Pharma Focus Asia - Issue 31

ISSUE 31 2018

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R &D DATA HUB

BREAKING SILOS TO ENABLE ANALYTICS

Stem Cell and Gene Delivery An update

Integrated Drug Development Strategy The nexus to value-based pricing www.pharmafocusasia.com

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Foreword Pharma R&D Data Integration and analytics Despite years of efforts, drug development continues to be challenging, complex, costintensive and time-consuming. The pharma R&D process requires years of research and huge data gathering. Through the whole process from discovery and development to clinical trial, a drug developer would have gathered massive data on compounds, diseases, patient information, test results, experimentation results, formula, dosage, and FDA compliance requirements. This data is kept in separate databases and it makes it challenging for pharmaceutical companies to utilise vast quantities of data.

Integration of the data collected from several internal functions and external partners is necessary to create a complete picture for the key stakeholders. With more players involved in the R&D process, pharmaceutical companies have to manage data sets coming from a larger number of databases.

Integrating and controlling clinical data at one place, a so called hub, can help life sciences organisations in making informed decisions based on more accurate and timely information. The hub collects clinical and non-clinical data from multiple sources into a single environment to analyse and report that supports informed decision-making and regulatory submissions.

With the growing need for adoption of digital technologies, companies have changed their approach by incorporating valuable insights from multiple sources of data, radically improving patient experience, enhancing clinical trial productivity, and increasing the amount and quality of data collected in trials. Different Electronic Data Capture (EDC) systems with its own portal, own system, own adverse-event reporting have been reducing the complexity in managing clinical data.

The global EDC systems market is expected to reach US$ 1.16 billion by 2025, according to a new study by Grand View Research, Inc. The process of assessment of data and uncovering

the patterns which are hidden in it is solved by big data analytics. Big data analytics also helps in maintaining drug efficiency and safety for regulators and pharmaceutical companies.

According to MarketsandMarkets, the global life science analytics market is expected to reach US$24.73 billion by 2021 from US$ 13.26 billion in 2016.Using analytics to improve the efficiency of clinical trials by utilising data would be a great gain for pharmaceutical companies.

However, security risks are even higher in these cases as data is shared among multiple stakeholders. Access to confidential information such as a patient’s Personal Health Information (PHI) from clinical testing or health histories increases the risks of critical information getting compromised as there are a greater number of data transfers and sharing. Life sciences organisations have to be compliant and responsive to regulatory requests.

Use of standards to facilitate increased R&D efficiency, while ensuring regulatory compliance with comprehensive security, an audit trail, and traceability is the key for the providers of EDC systems. There is a lack of data standards to monitor and regulate master data for data-sharing among multiple EDC systems, between EHR and EDC, and among stakeholders. This remains an inherent challenge for pharmaceutical companies.

In the cover story, Suresh Selvarangan of Navitas Life Sciences explains the role of data integration and analytics and how it helps in faster decision making and clinical trials.

Prasanthi Sadhu Editor

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CONTENTS

COVER STORY

R&D DATA HUB

BREAKING SILOS TO ENABLE ANALYTICS

INFORMATION TECHNOLOGY

Suresh Selvarangan

Head, Clinical Technology Navitas Life Sciences

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MANUFACTURING

06 Advancing Production Capabilities to Boost China’s Pharmaceutical Market

The path forward is paved with Industry 4.0 and brand security solutions alongside regulatory change and new infrastructure

34 Drug Concentration Assurance of Continuous Tablet Manufacturing

Advanced process control strategy

42 Pharmaceutical Crystallisation

Emerging process intensification technologies

Jerry Martin, Pharmaceutical and Life Sciences Consultant, PMMI The Association for Packaging and Processing Technologies

12 Integrated Drug Development Strategy

The nexus to value-based pricing

Leigh Farrell, Senior Vice President, Asia-Pacific Commercial Certara

18 Statin Drug Interactions and Related Adverse Reactions

24 Managing Clinical Trial Agreements

28 Stem Cell and Gene Delivery

An update

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Jiayuan Wang, Postgraduate Student, Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay

Fei Li, Assistant Professor, National Engineering Research Center of Industrial Crystallisation Technology, School of Chemical Engineering and Technology,Tianjin University

Richard Lakerveld, Assistant Professor, Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay

50 HPAPI Qualification Testing

Considerations in containment testing

Michael Avraam, Global Product Manager, ChargePoint Technology

Veronica Holloway, CRO, General Counsel, Novotech

RESEARCH & DEVELOPMENT

Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey

Stefano Bellosta, Assistant Professor of Pharmacology, Department of Pharmacological and Biomolecular Sciences, University of Milan

CLINICAL TRIALS

Ambikanandan Misra, Professor, Pharmacy, Faculty of Pharmacy The Maharaja Sayajirao, University of Baroda

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Advisory Board

EDITOR Prasanthi Sadhu Alan S Louie Research Director, Life Sciences IDC Health Insights, USA

EDITORIAL TEAM Debi Jones Grace Jones ART DIRECTOR M Abdul Hannan

Christopher-Paul Milne Director, Research and Research Associate Professor Tufts Center for the Study of Drug Development, US

PRODUCT MANAGER Jeff Kenney

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

SENIOR PRODUCT ASSOCIATES David Nelson Peter Thomas Sussane Vincent

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATES Austin Paul James Taylor John Milton

Georg C Terstappen Head, Platform Technologies & Science China and PTS Neurosciences TA Portfolio Leader GSK's R&D Centre, Shanghai, China

CIRCULATION TEAM Naveen M Nash Jones Sam Smith

Kenneth I Kaitin Professor of Medicine and Director Tufts Center for the Study of Drug Development Tufts University School of Medicine, US

SUBSCRIPTIONS IN-CHARGE Vijay Kumar HEAD-OPERATIONS S V Nageswara Rao

Laurence Flint Pediatrician and Independent Consultant Greater New York City

Neil J Campbell Chairman, CEO and Founder Celios Corporation, USA Phil Kaminsky Professor, Executive Associate Dean, College of Engineering, Ph.D. Northwestern University, Industrial Engineering and the Management Sciences, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

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A member of Confederation of Indian Industry

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Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US

Stella Stergiopoulos Research Fellow Tufts University School of Medicine, USA 4

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ADVANCING PRODUCTION CAPABILITIES TO BOOST CHINA’S PHARMACEUTICAL MARKET The path forward is paved with Industry 4.0 and brand security solutions alongside regulatory change and new infrastructure According to 2017's report by the U.S. Chamber of Commerce on the ‘Made in China 2025’ industrial plan, an innovation gap leaves the country dependent on foreign companies for patented pharmaceutical drugs.

As China aims to close that gap, companies must advance packaging operations to scale production with Industry 4.0 and sophisticated and sophisticated brand security.

Jerry Martin, Pharmaceutical and Life Sciences Consultant, PMMI The Association for Packaging and Processing Technologies

C

hina is the second largest pharmaceutical market in the world, according to a 2016 Top Markets Report on the country’s pharmaceutical industry by the International Trade Administration1. The same report also forecast the country to grow from US$108 1. https://www.trade.gov/topmarkets/pdf/Pharmaceuticals_China.pdf

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billion in 2015 to US$167 billion by 2020. However, despite the market’s sheer size, several hurdles line the path in moving China’s pharmaceutical, biomedicine and medical device sectors to the front of the pack in innovation—challenges which the industry hopes to resolve with the ‘Made in China 2025’ industrial plan. In fact, last year’s report by the

U.S. Chamber of Commerce pointed to statements made by President Xi Jinping regarding the ‘S&T [science and technology] bottleneck and wide innovation gap compared to advanced countries.’ These gaps fall into three designations: lacking self-sufficiency in critical high-end materials, relying mainly on imports for highend medical devices, and, importantly,

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depending on foreign companies for the vast majority of patented pharmaceutical drugs2.

As China carves a path to becoming a key producer of finished pharmaceuticals, two challenges underscore the innovation gaps mentioned above. The first is that much of today’s pharmaceutical manufacturing in China is dedicated to the processing of Active Pharmaceutical Ingredients (APIs) and intermediates (chemicals that convert to APIs). While these products can be filled into finished drugs, many Chinese manufacturers of intermediates and APIs export to western countries for finishing. These dynamics amount to the domination of lowertake and lower margin operations and they must change for China to advance its pharmaceutical and medical device sectors.

Another challenge is the implementation of critical manufacturing equipment and practices, such as Industry 4.0 systems and advanced brand security measures. In addition to making China’s pharmaceutical manufacturing capabilities more competitive by elevating productivity, efficiency and innovation, these solutions would also go far to alleviate both domestic and international concerns among consumers surrounding drug quality and counterfeiting. However, technological change won’t occur overnight—or in a silo. China’s pharmaceutical manufacturers will have to navigate their own projections and needs as well 2 https://www.uschamber.com/sites/default/files/final_ made_in_china_2025_report_full.pdf

as regulatory and infrastructure changes in order to sustainably advance.

Solutions to Pave the Way Forward

Industry 4.0 and brand security technologies are critical tools to advance the pharmaceutical and biomedicine sectors— not just in China, but also around the world. The regulations coming into play over the next year or two on serialisation and track-and-trace capabilities to guard against counterfeiting and theft are global. As China’s companies move further into the manufacturing of higher-value finished drugs, they will need to adopt these technologies. Eventually—over the next five years—these standards will also apply to the export of APIs and intermediates. Even more importantly, these companies must continuously anticipate the bar for automation and brand security to keep rising. As it does, so will the need to strategically build and update the technologies that ensure product quality, safety and security.

Today, pharmaceutical companies are exploring solutions beyond the current track-and-trace technologies. Blockchain technology not only offers the potential to change the way we purchase, sell and make transactions for goods and services, it also combines ease of use and the security of cryptography to allow the supply chain community to verify and monitor various intervals and exchanges throughout the product lifecycle. This is because blockchain allows each transaction to be recorded and later viewed in a permanent decentralised repository, reducing potential delays, added costs and human

error. Because the technology enables companies doing business with each other to record transactions indelibly and hold many more documents and data than traditional database storage, it allows for the sharing of more insights and analysis and provides a robust platform for drug brand security.

Other important considerations for Chinese pharmaceutical manufacturers include the use of more highly automated pick-and-place equipment to support greater hygienic standards and minimise the risk of human error on redundant tasks on the plant floor.

Additionally, temperature-monitoring packaging can indicate to shippers, pharmacists, hospital workers or patients whether the product has been outside of its designated temperature range, thus preventing patient receipt of drugs that have been compromised. Implementation of single-use equipment for aqueous fluid mixing, storage, formulation and filling can eliminate on-site sterilisation and cleaning operations that are often the subject of adverse regulatory observations.

Understanding and Clearing the Hurdles

For China’s pharmaceutical sector, the popularisation of blockchain, advanced automation and sensor-enhanced packaging may not occur instantly or without the use of international suppliers.

Achieving, maintaining and advancing innovation in pharmaceutical manufacturing is a constantly moving target.

Today’s complex global supply chain— and the threats that come with the www.pharmafocusasia.com

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As China’s pharmaceutical manufacturers make their contributions to realising the goals laid out in the ‘Made in China2025’ plan, it is critical to keep in mind the interconnectivity of these goals and implement changes that will ensure sustainable progress both today and tomorrow.

territory—makes it difficult for even the most reputable and well-resourced companies to maintain the lead. To secure solutions that foster growth both today and tomorrow, these companies can look to resources such as Healthcare Packaging EXPO3, co-located with PACK EXPO International 20184, (Oct. 14-17, 2018; McCormick Place, Chicago).

Owned and produced by PMMI, The Association for Packaging and Processing Technologies, the show can provide access to a wide range of pharmaceutical and packaging technologies and insights.

In addition to identifying the right technologies to scale production amid their own growth, goals and international regulatory challenges, China’s pharmaceutical manufacturers must also 3 https://www.hcpechicago.com/ 4 https://www.packexpointernational.com/

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juggle (and in some cases advocate for) changes to regulations and infrastructure that will facilitate their success. Before these companies can take the lead and minimise the country’s dependency on imported pharmaceuticals, several more measures must fall into place. These include policies to: • Simplify current clinical development requirements; • Build capabilities in contract manufacturing; • Establish a clear and agile pathway for China’s returning industry experts to start companies and develop drugs in China; • Provide much greater protections to both native and foreign intellectual property; • And strengthen IT, communications and transportation infrastructures to foster faster learning and business development.

Navigating Resting and Clinical Trials

To date, Chinese companies looking to introduce a drug into the domestic market must run clinical trials there, but cannot do so without passing at least two clinical trials elsewhere in the world.

In comparison, first-in-human (Phase One) and dose assessment (Phase Two) trials are commonly initiated in the U.S. and Europe. The limited presence of academic centres and minimal incentives for hospitals to forgo the treatment of patients with existing medicines in favour of clinical trials can create additional hurdles. As a result, China does not nurture the development of many experimental drugs. This creates an inevitable reliance on the importation of drugs from other countries and joint venture manufacturing operations. For the country to exit this “me-too” cycle of processing and packaging intermediates, actives and generics, the government must re-consider these restrictions.

Without doing so, current and pending measures to encourage the use of domestically made equipment and products will fail to bring about a sustainable path for continuous innovation and the country’s manufacturers will continually find themselves behind the curve.

Advancing Contract Manufacturing

Amid China’s lower-take and lower margin operations, domestic manufacturers also tend to focus on the contract manufacturing of small molecule generics. As with the joint ventures between lower-tech Chinese pharmaceutical manufacturers and multi-nationals for the finishing of some drugs, the partnerships of these generics manufacturers tend to lie with western drug brands. Until recently,

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drugs that didn’t fall under joint venture agreements could not be sold there. This is another factor that can slow Chinese drug innovation. Allowing contract manufacturing, but for export only, contributes to the country’s challenges in creating public confidence and familiarity with domestically manufactured drugs.

As the government evolves these rules, more western countries may more easily

be able to set up contract manufacturing operations and train more Chinese developers, operators and other personnel in state-of-the-art manufacturing.

Fostering a Culture of Innovation

In past decades, many Chinese seeking educational and workforce opportunities in these sectors left the country. China’s new initiatives, however, are attracting those minds back. The recent influx of internationally educated and trained professionals bringing their expertise to the country’s bioprocess manufacturing sector can provide a new backbone for a

rejuvenated and innovative workforce.

Hailing from Ivy League institutions and pharma’s top brands, they are ready to lead innovative companies in China. They are not here to oversee ‘me-too’ generic development. Loosened regulations on testing to incentivise more new drug development can keep them engaged and fostering domestic breakthroughs.

Greater flexibility in allowing companies to substantiate projects is also necessary. This means shaking loose the monolithic vision for ‘the best way’ in order to allow a greater variety of options that will continue to evolve and improve.

Additionally, China must also provide clear channels and resources for this new generation of innovators to bring new products to market, and importantly, protecting the intellectual property once they are out there.

Overcome Counterfeiting and Improve IP Protections

Counterfeiting is a global problem. The World Health Organization (WHO) estimates that about one million people die from taking counterfeit drugs

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Building the Necessary Infrastructures

The factor that often seems like the highest mountain to climb is the synchronising of infrastructures. Reliable internet access, extensive transportation networks and evolved communications platforms

are bedrocks of creating, nurturing, maintaining and evolving pharmaceutical and medical device businesses—especially as the world moves toward more highly automated solutions up and down the lines as well as an increasingly digitised model for operating, analysing and improving efficiencies, run-times and brand security.

These infrastructures are also critical to continuous workforce training. As China moves from manual to automated operations in keeping up with today’s leaders in pharmaceutical manufacturing, the country will be met with the same challenges in retraining operators and retaining talent. Some companies are already setting up web-based training to educate current operators on new and higher standards. By updating the country’s IT, transportation and communications infrastructures, the country will accelerate paths for workforce development and lay the foundation for widespread use of other industry-shaping technology.

Look Outward, not Just Inward

As China’s pharmaceutical manufacturers make their contributions to realising the goals laid out in the ‘Made in China 2025’ plan, it is critical to keep in mind the interconnectivity of these goals and implement changes that will ensure sustainable progress both today

AUTHOR BIO

each year. As a result, pharmaceutical manufacturers, pharmacies and healthcare agencies around the world are taking whatever measures they can to minimise the risks. This includes making investments in counterfeit drug detection equipment. A recent study from Research and Markets ‘Global Counterfeit Drug Detection Devices Market Assessment & Forecast: 2017—2021’ valued the global counterfeit drug detection devices market at US$904.5 million in 2016 and projects it to reach US$1,368.5 million by 2021, for a CAGR of 8.5 percent.

However, China’s current challenges in combatting counterfeiters and, more generally, in asserting protections to Intellectual Property (IP) infringement, are threats to the nation’s plans for growing and innovating its pharmaceutical sector. Many counterfeit drugs are made in China, posing serious concerns around quality issues, Good Manufacturing Practice (GMP) adherence, documentation, quality systems and most importantly, dangers to public health. Notably, the government has taken action to reduce the usage of such shortcuts and minimise their impact.

As a result of ‘Made in China 2025,’ the international community expects to see better policing of proprietary technology. Part of this effort requires better resourcing local inspection authorities.

China’s FDA has made significant strides over two decades, becoming more powerful and improving the capabilities of inspection agencies to track down all unregistered operations. Beginning June 30, 2004, all pharmaceutical companies in China were required to obtain GMP certificates from China’s FDA in order to be licensed to sell their drug products in China.

and tomorrow. The implementation of the technological updates necessary to enhance innovation, brand security and quality will not happen instantaneously.

It will require incremental, but steady progress as well as a continued focus on regulatory and technological change that will foster a habitat for innovation as well as consumer and industry confidence.

But even amid plans to strengthen a country’s own industries, the answers often lie in looking outward, not inward.

China’s regulatory decision makers and company leaders must more than ever anticipate tomorrow’s challenges in an increasingly intertwined and complex marketplace as they look to strengthen their domestic pharmaceutical production operations.

In addition to housing a wide range of packaging solutions, including industry 4.0 and brand security technologies, the co-located Healthcare Packaging EXPO and PACK EXPO International will feature insights and solutions in track-and-trace, automation and continuous processing, advanced automation, sensor-enhanced packaging, blockchain technology and more. To register, visit https://www.hcpechicago.com/

Jerry Martin, Pharmaceutical and Life Sciences Consultant, PMMI, The Association for Packaging and Processing Technologies also serves as a consultant to bio-pharmaceutical manufacturers and equipment suppliers in technology and business development.

He previously was Sr. V.P. Global Marketing and Scientific Affairs for Pall Life Sciences (retired 2015) and served 3 terms as Chairman of the BPSA trade association for single-use bioprocess equipment suppliers and users.

www.pharmafocusasia.com

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Integrated Drug Development Strategy

The nexus to value-based pricing

With only 12 per cent of drug candidates entering clinical trials resulting in an approved drug, and 20 per cent recouping their investment, there is an unquestionable need to change the way pharma develops drugs. This paper will show how a modern, state-of-the-art integrated drug development strategy uses quantitative methods to demonstrate safety, efficacy, and comparator effectiveness. By leveraging the full range of model-informed drug development solutions, we can more effectively pressure test and guide regulatory and payer success and deliver better outcomes for patients.

Leigh Farrell, Senior Vice President Asia-Pacific Commercial, Certara

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T

he burgeoning costs of healthcare globally are not sustainable. The Tufts Center for the Study of Drug Development reports that it costs on average US$2.6 million and 15 years to develop and obtain regulatory approval for a new drug. Driving up drug prices is the fact that only 12 per cent of drug candidates entering clinical trials result in an approved drug, and only 20 per cent of innovator companies recoup their investment. Ageing populations, with increased chronic healthcare needs, further add to healthcare costs. For example, more than one quarter of the Japanese population is older than 65 years of age, and this percentage is expected to rise to 45 per cent by 2050.1 To control these increasing costs, innovation and optimisation are required from all sectors of the healthcare ecosystem. This paper will show

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that by leveraging contemporary modelinformed drug development strategies, cost-effective medicines can be delivered to patients.

Inspiring Change

Certara believes in global equity in patient access to cost-effective medicines. To that end, the company strives to increase the efficiency of drug development through an integrated approach, informed by quantitative in silico models. These models inform clinical trial design and comparative effectiveness evaluation, optimise dosing, predict drug safety, and reduce the unnecessary exposure of patients and animals to experimental drugs in clinical trials. These methods have also driven new regulatory and drug pricing policies.

Regulatory Acceptance

During the past three years, Certara technology and services supported 90 per cent of drugs approved by the US Food and Drug Administration (FDA).

Further highlighting the importance of such quantitative methods, US FDA Commissioner Dr. Scott Gottlieb in 2017 stated that the FDA is using quantitative in silico tools as part of its comprehensive Innovation Initiative ’to predict clinical outcomes, inform clinical trial designs, support evidence of effectiveness, optimise dosing, predict product safety, and evaluate potential adverse event mechanisms.’

Many other global regulatory agencies such as the European Medicines Agency (EMA), Australian Therapeutic Goods Administration (TGA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) also embrace ModelInformed Drug Development (MIDD) and have issued guidances for its use to support regulatory filings.

Further underpinning the importance of MIDD, the PMDA announced that between 2014 and 2016, Physiologicallybased Pharmacokinetic (PBPK) modelling and simulation reports were included in 17 NDAs.2 In those instances, PBPK was used primarily to evaluate drug-drug

The P2P framework has major applications for preparedness, planning and deployment of medical countermeasures for infectious diseases.

women, and patients with renal or hepatic impairment.

QSP integrates quantitative drug data with systems biology knowledge, such as mechanisms of action. US FDA is interested in QSP for its ability to address the high rates of drug failure by providing the missing link between target modulation and clinical efficacy / safety outcomes. Certara routinely applies QSP in the lead optimisation phase to help determine which assets to progress.

MBMA

interactions (DDIs), predict drug exposure in paediatric patients, and determine the impact of ethnic differences and disease states on drug PK.2 Guided by the target product profile and the goal of developing cost-effective drugs, Certara supports the drug sponsor’s R&D program by employing MIDD to translate animal study data to humans, improve clinical trial design, determine the optimal drug dose and dose regimen, assess safety and efficacy across the exposure range, evaluate the potential for DDIs, and inform drug labels. The key result is expected improvement in technical and commercial success.

MIDD Solutions

MIDD technologies include Pharmacokinetic (PK) and Pharmacokinetic / Pharmacodynamic (PK/PD) modelling tools; PBPK and Quantitative Systems Pharmacology (QSP) platforms; and emerging strategies such as Model-based Meta-Analysis (MBMA) And Pharmacology to Payer (P2P).

PBPK and QSP

While PK and population PK (PopPK) modelling are drug focused, PBPK provides mechanistic detail, and QSP is more disease mechanism focused.

PBPK informs drug dose, dosing regimens and DDIs. It is also used for bridging studies to establish safety and efficacy in special populations, including paediatrics, ethnic, the elderly, pregnant

MBMA examines curated publicly-available data and proprietary clinical data for drugs in development or on market for a particular clinical indication and predicts the probability of technical and commercial success for a proprietary drug.

MBMA evaluates comparative effectiveness, safety and tolerability. It is also used to test target product profiles, optimise clinical trial designs, and provide decision support for portfolio and marketing strategy.

In parallel, the company provides due diligence services for investors, and pharma licensing evaluations. It also develops regulatory strategy, participates in regulatory meetings, and prepares new product filings for global regulatory agencies.

Communicating Drug Cost-benefit to Different Stakeholders

Regulatory approval alone does not guarantee drug reimbursement and patient access to new drugs. Payers and health authorities must be convinced of a new drug’s value for it to be placed on the formulary, factored into reimbursement rates, incorporated into treatment plans and prescribed to patients. Historically, discussions with payers only occurred in late clinical development. To facilitate earlier payer engagement, we have developed quantitative frameworks to provide value-based narratives for engaging stakeholders regarding the features and benefits of experimental drugs.

By integrating HEOR and real-world value assessments with pharmacometrics data, we can deliver safety, efficacy and www.pharmafocusasia.com

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effectiveness insights from as early as Phase 1 clinical trials, through the product life cycle, and into health technology assessment and payer decisions.

Certara has called one of these ‘end to end’ frameworks, Pharmacology to the Payer (P2P)3. The P2P framework provides an agreed lexicon between stakeholders which integrate data into an agent-based model incorporating

and to define the dose and dosing regimen in those populations.

Certara’s Simcyp® PBPK Simulator was used to gain a better understanding of Imbruvica’s PK profile and evaluate its DDI liability. The Imbruvica PBPK model was developed using in vitro and clinical DDI data, validated using known inhibitors and inducers of CYP3A, and applied to evaluate untested clinical DDI

Driving up drug prices is the fact that only 12 per cent of drug candidates entering clinical trials result in an approved drug, and only 20 per cent of innovator companies recoup their investment.

pharmacology, epidemiology, and health economics for a given drug. The P2P framework has major applications for preparedness, planning and deployment of medical countermeasures for infectious diseases.

The following two examples show how MIDD can solve different drug development challenges.

Oncology Case Study

Mantle Cell Lymphoma (MCL) is a rare form of non-Hodgkin lymphoma that affects about 3,000 patients per year in the US4. When Imbruvica, a tyrosine kinase inhibitor, was shown to be an effective treatment for MCL, it was submitted to the US FDA’s Accelerated Approval Program. That application was successful and Imbruvica became one of the first drugs to be awarded breakthrough status by the US FDA. Due to the known involvement of CYP3A in the metabolism of Imbruvica, it was necessary to identify potential DDIs in different patient populations 14

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scenarios. This PBPK model informed the Imbruvica label, providing guidance for clinicians on 24 untested DDI scenarios, and a dose optimisation strategy for individuals.

Imbruvica is now approved for MCL, first line treatment for chronic lymphocytic leukaemia, and for the treatment of adult patients with chronic graft-versushost-disease that is not responding to other standard therapies.

The US FDA highlighted this Imbruvica case study during one of its workshops as an example of a successful application of PBPK predictions to fill in clinical gaps during the evaluation of a breakthrough drug treatment. PBPK is a key tool in the MIDD armamentarium informing precision dosing in different patient sub-populations.

Respiratory Syncytial Virus (RSV) Case Study

In this case, PopPK and PK/PD, together with viral kinetic models and contemporary clinical trial design, delivered high

value in an RSV early development program. RSV often infects paediatric patients, the majority of which are under two years of age. While the morbidity and mortality are high in this patient population, there is no effective treatment and no precedent for regulatory acceptance of an accelerated development pathway for RSV therapeutics in infants.

Developing RSV medicines for paediatric patients is both scientifically and operationally challenging. As RSV infection is a seasonal disease, it is difficult to identify paediatric patients and execute clinical trials efficiently. Furthermore, some parents are reluctant to give consent for their infant to be included in such clinical trials.

ALS-8176, an anti-RSV compound, was being developed for paediatric patients. Its safety and PK had been characterised in preclinical disease models and clinical trials in healthy adults. The challenge was how to move from trials in healthy adults to infants under two years of age in a timely manner.

The development team considered a Human Challenge Model (HCM) — where healthy adults are infected with RSV and then treated with the drug — to be the most relevant translational medicine tool for bridging to children.

The development team was confident that the PK/PD determinants of ALS-8176 efficacy could be established in an HCM. These PK/PD readouts inform ‘therapeutic exposures,’ which PopPK and PBPK models then assist in converting from adult to paediatric doses to be evaluated in future paediatric clinical trials.

This type of translational medicine and MIDD bridging program also makes it possible to accelerate drug development for paediatric populations.

The cost and time required to conduct the HCM study were significant considerations for the biotech team. Therefore, it agreed to embark on a novel adaptive design for its HCM clinical trial, which used the evolving PK/PD data in real time to develop a picture of the underlying exposure response relationship for ALS-8176.

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Evolving clinical trial data for ALS-8176 were used to augment the MIDD model and predict subsequent cohort dosing decisions. Those dosing decisions included whether to increase or decrease the next dose, incorporate a loading dose regimen, recruit additional subjects at a given dose, and when to stop the clinical trial. This “learn-confirm” approach was continued during the clinical trial between cohorts, successfully identifying the PK/PD targets to inform the ongoing program. In this way, the exposure response surface was very efficiently established.

In this example, rich PK and PD data from the HCM were coupled with PopPK and PBPK, to deliver robust recommendations on dosing regimens to be studied in RSV-infected infants under two years of age.

The adaptive design of the HCM study required only about 50 per cent of the patients needed for a conventional placebo-controlled trial, saving an estimated six months of development time and more than five million dollars. The study was published in the New England Journal of Medicine.5 Furthermore, this integrated MIDD program set new precedent when EMA accepted this scientific strategy in support of an accelerated development pathway to paediatrics. It permitted the movement of ALS-8176 from healthy adults to RSV-infected children under the age of two very early in the drug development process.

Both case studies showcase compounds that helped strengthen the sponsor’s portfolio, whereby these small biotechs were acquired at a significant valuation by leading pharmaceutical companies.

Conclusion

These cases demonstrate the many ways in which MIDD adds value to a drug development program. It can provide strong scientific evidence to improve decision making; support leaner study designs and reduce time and costs; develop new regulatory pathways; and facilitate 16

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STRATEGY

Farrell is Senior Vice President-Asia Pacific Commercial at Certara. He has more than 20 years’ experience in the biopharmaceutical industry. He has served as VP of Business Development at Biota Pharmaceuticals, Associate Director at GBS Venture Partners, Research Manager at Johnson & Johnson Research, and CEO of Gene Shears. He is a Fellow of the Australian Institute of Company Directors and a member of the Walter & Eliza Hall Institute Board Commercialization Committee.

regulatory science innovations and ecosystem improvements. It can also demonstrate drug value to payers and help expedite getting new medicines to the patients that need them.

References 1.American Chamber of Commerce in Japan – European Business Council in Japan Health Policy White Paper 2017.

2.Sato, M., Ochiai, Y., Kijima, S., Nagai, N., Ando, Y., Shikano, M. and Nomura, Y. (2017), Quantitative Modeling and Simulation in PMDA: A Japanese Regulatory Perspective. CPT Pharmacometrics Syst.

3.Kamal MA, Smith PF,

Chaiyakunapruk N, Wu DBC, Pratoomsoot C, Lee KKC, Chong HY, Nelson RE, Nieforth K, Dall G, Toovey S, Kong DCM, Kamauu A, Kirkpatrick CM, Rayner CR.Interdisciplinary Pharmacometrics Linking Oseltamivir Pharmacology, Influenza Epidemiology, and Health Economics to Inform Antiviral Use in Pandemics. Br J Clin Pharmacol. 2017 Jul;83(7):1580-1594 4.http://www.focusonmcl.org/about-mcl 5.DeVincenzo JP, McClure MW, Symons JA, et al. Activity of oral ALS-008176 in a respiratory syncytial virus challenge study. N Engl J Med. 2015;373(21):2048-2058.

STRATEGY

Statin Drug Interactions and Related Adverse Reactions Statins are generally well tolerated, with a low frequency of adverse events, but since statins are prescribed on a long-term basis, many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment and potentially interacting combinations are still frequently prescribed and deserve particular attention.

Stefano Bellosta, Assistant Professor of Pharmacology, Department of Pharmacological and Biomolecular Sciences, University of Milan

S

tatins are a well-established class of drugs for the treatment of hypercholesterolemia with a proven long-term safety profile. Statins have been shown to reduce the risk of cardiovascular morbidity and mortality in patients with or at risk for coronary heart disease (Catapano et al., 2016). Statin use is expanding and approximately 25 per cent of the world population older than 65 years takes a statin on a long-term basis both for primary or secondary prevention of Cardiovascular Disease (CVD) (Gu et al., 2014). The recent recommendations by ATPIV (Stone et al., 2014) and ESC/EAS 2016 (Catapano et al., 2016) have further supported statin therapy for primary and secondary prevention of atherosclerotic CVDs. Thus, the safety and adverse effects of statins, especially in patients receiving multiple medications at risk of drug-drug interactions (DDIs), are a matter of special concern. Statin monotherapy is generally well tolerated but patients concomitantly receiving multiple medications are at an increased risk of adverse events including statin-associated muscle symptoms.

A DDI generally occurs when 18

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either the Pharmacokinetics (PK) or Pharmacodynamics (PD) of one drug is altered by prior or concomitant administration of another drug resulting in an effect different from the expected effects of each drug given alone (Wiggins et al., 2016). This may result in a change in either drug efficacy or toxicity for one or both of the interacting drugs (Corsini et al., 1999). Many clinically significant DDIs have a PK origin, and are often due to induction or inhibition of drug metabolising enzymes and/or transporter involved in drug disposition (Bellosta and Corsini, 2012). Drugs that induce the Cytochrome P450 (CYP) enzymes may reduce the plasma concentration of a drug metabolised via this pathway, whereas inhibitors of CYP enzymes, particularly CYP3A4, confer a risk for DDIs when co-prescribed with statins metabolised via this route. Statins are very selective inhibitors of HMG-CoA reductase and usually do not show any relevant affinity towards other enzymes or receptor systems (Corsini et al., 1999).

This implies that, at the PD level (i.e., at their site of action), statins do not interfere with other drugs. However, the available statins have important PK differences, including half-life, systemic exposure, peak of maximum serum

Many drugs have the potential to cause PK interactions with statins increasing the risk for myopathy and rhabdomyolysis.

concentration (Cmax), bioavailability, protein binding, lipophilicity, metabolism, presence of active metabolites, and excretion routes.

Statins are subjected to an important hepatic first-pass effect thus explaining their low systemic bioavailability. Most of the statins undergo extensive microsomal metabolism by the CYP isoenzymes system, while pravastatin is transformed enzymatically in the liver cytosol. The CYP3A4 isoenzyme metabolises lovastatin, simvastatin, and atorvastatin, while fluvastatin is metabolised primarily by the CYP2C9 enzyme, with CYP3A4 and CYP2C8 contributing to a lesser extent (Corsini et al., 1999). Lovastatin and simvastatin are more sensitive substrates of CYP3A4 than atorvastatin, thus they are more sensitive to CYP3A4 inhibition. Pravastatin and rosuvastatin do not undergo substantial metabolism via CYP pathways, although rosuvastatin interacts with CYP2C9 (Corsini et al., 1999).

Pitavastatin is protected from CYP3A4mediated metabolism by its cyclopropyl moiety on its base structure and is marginally metabolised by CYP2C9 and CYP2C8 (Corsini and Ceska, 2011).

Statins are also recognised by drug transporters in the liver, gut and kidney that modulate statin disposition and represent potential mechanisms for statin DDIs. Organic anion-transporting polypeptide 1B1 (OATP1B1, gene name SLCO1B1) mediates the hepatic uptake of all the statins (Ieiri et al., 2009).

Other transporter systems involved in the uptake and efflux of statins include OATP1B3 (SLCO1B3), OATP2B1 (SLCO2B1), multi-drug resistance associated proteins such as P-glycoprotein (ABCB1), MRP2 (ABCC2), breast cancer resistance protein (BCRP, ABCG2) and sodium-dependent taurocholate co-transporting polypeptide (NTCP, SLC10A1).

Drug-Drug Interactions with Statins

Many DDIs have been demonstrated in clinical experience with statins. The risk of DDIs varies among different statins thus affecting differently statin safety and tolerability (Bellosta and www.pharmafocusasia.com

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STRATEGY

Inhibitors and inducers of enzymatic pathways involved in the metabolism of statins Enzyme or Transporter System

Substrate

Inhibitors

Inducers

CYP2C8

Fluvastatin, pitavastatin

Fluvoxamine, gemfibrozil, ketoconazole, trimethoprim

Rifampicin

CYP2C9

Fluvastatin, pitavastatin, rosuvastatin

Amiodarone (genetic polymorphism), capecitabine, cotrimoxazole, etravirine, fluvoxamine, ketoconazole, fluconazole, metronidazole, miconazole, oxandrolone, sulfaphenazole, tigecycline, voriconazole, zafirlukast

Aprepitant, bosentan, carbamazepine, rifampicin, phenobarbital, phenytoin, St. John’s wort

CYP3A4

Atorvastatin, lovastatin*, simvastatin*

Alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atazanavir, azithromycin, bicalutamide, boceprevir, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, corticosteroids, crizotinib, cyclosporine, danazol, darunavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, fusidic acid, grapefruit juice, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lapatinib, lopinavir, mibefradil, midazolam, nefazodone, nelfinavir, nilotinib, pazopanib, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, sertraline, sildenafil, sirolimus, tacrolimus, tamoxifen, telaprevir, telithromycin, ticagrelor, tricyclic antidepressants, venlafaxine, verapamil, voriconazole, warfarin, zileuton

Aprepitant, armodafinil, barbiturates, carbamazepine, cyclophosphamide, dexamethasone, omeprazole, phenobarbital, phenytoin, pioglitazone, prednisone, rifampicin, St John’s Wort, vemurafenib

MDRP or P-gp

Atorvastatin, lovastatin, pitavastatin, pravastatin, simvastatin

OATP1B1

All statins

Clarithromycin, cyclosporine, erythromycin, gemfibrozil, gemfibrozil-O-glucuronide, indinavir, rifampicin, ritonavir, roxithromycin, saquinavir, telithromycin

UGT

Atorvastatin, lovastatin, pravastatin, simvastatin

Cyclosporine, gemfibrozil,

Cyclosporine, elacridar, erythromycin, itraconazole, ketoconazole, quinidine, ritonavir, verapamil

Rifampicin, St John’s Wort

--

Rifampicin

Table 1 CYP, cytochrome P450; MDRP, multi-drug resistance associated protein; OATP, organic anion-transporting polypeptide; P-gp, P-glycoprotein; UGT, uridine glucuronyltransferase. * More sensitive to CYP3A4 inhibition.

Corsini, 2012). The adverse effects that occur when statins are co-administered with other drugs usually correlate with increased systemic concentrations of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor which has been regarded as an index of potential untoward effects in peripheral tissues (Corsini et al., 1999). In particular, DDIs with a drug that increase statin exposure may lead to an increased risk of muscle-related adverse events such as myalgia, 20

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myopathy and (more rarely and more seriously) rhabdomyolysis (Bottorff, 2006).

Drugs that reduce statin metabolism by inhibiting CYP enzymes (mainly CYP3A4) or interfering with drug transporters (Bellosta and Corsini, 2012; Corsini and Bellosta, 2008; FDA, 2012), such as OATP1B1 and P-gp, (Table 1) can lead to increased systemic exposure of the statin and increase the risk of myopathy. The different physicochemical and PK properties of statins

may explain the significant differences in their interaction potential that are evident at the PK level affecting drug absorption, distribution, metabolism and excretion.

Many drugs have the potential to cause PK interactions with statins increasing the risk for myopathy and rhabdomyolysis (Table 2), highlighting the importance of considering their DDI profile when selecting a statin for an individual patient. Another potential risk of DDIs is represented by nutraceutical

STRATEGY

preparations containing red yeast rice, a popular nonprescription treatment for hyperlipidemia. Rice fermented with red yeast contains varying amounts of monacolin K (chemically similar to lovastatin) and side effects similar to those observed with statins have been reported in some people using this nutraceutical.

Combination of red yeast with statins is not recommended due to the increased risk of DDIs and myopathy (Catapano et al., 2016).

A comprehensive and updated review on statins drug-drug interactions has been recently published (Bellosta and Corsini, 2018).

Statins in the Elderly

As many patients receiving statin treatment are elderly and/or have comorbid cardio-metabolic conditions, they will generally be prescribed multiple medications that may increase the risk of DDIs. About 3 per cent of general hospital admissions occur as a direct result of DDIs (Shapiro and Shear, 1999), and the prevalence of DDIs in the elderly population is approximately 50 per cent (Venturini et al., 2011). DDIs represent approximately 15 per cent of avoidable prescription errors, and their consequences constitute a serious health problem in the elderly population (Santos et al., 2017). Furthermore, the effects of those consequences can be confounded by the worsening of pre-existing diseases or

treatment inefficacy (Hines and Murphy, 2011). In fact, DDIs are common among community-dwelling older adults and are associated with the number of medications and hospitalisation in the previous year (Hanlon et al., 2017).

As age increases, the majority of physiological processes decrease gradually, including renal and liver function (Kinirons and Crome, 1997). Indeed, all the PK phases, from absorption to excretion, are affected by ageing thus increasing the risk of DDIs. Elderly patients on multiple drugs should be regularly reevaluated for the risk of DDIs (Corsini and Ceska, 2011). Under-treatment is also frequently present in the elderly and a clear relationship between polypharmacy and under-prescribing has been established.

Elderly patients at elevated risk of CV disease almost inevitably are treated with statins and are likely receiving concomitant therapies that may increase their risk of DDIs (Corsini and Ceska, 2011).

Moreover, aging patients are more prone to statin-induced muscle problems since muscle mass and the activity of enzymes involved in drug metabolism and disposition are reduced by age (Kellick et al., 2014). Altogether, in elderly patients receiving multiple therapies, especially for those receiving agents with a narrow therapeutic window, is important to implement a systematic approach to drug monitoring for achieving a more

Drugs that may increase risk of myopathy and rhabdomyolysis when used concomitantly with statins CYP3A4 Inhibitors / Substrates Amiodarone, azole antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), calcium antagonists (mibefradil, diltiazem, verapamil), ciprofloxacin, colchicine, danazol, fusidic acid, grapefruit juice, hepatitis C drugs (boceprevir, telaprevir), HIV medications (amprenavir, atazanavir, cobicistat, darunavir, delavirdine, efavirenz, elvitegravir, etravirine, fosamprenavir, indinavir, lopinavir, maraviroc, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir), immunosuppressants (cyclosporine, tacrolimus, sirolimus), macrolides (azithromycin, clarithromycin, erythromycin, telithromycin), midazolam, nefazodone, sildenafil, sitagliptin, ticagrelor, warfarin Table 2

Others

Digoxin, fibrates (gemfibrozil), niacin

Grapefruit: should be avoided in combination with lovastatin/simvastatin.

appropriate prescribing model. Attention in the prescription of medications, a consistent review of medication lists, and a re-evaluation of the indications and outcomes of the prescriptions are essential to ensure that polypharmacy is minimised and safety for patients is maximised.

As stated above, the clinical benefits of statins have expanded their use in clinical practice in patients with CVD risk, especially in elderly populations who are often receiving multiple medications for comorbidities thus increasing the risk of drug-drug interactions with statins. Furthermore, the effect can be increased by the worsening of pre-existing diseases or treatment inefficacy. In addition, elderly patients consume the largest number of self-medications or over-the-counter medications, including vitamins, minerals, nutraceuticals and foodstuffs (e.g. grapefruit) that contribute to the complexity of the therapy but also increase adverse drug reactions due to DDIs, including statin-associated muscle symptoms (SAMS) (du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015), and statin-induced hepatotoxicity (Benes et al., 2016). The SAMS, that occur after a pharmacokinetic interaction, increase the systemic exposure to statins and are also responsible for nonadherence to and/or discontinuation of treatment (du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015), As a consequence the exposure of patients to CVD risk remains high. In perspective, www.pharmafocusasia.com

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STRATEGY

Statin Adverse Reactions and DDIs

A question, that still remains to be properly addressed, is which type of adverse drug reaction is related to DDIs with statins. Myopathy, due to an increased circulating plasma levels of statins following the co-administration with a CYP enzyme inhibitor, is a wellestablished phenomenon, which has been characterised either from a pharmacological point of view (Bellosta and Corsini, 2012; Catapano et al., 2016; Kellick et al., 2014) or from the evaluation of the pathophysiology of SAMS (Apostolopoulou et al., 2015; du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015). On the contrary, much less is known about the relationship between DDIs and other statin-induced side effects, including the alteration of blood glucose levels and the incidence of new onset of diabetes, cognitive adverse effects, proteinuria and liver toxicity (Catapano et al., 2016). Although FDA has determined that serious liver injury with statins is a rare adverse event and that periodic monitoring of liver enzymes is not useful (FDA, 2015), potential DDIs, particularly in older patients who may have multiple chronic conditions requiring concomitant therapies, can alter a drug toxicity profile and therefore potentially result in hepatotoxicity (Corsini and Bortolini, 2013). However, causality assessment in drug-induced liver injury (DILI) cases can be challenging and the last prescribed drug cannot be always assumed to be the culprit or the only responsible agent (Shapiro and Lewis, 2007).

The inhibition and induction of drug metabolising enzymes are important causes of DDIs leading to DILI. A 22

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Statin use is expanding and approximately 25 per cent of the world population older than 65 years takes a statin on a long-term basis both for primary or secondary prevention of Cardiovascular Disease (CVD)

build-up of drugs or their metabolites can be potentially toxic through competitive inhibition and lead to a greater risk of adverse events. Numerous drugs have been identified as CYP3A4 inhibitors, including antibiotics, anti-fungals, antidepressants, calcium channel blockers, steroids, and antiretrovirals (Table 1).

However, few evidence on statin-induced liver injury after DDIs have been reported so far, and additional investigations are required to better define this important aspect.

Another interesting question that will have to be fully explored in the future is the potential interaction between statins and therapeutic proteins such as monoclonal antibodies. The different pharmacological behaviours between these two classes of drugs is suggestive of a low risk of DDIs and of a safe profile. However, long term clinical data are still required before reaching a definitive conclusion on the log-term safety of this therapeutical combination. Finally, only few clinical data is available on statin DDIs in

AUTHOR BIO

to improve this clinical scenario, it will be important to define more appropriate interventions, for example, by providing physicians and clinicians with prescribing guidance and tools to support the delivery of effective medication protocols, with a rationalisation of prescribing needs and an effective communication of outcomes to patients and to all prescribers involved in providing health care.

special populations, such as patients with familial hypercholesterolemia, paediatric patients and different ethnic populations that require chronic therapy with statins (Kellick et al., 2014) and more information is needed to better define statin safety issues.

Altogether, although statins are a class of drugs which has been available in clinical practice for more than 25 years, their expanded use among patients leaves open several important questions that are still waiting to receive a definite answer. Only a better and more profound knowledge of the potential DDIs among statins and other therapeutic options will help physicians in selecting the more effective and less harmful treatment for their patients.

Conclusions

Statin clinical use is expanding particularly in elderly patients who are often receiving multiple medications for comorbid conditions, thus exposing them to an increased risk of ADR due to DDIs, including statin-associated muscle symptoms (du Souich et al., 2017; Mancini et al., 2016; Stroes et al., 2015), and statin-induced hepatotoxicity (Benes et al., 2016). Differences in pharmacokinetic profiles of the different statins may influence their adverse effect profile (Bellosta and Corsini, 2012; Corsini et al., 1999). This could be crucial when considering DDI risks when co-administering drugs in patients receiving a statin therapy. Caution should be taken to balance the potential clinical benefits versus the risks of statin treatment to improve overall outcomes and provide patients with an evidence-based, safe and cost-effective clinical support.

References are available at www.pharmafocusasia.com

Bellosta’s scientific interests focus on the cardiovascular system.

The goal is to unravel the knowledge regarding the basic processes involved in atherosclerotic plaque formation and stability and how to control them by using a pharmacological approach. Bellosta has published 104 publications with an average IF = 4.6 and an H index = 33. He is also author of more than 180 presentations to national and international congresses.

www.pharmafocusasia.com

23

CLINICAL TRIALS

Managing Clinical Trial Agreements

C

Clinical Trial Agreements set out how a clinical trial will be run at the site and are an essential GCP document. There are a number of key factors that determine whether a Clinical Trial Agreement is successful in achieving that purpose which we will review from Novotech’s perspective as an Asia Pacific CRO. Veronica Holloway, CRO General Counsel, Novotech

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linical trial agreements are an essential GCP document and are integral to achieving clinical trial success. They define the legal relationship between sponsors, Clinical Research Organisations (CRO) and sites, and establish the rules under which the clinical trial will be conducted. There are several key criteria which determine whether A Clinical Trial Agreement (CTA) is successful in achieving this.

In this article, we will review the development of CTAs from the CRO perspective – that of being the main party negotiating between sponsors, site management and principal investigators to draft an effective agreement which facilitates clinical trial start-up and the all-important patient recruitment.

Drawing from Novotech’s clinical trial industry experience, we have found negotiating CTAs in some countries can (unnecessarily) take months —these delays can impact investigator engagement and the enrolment of patients eager to be part of an upcoming clinical trial.

Key to reducing potential delays is ensuring a good working relationship between sponsor, CRO and site to conduct the clinical trial.

CLINICAL TRIALS

Below are four core elements to be considered when approaching the planning of a clinical trial and drafting CTAs: Choosing the Right Parties: Sponsor, CRO, Site and Principal Investigator

There are a number of combinations of parties to a CTA, many of which often depend on country or site-specific requirements. If a CRO is conducting the clinical trial for a sponsor, they will usually enter into a CTA with the site, with the site and principal investigator (PI) together, or with the site as a party but where the PI acknowledges their responsibilities set out in the CTA. In any given country, understanding the right combination of parties required for a successful CTA depends on local expertise and knowledge. It is crucial you ensure you have the right parties agreeing terms so your CTA accurately reflects what will occur during in the conduct of the clinical trial – and that this arrangement is consistent with locally accepted practice and global GCP standards.

In Australia, a specific CRO CTAdrafted by the industry body Medicines Australia1 is required for public hospital sites in the South Eastern Border States of Queensland, New South Wales, Victoria and South Australia. In practice, a form of this CTA is used by most public and private sites. Sponsors who often use CROs in Australia as a local legal entity are required to sign the CTA and provide the patient indemnity to the site – a service which CROs in Australia are able to provide.

In Asia, it is important to note that some country sites (including Hong Kong) may not agree to CTAs with CROs as they require an agreement directly with a sponsor, even though a CRO has been appointed to manage the trial on behalf of the sponsor.

Some countries (like the Philippines) are new to including sites as a party to 1 Medicines Australia; Clinical Trials Research Agreement – CTRA: Contract Research Organisation acting as the Local Sponsor

Clinical Trial Agreements include protections around confidentiality, personal information and use of the study drug which protects patients, PIs, sites, CROs and sponsors.

contact saves time and effort for both the sponsor and CRO going back and forth on minor issues.

An upfront discussion regarding CTA terms provides the CRO with an opportunity to demonstrate and clarify: • What works for CTAs within their region • What they have been able to negotiate in the past • How long negotiations are likely to take • What steps they have taken to reduce the timing and complexity of CTA negotiations with sites (such as agreeing template CTAs with key sites) Key CTA Clauses to Include

the CTA2. Previously, CTAs were signed between a CRO and the PI. This is because, unlike in other countries, PIs in the Philippines are not engaged by the site.

Providing the Appropriate Authority for the CRO

If you are a CRO or a sponsor using a CRO to conduct a clinical trial, it is imperative the CTA adequately and clearly outlines the CRO’s scope of authority to conduct the trial, so the site and PI are able to receive information, instructions and funds from the CRO. If the sponsor is a party to the CTA, including a clause to this effect in the CTA can often avoid the need to have separate letters of authority signed

by Sponsors.

Have an Empowered Sponsor Representative Involved in CTA Discussions

Any CRO negotiating CTAs needs to agree negotiation parameters with the sponsor upfront and have a point of contact at the sponsor who has appropriate authorisation to make decisions about CTA terms. Having this point of 2 A joint initiative between the Philippines Clinical Research Professionals Inc and Philippines Health Research Ethics Network to harmonise CTAs was recently achieved in April 2016

Clinical trials are increasingly global, multi-site and multi-regional affairs; and in this context, agreeing a standard CTA for your clinical trial can be challenging with local country templates and requirements taking precedence. However, outlined below are several key clauses which should clearly and plainly feature in any CTA: Good Clinical Practice (GCP)

CTAs need to include references to the latest regulatory requirements — which should also include references to the International Conference on Harmonisation Note for Guidance on Good Clinical Practice (ICH/135/95) and local law requirements around ethical conduct in human research and other applicable publications or guidelines relating to clinical trials.

All CTAs should expressly require the conduct of the clinical trial comply with GCP and that all parties to the CTA conduct their respective roles and responsibilities in accordance with GCP. Conduct of the clinical trial

The responsibility of the PI to conduct the clinical trial in accordance with the protocol, Ethics Committee (EC) / Institutional Review Board (IRB) conditions and relevant professional standards must be included in the CTA. Detail around EC/IRB approvals, study documents, cooperation with CRO, safety and reporting should be included for clarity as who is to do what and when. www.pharmafocusasia.com

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CLINICAL TRIALS

AUTHOR BIO

Protections

CTAs include protections around confidentiality, personal information and use of the study drug which protects patients, PIs, sites, CROs and sponsors. Crucial points which allow each party have confidence in the other party(s) conduct of the clinical trial include: • What information is considered confidential • How personal information will be handled • How the drug or product being investigated is to be managed at the site.

Veronica joined Novotech in May 2014 to formalise the legal function at Novotech. Prior to Novotech, Veronica held roles as Senior Legal Counsel at EY, Senior Solicitor at Clayton Utz and General Counsel (on secondment) at Novartis Pharmaceuticals Australia Pty Limited. Veronica has a broad range of legal experience encompassing commercial, corporate, litigation, regulatory and compliance and specialises in working in highly regulated environments. Veronica holds a BA/LLB/LLM.

Indemnities

Indemnities which provide compensation to patients who suffer personal injury, harm or death attributable to the clinical trial are a basic requirement. That said, the breadth and scope of an indemnity can vary from country to country.

It is preferable that the indemnity (and any applicable compensation guidelines) are part of the CTA. Some countries and sites may have a form of side letter which sets out the patient indemnity.

Either way, the availability and scope of the indemnity ultimately provided by the sponsor to patients participating in the clinical trial must be clear to all parties to the CTA— and of course to the patients themselves via the Informed Consent Form.

Publication

The ability to use results and research from a clinical trial is a key asset for both sponsors and sites in relation to funding for future activities. Sites will always require publication rights and sponsors will always want first right of review, authorship credits and time delays on publication.

A good publication clause should include reasonable detail about: • The nature of information which may be published • Credits given • Timelines and triggers for publication • The role of the sponsor to review and amend Intellectual property

Intellectual Property (IP) (such as data, documents, know-how, inventions, etc)

in relation to clinical trials can sometimes be difficult to negotiate. Both the sponsor and the site will want to leverage IP derived from the conduct of the clinical trial. What is often agreed is that the site will have rights to the background IP which it contributes to, while the sponsor will have full licence rights to use that background IP to market the study drug.

The Sponsor will usually require absolute ownership of IP created during or arising out of the clinical trial. To avoid any future issues around IP ownership, it is important to require the site warrants that any IP it creates or owns does not (or will not) infringe on any IP owned by a third party.

Insurance

Insurance is a given for sponsors and CROs. However, that isn’t always the case for sites and PIs as professional indemnity insurance is not always applicable in some countries or regions.

While an insurance clause requiring the site and/orPI3 to hold professional indemnity insurance during the clinical trial and for a reasonable time thereafter ought to be included in all CTAs; it may be that the site or PI do not hold the applicable insurance or that insurance is not locally available to them.

It is important to have an upfront discussion about applicable insurance 3 Depending on who is a party to your CTA

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with the site and PI. If the CTA is signed and is not correct (for example the site agrees to hold insurance when in fact they do not), the sponsor or CRO will have taken on additional risk without factoring this into their decision making around a site or country. There are options available to sponsors where a site or PI doesn’t hold insurance (such as taking out insurance on their behalf ).

Termination

Termination rights of all parties to the CTA need to be managed against the reality that clinical trials may discontinue at any given time for a variety of reasons.

A CRO must ensure they have the ability to terminate a CTA if the sponsor decides to end the trial early, reduce the scope of the trial to exclude a site (for example where no patients have been recruited by the site) or for safety reasons. Any early termination of a clinical trial often comes with a reasonable amount of effort and time to wind up the clinical trial, so there needs to be a term outlining cooperation between the CRO, site and PI if that occurs.

Getting your CTA right as early as possible in the clinical trial process will allow the sponsor, CRO, site and PIs to focus their full attention on patient recruitment and the successful conduct of the trial.

RESEARCH & DEVELOPMENT

STEM CELL AND GENE DELIVERY An update

These days, gene and stem cell therapies have the potential to make the substantial impact on the treatment of several diseases. However, there are pros and cons of each strategy, but the optimal selection of gene delivery vector or stem cell may often lead to better therapeutic effect.

Ambikanandan Misra, Professor, Pharmacy, Faculty of Pharmacy The Maharaja Sayajirao University of Baroda

T

his years, the interest in stem cell and gene-based therapy showed from industries and spinout companies have been exceptional which reflects the growing confidence in the field grounded on frequently reports of the therapeutic efficacy and the licensing of stem cell and gene-based therapies.

Yet, stem cell-based therapy remains in its early stages, akin to gene delivery two decades ago. However, some of the important delivery aspects and updates on the delivery of stem cells and genes are discussed herewith.

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Pluripotent Stem Cells

Embryonic Stem cells (ESCs) and Induced Pluripotent Stem Cells (iPSCs) are moving ahead into clinical trials considering their significant role as a therapeutic agent. Clinical Trial- (NCT02057900) was ongoing to assess the safety and feasibility of transplantation of cardiac-committed progenitor cells derived from human embryonic stemcells,inpatients with severe heart failure undertaken by the Department of Cardiovascular Surgery, Paris, France. It is an open-label, an

interventional study consisting of 10 participants where patients with is chemic heart failure are receiving an epicardial delivery of fibrin gel embedding human embryonic stem cell-derived CD15+ Isl-1+ progenitors.

The primary focus is to understand if clinical trials show any evidence for new clinical/biological abnormalities, the occurrence of arrhythmias or development of a cardiac or an extracardiac tumour.

Cell therapies utilising iPSCs are being explored in a significant way.

RESEARCH & DEVELOPMENT

Geng Z et al., from Stem Cell Institute, Minnesota, USA have reported the generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age-related macularde generation. They have successfully validated a standardised, iPSC derivation and RPE differentiation process that will be useful for applications which require the cost-effective generation of RPE from multiple individuals such as therapies requiring patient-specific RPE derivations, population studies or drug testing.

Mesenchymal Stem Cells (MSCs)

Stem Cell therapies using MSCs have increased in a notable way. These have the biological characteristics of immune regulation, self-renewal, tissue repair and multidirectional differentiation.

A recent clinical study being undertaken

by The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China aims to understand the efficacy and safety of Umbilical CordDerived Mesenchymal Stem Cells (UC-MSCs) in the treatment of Ocular corneal burn in humans

which is one of the causes of vision loss in China. Preliminary results suggest that UC- MSCs can accelerate corneal repair and inhibit angiogenesis. It is a PlaceboControlled, Randomised, Doubleblind, Interventional Trial consisting of 100 participants where the main focus is to understand the percent of corneal perforation.

Cerebral palsy refers to a neurological disorder caused by a non-progressive brain injury or malformation that occurs in early childhood. The First www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

Figure 1 explains the way of human stem cell therapy to the clinic.

Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China aims to evaluate the safety and efficacy of UC-MSCs and compare the efficacy of UC-MSCs administered through the intravenous, intrathecal, and intranasal routes, in the treatment of cerebral palsy in children through clinical studies (NCT03414697).

It will be an interventional, randomised study consisting of 44 participants focusing on gross motor function improvement.

Haematopoietic Stem Cells

Allogeneic haematopoietic stem cell transplantation has been successfully used for the treatment of haematopoietic malignancy. Tianjin Medical University Cancer Institute and Hospital have undertaken a clinical trial to evaluate the safety and efficacy of non-myeloablative 30

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haematopoietic stem cell transplantation in the treatment of pancreatic cancer (NCT03236883). It is an open-label, an interventional trial to understand the survival rate, response rate and report any cases of adverse events.

In addition, table 1 and table 2 give the brief information regarding the current clinical trials and granted patents on the stem cell-based therapy.

Revitalised Interest in Gene Therapy

In recent decades, the level of interest in gene therapy has been exceptional.

The licensing of the first gene delivery products (GlyberaÂŽ, uniQure), an intramuscularr AAV vector for the treatment of lipoprotein lipase deficiency which was approved by European Medical Agency in 2012 and Strimvelis TM (GlaxoSmithKline) for Adenosine deaminase deficiency (ADA-SCID),

which was approved in 2016. More recently, the first CAR T cell based gene therapy product, Kymriah (tisagenlecleu cel-T and CTL019) developed by Novartis, was approved in August 2017 by the United States of Food and Drug Administration. In addition, table 1 and 2 shows the recent clinical approaches and granted patents on the gene therapy.

There has also been an increase in the number of industry sponsored collaborations with the academic sector, which may further magnify the gene therapy developmental pipeline.

Although, with the clinical translation in mind, the more applied characteristics of gene delivery like optimising the protocols to manufacture the Good-Manufacturing Practice (GMP) grade based vector stocks and ensuring that these novel vectors are suitable for commercial manufacturing.

Improved assurance in gene therapy for

RESEARCH & DEVELOPMENT

clinical exposure has also created strong competition in the biopharmaceutical sector for potentially lucrative disease indications like by using AAV vectors in the treatment of coagulation factor disorders Haemophilia A and B, where more than ten companies have declared or initiated trials.

The ability of gene therapy to cure human disorders is now an established realism, but for now, many diseases and pathophysiological processes potentially responsive to this exciting therapeutic tactic lie beyond the reach of present technology. Despite the vast developments in gene transfer technology, the

ability to modify the cells for therapeutic advantage continues to limit the translation of pre-clinical replicas from bench to bed side and finally to standard clinical care. Such progresses are primarily dependent upon the sound basic and pre-clinical data coupled with iterative human clinical trials. Unwanted host-vector interactions i.e. immune responses against the vector and encoded transgene products, must also be better understood and avoided. Alternative approaches to prevent cell-mediated destruction of gene-corrected cells include modulation of the immune system, use of engineered vectors to

evade capsid specific immune responses or transient immune suppression. The latter has been used successfully in clinical trials for Haemophilia B to limit hepatocellular toxicity and preserve expression of transgenic factor IX, especially when treatment was initiated early.

With an increasing number of therapeutic successes being reported and investment in gene therapy technologies advancing rapidly, factors related to the manufacture and commercialisation of products also need to be considered.

Gene therapy also offers the potential of a single treatment resulting in a

Clinical Trials in Stem Cell and Gene Therapy Clinical Trial No.

Study Title

Phase

Inference

NCT03186417

Mesenchymal Stem Cells in Early Rheumatoid Arthritis

Phase I (Expected Completion DateDecember, 2019)

This study was primarily focused on demonstrating the safety and efficacy of allogenic mesenchymal stem cells in the treatment of Rheumatoid Arthritis.

NCT02611167

Allogeneic BoneMarrow-Derived Mesenchymal Stem Cell Therapy or IdiopathicParkinson's Disease

Phase I (Expected Completion DateNovember, 2019)

The purpose of this study was to assess the safety, feasibility, and efficacy of intravenous allogeneic bone marrow- derived Mesenchymal Stem Cell (MSC) therapy on the rate of progression of Parkinson's disease.

NCT03321942

Treatment of Chronic Renal Failure with Adipose Tissuederived Mesenchymal Stem Cells

Phase I/ II (Expected Completion DateDecember, 2018).

The purpose of the study to investigate the biological characteristics of adipose tissue- derived mesenchymal stem cells(AMSCs) and its effect on oxidative stress, inflammation and mitochondrial damage which ultimately delay the progression of chronic renal failure.

NCT03306277

Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 (STR1VE)

Phase III (Expected Completion DateMarch, 2020)

Study of AVXS-101 (gene replacement therapy) in patients with spinal muscular atrophy (SMA) Type 1 and are genetically defined by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2).

NCT02806687

Effect of Intratumoral Injection of Gene Therapy for Locally Advanced Pancreatic Cancer (THERGAP- 02)

Phase II (Expected Completion DateJune, 2019)

This phase II study was designed to compare the efficacy of intra-tumoral gene delivery of CYL-02 plus Gemcitabine treatment or Gemcitabine alone in patient with locally advanced PDAC.

NCT03029871

Oncolytic AdenovirusMediated Gene Therapy for Lung Cancer (NSCLC)

Phase I (Expected Completion DateDecember, 2022)

The primary objective of this phase 1 trial was to determine the dose-dependent toxicity and Maximum Tolerated Dose (MTD) of oncolytic adenovirus-mediated cytotoxic gene therapy in combination with SBRT in medically inoperable stage I/IIA (T1A - T2B) NSCLC.

Table 1 www.pharmafocusasia.com

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RESEARCH & DEVELOPMENT

Granted Patents in Stem Cell Therapy and Gene Therapy Patent No.

Study Title

Description

US9862925B2 (Jan, 2018)

Human stem cell-derived neural precursors for treatment of autoimmune diseases of the central nervous system

Invention relates to cell therapy and in particular to the use of Human Stem Cells (hESC) for the production of neural precursors for treatment of autoimmune diseases

US9901600B2 (Feb, 2018)

Methods and compositions relating to mesenchymal stem cell exosomes

Invention provides compositions comprising Mesenchymal Stem Cell (MSC) derived exosomes, and methods of their use in subjects having certain lung diseases including inflammatory lung disease.

US9877989B2 (Jan, 2018)

Use of preparations comprising exosomes derived from MSCs in the prevention and therapy of inflammatory conditions.

Invention relates to the use of exosome-preparations derived from neonatal or adult tissue-derived MSCs for the prevention or for therapy of inflammatory conditions or in complications following stem cell transplantation (‘graft vs host- disease’, GvHD).

Widespread gene delivery to motor neurons using peripheral injection of AAV vectors.

Invention relates to compositions and methods based on systemic injection of rAAV, for delivering genes to cells of the central nervous system in mammals. The invention stems from the unexpected discovery that peripheral injection of AAV vectors leads to a bypass of the blood brain barrier and a massive infection of motor neurons.

Gene delivery system having enhanced tumor-specific expression, and recombinant gene expression regulating sequence

The replication of the recombinant adenovirus of this invention is tumor-specifically regulated by the novel gene expression regulating sequence, thus enabling the recombinant adeno virus of the present invention to exhibit improved selective tumor cell cytotoxicity or apoptotic potential, and exhibit remarkably improved antitumor effects particularly in hypoxic conditions

US9926574B2 (March, 2018)

US9689000B2 (June, 2017)

Table 2

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reproducible and yield vector at the highest possible titers. To address these logistical and practical challenges, importance has been placed on developing procedures for the cryopreservation and transportation of gene-modified cells. This will allow the manipulation of patient cells to occur at centralised locations and may provide methodological consistency throughout the trials and has the potential to make gene delivery more accessible to patients worldwide.

AUTHOR BIO

life-long cure which has led to the discussion on how such therapies will be valued and how companies might recover the extraordinary costs associated with a gene therapy product reaching the marketplace, as well as the investment made in those that are unsuccessful. Also, practicalities associated with the clinical manufacture of bespoke therapies, with CAR-T cells being significant, require consideration. Recent CAR-T cell therapies depend on the ex-vivo alteration and expansion of T cells harvested from individual patients and require specialised teams and proper facilities for manufacture, and the ability to meet increased demand for this ground breaking treatment is reaching capacity. To facilitate clinical tails of virus-mediated gene delivery, production must be scalable,

Conclusion

In recent decades, the stem cell and gene therapies are an established reality and evolving at a rapid pace following the important foundations proved from predominantly early-phase trials, which have been basically ineffective in providing therapeutic benefit. These trials, however, have provided clear proof-ofconcept for stem cell and gene therapy demonstrated that the therapy is relatively safe, and highlighted important issues that must be considered to advance the field.

Ambikanandan Misra is Professor of Pharmacy at Faculty of Pharmacy at The Maharaja Sayajirao University of Baroda. He has been associated with the field of pharmaceutical sciences for more than 39 years. 43 Ph.D. and 132 Master students have completed their dissertation under his guidance. He has 7 books, 41 book chapters and 165 peer-reviewed publications in reputed journals.

He has filed 29 national and international patents out of which 9 have been granted so far.

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MANUFACTURING

Drug Concentration Assurance of Continuous Tablet Manufacturing Advanced process control strategy

In the pharmaceutical industry, Real Time Release (RTR) can be facilitated by the development of a highly efficient control system. The drug concentration in final tablet is one of the most critical quality attributes that must be assured before releasing the final product to the market. Therefore, a multilayer control strategy to assure the drug concentration in final tablet is highly desired. This work is focused on development of advanced multilayer control strategy to assure the drug concentration in final tablets. The feed forward and/or feedback control strategy has been utilised to correct the drug concentration in real time minimising the wastage. While, an advanced ‘tablet diversion strategy’ has been used to divert the non-confirming tablets in real time assuring the drug concentration in good tablet lots.

Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering Rutgers, The State University of New Jersey

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MANUFACTURING

C

urrently, pharmaceutical companies are going through a paradigm shift from conventional batch to Continuous Manufacturing (CM) process integrated with advanced automation and control system. In CM, Real Time Release Testing (RTRT) can be facilitated by the development of a highly efficient control system that can monitor and correct process variables in real time when a fault is detected. But, there may be also some out of specification tablets that need to be diverted in real time, in order to ensure the quality of final products. Specifically, the drug concentration of each tablet must be guaranteed before it can be released to the market. However, currently no methods

and tools are available that can assure the drug concentration and divert the non-confirming products in real time.

Therefore, the systematic methods and tools are needed for real time assurance of tablet drug concentration and diversion of non-confirming products.

The objective of this article is to describe the control system needed to assure the drug concentration of final tablets.

Process Description

A continuous direct compaction tablet manufacturing pilot plant has been developed, situated at ERC-SOPS, Rutgers University. The snapshot of the pilot plant is previously reported (Singh et al.,

2014a). The process flowsheet is shown in Figure 1. The pilot plant is built in three levels at different heights to take advantage of gravitational material flow.

The top level is used for feeder placement and powder storage, the middle level is used for delumping and blending, and the bottom level is used for compaction.

Each level consists of 10x10 square feet working area. There are three gravimetric feeders (K-Tron)-with the capability of adding more- that feed the various formulation components (API, excipient, lubricant etc.). A co-mill (Glatt) is also integrated after the feeder hopper primarily for de-lumping the powders and creating contact between components. The lubricant feeder is added www.pharmafocusasia.com

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after the co-mill to prevent over lubrication of the formulation in the co-mill.

These feed streams are then connected to a continuous blender (Glatt) within which a homogeneous powder mixture of all the ingredients is generated. The chute is placed in between blender and tablet press. The chute has interface to integrate the sensors. Finally, the outlet from the blender is fed to the tablet press via feed frame. The pilot-plant consist of some inbuilt local level control system in feeder (to control mass flow rate) and tablet press (to control main compression force) unit operation.

Multilayer Control Strategy for Drug Concentration Assurance in Continuous Pharmaceutical Manufacturing

the desired drug concentration in final table without the need of any additional control system. But, since the drug concentration could change is subsequent unit operation and therefore additional multilayer control systems are needed as discussed in following sections. The ratio controller is shown in Figure 2. The application of ratio controller has been previously demonstrated (Singh et al., 2014a).

Advanced model predictive feedback control of drug concentration

A feedback control system has been implemented to control the drug concentration (API composition) at blender outlet (Figure 1). The drug

concentration is measured in real time using Process Analytical Technology (PAT) sensor. This provides the inputs to Model Predictive Controller (MPC) which manipulate the ratio set point discussed in section 3.1.

There are different options to close the control loops depending on the preferred platform the industry would like to use. For example, the NIR can be used for real time scanning of blend coming out of the blender. The real time prediction engine is needed to convert the raw data (spectrums) into drug concentration signal. The prediction engine uses the NIR calibration model to make this prediction. A

Ratio controller

Multiple feeders are used in continuous pharmaceutical manufacturing to feed different ingredients. The composition of the ingredients is normally fixed for a given formulation but the total line throughput can be changed in continuous pharmaceutical manufacturing. Moreover, the same plant can be used for different formulation that may have different composition. The changing of line throughput and/or ingredient composition can be accomplished by changing the feeder flow rate set point.

Therefore, a control system is needed through which the feeders flow rate set point can be automatically changed. The ratio controller is needed to achieve this objective. The total desired flow rate (plant throughput) and ingredient compositions are the inputs for ratio controller. It provides the flow rate set point for feeders. In industrial manufacturing scenario, the number of feeders are relatively high depending on the complexities of the formulation and therefore the ratio controller is even more desirable. The ratio controller fixed the drug concentration of the tablet. Ideally, if the drug concentration doesn’t change in subsequent unit operations then one can achieve 36

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Figure 1 Overview of multilayer drug concentration control strategy

MANUFACTURING

PAT data management tool can be used to manage the PAT data and send the predicted signal to next level via OPC (OLE process control) interface. The drug concentration signal then goes to control platform. The MPC loop has been implemented into the control platform. A MPC model has been developed through step and pulse change experiments. The MPC utilizes this model and generates the actuator signals that goes to ratio controller discussed in section 3.1. The implementation of drug concentration feedback model predictive control loop and experimental results are described elsewhere (Singh et al., 2014a).

Feedforward control of drug concentration

The Feedforward Controller (FFC) for drug concentration may or may not be needed depending on the particular drug to be manufactured. Therefore, this controller can be considered as optional. The FFC takes the proactive actions and therefore mitigate the effects of disturbances before it can affect the final product quality. Therefore, the FFC has potential to reduce the rejections.

The FFC is essentially a mathematical model derived in a very specific way that takes the measured disturbance as the input and generate the corrective actions proactively in real time (Singh et al., 2015).

The drug concentration of powder blend measured by NIR is the input for this FFC. This is the same NIR used for feedback control as discussed in section 3.2. The FFC then manipulates the fill depth to keep the tablet potency at consistent level (Figure 1). Meaning that, if the drug concentration in blend detected by NIR is higher/lower than desired value then the FFC will reduce/ increase the size of the tablet so that the total drug contents in the tablet is same. However, the change in tablet size should be within the permitted limits by regulator. There should be one additional controller to maintain the consistent hardness. This controller manipulates the tablet thickness to keep the tablet hardens at consistent level.

Real time tablet diversion strategy to assure drug concentration

A drug concentration based diversion system is an intrinsic requirement for continuous pharmaceutical manufacturing.

Conventional pharmaceutical manufacturing was based on batch processes and therefore such a system was not needed before. In a batch process, the individual raw materials are mixed in a blender. The output from this is transferred into drums and is subsequently tested for content uniformity offline. If the product does not meet specifications, then entire batches maybe disposed. Product that meets regulatory constraints is then stored and transported to the next unit operation. On the other hand, for the continuous manufacturing process, an upstream disturbance could propagate downstream if it has not been controlled locally or if the local control is not efficient causing overshoots. Depending on the performance of downstream unit operations, this disturbance could amplify or diminish. Nonetheless, due to this disturbance propagation, there is a need to control or be able to mitigate situations that have the capacity to deteriorate end product quality. Drug concentration control as described in the following sections, although not traditional in the sense of control is a strategy that is necessary as it eliminates the need for offline testing post the compaction stage. It facilitates Real Time Release Testing (RTRT) as the tablets can then be seamlessly transported to the coating and packaging processes.

In Figure 1, such a “drug concentration based diversion system� has been schematically illustrated. As shown in the

Figure 2 Performance evaluation of tablet diversion strategy in continuous pharmaceutical manufacturing process www.pharmafocusasia.com

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Results and Discussions

The performance of Model Predictive Controller (MPC) for feedback control of drug concentration as well as the ratio controller has been previously reported 38

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and therefore has not been repeated here (Singh el at., 2014). The performance of tablet diversion strategy for continuous pharmaceutical manufacturing process has been shown in Figure 2. As shown in the figure, a pulse disturbance in API composition has been introduced (see Figure 1, top). This disturbance then got propagated in tablet as can be seen in the figure. A conceptual limit on drug concentration has been also provided for demonstration purposes. The Figure 1 shows that the tablet potency violate the upper limits for a short periods of time and therefore tablets need to be diverted.

Both, RTD based strategy and fixed window based strategy have been tested to divert these tablets in real time.

As shown in Figure 1, the concentration and potency exceed the toleration limits and the subsequently the diversion begins in both the RTD based approach and the Fixed window based approach. The cumulative production of good tablets is also shown in Figure (see Figure 2, bottom). As shown in the figure, there is no production of good tablets within the short time interval meaning that all the tablets have been rejected.

Figure also shows that only non-qualified tablets have been diverted in case of RTD based approach. While in the case of fixed window approach, some good tables have been also diverted. Therefore, the RTD-based approach gives more good tablet production efficiency.

AUTHOR BIO

figure, the blender is connected to the tablet press via a shoot that is designed to house Process Analytical Technology (PAT) devices. A spectroscopic device (NIR) is integrated here and data from this is collected and used for real time monitoring of drug concentration. This creates a real time availability of the inlet drug concentration data at the entry of the tablet press. The diversion strategy developed in this work then uses this inlet concentration to determine a signal for the diversion strategy that can accurately be used to reject tablets that are out of tolerance limits at the outlet of the tablet press. The tablet diversion strategy could be based on fixed window approach or Residence Time Distribution (RTD) approach.

Two strategies, i.e. ‘fixed window based strategy’ and RTD based strategy have been developed, compared and evaluated. In fixed window approach, the tablet diversion is facilitated through knowledge of time delays from the point of detection to the point of the affect (tablet press outlet gate) in the system.

The sensor that detects the concentration is connected to a comparator block which decides if the said concentration is within the specifications. If it is not within specification, the experimentally derived time delay is applied and post this the diversion begins. The diversion stops when a concentration within spec is detected and the another time delay is applied. In RTD based approach, the RTD is used to predict the outlet concentration from the inlet concentration. The predicted signal is then used to initiate the diversion. The first approach is simpler to implement but may lead to lower production efficiency.

The second approach is based on more advanced technique and will ensure more efficiency but is relatively complex to implement. Figure 1

Conclusions

The drug concentration is one of the most important CQA’s of pharmaceutical product and must need to be assured before releasing it to the market.

A multilayer control strategy has been developed for continuous pharmaceutical manufacturing process to assure the drug concentration in real time. The control strategy includes an advanced MPC for feedback control of drug concentration, a FFC for proactively mitigating the effect of disturbances in drug concentration, and a novel strategy to divert the nonconfirming tablets in real time. The real time assurance of drug concentration in continuous pharmaceutical manufacturing is a significant advancement in pharmaceutical industry and is considered essential for real time release as well as patient safety.

Acknowledgements This work is supported by the US Food and Drug Administration (USFDA), through grant 5U01FD005535, and National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, through Grant NSF-ECC 0540855.

References are available at www.pharmafocusasia.com

Ravendra Singh is Research Assistant Professor at C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA, working in Pharmaceutical System Engineering research field.

He is also serving as a manager and key researcher of “multi million dollars projects funded by NSF, FDA and pharmaceutical companies. He is the recipient of prestigious EFCE Excellence Award given in Recognition of an Outstanding PhD Thesis, from European Federation of Chemical Engineering. He has published more than 53 research papers, written11 book chapters, presented at over 95 international conferences and edited one pharmaceutical book from Elsevier. He is actively serving as a conference session chair, Journal reviewer and editor.

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MEDICAL MANUFACTURING ASIA 2018 Delivering solutions for the future of medtech 29 - 31 Aug 2018 | Marina Bay Sands, Singapore

Innovative medical technology is an increasingly important driver for delivering efficiencies in the global healthcare system. Through advances in medical technology, precision engineering, micro-manufacturing processes, and IT, medical devices and solutions have become more sophisticated, accurate and effective.

As a specialist exhibition on manufacturing processes for medical technology, the 4th edition of MEDICAL MANUFACTURING ASIA will focus on new manufacturing technology and automation which play vital roles in driving innovation and operations. The upcoming edition will highlight companies that cover the spectrum of additive manufacturing or 3D printing technologies, imaging and diagnostic

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imaging solutions, as well as nano manufacturing and automated solutions.

Singapore continues to grow its medtech presence on the world stage, with a sizeable number of complex scientific instruments already designed and manufactured in the country, the 3-day exhibition strongly reflects Singapore’s focus on moving upstream to not just production but also value engineering. For companies keen on engaging global medtech companies and see Singapore as an ideal base to develop products for the Asian region, MEDICAL MANUFACTURING ASIA 2018 provides a highly relevant springboard.

MEDICAL MANUFACTURING ASIA 2018 comes against a dynamic backdrop which sees the Asia

Pacific medtech market expected to surpass the European Union by 2020 as the world’s second largest medtech market after the United States1, while on the global front, the medtech sector is expected to grow 5 per cent or more annually through to 2022, to reach nearly US$530 billion2.

With Singapore’s positioning as Asia’s top location for medtech and home to over 30 globally recognised medtech companies, MEDICAL MANUFACTURING ASIA 2018 continues to attract a highly international exhibitor base coming mainly from Asia and Europe and a trade visitor base that is predominantly represented by the medical devices and instruments, medical and healthcare, and electrical and electronic sectors from around the region.

Complementing the exhibition is the half-day forum on High-technology for Medical Devices where exhibitors will present and share latest developments and trends on the global and domestic fronts and market opportunities for medtech products from Europe. Organised by IVAM Microtechnology Network, the German-based international association has an extensive membership with companies in the fields of microtechnology, nanotechnology, advanced materials, and photonics.

1. APACMed Annual Report 2016 2 EvaluateMedTech™ World Preview 2018

MEDICAL MANUFACTURING ASIA 2018 is also synergistically co-located with the region’s leading medical and healthcare exhibition, MEDICAL FAIR ASIA – thus providing an end-to-end solutions and business sourcing platform across the entire value chain for the medical, healthcare, medical manufacturing and medtech sectors. MEDICAL MANUFACTURING ASIA, jointly organised by SPETA (Singapore Precision Engineering and Technology Association) and Messe Düsseldorf Asia, is modelled after the No. 1 global trade fair in the medtech sector, COMPAMED, that is held in Düsseldorf, Germany.

The 4th edition of MEDICAL MANUFACTURING ASIA is fast gaining traction as the region’s leading specialist trade exhibition for the medtech and medical manufacturing sectors. Following the success of the 2016 edition, the exhibition welcomed 200 companies from 18 countries, and 5,420 trade visitors from 52 countries. The 2018 edition will feature even more innovations from an expected 250 companies from 20 countries and see more than 6,000 trade visitors.

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Advertorial www.pharmafocusasia.com

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PHARMACEUTICAL CRYSTALLISATION Emerging process intensification technologies

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MANUFACTURING

Crystallisation is used extensively in the pharmaceutical industry for the separation and purification of chemical compounds. Recently, radically new technologies have been developed that allow for step improvements in the performance of pharmaceutical crystallisation. This article provides a brief overview of such technologies and discusses the opportunities for industry.

Jiayuan Wang, Postgraduate Student, Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay Fei Li, Assistant Professor, National Engineering Research Center of Industrial Crystallisation Technology, School of Chemical Engineering and Technology, Tianjin University Richard Lakerveld, Assistant Professor, Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay

S

olution crystallisation is the formation of a crystalline solid state from a homogeneous solution.

Different methods exist to create the driving force for crystal nucleation and growth. Common crystallisation methods are based on strategies to lower the solubility (e.g., via cooling or the addition of a so-called anti-solvent) or to increase the solute concentration via solvent removal. Crystallisation can easily achieve a product purity in excess of 99 per cent in a single step at mild operating conditions, which explains its wide application for the separation and purification of intermediate compounds and Active Pharmaceutical Ingredients (APIs) in the pharmaceutical industry.

However, pharmaceutical crystallisation is also a complicated process with many interacting physical phenomena and its design and operation is challenged by the need to optimise process performance criteria related to aspects such as throughput and stability. Furthermore, tight requirements related to intrinsic crystal quality attributes such as size distribution, shape, and solid-state

form often have to be considered. Such quality attributes will always have some impact on downstream processes (e.g., filtration, drying) and may also affect the final product performance (e.g., bioavailability).

During the last decades, radically new technologies have been developed to achieve step improvements in the performance of chemical processes for applications in other branches of chemical industry, which fall under the umbrella term of Process Intensification (PI). More recently, such technologies have been adopted and optimised for pharmaceutical crystallisation, which provide new opportunities to improve the design and operation of pharmaceutical crystallisation. The success of those technologies is the result of a significant amount of research, industry and regulatory support, and the recent availability of enabling technologies such as advanced real-time Process Analytical Technologies (PAT), reliable process models, and the trend towards continuous manufacturing in pharmaceutical industry. This article aims to

In recent years, driven by competition from the growing generic drug market, increasing cost in drug R&D and incentives from regulatory authorities, pharmaceutical industry becomes more involved in embracing innovations for advanced manufacturing.

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Figure 1 An overview of process intensification approaches for pharmaceutical crystallisation (adapted from Wang et al.)

provide a brief but systematic overview of the principles of selected PI technologies for pharmaceutical crystallisation.

A more rigorous discussion has recently been provided by Wang et al.

Process Intensification

Process intensification aims to enable step changes in the performance of chemical processes by deploying radically different processing technologies.

Prominent examples include the development of reactive distillation and catalytic membrane reactors. The pharmaceutical industry is traditionally not among the frontrunners of PI. However, in recent years, driven by competition from the growing generic drug market, increasing cost in drug R&D and incentives from regulatory authorities, pharmaceutical industry becomes more involved in embracing innovations for advanced manufacturing.

PI approaches for pharmaceutical crystallisation (Figure 1) can be organised according to a fundamental view 44

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on PI proposed by Van Gerven and Stankiewicz, which is based on a classification into four domains (space, time, function, and energy).

PI Approaches for Pharmaceutical Crystallisation Space domain

Significant spatial inhomogeneity often exists in crystal suspensions. Besides gradients in concentration, temperature and momentum, the distribution of the solid phase in the vertical direction is also often non-uniform. Such inhomogeneous conditions are usually undesirable, as the crystal formation may occur at unintended conditions leading to an offspec final product quality. Furthermore, inhomogeneous conditions lead to a non-uniform product quality. Various PI approaches have been developed in the space domain, which can be divided into two directions: miniaturisation and structurisation.

Miniaturisation refers to crystallisation in a confined space. The confined

space helps to create a well-defined and homogeneous solution environment and offers different crystallisation behavior compared to bulk crystallisation due to inherent surface and volume effects. For example, a miniaturised space can offer a large surface-to-volume ratio, which provides opportunities for surfaceinduced heterogeneous nucleation to control crystal formation. Furthermore, crystal growth can be restricted due to physical barriers and fast depletion of supersaturation in a small volume avoiding large crystals. Commonly applied enabling technologies for miniaturisation include emulsions, patterned surfaces and porous materials. Crystallisation inside the dispersed phase of an emulsion has been used for the production of small crystals, drug encapsulation and drug delivery. A patterned surface offers an array of small wells for crystallisation, which can be fabricated by standard lithographic techniques.

Although a patterned surface may not be practical for manufacturing, it can

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be a useful tool for screening optimal crystallisation conditions in the early R&D phase. Finally, porous materials such as porous glasses, MCM-41 silica and alginate gel offer another possibility to confine crystallisation. The use of biocompatible porous materials offers new opportunities to integrate crystallisation with downstream formulation steps to produce drug products with high bioavailability.

Structurisation refers to the use of specific structures within a crystalliser to intensify the mixing of a crystal suspension, which is particularly important when the supersaturation is generated rapidly. For example, in the case of reactive crystallisation or anti-solvent crystallisation, a lack of fast mixing can lead to high local supersaturation, which makes the crystal product quality poorly predictable. Recently, a new generation of tubular crystallisers has been developed, as mixing problems are frequently encountered when operating a tubular crystalliser at low flow velocities. Different mixing principles have been exploited. Static mixers have been used at the inlet of the crystalliser to improve the radial mixing for homogeneous supersaturation and within the crystalliser to keep crystal suspended.

Furthermore, plate-type static mixers or baffles have been adopted in the oscillatory-baffled crystalliser design, which is based on an oscillating flow.

In a segmented-flow crystalliser, the slurry is divided into small segments that are separated by gas or immiscible liquid, which improves mixing behaviour in tubular crystallisers. Each segment acts as a tiny crystalliser and mixing within the segments is enabled by internal circulation.

Time domain

PI approaches in the time domain have been developed along two directions: manipulating process time scales or introducing dynamic states. The switch from batch to continuous operation is an important PI approach for pharmaceutical crystallisation processes, which aligns well with the trend in

The current business environment in pharmaceutical industry and the development of new technologies provide a favourable ecosystem for future adoption of PI for pharmaceutical crystallisation.

undersaturated after heating, which leads to partial dissolution of small crystals. After a slight increase in solute concentration, cooling will be employed leading to the growth of the remaining crystals and the possible formation of new nuclei. This successive dissolution-recrystallisation can be considered as an intensified ripening process, which promotes the formation of thermodynamically favoured states.

Temperature cycling has already found applications for the control of various crystal quality attributes, such as polymorphic form, chirality, shape, and size distribution.

Function domain

pharmaceutical industry. Furthermore, periodic operation has been investigated as a PI approach to provide a desired dynamic profile of operating states.

A continuous crystalliser can be a single or cascade of Mixed Suspension Mixed Product Removal Crystallisers (MSMPRC) or a Plug Flow Crystalliser (PFC). A single MSMPRC is robust, but exhibits a broad residence time distribution, which may lead to a non-uniform crystal product quality.

In this respect, a cascade of MSMPRCs is preferred to obtain a narrow residence time distribution and more uniform product quality. Moreover, the use of multiple MSMPRC in sequence also gives more flexibility to optimise operation. The PFC inherently provides a narrow residence time distribution and, therefore, usually has a higher throughput and more uniform product quality compared to an MSMPRC. The supersaturation profile along the tube can de designed by adding anti-solvent or manipulating the cooling rate at different segments.

Temperature cycling is an example of periodic operation and involves alternating heating and cooling of the crystal slurry. The solution becomes

One important general PI principle relates to the execution of different process functions in a single physical space, which aims to achieve synergistic effects and to reduce the number of equipment. Crystallisation has inherent thermodynamic and kinetic limitations.

Therefore, combining crystallisation with other separation technologies to create a so-called hybrid separation process can lead to synergistic effects improving the overall separation performance.

Membranes have several advantages for solvent removal, which can be combined with crystallisation to generate supersaturation in a more controlled way and potentially with lower energy consumption. Such membrane-assisted crystallisation based on reverse osmosis or membrane distillation has been successfully demonstrated on a small scale. Compared to solvent evaporation, membranes offer a larger surface area for solvent removal which allows for more compact equipment. Another promising hybrid crystallisation process involves the combination of chromatography and crystallisation, which has demonstrated excellent performance for chiral separations. Chromatography is used to enrich one of the enantiomers, which will then be separated sharply by preferential crystallisation to produce the pure enantiomer.

The integration of crystallisation with downstream operations can www.pharmafocusasia.com

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Energy domain

The use of external fields is one of the most studied PI approaches in the energy domain for crystallisation processes, as external fields can manipulate crystallisation conditions on a local scale, which is not well possible in traditional crystallisation equipment. Ultrasound has been investigated as a method to control nucleation in crystallisation processes for many decades. Such so-called sonocrystallisation can lead to either an increased or decreased induction time for crystal nucleation depending on the operating conditions and can manipulate the crystal size distribution. Ultrasonic waves create cavities in solution, enhance mixing and provide heat, which are all effects that can have an important impact on the crystallisation kinetics.

Sonocrystallisation is especially useful for making small API crystals. Moreover, sonocrystallisation has also been demonstrated to accelerate the crystallisation of large biomolecules such as proteins, which are often notoriously difficult to nucleate.

The interest in the use of electric fields (both AC and DC) to manipulate crystallisation has increased significantly during the last two decades, which is especially the case for large biomolecules such as proteins. An electrical field can provide some temporal and spatial control over crystallisation kinetics, which can be used to control crystal 46

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formation and growth. Traditionally, electric-field assisted crystallisation has been used to produce single highquality protein crystals for X-ray diffraction analysis. However, recently, electric fields have also been used to increase the yield of protein crystallisation in continuous flow.

The application of other external fields for crystallisation, including microwave, magnetic fields and laser, has also been reported. Microwaves can be used for rapid heating, which can be used for fast temperature cycling or solvent evaporation. The use of magnetic fields has been demonstrated to enable better control over the polymorphic form and spatial orientation of crystals for some cases. Finally, laser is mainly used to enhance the nucleation rate by either photochemical or non-photochemical effects.

Conclusion and Perspective

This article provides a brief overview of PI approaches used for pharmaceutical crystallisation based on a fundamental framework for classification of PI methods. There exists a significant

amount of literature on this topic, which demonstrates that much opportunities to intensify pharmaceutical crystallisation processes exist. However, commercial applications of PI for pharmaceutical crystallisation published in open literature are rare. Nevertheless, the current business environment in pharmaceutical industry (a changing mindset, increased competition, good regulatory support) and the development of new technologies provide a favourable ecosystem for future adoption of PI for pharmaceutical crystallisation. Those new technologies include specific technological innovations based on the fundamental principles of PI as well as enabling technologies such as PAT and continuous processing. Much of the work mentioned in this article is recent, which emphasises the strong current interest in the topic. Consequently, a broad window of opportunities exists for enabling novel PI approaches for pharmaceutical crystallisation due to a favourable combination of regulatory, economical, and technological developments.

References are available at www. pharmafocusasia.com

Jiayuan Wang is a senior research postgraduate student at the Hong Kong University of Science and Technology.

He reveived his BSc degree from East China University of Science and Technology and his MSc degree from Otto von Guericke University Magdeburg.His research and career interests are on industrial pharmaceutical crystallisation.

AUTHOR BIO

lead to a more efficient and compact pharmaceutical manufacturing process.

For example, so-called spherical crystallisation, which integrates crystallisation and agglomeration in a single processing step, has been developed. Agglomeration is induced conventionally by granulation to improve the powder properties for tableting.

With the help of different spherical crystallisation methods, agglomerates can be formed directly. The commonly used spherical crystallisation methods include spherical agglomeration, quasiemulsion solvent diffusion, crystalloco-agglomeration and ammonia diffusion.

Fei Li is an Assistant Professor in the School of Chemical Engineering and Technology at Tianjin University. She received her Ph.D. degree from McGill University and was a Postdoctoral Associate at The Hong Kong University of Science and Technology.

Richard Lakerveld is an Assistant Professor in the Department of Chemical and Biological Engineering at The Hong Kong University of Science and Technology and an Honorary Assistant Professor in the Department of Pharmacology and Pharmacy at The University of Hong Kong. He received his PhD from Delft University of Technology and was a Postdoctoral Associate at MIT.

MEDICAL FAIR ASIA 2018 LEADS THE INDUSTRY THROUGH FUTUREREADY PRODUCTS AND INDUSTRYLEADING CONFERENCES & FORUMS 29 - 31 Aug 2018 | Marina Bay Sands, Singapore

Asia’s top medical and healthcare exhibition, MEDICAL FAIR ASIA 2018, is set to continue its growth path with its 12th edition. An expected 1,000 exhibitors from 50 countries and 20 national pavilions will grace Asia’s largest medical and healthcare exhibition. Visitors will get to source from a comprehensive range of more than 5,000 products ranging from digital health technology, electromedical equipment, rehabilitation supplies to consumables.

Debuting National Pavilions The must-attend exhibition continues its stronghold as Asia’s most holistic and progressive exhibition.

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Beyond the showcase of a myriad of exhibits, MEDICAL FAIR ASIA continues to break new grounds. There will be a total of 20 National Pavilions and Country Groups, this edition will see debut group participations from Belgium, Brazil, the Netherlands, Iran, Denmark, European Union, Russia, Spain and Qatar, adding to the internationality of the exhibition.

Inaugural Community Care Pavilion On the show floor, visitors can also expect to see products relating to the current healthcare trends and needs of the Asian region. The debuting Community Care Pavilion, with its keen focus on geriatrics and digital health technology seeks to address the healthcare needs of both the ageing population and the region’s remote population by bringing healthcare beyond traditional healthcare institutions and into the community. Exhibitors have already arranged for product launches to take place during the 3-day period. France Bed Co Ltd will be showcasing their unique powered turning bed. It features an automatic turning support function that prevents users from bed sores. Xiaoniu Health Co Ltd will be unveiling their intelligent sleep machine that can perform both CPAP and AutoCPAP to sleep apnea patients.

Another first on the show floor is the inaugural Start-Up Park. Providing a platform for young and exciting start-ups, the exhibits will feature products that could transform the market in the near future.

Expect to see the latest innovations in big data, IoT, as well as attend product presentations. Australian start-up Rapid Response Revival Research will unveil a prototype of their phone case defibrillator, CellAED, the world’s smallest, lightest and first truly mobile AED, to the world for the very first time.

Knowledge Exchange through conferences and forums

Back by popular demand, the exhibition will play host to the second edition of the MEDICINE + SPORTS Conference. This benchmark event for sports medicine will discuss topics ranging from digital innovations in sports and healthcare, exercise medicine to tailored exercise programmes for patients and athletes.

A stellar lineup of speakers including experts Dr. Paul Gastin, Director for the Centre for Sport Research at Deakin University, Mr. Christian Stammel, CEO of WT | Wearable Technologies and Prof. James S. Skinner, Professor Emeritus in the Department of Kinesiology, Indiana University, have been confirmed.

With Start-Ups and SMEs deepening their presence in global business, the exhibition will also host the Medtech SME Workshop. Organised by the first and only regional medical technology association, Asia Pacific Medical Technology Association (APACMed), the workshop will provide small businesses with concise knowledge on clinical trials, product validation, patent laws and many others. Through this workshop, Medtech start-ups and SMEs can learn to navigate processes to develop cost-effective solutions to meet the region’s healthcare needs.

In line with the highlight on Community Care, the exhibition will also feature the first-ever Paradigm Shifts in Healthcare seminar from 30 – 31 August.

Leading speakers will discuss the evolution of the healthcare industry as attendees learn how to overcome future challenges as healthcare goes beyond hospitals to the community.

Supported by Robotic Surgery Society of Singapore, the Medical Innovation & Technology Forum will focus on robotic surgery and discuss how patients evolve from passive healthcare recipients to active value-seekers, as such healthcare providers must tap into the latest technological advances to provide more efficient treatment options.

The Asian market offers many opportunities for businesses from all over the globe. MEDICAL FAIR ASIA 2018 is the best platform for companies to value-add to their business through its range of in-demand products and industry-leading concurrent events. With more companies keen on strengthening and gaining a foothold in the Asian market, trade visitors will be able to source from an exhaustive range of products, network, as well as gain key insights at MEDICAL FAIR ASIA 2018, 29 – 31 Aug 2018, Marina Bay Sands, Singapore.

For more information, please visit www.medicalfair-asia.com

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HPAPI Qualification Testing Considerations in containment testing Containment is critical in oral solid dose drug production, particularly if it involves Highly Potent Active Pharmaceutical Ingredients (HPAPI).

This article examines how containment valves and wireless monitoring can keep employees safe and improve manufacturing efficiency.

Michael Avraam, Global Product Manager, ChargePoint Technology

G

rowing demand for High Potency Active Pharmaceutical Ingredients (HPAPI) and the rising prevalence of therapy areas such as oncology, immune-suppressants and hormone-based products are fuelling the need for high potency handling capabilities. As the use of high potency containment systems is rising, manufacturers are looking at more innovative containment 50

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strategies and qualification has never been so important. But it’s critical to understand the variations in testing and the challenges posed by potential differences in the interpretation of results.

In this article, Michael Avraam, Pharma Safe Global Product Manager at ChargePoint Technology discusses the potential issues with containment performance testing, the data collection

methods and how the results are interpreted, as well as the impact this may have on the end user. He also describes some considerations and developments that may help to ensure efficient containment performance testing.

Industry and Regulatory Outlook

The global HPAPI market was valued at US$14.4 billion in 2016 and is expected

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to grow at a CAGR of 10.3 per cent, reaching US$34.8 billion by 2025 .

The API outsourced manufacturing market is predicted to reach US$101 billion by 2027 out of a total market of US$157 billion, with the fastest growing sector being HPAPI, driven by increased demand for cytotoxic APIs .

By the end of 2024, the cancer segment is projected to reach close to US$100 billion in value, expanding at a CAGR of 6.5 per cent . This is fuelling the growth of the biotech HPAPI segment which is predicted to be the fastest growing due to the rising demand for cancer drugs and is in turn driving research and development activities pertaining to it .In addition, rising usage of HPAPI in gynaecology and cosmetics are accounting for further growth.

This all leads to a much higher demand for more advanced control strategies in facilities where HPAPIs are being manufactured to ensure both the quality of final products and, critically, operator safety is properly achieved.

There has been much documented on market diversification in recent years for example, the onset of technologies including isolators and Restricted Access Barrier Systems (RABS) which are frequently used to safeguard products and operators throughout the manufacturing process. However, closed transfers, for example split butterfly valves (SBVs), are growing in demand due to benefits such as the reduced need for operator intervention. This limits the risk of cross contamination as well as the presence of airborne dust particles, in turn increasing operator safety.

However, as with all containment equipment, it should be qualified in accordance with the International Society for Pharmaceutical Engineering’s (ISPE) SMEPAC (Standardised Measurement of Equipment Particulate Airborne Concentration) guideline before its use within the process. But with so many factors up for interpretation, what should manufacturers be looking out for during this testing?

Performance Qualification Perspectives

ISPE SMEPAC addresses a broad selection of containment technologies and processing equipment, providing technical guidance and consistent methodologies for evaluating the particulate containment performance of pharma equipment and systems . It is only intended as a guide, demonstrating how the containment device will perform as part of a laboratory condition test, not in a particular process in a real-world manufacturing environment. So why is it important?

The guide aims to define current good practices, providing information to allow organisations to benchmark their practices and improve on them. Specifically, the guide provides a methodology to derive data associated with handling of pharmaceutical ingredients that is useful in the assessment of potential risks.

When qualifying containment equipment, occupational health professionals focused heavily on worker exposure measurement as the primary target during

Global HPAPI Market by Therapy ($USD million)

Figure 1

Source: Transparency Market Research www.pharmafocusasia.com

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the late 1990s. The method was formalised as SMEPAC shortly after and later adopted and revised by the ISPE. It is now widely welcomed and implemented by the industry. However, the nature of this guidance on sampling methods and distribution makes it difficult to compare results between technologies. The data lacks statistical rationale and more importantly, the method would be better suited if it provided a baseline dataset for future integrity testing.

The global HPAPI market was valued at US$14.4 billion in 2016 and is expected to grow at a CAGR of 10.3 per cent, reaching US$34.8 billion by 2025.

Interpretational Variants

There are many factors that can affect the interpretation of the SMEPAC test results, including the testing procedures, test equipment, the placebo and the statistical analysis.

If we examine the testing procedure first as detailed by SMEPAC, it allows for a certain amount of variation. For example, referring to transfer measurement, the SMEPAC guideline notes that ‘the masses’ are mostly meant to completely coat the unprotected seal and operational area. However, by suggesting a range of weights, this surely means that the variation in volumes may result in data that is inconsistent?

Furthermore, there is considerable differences in results from the use of various samplers, when sampling with the very same placebo under the identical test conditions. In addition, there are varying types, particle sizes and detection levels of placebos too that the SMEPAC guide recommends. Lactose, paracetamol, mannitol and naproxen are recommended suggestions and it’s important for manufacturers to ask themselves which test placebo is most relevant to the real-life API eventually to be used and has each supplier tested with the same placebo?

Ensuring these points are both covered will result in a much more tangible and comparable analysis in the end.

Moving on to the matter of statistical analysis, it is surprising that in an industry where statistics are so important, there is so much variation permitted.

Manufacturers often review the data following this SMEPAC laboratory 52

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test and use it to qualify the choice of containment controls for their required process. However, comparing these tests on a like for like basis could prove to misrepresent it’s performance from its final working environment.

There are so many variations in the way the containment performance tests are carried out and as discussed above, the interpretation and utilisation of the results obtained can be inconsistent. There is therefore a real risk for manufacturers to presume that performance will be identical, whether it’s in the laboratory test or in the real manufacturing environment? That said, in a risk-based era, it’s important to consider all variables and examine how these could lead to issues, if not addressed earlier in the qualification process.

The Need to Consider the Realworld Environment

Reducing the need for operator intervention and limiting contamination is a priority during high potency manufacturing. Operator intervention is present Diameter

Mass

0 to 100 mm

0.5 Kg or more

100 mm to 200 mm

5 Kg or more

200 mm or more

25 Kg or more

Figure 2 Test material mass to be used for each test cycle (example test table)

throughout most of the pharmaceutical manufacturing process so it’s essential that manufacturers ensure that there are controls in place to counter the possible hazards. However, it goes without saying that these solutions need to be reached without impacting on ergonomics and productivity. Finding the most appropriate solution can therefore be a challenge and qualification testing needs to reflect these challenges.

Verification of the containment performance should also be implemented at each stage where possible exposure could be present within its normal environment. For example, a charging application that has not undergone contained dispensing operation prior to being within the test environment, cannot be compared like-for-like to its real working application within its manufacturing setting.

The state of the device, for example, the identification and rectification of any damage, introduces further risk and should be questioned during this qualification process. Frequent observation and precautionary maintenance helps to protect the reliability of the containment solution and limiting operator intervention will also help to maintain a more reliable result.

Technological Innovations

The presence of SBVs has helped to address the more rigorous containment challenges when handling potent compounds and removes the risk of airborne exposure. Capable of integration with other containment systems, SBVs allow for a much quicker transfer of potent compounds and can be implemented in other applications where dust restrictions, product flow, yield and contamination are factors.

Commonly, containment performance has mostly been perceived as being directly associated to the levels of particle residue visible after separation of the containment device, but tests have proven that this is not the case.

As extraction methods have developed, it has led to the recovery of potentially airborne particles, which greatly reduces

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the level of visible particles. This offers an exceptional, robust answer to realising repeatable operation.

Double gloving, rigorous wiping procedures and waste disposal are all proven to reduce exposure but by further reducing operator intervention by introducing automation, could there be potential to reduce risk even more?

Smart machines and sensor technologies have been talked about a lot recently in the era of industry 4.0. With the pressures that exist within production, managing the ongoing risks associated with Industrial Hygiene and Quality can be challenging. By incorporating smart monitoring technology into SBVs, it could provide the power to control risk and improve productivity as part of a transfer system that continuously records usage data and delivers alerts back to the team. The technology can provide operators with visual, real-time feedback giving them, as well as quality teams, confidence and peace of mind.

If the health of the device is at risk, the smart technology creates alerts to ensure that maintenance can take proactive action to maintain system integrity, resulting in less downtime and improved productivity.

Such technologies will add a new dimension to traditional containment strategies, allowing manufacturers to adhere to their most rigorous regulatory responsibilities in the most efficient way possible. With the ability to closer monitor the sterile health characteristics that influence performance, they offer manufactures a hugely improved process and provide ongoing monitoring.

Final Thought

AUTHOR BIO

There are many considerations for manufacturers when it comes to containment testing. Due to the notable differences that exist between laboratory

((

References are available at www.pharamafocusasia.com

Michael Avraam is the global product manager at ChargePoint Technology for the PharmaSaferange of products. He is responsible for the development and evolution of ChargePoint’s split butterfly valve technology, including containment performance testing as well as developing new products and technologies. With more than 20 years’ experience in the pharmaceutical industry, Michael has been instrumental in the design of turnkey containment systems, integrating an array of process equipment. He has also been responsible for innovating and directing the development of new high containment split valve technology to service the handling of HPAPIs. Michael is responsible for consulting with senior process specialists at global pharmaceutical facilities, OEMs and engineering organisations within the USA, Europe and Asia, to review, support and identify appropriate process containment solutions and process requirements. Michael has a BEng in Mechanical Engineering.

Tailor-made containment system for toxic and sterile products

1

2

and real manufacturing environments, it is imperative to appreciate the potential boundaries of the SMEPAC guideline, as this is based on a laboratory test.

However, as the industry continues to forge ahead with technological developments, like smart monitoring to capture more repeatable and consistent data, is there an opportunity for the industry to improve containment performance and qualification testing, and maybe eventually adopt a new test, in place of a single laboratory test?

different technologies integrated on a single system Full access to the micronization unit and the dispensing station installed inside the isolator.

A CHEM PS at A 3 F it is V 6D3 stand

Multi-chamber design providing defined barrier between the process and surrounding environment.

www.fps-pharma.com | info@fps-pharma.com

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flights are operated via ABC’s cargo hub in Moscow Sheremetyevo airport, featuring up-to-date equipment and guaranteeing seamless connection throughout the airline’s expanded international network within a 48-hour delivery time, including handling, all managed by highlyskilled and qualified ground handling personnel. ABC’s

fleet of 18 Boeing 747 freighters is one of the youngest and modern in the airline industry.

abc pharma ABC is the best partner with an in-depth knowledge of the healthcare and pharmaceutical industry. We have developed special abcPharma product that meets the highest requirements for transportation of pharmaceuticals.

Benefits and special solutions of abcPharma: • Dedicated, skilled staff trained in handling healthcare products; • Full compliance with IATA TCR and CEIV certification; • Exact temperature monitoring from acceptance to delivery; • abc PHARMA Active and abc PHARMA Passive solutions; • Customer service support, online track&trace option for all shipments; • Boeing 747-8 and 747-400 with three compartments enabling different temperature settings from 4°C to 29°C; • QEP certified network and temperature control

facilities on majority of stations throughout the ABC network; • High-tech pharma hub at Moscow Sheremetyevo International Airport with effective connections to deliver cargo worldwide; • Adoption of the latest digital technologies (Sky Fresh for automated notifications, temperature data loggers to monitor conditions) • Tailor-made logistics solutions with transparency of operations and full traceability; • Sophisticated and forward-thinking approach based on peer learning and networking through industryrelated initiatives - Pharma Gateway Amsterdam (PGA), Pharma.aero.

From vaccines, laboratory equipment, MRI/MRT machines to blood samples and beyond – we, at ABC, will always find the best logistics solutions to cater your needs and expectations.

Contact information: pharma@airbridgecargo.com www.airbridgecargo.com Advertorial www.pharmafocusasia.com

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COVER STORY

INFORMATION TECHNOLOGY

R&D DATA HUB BREAKING SILOS TO ENABLE ANALYTICS

Faster decision making and better trial oversight at all levels requires truly next generation data integration and analytics. Source and format agnostic data aggregation aided by modern data lake architecture and advanced analytics deliver interactive visualizations to identify new signals, discover hidden insights, minimize risks to trial success enabling data-driven faster decisions and successful outcomes.

Suresh Selvarangan, Head, Clinical Technology, Navitas Life Sciences

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INFORMATION TECHNOLOGY

T

raditionally, controlled trials have dominated drug development.

Increasing focus on rare diseases and access to relevant patients have led to challenges where no single dataset can fulfil all research and development requirements. Biopharmaceutical companies need to prioritise their business questions and map them to the appropriate source. Constructing a portfolio allows maximum value to be derived from data sources and enables deep analyses. Historically, this has meant large trials and a focus on data gathering, collection and analysis. This approach

increases costs but does not consistently improve outcomes.

Targeted Trials Show Greater Promise

As regulatory requirements continue to tighten and research and development costs continue to rise, there is an evergrowing need to: • ‘Connect the dots’ across studies / compounds / patients - search for association across a large spectrum of data such as genomic, transcriptomic, proteomic, metabolomic, cellular and clinical

• Enable faster preclinical candidate decisions and provide better regulatory responses –to increase productivity of R&D pipeline • Move from historical analysis towards prediction – hidden relationships between compounds and target genes, molecular pathways, diseases and side effects form a combination of structural, biochemical and cellular data to inform molecule design.

In a recent case of a cancer immunotherapy drug trial failure1 was attributed to the fact that the study examined a patient sample that was too broad while it should have selected only those patients that have a specific immune response. Regulators today demand personalised immunotherapy to identify who will benefit from drug A as against who will benefit from drug B. Such demand for greater focus on value and patient outcomes highlights the need to leverage an unmatched dataset to address critical issues in clinical trials, thereby escalating the demand for real world data. There is an imperative for accelerating pharmaceutical R&D through targeted patient recruitment for clinical trials by: • Using claims data, EMR databases, and genomic data to quantify the number of patients with a specific profile as defined by inclusion and exclusion criteria to develop new personalised medicines and support the study design and participant selection for clinical trials • Analysing physician prescribing behaviour, influence networks, patient mix, payer reimbursement, and estimated retention and lifetime value to determine the most profitable physician targeting strategy • Seeking of medical scientific information and advice from healthcare professionals and patients, while avoiding the risk of antibribery/anti-corruption regulations 1 https://www.cnbc.com/2018/04/06/incyte-merck-trialfailure-deals-blow-to-cancer-immunotherapy-hopes.html

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Risk-based Monitoring (RBM) With the majority of clinical trial cost spent performing on-site monitoring, a new method is needed for an efficient, targeted approach. As TransCelerate BioPharma describes, ‘The principles of centralised analytics can be effectively applied to pharmaceutical development and clinical trial monitoring through RBM, impacting the earlier detection of data quality issues, making possible a string of actions such as: • Controlling and ensuring that clinical data quality is accurate, complete and verifiable • Enhancing the safety of patients in a clinical trial, ensuring the rights and well-being of human subjects are protected’ RBM brings data collection and tracking in real-time, and trends and analytic capabilities to the forefront with a direct result in reduction in on-site monitoring cost. For many years, the gold standard in clinical research to achieve these goals has been 100 per cent Source Document Verification (SDV), where Clinical Research Associates (CRAs) check every data point on the information reported by investigators against source records to ensure the information is complete, accurate and valid. However, SDV has shown a negligible effect on data quality. TransCelerate indicated that only 2.4 per cent of all queries generated were SDV related on critical data and thus stated that “SDV has a negligible effect on data quality.”

As risk-based approaches focus on demonstrating actual outcomes, R&D organisations have an oppor tunity to improve productivity using data analytical capabilities. By combining real-world outcomes data with clinical data, genetic data, and more broadly understanding regional and population data, analytics-savvy organisations can gain insights to recognise research failures faster, design more efficient streamlined clinical trials, and speed the discovery and approval of new medicines while reducing the cost burden.

• Leveraging molecular biomarkers to select clinical trial participants more effectively.

An instance of a targeted patient R&D success story2 is the approval received for a lung cancer drug for a 5 - 7 per cent patient subset in 2015.

The trials were conducted on only 255 patients and took a total time of three years from discovery to approval, less than half of the typical timeframe!

2 http://www.ascopost.com/issues/march-10-2015/crizotinib-crosses-another-finish-line-in-lung-cancer/

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Need for Centralised Data Assets

The following are some of the major reasons for clinical trials becoming increasingly complex: • Regional regulatory authority requires trials to be conducted on the local patient population (upto a certain percentage of total patients in the trials) for marketing approval in the region • Trials spanning multiple countries require oversight and ability to identify key risk areas

• Disparate data capture systems store data differently • Variety of data formats from lab vendors across the countries • Trials require the processing of data from images which necessitates special software packages.

Consequently, the success of clinical trials is based on retrieving trial data of uncertain quality from disparate electronic systems. This data is critical for understanding the value of pharmaceuticals and their place in an efficient healthcare delivery system, based on real-world evidence.

Biopharmaceutical companies continue to seek access to a variety of healthcare data sources to help improve development programs and to provide better evidence of the value of treatments to patients once a drug is in the market. Companies are unable to leverage their own internal data as the information resides in structured and unstructured sources across a multitude of systems/databases.

Companies must not only cope with this flood of information but also access and harness it to improve the efficiency and perceived value of the innovation effort. A key component of the healthcare value equation is data mining; either to address scientific endpoints or to determine the comparative cost and quality outcomes of a drug candidate.

While in the past, integrating data from multiple sources into an electronic data capture platform or building a data warehouse solution might have worked, it is very restrictive, cost prohibitive and not sustainable any more due to the varying and dynamic nature of the data sources.

Overall, there is a need for moving from a world characterised by fragmented knowledge and processes driven by silos of data sets, to a world where one central data repository holds data derived from scientific discovery, clinical trials, commercial research, enabling data analytics and generating insights across the entire spectrum of

INFORMATION TECHNOLOGY

the drug development process. This fundamental change is no longer an option, but a necessity for the industry.

Aligning End-to-end Data Assets for Competitive Advantage

Surveys exploring performance of the R&D function and its ability to generate returns have shown that ‘Strategic choices during the drug development can have a significant impact on long term commercial value’.

These choices can only be made by aligning end-to-end decision making across the organisation.

The imperative is capitalising on modern data architectures and analytics frameworks.

To access the vast amount of data available, there must be collaboration among data providers, laboratories, hospitals, pharmacies, research groups, and universities, and numerous other sources.

The quality of the data and analysis will ultimately determine the additional value that it can add.

Over time, providers with quality data and robust analytic capabilities will be able to differentiate themselves from their peers. The new paradigm is about unlocking the value of the data that is available and combining it with increasing volumes of new data.

Clinical Data

Operational Data

Figure 1

Large organisations have the technology, processes and data analytics capabilities in place, which gives them a competitive edge. Many of them also have integrated technology platforms that provide real-time monitoring during clinical studies. These companies can potential adapt these platforms to monitor the market in real-time once a treatment is launched. Despite their competitive advantage, the ongoing challenge of data integration and contextualisation remains.

Insights Driven Decision Making through Analytics

While most organisations remain focused on applying data for reporting, market leaders use analytics to evaluate risks and tradeoffs, understand cost and

Multi Structured

Source Agnostic Format Agnostic

Real World Data

revenue drivers, and predict trends to help drive performance and innovation.

Analytics pushes the innovation agenda forward to create value and provide a comprehensive and informed view of factors that impact R&D outcomes.

A platform with access to real world evidence, clinical trials data, regulations, health information exchanges and electronic health records etc enables companies to leverage advanced analytics. This would have a significant impact on drug research and development, clinical trials, patient care and safety monitoring.

A refreshed analytics strategy that can make information accessible across business units, departments and geographies is required. This solution must bring in a modern approach to

Dashboards Guided Analytics Analytical Applications

Data Storage and Processing

Data Access Exploratory/ Advanced Analytics

Social Media Data

Data Integration

Insights

Data Governance/Metadata/Data Validation/Data Privacy and security Figure 2

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INFORMATION TECHNOLOGY

address the data aggregation challenge – one that is not relational database oriented. A schema must be defined upfront outlining a flexible solution that can handle any data from any data source, shifting from reactive to realtime decision making.

The proven ‘data lake’ architecture fulfils the need of clinical data integration and aggregation, using AI and machine learning techniques.

This alleviates the need for pre-defined structures and stringent rules-definition employed by legacy software.

The platform should: • Have the ability to process data in a ‘source agnostic and format agnostic’ manner into a central data repository • Have a short set-up time with low fixed costs, while providing global accessibility and near real-time data analytics and visualisations. This

AUTHOR BIO

Suresh Selvarangan has 20+ years of cross functional experience in the IT industry with great track record of implementing unique solutions to enable business efficiencies. He has served as strategic technical leader for global organizations delivering clinical technology and advanced analytics solutions.

He currently serves as Head of Clinical Technology for Navitas Life Sciences.

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enables effective trial oversight at all levels, enhanced patient safety and faster decision making.

• Enable interactive visualisations and data discovery • Offer a revolutionary risk analytical platform encompassing study/ site/country level dashboards with actionable insights, review and workflow for holistic trial oversight • Deliver a scalable solution to accommodate the ever-changing business and regulatory needs of clinical research including, ICH E6 R2 Once broken down from their silos, these data from myriad sources serve multiple functions as they traverse the clinical R&D landscape. This enables an ‘analytics ecosystem’ with easy access to variety of data sources, tools and capabilities to perform both exploratory and defined analytics. Data analytical teams appreciate the ability to source data from a centralised repository, and gain access to dynamic real-time visualisation, medical reviews and riskbased monitoring.

Thus, an analytics platform will help the sponsor: • visually get a handle on multiple studies in near-real time • help retain control while working with multiple outsourced providers across different geographies • help monitor the safety aspects of the studies • enable comprehensive risk-based analysis and • gain a comparative edge.

References: 1. https://www.cnbc.com/2018/04/06/ incyte-merck-trial-failure-deals-blow-tocancer-immunotherapy-hopes.html 2. http://www.ascopost.com/issues/ march-10-2015/crizotinib-crosses-another-finish-line-in-lung-cancer/ 3. http://www.transceleratebiopharmainc.com/rbminteractiveguide/whatis-risk-based-monitoring-rbm/benefitsof-rbm/

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