasingly interested in. We are procedures, as well as tips and tricks that ER]YWIVTVSGIWWFYXRI[YWIVWGER½RH working to ensure that our equipment we have learnt along the way. Examples new, robust equipment a bit daunting can be integrated into a digital platform of the topics covered are listed in the and it is often one of the biggest fear that allows users to see the whole sidebar, CELLT1 Topics. Obviously, the factors during manufacturing. This topic scale of the process, such as setting up GIPPXLIVET]½IPHMWWXMPPIZSPZMRKWSXLI is covered in detail within CELLT1 – and instruments using the digital cloud and course will evolve over time too. It can it is also the most customizable aspect of showing potential warning errors as they also be tailored to individual needs. the course; everyone will have different pop up, which you can access both inside One common challenge in the cell processes and expectations for how cells and outside of the laboratory. In doing so, therapy manufacturing process is cell are to be cultured and expanded. we hope to increase usability and control.

gelifesciences.comgelifesciences.com 32  Sponsored Feature

• implement strategies used for process optimization and evaluation.

It may seem easy to overlook the need for a truly skilled workforce, but cell therapy manufacturing requires many TISTPI8LI¾I\MFMPMX]SJSYV)RXIVTVMWI Solutions is that it allows users to easily scale out into multiple manufacturing suites – companies will need trained staff to work in those suites and standardization to ensure that processes are reproducible anywhere in the world. Cell therapy is an important component towards a future of personalized medicine; it has long been a goal of the healthcare industry, and to see it unfolding in our lifetime is incredible. Now that the industry has a better grasp of cell therapies and their manufacturing processes, we can really push forward The course will include two different [MXLHIZIPSTMRKQSVIWTIGM½GXIGLRSPSK] formats. One will be styled like a lecture platforms. In time, standardization CELLT1 Topics or presentation, with the aim of teaching and optimization of the manufacturing the principles behind the technologies. TVSGIWW[MPPFSPWXIVXLI½IPHJYVXLIVF] • Overview of cell therapy The second format will be “hands on” in reducing costs, accelerating processes, [SVO¾S[WERHGIPPX]TIW the lab, showing students the equipment ERHWLSV XIRMRKXLIXYVREVSYRHXMQIW%X • 8YFI[IPHMRKERHEWITXMG¾YMH in action and testing the knowledge they the moment, it is a massive undertaking transfer have learned in the lectures. for companies to develop a cell therapy, • Cell counting FYXVIGIRXWTIIH]*(%ETTVSZEPWLEZI • Isolation technologies Graduation day given the industry greater momentum • Transduction and vectors CELLT1 has been developed to pair with to continue advancing technology to • %GXMZEXMSRTVSGIWWERH our Enterprise Solutions, so “graduates” ultimately provide lifesaving therapies technologies should be able to walk out of training to patients who need them. • Cell culture media development and straight into one of their Enterprise Seeing our work having a direct impact and design WYMXIW¯ERHFIGSR½HIRX[MXLQEREKMRK on patients is really what drives me in all • Cell expansion and perfusion XLITVSGIWWIW%JXIVXLIGSYVWIWXYHIRXW of this. I see products launch – I know applications should be able to: they optimize a customer process and • Harvesting platforms this optimization will generate more • Final formulation and • apply detailed theoretical cell effective therapies for patients… it’s cryopreservation therapy process knowledge work we can all feel proud of. I think • Scale-up and scale-out to applications across the this is the time for companies to work • Development of standard QERYJEGXYVMRK[SVO¾S[ together and to recognize any success as operating procedures • identify bottlenecks and EWYGGIWWJSVXLI½IPHEWE[LSPI • Process evaluation and XVSYFPIWLSSXWTIGM½GTVSGIWWIW optimization • perform industry standard Trevor Smith is an R&D Leader at GE techniques related to cell therapy Healthcare Life Sciences, based in manufacturing Marlborough, MA, USA. Business Economic drivers Emerging trends Business strategies

34-39 Hold Me Closer, UK Pharma With ingredients and products crossing multiple UK/EU borders during the manufacturing and distribution process, will pharma’s fragile supply chains be able to adapt to new customs checks and tariffs after Brexit? 34  Business

that “sufficient progress” has been made Davis, said in January (1). Hold Me Closer, on the three main issues: citizens’ rights, A key feature of the phase one agreement the Irish border, and the financial was the UK government’s commitment UK Pharma settlement. Despite this, we still know to avoiding a “hard border” in Ireland, little about what the future arrangement including “physical infrastructure or Pharma calls for close will actually look like. A soft landing related checks and controls” (2). Critically, cooperation and clarity as – continued membership of the single the UK committed, in the absence soon as possible. market via the European Economic Area of agreed solutions, to fully “align” (EEA) – has been repeatedly ruled out by its regulations with the EU’s so as to By James Strachan, Deputy Editor the British government, but there’s been avoid such a border. Exactly what “full little talk of walking away without a deal alignment” means should become clearer Brexit negotiations between the UK and in recent months, perhaps signaling that once the phase one agreement is transposed the European Union have moved onto the hardest possible Brexit is “incredibly into law. As it stands, if the UK is serious phase two after the EU Council concluded unlikely,” as UK Brexit negotiator, David about eliminating the need for physical Business  35

times in the past 20 years. On 24 June Operation Stack 2015 Operation Stack was enacted due to industrial action taken by The Channel Tunnel and the Port of French employees of the MyFerryLink Dover handle 90 percent of freight company. This was the first time “Phase traffic between the UK and mainland 4” of Operation Stack was used, which Europe. Around £119 billion of goods involved clearing 30 miles of parked pass through Dover every year – about Heavy Goods Vehicles. Between one sixth of British trade by value. January and November 2015 On average, around 10,000 freight Operation Stack was implemented vehicles pass through Kent every day on a record 32 days, including three and the demand is predicted to rise five-day stints. by over 50 percent in the next decade. The UK Freight Transport There is a real concern that new Association (FTA) estimated customs checks at the border could the cost of the delays to the UK cause lengthy delays, with severe International Road Freight industry consequences for pharma supply at £750,000 per day. The FTA has chains. The flow of goods through estimated, based on Border Force KPIs, the busiest ferry terminal in Europe that passport checks alone cost £1 per is currently “frictionless,” yet delays minute. “It is therefore highly probable are not uncommon. Bad weather, that costs related to customs checks operational problems, industrial being performed at the border would References action, and more recently, migrant be much greater due to time spent by 1. FTA, “Written Evidence action at Calais, have caused delays. customs officials to check goods against submitted by the Freight Transport Association And in cases of severe disruption, documentation,” they said (1). (UKT0033)”, (2017). Available: http://bit. Operation Stack is implemented. In an interview with The Times, ly/2EqEvCr. Accessed 24 January, 2018. Operation Stack is a procedure Tim Waggott, the Port of Dover chief 2. The Times, “Dover fears hard Brexit as used to park (or “stack”) lorries on the executive said, “We will see [Operation election approaches”, (2017). Available: M20 motorway in South East Kent. Stack] every day of the year in perpetuity http://bit.ly/2EqEvCr. Accessed 24 The system has been implemented 74 if we don’t get this sorted” (2). January, 2018.

infrastructure at the Irish border, while business (3). The industry was united in its simultaneously ruling out trade barriers desire for Brexit negotiators to agree a deal “Importantly, any between Northern Ireland and the rest of that would keep the UK closely aligned the UK (which the government also did to the EMA’s regulatory sphere – and, delays at borders as part of the phase one agreement), the if possible, continuing to participate in final relationship will likely be very close the agency. run the risk of – which will be a relief for the European pharma industry. “The closer the better!” Save our supply chains disrupting patient was the call that came from several global The number one concern for pharma pharmaceutical companies and industry companies is being able to deliver supply of organizations in their submissions to medicines to patients, without delays, the UK Business, Energy and Industrial after the UK leaves the EU. Pharma medicines.” Strategy Committee’s recent inquiry supply chains are fragile and highly into Brexit and the implications for UK dependent on frictionless trade, a point

www.themedicinemaker.com 36  Business

their intention to seek alternative suppliers based in the EU.” Johnson & Johnson raised similar concerns, warning that “ingredients and products can cross the border multiple times in the manufacturing and distribution process [...] Systems must be put in place to ensure that this can continue without the need for Border Inspection Post Personnel checks and tariffs.” As one example, a company that manufactures products in the North West of England identified four occasions where its products cross UK/EU borders before reaching the end user. They added, “Currently this is frictionless, so there is a high risk that any new arrangements will add cost and/or bureaucracy, changing decision-making about both ongoing and future manufacturing.” Eli Lilly’s Kinsale site in Ireland is one of the company’s major centers for API manufacturing. “As a measure of the integrated nature of our supply routes, products manufactured in Kinsale cross the border from Ireland into the UK before being exported to Europe and beyond,” says Chris Lowry, Public Affairs Manager at Eli Lilly. “The fact that these products cross between the UK and the EU multiple times evidently leaves them particularly exposed to any potential customs and border controls. We would be extremely dismayed to see such impediments put in place. Importantly, any delays at borders run the risk of disrupting patient supply of medicines.” well made by many of the submissions to transportation; they point out that the “We are a global industry, and Merck the Committee. For example, according refrigeration system is maintained by Sharpe & Dohme (MSD) is a great to Merck KGaA, around 12 percent of the running engine of the vehicle in example of a multinational operation, their products are “dropshipped” directly which they are transported. “If delays working across complex environments to customers from Germany “within at ports become consistent, the whole that change over time,” says Virgina 24 hours of an order being placed,” so sector will have to develop new ways Acha, Executive Director of Global any delays at UK ports would have a of transporting and storing goods and Regulatory Policy at MSD. “Biopharma “significant impact” on the company’s medicines to mitigate the risk of a product discovery, development, manufacture ability to meet the needs of its clients. overheating and becoming unusable,” said and supply chain arrangements take Merck KGaA also highlighted that Merck KGaA. They went on to explain many years to undertake and many products that must be kept cold during that several customers have “already stated years to change. There are long cycles in Business  37

planning schedules, with some speciality UK exporters would end up stuck in the biological products, for example, only “We’re actually in the same queue when trying to get back to having a production run every one to two the continent – a nightmare scenario for years. Supply is carefully allocated in this countdown phase pharma supply chains. global planning. The relatively sudden, exceptional and across the board changes to the rocket launch Calls for clarity that Brexit seems likely to generate will Though the UK has committed to doing profoundly challenge biopharmaceutical now and there comes what is required to avoid customs checks businesses.” between the UK and EU – allowing Lowry concurs, adding, “Imposing a point where we’re pharma supply chains to operate as-is barriers would levy substantial cash flow post Brexit – nothing is set in stone. The costs to companies and disrupt the close beyond the no-go uncertainty over the future relationship intertwining of trade and regulation. means that companies must take action Mitigating these impacts may require us period. For matters now to ensure their medicines can to explore and validate new supply routes, continue to reach their destination post- which given the distribution and storage like batch release, we Brexit – regardless of what happens in requirements of some products, is not a April 2019. simple task.” need to make When the UK leaves the EU, it will The Association of the British become a “third country.” And so, aside Pharmaceutical Industry pointed out the decisions relatively from supply chain issues, another area of challenges associated with cell and gene concern for UK-based pharma companies therapies, which tend to be extremely time soon – but we’re is the impact of Brexit on current quality sensitive. Novartis’ Kymriah, for example, control testing and Qualified Person (QP) is set to launch in the EU next year. The already spending batch release systems. Each production therapy involves removing the patient’s batch of medicinal products imported own white blood cells, freezing them, and money.” from third countries must undergo shipping them to a Novartis site within 24 “qualitative analysis, a quantitative analysis hours. The T-cells are then treated, before of at least all the active substances and being transported back to the patient for report on Brexit and customs (4); one of all the other tests or checks necessary to reinjection, again within 24 hours. “The if its senior researchers, Joe Owen, points ensure the quality of medicinal products turnaround time is very tight,” says Sascha out that the need for new customs checks in accordance with the requirements Sonnenberg, VP Commercial Operations could severely disrupt the flow of traffic of the marketing authorization,” in an Americas and EMEA at Marken – a from the UK to the EU, and vice versa. EU Member State (5). In other words, company that specializes in supply chain “If the UK is treated in the same way as companies exporting from the UK to the solutions for clinical trials. “These are any other third country, there could be EU after Brexit would, therefore, have to life-saving medicines, and any customs severe border delays. Take Agri-food for carry out additional batch release testing delays – even a six hour delay at the border example: between 20 and 50 percent of in an EU member state. – could mean you miss the turnaround shipments of beef and lamb imported “You’re looking at new premises and time and the treatment cannot be used. from outside the EEA must be checked distribution; and when you add in the We’re talking about late-stage cancer at the border. The capacity is not there possibility of having to transfer your treatments where the patient might not to cope with the volume of beef and marketing authorizations to the EU, for be in a position to donate additional cells.” lamb that would need to be checked,” us the overall cost will be in the region of To prevent customs delays, the pharma he says. Not only is capacity lacking, £5 million,” says David Jefferys, Senior industry is relying on Brexit negotiators but there also isn’t enough space to build Vice President for Global Regulatory, to agree a deal that covers the entire the capacity, argues Owen. The result Healthcare Policy and Corporate Affairs economy – delays for other industries could be queues of traffic in motorways for Eisai Europe, and Chairman of Eisai’s could indirectly impact the pharma leading up to the UK’s borders with the Global Regulatory Council. “We’re industry. The Institute for Government, EU. Not only would this impact exports actually in the countdown phase to the a UK-based think-tank, published a from the UK to the EU, but any EU to rocket launch now and there comes a

www.themedicinemaker.com 38  Business

ensure that the UK processing above a The Keys to continues to align its certain threshold – done Frictionless Trade regulations with those of on them in the UK. Border the single market. The EFTA officials check Origin documents Regulatory alignment court, via the EEA Joint Committee, at the border, which requires physical Preserving the integrity of its internal performs this function for Norway, infrastructure. Such checks will allow market is of vital importance to the Liechtenstein and Iceland. Whereas the EU to ensure that countries trading EU. If the UK is able to diverge from for Switzerland’s bilateral agreements with the UK after Brexit – perhaps with single market standards, there is a risk with the EU, a Joint Committee (made lower tariffs on certain goods – do not it might loosen its regulations and up of Swiss and EU officials) resolves use the UK as a means of circumventing begin importing faulty toys, diseased disputes diplomatically – not legally. the EU’s Common External Tariff. animals, or counterfeit medicines from It remains to be seen whether a third The UK could agree to maintain the other countries, which could then make way can be found. Common External Tariff or enter into a their way from the UK to the EU. The customs union agreement with the EU EU cannot allow the free movement A customs agreement to eliminate need for Rules of Origin of goods with the UK to continue The UK and EU will need to enter checks. And though such checks are after Brexit without an agreement into a customs agreement if Rules of unlikely to be a direct issue for the on regulatory alignment – at least for Origin checks are to be avoided. Rules pharmaceutical industry (the WTO product standards. of Origin are used to determine the Pharmaceutical Tariff Elimination national source of a product. To take Agreement reduces tariffs to zero Surveillance and dispute resolution advantage of preferential tariffs agreed percent for many pharmaceutical Any agreement on regulatory in trade agreements, for example, products), the effect on other products alignment will have to include UK exporters must prove that their could indirectly impact pharma supply appropriate surveillance mechanisms goods come from the UK or have chains, if only by causing port and and dispute resolution procedures to had sufficient work – any amount of road congestion.

point where we’re beyond the no-go cost of almost £1 million per year. won’t be able to cope with the demand period. For matters like batch release, we A Mutual Recognition Agreement for testing facilities, post-Brexit. “Today, need to make decisions relatively soon – (MRA) between the UK and the EU 1,300 products produced by EFPIA but we’re already spending money.” would allow companies to base their members are batch released or tested in the Jefferys’ concerns were mirrored by contract testing laboratories in the UK, UK,” says Acha. “Forty percent of these Lisa Anson, president of the ABPI and but that isn’t the default – and there are EFPIA members anticipate challenges to chairman of AstraZeneca. “If we look some concerns over whether an MRA ensure that there is sufficient capacity in at the frictionless trade, AstraZeneca would do what it’s supposed to do in the EU27 to replace this infrastructure.” is already looking at contingencies to practice. “We see that the MRAs between The scale of the work that would duplicate the quality control release Switzerland or the US and the EU are need to be done is significant. The processes in the UK and in Europe, supposed to eliminate the need for QP EFPIA also revealed that 70 percent of because we can’t afford to wait to know if testing on the EU side for imports from all investigational medicinal products there’s going to be customs tariffs or any these countries,” says Sonnenberg. “But (IMPs) in ongoing EU trials are QP- other sort of barrier,” (6). what I have seen in clinical supply is that released from the UK; and more than In their submission to the Business, there tends to be a simplified release by an half of EFPIA members have 100 percent Energy and Industrial Strategy EU-based QP in addition to the testing of their IMPs in ongoing EU trials QP Committee, J&J estimated that the done in the exporting country – even with released from the UK. company would have to conduct 50,000 an MRA in place.” “We see major companies already additional tests every year, with a combined There are also concerns that the EU investing in the EU, building up additional Business  39

storage and lab capabilities – the larger put forward by both sides is that medicinal and so on.” companies are quite well prepared,” products that have been tested and When it comes to the final arrangement, says Sonnenberg. “But some smaller released prior to the Brexit date should Sonnenberg just hopes the negotiators companies, especially Asian and American continue to be freely available in the EU understand what is at stake for those who companies, do not have Brexit on their even if that testing and release is carried rely on the life-saving medicines produced radar. I worry about a bottleneck on the out in the UK and the goods are shipped by pharma industry. “We are talking EU side – especially human resources like to other EU countries after the UK about patients’ lives,” says Sonnenberg. QPs – as companies rush to make sure withdraws. “This is an important detail “Particularly when it comes to clinical they’re ready to carry out QP in the EU for global companies deciding how, and trials, oftentimes these drugs are the only once the UK leaves. This could potentially crucially when, to progress existing Brexit option for patients. There are so many delay or endanger ongoing trials.” contingency plans,” she says. uncontrollable events that could lead to Another important factor is whether or drug shortages; if we make Brexit one of Hope for the best, plan for the worst not the UK will have access to the EU’s those, then I think we all fail.” Companies are optimistic that the final trade and mutual recognition agreements deal will facilitate the continued free during the transition period. As things References movement of goods post-Brexit (see our stand, unless Article 50 is extended, the 1. Exiting the European Union Committee, “The sidebar for the main elements of such UK will leave the EU on March 30, progress of the UK’s negotiations on EU an agreement), but that doesn’t (and 2019 and drop out of several hundred withdrawal”, (2018). Available: http://bit. perhaps shouldn’t) stop them preparing EU agreements – including free trade ly/2DtYnDj. Accessed 24 January, 2018. for the worst. “We need to be prepared agreements with Canada, Switzerland and 2. EU Commission, “On Progress during phase 1 of for all eventualities, and this includes a ‘no Turkey (7). However, if the UK is bound negotiations under article 50 TEU on the deal’ scenario,” says Acha. “Our objective by the rules of the single market and the United Kingdom orderly withdrawal from the is to undertake the investment and customs union during the transition, it European Union”, (2018). Available: http://bit. changes needed to ensure that following will likely be bound by the obligations of ly/2iGFODe. Accessed 24 January, 2018. Brexit, regardless of the outcomes of the the EU’s trade deals. Canadian or Korean 3. Business, Energy and Industrial Strategy negotiations, on March 30, 2019, MSD exporters should be able to sell to the UK Committee, “Brexit and the implications for UK can provide its medicines to patients as though it was an EU member during business: Pharmaceuticals inquiry – publications” across Europe as if it were any other day. the transition, but UK-based exporters (2018). Available: http://bit.ly/2GbJU0D. We are working across our business to would not be able to benefit from the EU- Accessed 24 January, 2018. meet this objective. However, industry Canada or EU-Korea FTAs (8). 4. Institute for Government, “Implementing cannot resolve all of the issues on its own.” Could the UK roll over the EU Brexit: Customs”, (2017). Available: http://bit. In phase two, UK and EU negotiators agreements on March 30, 2019 or agree ly/2gZ6nGb. Accessed 24 January, 2018. will begin discussions over the transition a legal fudge whereby the UK continues to 5. EU Commission, “EU Guidelines for Good period. The European Council is be covered by the EU’s external trade policy Manufacturing Practice for Medicinal Products proposing a period of two years, in which as a non-EU member for the transition for Human and Veterinary Use. Annex 16: the UK would lose all EU voting rights, period (the so-called “Guernsey option,” Certification by a Qualified Person and Batch but would continue to participate in the 8)? Well, that remains to be seen. And Release”, (2015). Available: http://bit. Customs Union and Single Market (7) the uncertainty, both over the nature and ly/2BqrtBP. Accessed 24 January, 2018. – potentially providing some continuity length of any transitional arrangements, 6. Sky News, “Pharma sector warns of ‘dire’ for businesses. as well as the future relationship, is an consequences without Europe regulation deal”, “We welcome the recent agreement ongoing problem for pharma – forcing (2018). Available: http://bit.ly/2rDBf3M. to progress to phase two of the talks,” companies to defer investment decisions. Accessed 24 January, 2018. says Laura Collister, the UK Bioindustry “When companies are thinking about 7. EU Commission, “Annex to the Association’s (BIA’s) Brexit Lead. “It is investing in the UK, the uncertainty is Recommendation for a Council Decision”, now crucial that the UK and EU agree definitely having a negative impact,” says (2018). Available: http://bit.ly/2kuG0a3. a transition period to ensure that the Jefferys. “And I would say the choice isn’t Accessed 24 January, 2018. supply of medicines to patients in the just between London and Frankfurt or 8. CER, “Of transition and trade deals”, (2018). UK and across Europe is not affected.” Milan, for example. It’s London versus Available: http://bit.ly/2nbrK6n. Accessed 24 Collister’s initial reading of the proposals New York versus Singapore versus Tokyo, January, 2018.

www.themedicinemaker.com Premier Association Sponsor

Based in New York, INTERPHEX brings over 11,000 global industry professionals and 650+ leading suppliers together to “Learn It, Experience It, Procure It” through a combination of no cost technical conference, exhibits, demonstrations, and networking events to leverage quality, efficiency and cost effectiveness in today’s ever-changing global market.

SOLUTIONS TO COST FORMULATIONX EFFECTIVELY DEVELOP & DEBUTING AT MANUFACTURE PRODUCT INTERPHEX 2018

EXPERIENCE REGISTER AT: SCIENCE THROUGH INTERPHEX.COM/REGISTER COMMERCIALIZATION Best Practice Technology Quality Compliance

42-45 A Problem Shared… Towards the end of 2017, Boehringer Ingelheim launched an open innovation portal called opnMe.com – and now Adrian Carter is calling on other companies to join the crowdsourcing revolution.

46-49 Fumigation: Choose Your Weapon! Are you tasked with finding a new fumigation system? Andrew Ramage discusses key criteria to consider, and the pros and cons of different approaches. 42 Best Practice

A Problem Shared…

It’s time for pharma to join the crowdsourcing revolution. Open access science may seem counterintuitive to some objectives but by joining forces with the broader scientiﬁc community, we will be far stronger together than we are alone.

By Roisin McGuigan, Deputy Editor

The ways in which individuals, organizations and companies can find solutions on the Internet is constantly expanding – from naming a new polar research vessel using an online vote (the Royal Research Ship Sir David Attenborough, if you’re interested) to funding innovative projects in art, science and technology through crowdfunding platforms like Kickstarter. But how can the crowdsourcing revolution benefit “dark side” – I moved into business assessed not only where and how we could pharma? And how can companies strike development and spent 10 years there. find innovative ideas and approaches, but the right balance between sharing their In 2011, I moved back to research in also how we could turn them into new own data and protecting intellectual a networking and coordination role at medicines. One concept we hit upon was property? We spoke with Adrian Carter, Boehringer Ingelheim that allowed me the idea of “opening up” the innovation Corporate Vice President and Global to bring together these two different process and inviting contributions from Head Discovery Research Coordination parts of the collaboration puzzle. My the scientific community to help solve at Boehringer Ingelheim, Germany, to broad aims were to examine how the current research puzzles. find out why he believes open innovation pharmaceutical industry and academia This idea has its pros and cons: on the is important for securing a better future could best work together, what one side, you have the opportunity to for pharma research and discovery. advantages that brings, and also what tap into the creative power of scientific needs to be done from the operational minds from all around the globe – How did you become interested in side to make it work well. It made me someone might just hold the answer open innovation? realize that, as an industry, we need to to the conundrum. The downside? I “grew up” in discovery research – I’m look further afield for new ideas. You have to share some of your own a pharmacologist by training. But when It’s important to recognize that many hard-won knowledge. Some people I moved from the UK to Germany for discoveries in a pharma company do not within industry will balk at the idea of a postdoctoral position in the research actually come from inside their own four sharing propriety information with the organization at Boehringer Ingelheim, walls; to be successful in research and public, but if you do it right, the pros far I quickly developed an interest for discovery, you need to seek out creative outweigh the cons. neurobiology and spent 15 years working ideas from elsewhere. With this in mind, The practice of opening up in that area. And then I crossed to the we developed a strategy document that collaboration and publicizing data has Best PracPractice 43

its roots in the software industry in the that everyone gets to participate in theh 1980s. The industry was revolutionized scientific process – but don’t let that by Richard Stallman, who used the open put you off! You don’t have to give source approach to create an alternative everything away for free to participate to Unix, the operating software that in open innovation. Different degrees large mainframe computers ran on of openness in the forms of project at the time. He encouraged software participation, scope and access may be programmers around the world to work appropriate, depending on your goals. together to develop operating software Open innovation has clear benefits for Adrian Carter’s for mainframe computers that wasn’t both pharma and academia. Developing tied to Unix’s developer, AT&T, who new drugs is an expensive business model Key Messages subsequently licensed it to IBM. The with a high failure rate. I call it the rule effort resulted in an alternative called of 10: by the time you get a molecule • Open innovation is evolving. Gnu, a recurring acronym “Gnu is to the preclinical development stage Originally used to describe a not Unix”, which was combined with (which takes a huge amount of work), closed collaboration between another open source software kernel, the chance it will make it from there two organizations, today it Linux – eventually going on to enormous to market is around 10 percent – and if covers much more – from success. Most of the computers in the it does, it will take around ten years on crowdsourcing problems to world now run on Gnu/Linux software average. Despite all the effort, there’s open access data. – and huge brands like Amazon, Google no guarantee of success. I believe this • Pharma must embrace a more and Android, and many more, all use is down to a lack of efficacy – candidate open way of working; fresh this open access software as the basis drugs often tick all the safety boxes, approaches will improve our for their large servers. I think many but fail because they don’t exhibit the understanding of human people don’t fully appreciate how much desired improvements for patients. biology and lead to new drug of our modern technology is driven by Why? One theory is that we simply targets, ultimately helping us this open access source material. And if don’t understand enough about human provide novel therapies for an open access approach can have such biology, and I believe that increasing patients in need. a far-reaching impact on the software our knowledge will help us overcome • There are challenges ahead industry, just imagine what it could do the efficacy wall we keep hitting. but, with the right approach, for pharma! Meanwhile, many academic we can create trust and foster institutions worldwide, which are filled true collaboration between What does open innovation mean with brilliant scientific minds, are companies, research institutes to you? lacking research funding and resources. and individuals. “Open innovation” is a term that has Collaboration with the private sector is • There is strength in numbers evolved over the years. As it’s taken an attractive prospect in this climate – as – the more we all buy into off, we’ve developed a variety of terms long as both parties benefit and as long as open innovation and the more to describe the free movement of ideas researchers are not subjected to hidden we share resources, tools, and and data (see “Behind the Buzzwords”). and unnecessary “strings attached.” knowledge, the more we all Science is seeing the effects too – stand to benefit. many scientific journals today require How did opnMe come to be? • Boehringer Ingelheim has scientists to make their data public so Boehringer Ingelheim’s open innovation recently launched its open that others can use it, and more journals portal – opnMe.com – started with our innovation portal opnMe.com are making their papers open access. work with the Structural Genomics to provide access to scientists Large commercial publishers may prefer Consortium (SGC), a public/private from all around the world to to keep their content behind a pay wall, partnership involving nine pharma a unique selection of well- but public funders are challenging the companies. The idea was to encourage characterized, pre-clinical idea and demanding that the research the scientific community to work on probe compounds. they pay for is made publicly available. particular proteins that may be of An open approach to science means interest by providing them with new

www.themedicinemaker.com Behind the Buzzwords Open innovation: Originally defined by Henry Chesbrough tools. One such tool was a chemical traditional collaboration. Providing as a closed collaboration between probe for the bromodomain (BRD) these two options in our portal allows two organizations, the meaning family member BRD4; making it us to monitor what information we’re has evolved to include a variety of freely available catalyzed a great deal of sharing, and how we share it. opnMe. strategies and practices that allow research, thereby leading to a number com launched in mid-November 2017 – ideas to flow between businesses, of clinical programs and new biological we are still working to spread the word research organizations and the knowledge on BRD4 (1). and seek feedback from our users to help scientific community. Our work with the SGC helped us us improve the portal. Nevertheless, we to understand the potentially huge have been pleased to see that the site Crowdsourcing: A way to elicit ideas advantages of making our chemical tools has been frequently accessed thus far, and services from the scientific available to a wider scientific audience. and we have already received a steady community at large, usually via We also learned that you get much better stream of new orders. Embracing open the Internet. uptake if you provide the tools free of collaboration is a process and I believe charge – and without any catches. The pharma will go through a similar Bilateral collaboration: The minute you start charging and adding transformation to the software industry traditional way in which pharma caveats to the use of the tools you’re as we seek new and better ways to work often collaborates, involving offering, people lose interest. together. I would encourage other a closed partnership between The success we saw with BRD4 led companies to follow suit and look at one company and one academic us to launch opnMe.com, a project with what information they could afford to investigator or institution. two main aspects: “molecules to order share to help move science forward. (M2O)” and “molecules for collaboration Precompetitive public/private (M4C)”. M2O are chemical probes What’s your top advice for other partnership: A partnership in which freely available to the academic world. companies wanting to establish an private and public funders identify an These are molecules we’re no longer open innovation initiative? area of research and share their ideas, pursuing, for various reasons. Instead of Internally, you may face resistance: our protocols, and tools. having them sit in our vaults, gathering industry is traditionally a conservative dust, we have made them available for one, and some people may view sharing Selective revealing: The practice other people to experiment with. And proprietary information as a big risk. of revealing some proprietary this option is truly free – no intellectual You’ll need to develop a release procedure information in return for insights property restrictions, and no usage and criteria for choosing what you want and ideas, while keeping other restrictions other than requiring that to share, and how you’ll share it. The information private. people don’t do anything irresponsible or most important external consideration dangerous, such as using an unapproved is how you’re going to connect with Open source: An idea pioneered in molecule in humans. We’d like nothing the people you need to crowdsource software development, which aims better than to have someone take one the answer to your problem. In short, to make the results of collaborative of these molecules, develop a new you need a reliable Internet portal projects free for anyone to access. mechanism or make a discovery, and that functions well; people won’t be publish that in a high quality journal. interested in what you’re offering if it is Open data: Data that anyone can Using this approach, we can advance difficult to access. access, use and share. scientific knowledge and provide helpful Trust is also crucial. Academics can tools to researchers, at very little cost to be wary of industry, so you may need to Open science: The practice of sharing the company. take the brave step of making the data lab notes, methods, data, and We’ve taken a different approach with or tools you want to share truly free – if research outcomes with the scientific our M4C, which are still part of our you try and retrain too much control or community, allowing others to benefit ongoing programs. For organizations place too many restrictions, people will from or contribute to the work you interested in working with us on these be reluctant. Remember: the more you are doing. molecules, we provide them under a share, the more you stand to learn! standard material transfer agreement, There are many passionate scientists and this forms the basis for a more in both industry and academia. And Best Practice 45

On the the assays used and will own the libraries, technologies and services. produced data. Partners do not • Merck Mini Library: Open Road have to disclose the structure of Organizations and individuals their compounds, which helps can apply for free access to Many companies and organizations maintain confidentiality. Read a collection of former R&D already have some form of open more at http://bit.ly/1pHh4M1 compounds. innovation platform, but restrictions, • Eli Lilly – Open Innovation • The European Lead Factory: A confidentiality, and intellectual Drug Discovery: A platform public/private partnership that property rights can vary. Some notable focused on neglected and provides free access to up to examples include: tropical diseases, diabetes and 500,000 novel compounds. oncology. Researchers get access • Structural Genomics Consortium: • LEO Pharma Open Innovation: to computational design tools A project that aims to accelerate an open drug research platform and can submit compounds for research by making its output that makes research tools screening. available to the scientific available to external partners. • AstraZeneca Innovative Medicines community without restrictions, LEO Pharma tests compounds and Early Development biotech and create an open network of for free, but the partner will unit: The company gives partners scientists and pharmaceutical receive full scientific insight into access to compounds, compound companies.

when you bring them together, the energy and enthusiasm you can generate is incredible. If we pursue the right environment of openness and collaboration to bring people together, Serialization & Aggregation I believe we can begin to push the boundaries of biological knowledge and ARE YOU READY FOR see some truly exciting progress. To do that, we need the courage to do things THE WORLD MARKET? differently. Some companies are already joining in (see “On the Open Road”), but I want to see everyone getting involved! WE ARE! The more we can get industry, academia www.r-pharm.de and individual scientists to participate, 3 We serialize and aggregate your Full Service CDMO the more we all reap the rewards. products according to all known regulatory requirements Reference 1. AJ Carter et al., “Establishing a reliable 3 We offer smart and convenient framework for harnessing the creative power of customer onboardings the scientific crowd”, PLoS Biol, 15, e2001387 (2017). PMID: 28199324. 3 Benefit from our long-term experience and join the Further Reading TRACK & TRACE USER ACADEMY Boehringer Ingelheim has written Contact: [email protected] extensively about open innovation. Read more at http://go.nature.com/1YuLb5l 46 Best Practice

formaldehyde as a fumigant is currently been a requirement for many years in Fumigation: in preparation and will be available from the HSE advice – and in many other the HSE website.” The HSE has released countries – on the management, design Choose Your nothing yet, so formaldehyde is still the and operation of microbiology labs, with recommended fumigant – backed up specific advice in appendix 3 (5). Ease Weapon! by a study from the HSE’s Health and of use is vital, as most operators will Safety Laboratory (HSL) (4). not perform fumigations on a regular Do you want to replace a basis; in short, the easier the better. fumigation system that is Factors to consider Corrosiveness is a greater issue in areas no longer up to scratch? Are When it comes to choosing your where there are frequent fumigations. you looking to switch out fumigant, there are a number of criteria Chemical incompatibilities can be formaldehyde – before it’s to consider. Here is my list, based on managed by removing or isolating the phased out? As a former site order of importance: incompatible chemical. For example, fumigation lead, here is how I with formaldehyde as the fumigant, would go about it. 1. Active substance registered in or any chemical containing chlorine needs exempt from Biocidal Products to be removed from the area before By Andrew Ramage Regulation (BPR) category PT2 fumigation begins. The amount of 2. Repeatable process downtime for the fumigation process Previously in The Medicine Maker, I 3. Efficacy of the fumigant/biocide must be sensible, but isn’t crucial. The recognized the challenges of selecting 4. Penetration of spills cost also has to represent value, and there the right fumigant for microbiological 5. Ease of use is often a prudent limit on what can be safety cabinets, high containment level 6. Corrosiveness of biocide to spent. Notably, most of the cost comes areas, and cleanrooms (1). I noted my fixtures, fittings and equipment from the setup and validation rather relief that it was no longer my job to 7. Chemical incompatibilities of the than actual future usage. choose a new fumigation system (I’m fumigant There are other factors that will affect now based on the vendor side), but for 8. Cost the relative importance of the above the purpose of this article, I am going to 9. Downtime from criteria. For example, choosing a new put myself back into the shoes of a site fumigation process system for a clean room where pathogens fumigation lead and think about how I are not handled will mean a number of would approach the task of replacing an As soon as you start looking at a the above criteria need not be considered existing system. new fumigation system, make sure at all. Also, in areas where there is no From a formaldehyde user’s the active ingredient is registered as chance of spillages, efficacy in most perspective, at the time of writing, a PT2 biocide – or exempt from that cases need only be demonstrated against we are still waiting for the Biocidal classification. Exempt disinfectants (or the recommended biological indicator Products Committee to decide whether more precisely the active ingredient) for that biocide, so will come lower they will approve or reject its use in the will be registered under the EU Medical EU Biocidal Product Regulation (EU- Devices Regulations. If it isn’t, then BPR) usage classification PT2 category. you are breaking the law by using it as a A decision on formaldehyde usage was fumigant. If you are not based in the EU, originally expected in the summer of you will need to check what regulations “Ease of use is vital, 2016 (2), but there is still no news. The you should be adhering to. Arguably British Health and Safety Executive the next two criteria (repeatability and as most operators (HSE) document, “Biological agents - efficacy) are equal in their importance The principles, design and operation of with CL3 and CL4, but in the end will not perform Containment Level (CL) 4 facilities” whatever fumigation system you choose (3), has a whole appendix related to must be robust – and you must have total fumigations on a fumigation advice. At the very end confidence that it works every time. of the appendix, it quotes, “Further Penetration is very important when regular basis.” guidance on the use of alternatives to decontaminating spillages, and it has Best Practice 47

down the list. Certainly in the private fumigation study (4), in which hydrogen fumigation service is usually a cost- sector, cost and downtime will be of peroxide (H2O2), chlorine dioxide and effective solution to users who do not greater importance, where other factors ozone based fumigation systems were require frequent fumigations and do not such as chemical incompatibilities and assessed. Starting with H2O2, two have the expertise internally to perform corrosiveness can be controlled, or are systems (where H2O2 is the active the task in house; however, should you less of an issue because of fumigation substance) were assessed in the HSL purchase either of the systems assessed infrequency. study – either can be provided as a in the study, then the initial setup service offered by the manufacturer, costs are considerable. The amount of

Weighing up the options or the equipment can be bought. H2O2 H2O2 required and the cycle length is The basis for my search for an alternative is registered as a PT2 biocide so can calculated by the equipment based on a to formaldehyde began with the HSL be legally used as a fumigant (6). The number of factors such as room volume

www.themedicinemaker.com 48 Best Practice

“The fast turnaround time is clearly an advantage, but it does leave a slight acetic acid odor after fumigation.”

to 60-75 percent where ClO2 is most effective. The humidity is then held

for 30 minutes, and then ClO2 is generated and delivered into the room and controlled at the appropriate level. The final stage is aeration (extraction). It

should be noted that the ClO2 system is operated externally, so any connections to the control system must pass through an aperture into the room. Also, as a true gas system that can penetrate most crevices, you must be able to guarantee sealability of the area to prevent leakage. Another system to be considered and pre-conditioning stages. over its potential corrosiveness and uses hydrogen peroxide/peracetic acid,

Both of the assessed H2O2 systems toxicity. It is not considered a substance although not assessed in the HSL study, have been in use for many years and of concern by the ECHA, so is exempt it has a number of existing customers arguably are the most mature of the from BPR PT2. ClO2 fumigations are in the pharmaceutical sector. The formaldehyde alternatives on the market. actually not corrosive, but a controlled proprietary chemical – 22 percent H2O2 One system generates a layer of micro- study by the US EPA showed it can be and 4.5 percent Peracetic acid – which condensation (above the dew point) corrosive inside functioning computers is diluted down for use as a 10 percent and the other maintains the vapor level due to the heat from the CPU (7). solution, claims a broad range of efficacy below the dew point. An independent The HSL study gives this system against all types of microorganisms. The study from the HSE does acknowledge the thumbs up in terms of its efficacy delivery system uses compressed air to that both H2O2 systems frequently gave and reliability in comparison with pressurize the unit, forcing out ultrafine, good results against all pathogens (4). formaldehyde against a range of tough- atomized droplets into the atmosphere

Chlorine dioxide (ClO2) is gaining in to-kill pathogens and spores. It is also (fogging). popularity. Although its anti-microbial excellent at inactivating beta-lactams The amount of the chemical to use properties have long been known (it is and, thus, ideal for decontamination is easily calculated based on the room commonly used as a disinfectant in other of those facilities (8). The cycle starts volume. Fogging starts as soon as the areas), ClO2 struggled to be accepted with a pre-conditioning step, which compressed air is switched on and initially as a fumigant because of fears increases the humidity in the room following a one-hour hold time the F3 fumigant is vented – the whole process Andrew Ramage is Microbiology Product U2 takes around 2-5 hours from start to Specialist, at Cherwell Laboratories, finish. The fast turn-around time is Bicester, UK. clearly an advantage, but it does leave a TU slight acetic acid odor after fumigation References (which should clear fairly quickly). The 1. A Ramage, “Finding a Fumigant”, other main advantages of this system are The Medicine Maker, (2016). Available at: NE3 RE4 that the room humidity does not need http://bit.ly/2zSSQru. to be raised pre-fumigation, so there is 2. J Chewins, “Is this the death of formaldehyde?” TW little chance of the chemical pooling Laboratory News, 37-38 (2016). in cooler areas. It is also considerably 3. The Health and Safety Executive, “The cheaper than H O systems. My main Principles, Design and Operation of 2 2 O4 concern for this system is that the Containment Level 4 Facilities”, 2006, chemical might corrode copper over Available at: http://bit.ly/2jFXMcK. Last multiple fumigations. But in cleanrooms accessed November 20, 2017. GL RK with predominantly stainless steel and 4. A Beswick et al. “Comparison of Multiple plastics, this will not be an issue. The Systems for Laboratory Whole Room 0 proprietary chemical is registered as a Fumigation”, Applied Biosafety, Vol 16, No.3, 3 medical device and so is exempt from pp.139-157 (2011). the EU-BPR. 5. The Health and Safety Executive, “The B2 Ozone fumigation systems are management, design and operation of another alternative. Although aimed microbiological containment laboratories more at the food, water treatment and Guidance”, HSE Books 2001 ISBN 0 7176 AL2 clinical sectors to reduce bioburden 2034 4. (2001). and undesirable microorganisms, such 6. Biocidal Products Committee, “Opinion on the systems were also tested by the HSL approval of active substance: Hydrogen study. However, I could not find the Peroxide: Product Type: 2 ECHA/ system described in the report. Also, BPC/40/2015”, (2015). Available at: Highlights in 2018: although the anti-microbial properties http://bit.ly/2zkGLM8. Last accessed Live Labs and of ozone are well documented (9), I have November 20, 2017. Digital Trans- not found any ozone fumigation system 7. United States Environmental Protection formation being marketed for the fumigation Agency, “Compatibility of Material and of laboratories or cleanrooms in the Electronic Equipment with Hydrogen pharmaceutical sector (if you know of Peroxide and Chlorine Dioxide Fumigation any then I’d be interested to know more). – Assessment and Evaluation”, (2010). The World’s No. 1 Drawing from the results of his Available at: http://bit.ly/2z4EwIy. Last The largest laboratory trade fair in the world findings, in a presentation to the Annual accessed November 20, 2017. features the entire range of products and solutions for industry and research laboratories. Biological Safety Conference in 2012 8. K Lorcheim, “Chlorine Dioxide Gas (10), Alan Beswick, principal author Inactivation of Beta-Lactams”, Applied The first-rate scientific analytica conference, of the HSL study, offers advice to both Biosafety Vol 16, No.1, pp34-43. (2011). world premieres, the latest product developments, unique Live Labs, special shows, forums end user and manufacturer. To the end 9. MA, Khadre et al., “Microbiological aspects of and Focus Days await you! user, he emphasizes the importance ozone applications in food: a review”, Journal of validation, especially against target of Food Science 66, 1242–1252 (2001) organisms where high containment 10. A Beswick, “Green gas, dry mists and dense April 10–13, 2018 I analytica exhibition laboratories are concerned; to the vapours: An overview of independent April 10–12, 2018 I analytica conference manufacturer, he asks for both reliability fumigant testing at the UK Health and Safety 26th International Trade Fair for Laboratory Technology, in terms of the consistency of fumigation Laboratory (HSL)”, (2012). Available at: Analysis, Biotechnology and analytica conference cycles and technical reliability of the http://bit.ly/2zYlF3j. Last accessed November www.analytica.de equipment provided. It is sound advice! 20, 2017. From Strength to Strength

Sitting Down With… Nigel Darby, Advisor, GE Healthcare Life Sciences, Sweden. Sitting Down With  51

Why did you choose science? fix it, and that will go a long way towards Now, in the immunotherapy market you I grew up in the 1960s, and there was so helping you move forward with your career. might see as many as ten different molecules much happening in terms of science and appearing almost simultaneously. Being technology: the moon landing, the first How did you find the jump from research second on the market might be okay, but heart transplant, Concorde... Nowadays, to GE? being fifth probably isn’t – and the time technology is so commonplace and I used to work in the very early parts of difference between being second and fifth disposable that we take it for granted, but pharmaceutical discovery, so the molecules is not large. Time to develop manufacturing when I was a child, each and every one we discovered would still have at least ten processes, deliver molecules to the clinic and of these things was a miracle – and that years before they came to the market – and build manufacturing infrastructure plays a definitely influenced me. we met with failure probably 99.9 percent of key role in competitiveness. I also think my parents had a big impact. the time. In GE the work has mainly been When I speak to folks in the industry, They encouraged my curiosity, and let about developing new biopharmaceutical I often hear “Yes, we know this new me do a lot of things that many modern manufacturing technology. It means I’ve manufacturing technology is great and parents would not! I remember performing moved much closer to the customer – that it works, but honestly? We just don’t chemistry experiments on the gas stove product cycles are much shorter, and when have time, we’re focusing on getting our – I destroyed a number of my mother’s you develop a product it goes to the market product to market as fast as we can.” For a saucepans by melting sulfur and boiling in two or three years. It’s great to actually blockbuster drug, every day that you lose is acid in them... I also broke quite a few get to launch products! When I first came to costing you millions of dollars – far more things around the house by taking them GE we were launching perhaps 20 products than the cost of using slightly older but still to pieces to see how they worked. But my a year. In early stage pharmaceutical adequate technology. People in pharma parents never stopped me or yelled at me research, you feel lucky if you participate love new technology – they’re scientists, for being curious. in one project in your entire lifetime that they want the best and latest – but they’re results in a drug reaching the market. also aware of the highly competitive race How did your pharma career get started? On the flip side, there’s been more to market, so they have limited time to I spent 18 or 19 years doing academic commercial pressure in my GE roles. explore other considerations. Once you research, so I didn’t enter industry until I I’m much closer to the financial realities design a process and put products into that was nearly 40, which is a bit unusual. I was of the business; if something goes out process, it’s difficult to change it. But given fortunate enough to spend time in a number into the market and does not do well, it that you’ll have to live with the decisions of very good research institutions, which has consequences. In early stage pharma you make today for the next 20 years, you taught me a lot of humility. When you meet research, one tends to be more distant from better make sure it’s a good decision! so many people who are simply orders of that (or at least we were in my day). When I magnitude smarter than you are, you first joined GE, I didn’t even know what a What do you think should be a priority realize you have to figure out what makes profit margin was! But providing you have for 2018? you unique, because you can’t compete with an interest you can pick that sort of stuff up. Over my career, I’ve seen biopharmaceuticals people on pure cleverness! I learned a lot of go from a niche interest to a big part of the lessons from my time in academia. What trends do you see in drug market – and to be a little part of that When I entered industry – AstraZeneca technology adoption? is so gratifying. We are on a tremendous – I originally managed a group of three The speed at which the industry adopts trajectory: biopharmaceutical sales will people working in drug discovery. Three new biopharmaceutical manufacturing probably grow in double digits for the next years later, I was heading a group of maybe technology is always a major challenge. The five years. The big question is how to get 500 people all around the world – mainly lack of pace means missed opportunities enough capacity in terms of manufacturing. because of so many changes, mergers and to improve. Right now, the market for There is a very complicated supply chain acquisitions and so on. Someone said to me: individual therapeutic indications is very behind manufacturing, and we need to “Will you have a go at managing this? You competitive. If you look at the explosion in consider whether it is robust enough to always try hard, and perhaps do the things immunotherapies, there are many molecules support long-term growth. We need to other people don’t like doing.” competing for the same or similar indications. find a balance between making sure that So the advice I give to people is to be The question of how to get to the clinic faster we build on the strength and security of patient in times of difficulty, such as when is becoming more important every year. our past, and embracing new tools and everything is falling apart around your Twenty years ago, there were perhaps one technologies that are going to make us even ears... Be the person to stand up and try to or two molecules for a particular indication. better tomorrow.

www.themedicinemaker.com development your molecule has so much potential. our passion for development will help unlock it.

As the #1 global leader in drug development, Catalent's comprehensive development offerings: comprehensive capabilities, robust scientific approach, candidate selection & dmpk modeling and broadest selection of enabling technologies can help solid state & preformulation preclinical & clinical formulation you overcome the toughest development challenges. Our bioavailability enhancement formulation experts have experience with thousands of clinical cgmp manufacturing new molecules to customize your project, doing it right comprehensive analytical solutions the first time based on science and technology fit. clinical supply services new, expanded optiform‰ solution suite One accelerated, flexible, and data-driven solution combines all analytics, services and materials your molecule needs from candidate selection into Phase 1.

Catalent. More products. Better treatments. Reliably supplied.™ us + 1 888 SOLUTION (765-8846) eu 00800 8855 6178 catalent.com/optiform