Pharma Focus Asia - Issue 29 by Ochre Media Pvt. Ltd.

Issue 29 2017

Wearables in Clinical Trials Where we are & where we are going Patient Recruitment in Asia Reducing the clinical burden

www.pharmafocusasia.com

High performance spherical silica HPLC columns and bulk media for analysis and API puriﬁcation by industrial-scale chromatography

For the purification of • Peptides • Small proteins • Oligonucleotides • Small molecules kromasil@akzonobel.com India & Middle-East: +91 22 2778 7338 Worldwide: +46 31 58 70 00 www.kromasil.com

Foreword Human-Centred Design in Biopharma Need of the hour If we hope to create something of lasting value,

market. Design thinking enables organisations to

we need to start with what people want — not

bring-in cross-departmental innovation, deliver

just with what’s technically possible! IDEO, a

value-added solutions and unleash market

global design firm.

opportunities. HCD brings together company

Innovation and technology advancements play

leadership both strategic and operational,

a key role in product design and development,

stakeholders that work in a collaborative

but it is imperative that companies bring in a

environment with uniform goals and unified

human-centred approach. The advent of new

approach to solutions. This process includes

technologies such as virtual reality, augmented

defining roles and responsibilities for all those

reality, digital assistant etc. throws light on

involved.

integrating those into human lives for better

By integrating human-centred research, the

application and experience. Think of a Fit-bit –

molecular development process benefts from

it tracks one’s physical activity, sleep and throws

parallel human-centred research throughout

inputs on areas of improvement thus helping an

the discovery and development phase. This

individual stay physically active. Human Centred-

also helps in increasing the productivity by

Design (HCD) is a methodology that focuses on

choosing the most useful potential medicines

the people that you serve and places them at

among many alternatives and help articulate

the center of design and implementation. HCD

real value to users for a given medicine. By

combines research and insights with business

supporting human-centred research, R&D

and technology requirements to produce the

organisations can signifcantly augment their

best output. It is indeed more relevant for the life

tools for guiding personalised medicine and

sciences and healthcare sectors as the onus is

create robust portfolios of products that users

on producing effective drugs and care.

strongly value.

From the pharma industry perspective,

In the cover story of this issue, authors

design thinking could be using design to come

Andrew Parsonsand Susan Cruse suggest that

up with ideas to effective connect with and offer

a human-centred experiential learning process

care to patient. A study conducted by the Drug

to develop leaders, managers, and employees

Information Association (DIA) in collaboration

is quintessential for success. Paying attention to

with the Tufts Center for the Study of Drug

the ‘human’ will enable development of solutions

Development (CSDD) indicates more than 65

for addressing leadership challenges.

per cent of pharma and biotech companies are inclined to invest in drug development through patient centric initiatives. As the demand for patient-centred drug development and service continues to rise, a human centred approach

Prasanthi Sadhu

could be the differentiator for companies in the

Editor

Contents Strategy 06 Future Prospects of Biotherapeutics and Challenges

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

Clinical Trials 26 Patient Recruitment in Asia Reducing the clinical burden

COVER STORY

The Human-Centred Biopharma Organisation Andrew A Parsons, Reciprocal Minds Limited Susan M Cruse, Leadership Mastery Limited

David Yoshii, Senior Director, Global Site Solutions PAREXEL International

30 Low Rates of Stroke and Major Bleeding with Rivaroxaban Confirmed by Global Study XANTUS pooled results study

John Battersby, Medical Writer, Bridges Publishing Pte Ltd

36 Wearables in Clinical Trials Where we are & where we are going

Xavier Flinois, President, PAREXEL Informatics

Research & Development 40 Merging Technology Transfer with Knowledge Translation Academic to industrial research Vivek Dave, Sachdev Yadav, Harshavardhan ML Yadav Isha Mehta

Department of Pharmacy, Banasthali University

48 Creating the Perfect Capsule Choosing the right shell excipient for your formulation challenges

Bjorn Vergauwen, Principal Scientist, Rousselot

Manufacturing 52 The Rise in Sterile Manufacturing A focus on containment

Christian Dunne, Global Product Manager ChargePoint Technology

Information Technology 58 Take a Pass on the 3pm Samples

Steve Madden, Software Product Manager Mass Spectrometry Agilent Technologies

62 Books 2

P h a rm a F o c u s A s i a

ISSUE - 29 2017

130%6$54 ."/6'"$563&% */ 10356("3JCFJSB EPT $BMEFJSร FT 8BUFSGBMM r "[PSFT r 1PSUVHBM

/05)*/( #65 163& 5BMLJOH PG 1VSJUZ JT OPU POMZ BCPVU UIF QMBDFT XIFSF ZPV DBO รถOE JU CVU BMTP PO IPX ZPV DBO BDIJFWF JU

1SPEVDUT GPS DMFBO TUFBN BOE JOEVTUSJBM HBTFT

UIFTJMWFSGBDUPSZ QU

XXX WBMTUFBN DPN

1IBNB 'PPE $IFNJDBM $PTNFUJD ;POB *OE EB (VJB 1BW #SFKP r (VJB 1#- r 10356(" r BEDB!WBMTUFBN QU www.pharmafocusasia.com

Strategy

Advisory Board

Editor Prasanthi Sadhu Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Director of Research, Tufts Center for the Study of Drug Development, Tufts University, USA

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA

Editorial Team Debi Jones Grace Jones Art Director M Abdul Hannan Product Manager Jeff Kenney Senior Product Associates David Nelson Peter Thomas Sussane Vincent Product Associates Austin Paul Ben Johnson Veronica Wilson

Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany

Circulation Team Naveen M Nash Jones Sam Smith

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

Subscriptions In-charge Vijay Kumar Gaddam

Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA

Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK

Head-Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA

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

Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US

Confederation of Indian Industry

Ochre Media Private Limited Media Resource Centre,#9-1-129/1,201, 2nd Floor, Oxford Plaza, S.D Road, Secunderabad - 500003, Telangana, INDIA, Phone: +91 40 4961 4567, Fax: +91 40 4961 4555 Email: info@ochre-media.com www.pharmafocusasia.com | www.ochre-media.com ÂŠ Ochre Media Private Limited. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, photocopying or otherwise, without prior permission of the publisher and copyright owner. Whilst every effort has been made to ensure the accuracy of the information in this publication, the publisher accepts no responsibility for errors or omissions. The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates. Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

P h a rm a F o c u s A s i a

ISSUE - 29 2017

From clinical development to commercial production

It takes a unique blend of expertise to deliver the right results At Vetter, we look at your product from every angle. And help you find answers that make a difference in efficiency, productivity, safety, quality, and growth. From initial process design through high-speed fill and finish, learn how a partnership with Vetter will keep your product moving smoothly towards success. Q

More than 35 years of experience in aseptic ﬁlling

Expertise with many compound classes, including biologics

Highly trained experts in key technical areas

Integrated life cycle management

Innovative drug delivery options

State-of-the-art cGMP manufacturing

Excellent global regulatory support

Vetter Development Service

Vetter Commercial Manufacturing

Vetter Packaging Solutions

Answers that work US inquiries: infoUS@vetter-pharma.com • Asia Paciﬁc inquiries: infoAsiaPaciﬁc@vetter-pharma.com • Japan inquiries: infoJapan@vetter-pharma.com • EU and other international inquiries: info@vetter-pharma.com

www.vetter-pharma.com

Strategy

Future B Prospects of Biotherapeutics and Challenges Advancements in the biotechnology have presented pharmaceutical manufacturing industries biotherapeutics which are promising as potential future therapeutics. Diverse categories of biotherapeutics are coming into the market which range from monoclonal antibodies, growth hormones and cytokines to vaccines. Present topic will cover the future prospects and challenges to the biotherapeutics. Ambikanandan Misra, Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda

P h a rm a F o c u s A s i a

ISSUE - 29 2017

iotherapeutics or biological products are generally produced using living cells or organisms (recombinant DNA technology, controlled gene expression and antibody technologies). It may be manufactured using biotechnology derived from natural sources or produced synthetically. Recombinant hormones, vaccines, monoclonal antibody based products, growth factors, blood products and advanced technology products (gene and cell therapy biological products) are few of the biotherapeutics. According to definition of the PHS (Public health service) act of USFDA, biological products are defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesised polypeptide), or analogous product which are applicable to the prevention, treatment, or cure of a disease or condition of human beings. Proteins

Strategy

are classified as drugs as well as biologics in USFDA but proteins are regulated as a biological product, except any chemically synthesised polypeptide, under the BPCI act. Difference between Biologics, Biosimilars and Generics

The generic version of biologics are known as biosimilars in Europe, Similar biologics in India, follow-on Pharmaceutical in USA and Japan, subsequent entry biologics in Canada, and biocomparables in Mexico. The origin of the terminology lies

Gene screening & vector insertation Host cell expression & cell culture Protein production and purification Formulation & Development and Analysis Storage & handling

www.pharmafocusasia.com

Strategy

in the loss of patent protection of first generation innovator biologics in last decades. Biologics are at least 1000 times larger than conventional drugs or generic drugs in size containing hundreds of amino acids joined by peptide bonds to form a polypeptide. It is very difficult to establish reproducibility for biosimilars whereas reproducibility can be easily achieved by generics or small molecules conventional drugs. Biologics, biosimilars and generics are needed to exhibit comparability, biosimilarity, and bioequivalence respectively. The non-medical switching is not allowed in biologics and biosimilars whereas it is allowed in generics. Biopharmaceutical productions methods are more complex than chemical production methods so production cost automatically goes higher than generic counterparts. Although the goals are same — to treat the disease—biotherapeutics and generics differ substantially in ways that might affect innovation, safety, costs, clinical adoption, patient access, and pricing.

Parameters Primary sequence (peptide map andamino acid sequence analysis), immunogenicity (immunoassay) other identity indicators

P h a rm a F o c u s A s i a

ISSUE - 29 2017

IE, HPLC, gel electrophoresis

Potency

Cell-based bioassay, gene expression bioassay, ADCC, CDC

Conformation

Near/far UV circular dichroism spectroscopy, Fourier transform infrared spectroscopy, X ray crystallography and differential scanning calorimetry

Glycosylation

onosaccharide composition analysis, oligosaccharide profile, CE, LC-MS, MS/MS, ESI, MALDI-TOF

Phosphorylation

Peptide mapping with MS

Truncation

SE-HPLC, gel electrophoresis, AUC, peptide mapping with MS, RP HPLC

Glycation

Peptide mapping with (MS, HPLC), methylation, isomerisation (RP HPLC)

Pegylation

HPLC, CE

Aggregation

SE-HPLC, gel electrophoresis, Light scattering and AUC

Oxidation

Peptide mapping with MS

Deamidation

Capillary IEF, peptide mapping with MS, and CEX-HPLC, C-terminal lysine (capillary IEF, peptide mapping with MS, and CEX-HPLC), misfolds (RP-HPLC)

Host cell proteins

ELISA, DNA, endotoxin (Limulus amoebocyte lysate assay)

Binding

Cell assays, spectroscopy, ELISA

Biological activity

Cell assays, animal models

Manufacturing of Biotherapeutics

The stable Biotherapeutics consist of Primary (amino acid sequence) and Secondary structures (α-helix and β-sheets) which are folded to form 3D-Tertritary structures that is converted into quaternary structure. The biological activity can be attributed to glycosylation and sialylation. The characterisation remains the challenge for biotherapeutics due to larger size and structural complexity. A typical biotherapeutics production involves following steps: The methods of biotherapeutics characterisation are divided into quality, safety and efficacy of product which requires clearance by regulatory body and further comparability exercise. There is a significant improvement in formulation of biotherapeutics and characterisation of the products due to recent guidelines on the International Conference on Harmonisation Q8

Characterisation technique

Abbreviations: IE, ion exchange; HPLC, high performance liquid chromatography; ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; CE, capillary electrophoresis; LC–MS, liquid chromatography–mass spectroscopy; MS/MS, tandem mass spectrometry; ESI, electrospray ionisation; MALDI-TOF, matrix-assisted laser desorption/ionisation time of flight MS; AUC, analytical ultracentrifugation; CEX, cation exchange; IEF, isoelectric focusing; SE, size exclusion; RP-HPLC, reverse phase HPLC; ELISA, enzyme-linked immunosorbent assay; QSE, quality safety and efficacy.

Strategy

on pharmaceutical development and the roll-out of the Quality by Design and Process Analytical Technology, comparability of biotechnological / biological Products subject to changes in their Manufacturing process Q5E and quality of biotechnological products: stability testing of biotechnological / biological products Q5C. There are methods for characterisation of biotherapeutics as mentioned in the table. Switching and Interchangeability in Biosimilars

Reference product biologics and their biosimilars are very important treatment options for multiple diseases and have the potential to expand the possibilities for our patients. Switching studies evaluate all the parameters change with exposure to interchangeable product with reference one. The main purpose of this study is to demonstrate the risk in terms of safety or diminished biological activity between interchangeable molecules. As per FDA a product is interchangeable with biosimilars, if the manufacturer proves that it is expected to produce same clinical result in same patient only is product considered as safe. Comparability studies are performed between a biosimilars and its reference product, but studies between one biosimilars and another are not done; two separate biosimilars may have been compared to the same reference but not between themselves.

Challenges in Development of Biosimilars

European Medicine Agency (EMEA) has first issued guidelines defining biosimilar approval pathway which has been adopted and/modified by several countries. Guidelines issued by WHO are almost similar to EMEA guidelines. However, similarities in the guidelines is just the tip of the iceberg, and there is an intense need for streamlining the standards. Furthermore, companies are suspending the development of biosimilars at clinical stages, hesitating to conduct single and global development programmes due to the changes in the IP rights, evolving guidelines (many countries are changing their guidelines abruptly as the understanding and definitions of biosimilarity, interchangeability, substitution etc. evolve), unknown

patient-to-patient variability between the biosimilar and reference biologic in Phase I/II studies, large variability encountered in PK/PD studies, safety, efficacy and immunogenicity profiles due to manufacturing quality, uncertainty in Phase III trials (whether to consider the Phase III trials as non-inferiority trials or bioequivalence trials) etc. Many countries require that the reference biologic be approved /licensed/ marketed in the country. So, it becomes very difficult for the companies to target other countries using same biosimilar, as it would raise the questions due to large number of quality comparisons to be established, number of different toxicology and clinical studies to be performed. High development costs force companies to focus first on developed nations with large market size which will delay/limit development of biosimilars

Current trends in biosimilars 2014

• No guidelines on bio similar in the U.S. • Debate on key issues

2008

2009 • Implementation of the Biologics Price Competition and Innovation Act

• Purple Book published

2012 • Pathway passed as part of the ACA

2010

• Draft guidence issued from U.S. FDA with • Clarity on biosimilar approval pathway

• $42B Total global sale

2013

• Sandoz and Celltrion field biosimilar candidate applications for regulatory approval • 97 biosimilars in development

www.pharmafocusasia.com

Strategy

Regulatory frameworks in biosimilars in EU & USA Source of RWD

United States

Approval Procedure

Approval is based on the information indicative of the biological product is highly similar along with no meaningful discrepancy in their safety, potency and / or the purity to that of the reference biological product (1)

Approval is based on by comparing the biosimilar product with its reference biological product demonstrate that there are no significant changes between them (Applicable clinical data necessary to compare with the inventor) (2)

Naming

Manufacturer and FDA determines the naming of biosimilar product (3)

Approving body of the individual member states determines to name of the biosimilar product (3)

Labeling

A statement has to be written on the product that it is a biosimilar for specified indication(s) as well as administration route(s), and if biosimilar is interchangeable with reference biological product (1)

A clear indication on all the biosimilar products with the black symbol and standardised descriptive statement (4)

Interchangeability

FDA determines the interchangeability of the biosimilar product to the reference biologic based on the optional evaluation (5)

EMA declines interchangeability of the biosimilar product to the reference biologic (6)

Automatic Switching

Executed by state laws (7)

Executed by individual member states (6)

Pharmacovigilance Endorsements

Regulation and the awareness of the product specific postmarketing safety monitoring by FDA (1)

Product name and Batch number are the identities of all biologics (4)

P h a rm a F o c u s A s i a

ISSUE - 29 2017

cause multiple revisions of clinical trials and marketing authorisation applications for consistency with guidelines and regulations. The Potential of Biosimilars

A number of key biologics are going off patent by 2020, thus there is a huge potential for Biosimilar version of these

A u t h o r BIO

for countries with smaller markets. All of this mandates that the biosimilar guidelines evolve and be streamlined as soon as possible. Until then, there is no option other than to consider the specified pathways of each country. Streamlining will surely take time; but once done, there will be a step-wise approach for biosimilar authorisation /marketing in several countries. Thorough and defined quality characterisation tests, non-clinical studies, extent of clinical studies and standards for reference biologics will be specified which will help extrapolation of data from one indication to other approved indications of innovator product. It will also resolve the differences in nomenclature that may 10

European States

medicines. The cumulative market potential may reach beyond EUR 100 billion in next five years. There are at least 50 distinct biosimilars in pipeline and will be delivered successfully in next five years. Biosimilars can bring improvements to patient outcomes by providing more treatment options to physicians and reducing the need for rationing. Conclusion

Though adopted and evolved from similar background, a large amount of discrepancies exists between regulatory guidelines being followed in different countries. There is a mandate for harmonising the guidelines at global level which will ease the biosimilars product manufacturing in several countries enabling the companies to globally market their biosimilar products. There is a potential opportunity for biopharmaceutical companies for low-cost manufacturing in semiregulated and non-regulated markets. Companies need to review and follow all quality, safety, and efficacy parameters of different countries and revising the development plan for biosimilars from time to time addressing the country-by country differences. India is gearing up with the companies that are adopting guidelines more in line with EU and USA. Soon, more Indian companies will get through the rigid approval framework including refined requirements of non-clinical and clinical evaluations; India is going to make its stance as a provider of low-cost biosimilar products.

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 38 years. 42 PhD and 128 Master students have completed their dissertation under his guidance. He has 7 books, 40 book chapters and 156 peer reviewed publications in reputed journals. He has filed 29 national and international patents out of which 8 have been granted so far.

Strategy

How Best to Introduce Medical Devices Class II Products into the Chinese Market How best to introduce medical devices class II products into the chinese market? Many Pharma companies are still bothering from China regulations. Having a partner who understands the opportunity and competitive environment of the Chinese marketplace is absolutely essential and can be the difference between success and failure. Phillips-Medisize explains the work to bring a rapid development of a variable dose pen injector in China through regulatory approval. Bill Welch, CTO, Phillips-Medisize

Finding the most appropriate foreign manufacturing partners for Chinese companies in the medical devices marketplace involves complex studies and background research for suitable partnership candidate companies into a number of key issues. Foreign drug companies need to understand this marketâ&#x20AC;&#x2122;s challenges to capitalize on the opportunities and obvious long-term benefits for both parties. By

P h a rm a F o c u s A s i A a

ISSUE - 29 2017

gaining an in-depth knowledge into the countryâ&#x20AC;&#x2122;s regulatory body, an organization can leverage this experience to both advance its product and to create a solid and sustainable foundation for an expanding manufacturing strategy in China. With a sales volume of $ 48.5 billion in 2015 China is one of the worldâ&#x20AC;&#x2122;s largest and fastest growing medi-

cal device markets. This represented a Compound Annual Growth Rate (CAGR) of some 22.3 percent between 2010 and 2015. Today, China is the world’s 2nd largest medical device market with overall healthcare expected to reach $ 1.3 trillion by the end of 2018. This market is expected to continue to grow strongly, with pharmaceutical expenditure expected to increase at a rate of almost 70 percent over the next five years. Finding the most appropriate reliable longterm global partners is an essential part in securing ongoing sustainable growth in that sector to satisfy demand. Currently, approx. 300 million Chinese patients are suffering from chronic diseases alone; this number is bound to rise over time. Such diseases include diabetes and many other conditions requiring treatment with medical devices for diagnostics and drug delivery. And this is just the home market – not taking product exports into consideration. Only the most advanced high-tech organizations with a global presence producing innovative medical devices can meet the multi-faceted requirements in such a complex market place. The principal criteria include: 1. Speed of innovation, passage time to market – critical assets assessment to reach market viability 2. From Part to Market 3. Product Approval and Registration–knowledge and experience in and speedy execution of As a contract manufacturing organization (CMO) and a contract development and manufacturing organization (CDMO), Phillips-Medisize is one such forward-looking company satisfying the critical factors relevant for the vast Chinese markets in the Medical Devices Class II sector. More than just a molder, the company specializes in design through distribution services and has created an environment focused on high quality and adherence to rigorous time-to-market schedules. Furthermore, the company has had a design and manufacturing center near Shanghai for the past three years. A newly added medical devices registration operation has been given to the medical device production facility that

has Good Manufacturing Practice (GMP) from the China Food and Drug Administration (CFDA). This means that the paths – innovation and part to market – have already been cleared to a great extent. Phillips-Medisize already has in-depth insight into the many regulations, guidelines, protocols, procedures and codes of practice for Medical Devices Class II products and their timely implementations are the cornerstone of a long-lasting productive partnership. Last, but not least, the ability to recognize the unique market trends within China are part of the company’s strength. This gives this organization a vitally important competitive edge. In addition, familiarity with product testing and the final product registration are an important part of what Phillips-Medisize can offer potential partners in China. When it comes to Medical Devices Class II products, the variable auto-dose pen injector insulin pen, manufactured by Phillips-Medisize for it´s customer, is a prime example of the classification.

1. Speed of Innovation The time between initial concept of the product or product development must be kept to an absolute minimum and without compromising fundamental parts of the process. Here, the knowledge of all vital segments of state-of-the-art technology is, at the very best, a routine part of any appropriate company’s remit. Suitable partners must possess the critical assets essential to satisfy Chinese manufacturers. Commercial viability and market maturity are familiar phrases to any suitable candidate. Criteria include global presence, in-depth market knowledge in the guest country, fully trained design, development and implementation personnel able to work with its customers to deliver advanced automated assembly and quality control technologies on a long-term basis, which reduce manufacturing cost while, in tandem, improve quality.

2. From Part to Market Serving such a large, fast growing market such as China, and allowing for potentially prolonged approval times requires that device producers keep the time to market readiness for new products to an Advertorial www.pharmafocusasia.com

By adopting a systems engineering approach at an early proof-of-concept stage, the company also aims at reducing financial and other risks in efficient device development to meet more advanced technical requirements, as well as ensuring that required devices reach the market within agreed schedules. This is achieved by paying particular attention to each individual component contained within the drug delivery systems, as well as to the method by which the components, sub-systems and complete systems are fully integrated and work effectively with each other. The systems engineering approach is more robust than with linear product development, as it requires some engineers dedicated to systems and others to sub-systems development. For example, Phillips-Medisize states that although this involves higher up-front early development stage costs than with linear product development, it saves other expenses later on, e.g. if the need arises to trace back the cause for a device not properly functioning at a later stage in development or marketing.

absolute process.

minimum

without

compromising

the

3. Product Approval and Registration

Instead of a conventional â&#x20AC;&#x2DC;linearâ&#x20AC;&#x2122; product development life cycle with manufacturing development and manufacturing stages after a large part of the product development phases has been completed, Phillips-Medisize has considerably shortened lead times to market by bringing forward two manufacturing stages to start and run parallel with the product proof of concept stage of development. Thus the concept development stage has become a concept and manufacturing development stage and the validation stage includes both product development and manufacturing elements.

P h a rm a F o c u s A s i A a

The potential higher up-front development costs are minimized by integrating Design for Manufacture (DFM) and Design for Assembly (DFA), as 80 percent of product cost and quality are often determined during the first 20 percent of the product development cycle. Manufacturing strategy must be fully aligned with device strategy in order to avoid end stage changes which may compromise stakeholder requirements or program feasibility.

ISSUE - 29 2017

Phillips-Medisize, explains approval process:

the

registration

and

Any serious contender, contract development and manufacturing organizations (CDMO), keen to enter the Chinese medical devices market, must be totally familiar with the time-consuming regulatory approval procedure. Again, taking the insulin pen as an example, the initial step to be taken is the appointment and retention of a qualified agent based in China who will coordinate registration with the CFDA, also known as the State Food and Drug Administration (SFDA).

This approach applies in a formal review process for the single device, the device and the drugs it delivers or in parallel reviews for the device and drug. Products should be treated both as the sum of the constituent drug and delivery device parts, but also as a complete treatment system. All the different routes along the registration and approval path influence the time to market speed. They are equivalent to speed control bumps along a motorway impeding rapid progress to a successful conclusion. Documents submitted in approval applications should include not only data on product performance, but also on, for example, risk analysis and technical requirements, animal trials, biocompatibility, bio safety, drug expiry and package as well as software aspects. The review process takes into account whether the device is produced in China, requiring a Device Manufacturing Permit (DMP), or imported from abroad, either in part or as a whole. Domestic Chinese and international approval status is taken into account, as well as whether production takes place as a certified GMP process and, in the case of a drug, whether it already has an import license. Authorization is granted if already approved in the producer’s home country. It is less complex to introduce new products into the Chinese market if they are produced in China, specifically or mainly for the Chinese market. Failing that, products should, at least, be either clinically trialed in their country of origin or supported by data showing that a medical device is ‘substantially equivalent’ to those already produced in and, therefore, approved in China. The local agent submits the device at a medical device evaluation center for approved by the CFDA and at provincial FDA locations, as both these bodies are responsible for regulations and guidance. They may well request additional clinical trials if new first of its-kind devices are submitted. Producers should have a well-developed clinical strategy and have backing of, for instance, riskbenefit analyses by an ethics committee in the EU or an equivalent Institutional Review Board (IRB) in

the USA, which formally approves, monitors and reviews biomedical and research involving humans. The registration partner can encounter challenges during the approval process, such as substantial regulatory changes or newly introduced registration and certification requirements. It is therefore diligent to conduct gap analysis, to compare actual and desired performance, as a basis for timely corrective action. Information should be submitted in an easily understandable form and available in the appropriate local Chinese language at all levels. CFDA nationally and FDA at both provincial and city levels are involved with quality system inspection and post-market surveillance, the FDA city level for manufacturing site licensing. The entire process can be challenging as FDA officials are known to be inundated with drug and delivery device applications over past years. The CFDA receives over 10,000 new drug applications each year, but is limited by its review capacity of 5,000 to 6,000 pa. This has resulted in a backlog, estimated currently at around 21,000 submissions. The result is that foreign companies face potentially longer waiting times for approval than Chinese companies. In addition, approval times for new products can take longer than renewal approvals for existing products, some 20 percent or so longer for Class III devices and between 15-25 percent for new drugs and biologics (genetically-modified proteins derived from living entities).

Longer and more costly registration times may also be expected due to medical device classification in China according to CFDA’s Order Number 15 differing significantly from EU and US classifications. For example, a Class II device in the USA or a Class IIa/ IIb device in the EU could be considered Class III in China. Advertorial www.pharmafocusasia.com

This pressure on the regulatory and approval system is a development mainly as a result of the size and speed of growth of the Chinese healthcare market.

Variable Dosing Prospects Medical device research consultancy Quality Invention (QI LLC) was involved with Phillips-Medisize in injection device development. According to QI LLC, the consultancyâ&#x20AC;&#x2122;s prime goal is the design and development of medical devices to address combination product challenges in the pharma industry.

FDA offices are not only suffering from staff shortages thus increasing work load for officials, they are also required to cope with the decentralized regulatory structure, absence of a common IT infrastructure and a lack of consistent policies which hinder effective communication between the various FDA offices. There is also limited ability to track national and global databases for adverse events, unlike tracking procedures that have become well established in the EU and North America. Apart from CFDA and FDA offices, establishment of contacts and a local interface with the Centre for Medical Device Evaluation (CMDE), the Centre for Drug Evaluation (CDE) and the General Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ) are also advisable.

P h a rm a F o c u s A s i A a

ISSUE - 29 2017

The consultancy is headed by Dr Min Wei, a registered patent agent, who not only holds a PhD in Material Science, but also MSc qualifications in Polymer and Computer Sciences, supplemented by a Masterâ&#x20AC;&#x2122;s degree in Business Administration (MBA). Unlike variable-dose auto-injectors, Wei points out that fixed-dose auto-injectors do not address individual personalized medication needs for multiple doses, fail to meet different dosing needs of adults and children, present challenges to registration and compliance as combination products (combination of the drug and its delivery device), and are expensive if integrated into adaptive clinical trials. More usability data can be collected in clinical trials with variable-dose auto-injectors and they have greater dosing accuracy than conventional vial and syringe dosing. He states that variable-dose auto-injectors can be easily adopted for use with medicines that are already available in graduated pre-filled syringes, enabling a smooth transition into variable dosing for both patients and their doctors and other medical staff. According to Wei, the medicines so far available in this form and already administered in millions of units per year are Epoetin alfa (Epogen), Filgrastim (Neupogen), Enoxaparin sodium (Lovenox) and Methotrexate. But Relistor, Sumatriptan succinate, Invega, Stelara, Procrit and Humira are additional medicines calling for variable dosing and which could also be efficiently

dosed by a variable does injector. Wei adds that many more are in the pipeline. Due to greater fear of injections than adults, children (pediatric patients) have the greatest need for variable dosing, the quantity being determined by body weight or surface area. Phillips-Medisize is of the opinion that there is evidence that adaptive clinical trials (CTs), those where multiple formulations can be evaluated and where there is a prospect of modification later on in the trial. They are gaining in popularity, as they shorten study duration and reduce costs, improve chances of success, and are ethically superior. Most importantly, PhillipsMedisize maintains that variable-dose auto-injectors provide the flexibility to run adaptive CTs without design modifications or in excessive production quantities. The company illustrates this with an example where a CT with a variable-dose auto-injector can reduce drug quantity needed by a factor of seven, compared to running the CT with fixed dosing, resulting in estimated cost savings of $12 million, based on seven doses per week over 52 weeks, with 400 patients, and assuming a $100 preparation cost for each CT drug unit. He refers to data in a report by K. Spenceret and others in the Journal of Diabetes Science & Technology; issue 6:1296, 2012.

Typical Auto-Injector Design

Phillips-Medisize points out that such pens can be designed as a platform that enables 1mL long or 2.25mL variable-dose auto-injectors to be easily transformed into fixed-dose disposable and fixed-dose reusable versions without complete redesign, as the housing and many other components are identical across the entire platform, also when, for instance, a fixed-dose auto-injector is supplied with a connectivity function. This means that different types of auto-injectors can be produced on one assembly line. By gaining in-depth knowledge of the countryâ&#x20AC;&#x2122;s regulatory procedures, an organization can leverage this experience to both advance its product and to create a stable foundation for a global expansion strategy in China and beyond. This means that proven success in China serves as a valuable marketing tool and the experience and knowledge can be invaluable for medical device manufacturers when entering other countries across the globe. The Chinese medical device market was recently valued at $27.7 billion and is projected to grow to an estimated $50.8 billion in 2020. Given the growth in medical device sales and the predicted rise in population in China at a rapid pace, this is undoubtedly a market that medical device companies are keen to enter in order to take advantage of the obvious and exciting opportunities.

A typical variable-dose auto-injector is a graduated pre-filled syringe, which can be seen by the user via a viewing window in the pen housing. The user rotates a dialing cap on the top of the pen, so that it moves along a dosing scale marked on the pen body for the correct dose required. The user then removes the bottom cap and needle shield, removing the dialing cap to expose the actuation button, before placing the bottom of the injector against the area to be injected. Pressing the actuation button then triggers auto-injection. When the pen is removed from the injected area the user is required to replace the needle shield, or sharps cover, for safety reasons.

A u t h o r BIO

Bill Welch has over 25 years of contract design, development and manufacturing experience, primarily serving customers in the drug delivery, health technology and diagnostics markets. In his current capacity as Chief Technical Officer at Phillips-Medisize, he leads a global, over-600 person development, engineering, tooling, programme management and validation organisation. Bill has been with Phillips-Medisize since 2002.

Advertorial www.pharmafocusasia.com

COVER STORY

Strategy

The Human-Centred Biopharma Organisation The biopharmaceutical industry is in continual change. Increased competition and diversity in business models creates a leadership challenge of sustaining growth and performance. To address this challenge, we outline a focus on Human Centred Organisations, with Leaders creating meaningful and engaged work environments to maximise performance sustainably. Andrew A Parsons, Reciprocal Minds Limited Susan M Cruse, Leadership Mastery Limited

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Strategy

o maximise performance, it is time to put the human in the centre of the complex, multicultural and dispersed ecosystem of biopharma innovation.

The Challenge of Sustainable Growth - The Current Scenario

The pharmaceutical industry has changed dramatically over the past 10 years. Despite a range of merger and acquisitions within large companies, the industry has grown in the number of companies selling products within the market. Comparing 2003 to 2015, the global industry has grown 41per cent in terms of revenue, 53 per cent in terms of R&D spend with a 100 per cent increase in clinical projects. Organisationally, the dispersed nature of the sector supports increased number of deals resulting in merger and acquisitions or IPO. The industry is therefore becoming increasingly fragmented and competitive in terms of revenue and organisational autonomy. Against this backdrop of increased fragmentation, it is apparent that successful projects and products remain elusive. The cost of development and easy access to medicines is a persistent issue that regulatory agencies and industry professionals are increasingly aware. There is an inherent tension within the system between the high levels of failure, the costs involved in development and commercialisation and the needs of public and private healthcare providers. Big Pharma has consequently adapted its strategy with wider global networks of research and development across hubs and a focus on the emerging markets. The

www.pharmafocusasia.com

Strategy

dispersed and global nature of the business has resulted in reductions within the knowledge base of discrete organisations and a drive to collaborate and gain expertise and know how from collaborators. A recent academic review highlighted key areas of collaboration including sharing and learning at organisational and team levels, and access to infrastructure and management expertise with appropriate governance control points of projects. These macro level changes in the pharma sector are evidence of some dramatic changes in operational business models. The days of large fully integrated pharmaceutical companies with depth and breadth of R&D projects and finances appear long gone. No doubt the model will continue to develop further over the next 10 years. The Leadership Challenge

At a more specific or micro level of leaders and managers within individual companies, these macro level changes create some difficult challenges. Some key issues include how to create impact in decision making when you may work virtually or remotely? How to ensure effective and efficient communications

across cultural boundaries and how to create engaged and productive teams and collaborations? There are no simple answers to these questions. We often focus on how to better use technologies and information. However, there are other approaches commonly used to ensure the most productive interface between people and what they do. In this article, we aim to raise awareness of human factor approaches and outline some pull and push approaches to ensure people can operate at their best, especially in the fast paced, multicultural, and global biopharma industry of today. What are Human Factors?

Human factors encompass a professional science often known as ergonomics. It relates to the understanding of interactions among humans and other elements of a system. Human factors research has been applied across highhazard sectors to develop safe practices that not only anticipate, but also mitigate, human error. Within the U.K. NHS, the importance of human factors has been highlighted and identified as an avenue for collaboration between disciplines providing key benefits in

the utilisation of people, their needs and containing costs. Human-Centred Organisations

In 2016, some guiding principles were developed by the International Standards Organisation (ISO) for developing human centred organisations. Part of the rationale for developing this standard was the recognition that human well-being is an important measure to complement the traditional measures of output. The standard, ISO 27500, is not an operational standard but highlights the principles, values, and beliefs that make organisations human centred. The standard draws on a wealth of ergonomic and human factor design principles that are known to be successful across a range of organisational structures from large to small private or public organisations. Seven principles were identified that characterise a humancentred organisation that encompass individual perspectives, usability of products and systems, and social responsibility that includes being trustworthy. Through efforts based on a systems approach encompassing human factors these principles are known to make significant contributions to overall productivity. Engaging a Diverse Multi-National, and Multi-Cultural Workforce

Comparing 2003 to 2015, the global industry has grown 41per cent in terms of revenue, 53 per cent in terms of R&D spend with a 100 per cent increase in clinical projects.

We suggest at least two of these principles have high relevance to the complex, multidimensional, and fastpaced world of the biopharmaceutical sector that operates across multiple organisational and cultural boundaries. Attention to the principles of ensuring individual differences is an organisational strength and valuing employees to create a meaningful work environment will have positive impact in a multicultural environment. Create a Meaningful Work Environment that Values Employees â&#x20AC;&#x201C; the Engaged Workforce

It is important to remember that people deliver on organisational objectives 20

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Strategy

Disengaged

Engaged

Leader The Lens of Culture Leadership Effectiveness The Lens of Culture

Team The Lens of Culture Team Effectiveness

Productivity Figure 1 The impact of engagement and dis-engagement on Leader and Team Behaviour. Awareness of multicultural dimensions is key

and utilise their skills and capabilities to adapt to a variety of situations. Not surprisingly, therefore, there is evidence that indicators of worker wellbeing are linked to performance. Meaningful work supports not only our wellbeing but also our engagement and absorption into the work that we do. These are essential ingredients for releasing the creativity of research and development scientists to bring new products into the market. Innovation in both developing new products and processes requires individuals who are engaged and confident within their roles. Innovation is hampered by stress and distraction, particularly by the distraction of leadership when it is inconsistent,

irresponsible, excluding, silent, and by the distraction of conflict or lack of connection and understanding between individuals. It is supported by tuning into the bigger picture the benefits to those who use our products; in other words, each seeing the value of their contribution and how their work makes a difference. Within the healthcare industry, our ultimate endgame is to improve human health through whatever aspect our work may involve. However, it is perhaps too simplistic to assume these links drive a meaningful work place. For front-line medical Staff there is a risk of compassion fatigue and burnout often related to workplace stress.

A human-centred approach would suggest that the balance needs to be struck between financial rewards and the meaning the work brings to the individual in terms of their own sense of being and what matters most to them. Creating the right blend of performance measures that are linked to the ultimate patient value will provide transparency in decision making. Organisations make work meaningful by: • Identifying the meaning • Expressing the meaning • Living by the meaning (all efforts aligned to it) • Repeating it often www.pharmafocusasia.com

Strategy

Human factors also indicate that people work best when they are valued and feel included in the workplace. This has an important aspect in the biopharmaceutical world of the 21st Century. With so many enterprises working across wide cultural and organisational boundaries, the industry is one of collaboration and partnerships. To get the best from these collaborative networks, the individuals need to feel valued, that they have a voice and are invited to use it, and that they contribute to meaningful goals. Failure to satisfy these basic human factors creates a risk that the performance of the teams becomes transactional, adhering to the status quo and focussed on intermediate goals. Figure1 outlines the influence of engagement and disengagement of leaders and their staff on their own and their teamâ&#x20AC;&#x2122;s performance. Supportive leaders develop human centred and 22

P h a rm a F o c u s A s i a

ISSUE - 29 2017

holistic approaches that significantly modify team behaviours. Measures of Engagement

The difficult aspect of working with people across the multidimensional matrices involved in biopharmaceutical innovation include how to measure the engagement of individuals, and how their experience of work relates to how they feel. A variety of methods are present to measure work engagement, and are all self-reported measures. Engagement is an experiential state, an experience that is very personal to the individual involved and covers many aspects of thoughts, feelings and autonomy. Individuals are engaged when they experience their work as being part of something with colleagues they trust. The converse of engagement relates to high levels of work place stress and an absence of absorption in work. Dis-engagement

can limit performance of leaders and impact their teams. Leaders need to be trusted and engender trust between their colleagues. Much research has been undertaken in this area but some early work provides some simple rules that openness / congruity in actions of leaders, having shared values and understanding the limits of decision making with feedback provide a guide that appears relevant to the complex multi-organisational and cultural biopharma ecosystem. Individual Differences are an Organisational Strength

A recommended Human-Centred principle is to see individual differences as an organisational strength. There are no â&#x20AC;&#x2DC;standard personsâ&#x20AC;&#x2122;. An ergonomic approach takes into consideration the whole, allowing multiple viewpoints and create environments that support a range of body types and social networks.

WE CARE & CONNECT YOUR PHARMA

www.pharmafocusasia.com

Strategy

Push and Pull Approaches to Ensure Human-Centred Leadership

Many industries have embraced ergonomic approaches to ensure critical performance. This is especially so in the case of high hazard industries such as the nuclear and aviation industries. Within these areas, a focus on safety is also a key property of the sector. Perhaps it is time to learn from professional ergonomists / human factor professionals in creating systems that enable performance across the complexity of the biopharma industry? As the industry continues to fragment and disperse, the tacit knowledge that resides in the experience of skilled professionals is likely to be lost. Drug discovery is a socio-technical enterprise that crosses the boundaries of hard experimental data and a huge range of uncertainties regarding prediction of ultimate clinical safety and efficacy and value. This system has some similarities with other high technology industries that span the divide between hard empirical observations and the human perspective. A recent development in engineering systems to allow appropriate control of safety aspects in these sociotechnical enterprises has been proposed. Approaches such as these may well provide the appropriate risk management infrastructure—the pull—to ensure appropriate performance. In this context, we suggest push approaches are based on building individual skills and an infrastructure to create feedback and learning. Challenges of mental health issues related to work place stress are becoming apparent in many cultures. Whereas a engaged workplace facilitates performance, prolonged periods of stress can have significant negative effects. Salutogeneis is a concept developed by Aaron Antonovsky that focuses on an individual’s ability and resources to promote health rather than on treatment or managing risks. This approach 24

P h a rm a F o c u s A s i a

ISSUE - 29 2017

is widely used in public health and seems appropriate in the workplace setting. The key elements of a salutogenic approach are the ability to develop and utilise general resources of wellbeing and maintain a problem solving orientation through a sense of coherence and meaning. Developing general resources across a multicultural workforce requires a focus on the individual. Building on psychosocial approaches provides an individual framework to work cohesively within the community. Several areas of individual skill modelling are appropriate within the salutogenic approach to build engagement and include the five factors of wellbeing, building mindfulness skills and being in flow are part of being actively and attentive. A recent model also highlights individual skills to enable presence with self and others as a leader. Push programmes to enable engagement across multicultural boundaries should focus on the following areas to maximise value to the individual and organisation • Mindfulness/paying attention • Managing emotions • Building self-awareness of values, beliefs, and meaning • Solution focus Conclusions

A focus on how people interact with their work is an established scientific discipline that has been widely used

A u t h o r BIO

This is perhaps even more important in the multi-cultural and global nature of business today.

in other safety-critical industries. The international standards organisation has developed a series of principles to support orientation of work activities at a board level to ensure that companies develop appropriate working practices to maximise their performance. We suggest that in the fast paced, multicultural, and dispersed biopharma industry today these principles are critical to the success of the socio-technical endeavour of Pharmaceutical R&D. All these principles are important and we suggest an initial starting point would be to focus on the level of employee engagement across the system to ensure adherence to principles relating to diversity and meaning in the workplace. The opportunities presented in the biopharmaceutical business sector can provide significant value to everyone involved — from investors to customers. Adopting a push and pull approach to what is done is essential to maximise performance. A humanCentred experiential learning process to develop leaders, managers, and employees is also an essential prerequisite for success. Paying attention to the ‘human’ will enable solutions to be developed for the essential leadership challenges mentioned above. References are available at www.pharmafocusasia.com

Andrew A Parsons PhD has worked in Biopharma in a variety of Senior Executive and Non-Executive Roles. Initially trained in Pharmacology and Neuroscience he worked in External Innovation to maximise performance across organisational and cultural boundaries. He is an accredited coach and has interests in systems design.

Sue Cruse has extensive experience as a leader and as a coach, working at senior levels across a range of sectors and organisations. She has led building energy, resilience and resourcefulness, across an employee population, to support sustainable high performance. An accredited Executive Coach with an MSc in Behavioural Change.

Exclusive 10% Discount for PharmaFocusAsia subscribers. Please use the code MPM17PFA to avail the discount.

Some Key Speakers Bahaa Aboud, National Operation Manager, Tamer Group, KSA

Dr. Bassam M. Alwon, Director, Establishments Inspection Saudi Food & Drug Authority Department, Drug Sector, SFDA, KSA

Faisal Dail, General Manager, AJA Pharmaceutical IndustriesCo. KSA

Mohamed Al Rifai, Quality Operations Senior Manager, Pfizer, KSA

Salah Alkowaiter, Director of Quality and Compliance, SPIMACO, KSA

Suleiman Aldajeh, Head of Research & Development, SAJA Pharmaceuticals, KSA

Wasif Azeem, Director Quality Operations, Jamjoom Pharma

Andrew East, Production and Engineering Director, ARABIO, KSA

Key Benefits of Attending • Meet with key local, regional, and international pharmaceuticals manufacturers • Learn about the latest technologies used in pharma manufacturing • Hear from leaders and key decision makers about strategic visions and initiatives for the industry • Understand the level of collaboration between the different stakeholders to advance the pharma market in the region • Gain insights about the latest global technical and operational trends • Network with your peers from the industry • Get CME credits and boost your career SUPPORTED BY

AN INITIATIVE BY

MEDIA PARTNERS

+971 4 361 9616

For more information or to register, contact us at info@pharmamanufacturingmena.com or visit www.pharmamanufacturingmena.com

Clinical TriAls

Patient Recruitment in Asia Reducing the clinical burden Innovations in patient recruitment coupled with thoughtful local implementation are a step forward in our relentless pursuit to simplify the patient journey. David Yoshii, Senior Director Global Site Solutions PAREXEL International

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Clinical TriAls

oday, there are many innovative, new approaches to patient recruitment and the number continues to grow. The driver behind these innovations is the challenge that many western countries face in recruiting patients for participation in clinical studies. The concept of patient recruitment is quite simple. It involves recruiting the right patients, at the right time, and in the right numbers. However, we encounter hurdles in applying a ‘one size fits all’ approach for these innovations, and to ensure successful enrolment, the recruitment tactics should consider local needs and challenges.

Challenges for Different Geographies

In Asia, there are challenges unique to the region for clinical trial recruitment, compared to the western world. For example, in China with a population of 1.4 billion people, the shortage is not in patients, but in site staff capable and experienced at delivering quality clinical trial results. On October 8 this year, the China Food and Drug Agency (CFDA) announced a new site certification process. Hospitals are now able to self-register as a clinical trial site, with the responsibility for qualifying such sites lying with the study sponsors. As a result, the

number of clinical sites is expected to rapidly increase within the next few years. For the coming wave of new sites in China, strong partnerships/ collaborations with investigators and sites that enable them to deliver will be a key factor for success. In Japan, the challenges are different, and more similar to western countries. There is more competition for a limited patient pool and the population is shrinking. Frustration with the limitations to the current approaches is creating a market that is more and more open to new ideas. Datadriven feasibility is just beginning to gain acceptance and patientcentric approaches are also attracting attention. Such an environment requires innovative approaches and strategies, which are tailored to these markets. Keys to Innovation

Innovations can come in the form of products and process improvements. Global innovation coupled with thoughtful local implementation is essential to succeed. To accomplish this, one needs to hire and develop the right talent, and work with the right partners, to foster innovations, develop them, and subsequently implement them in the best possible way. Local implementation of patient recruitment innovation requires knowledge of not only the challenges, but also the needs of the specific markets. Proof Point: National Cancer Centre Singapore (NCCS)

In 2016, BMC Women’s Health published a study1 titled “Barriers and facilitators for clinical trial participation among diverse Asian patients with breast cancer: a qualitative study.” The study was conducted in the NCCS, which treats 75 per cent of cancer patients in Singapore and has a yearly outpatient 1 https://bmcwomenshealth.biomedcentral.com/ articles/10.1186/s12905-016-0319-1

www.pharmafocusasia.com

Clinical TriAls

attendance of more than 130,000. In this study, various focus groups studied females over the age of 21 with breast cancer, who were able to provide informed consent and attend the focus group by themselves. The study examined the factors that influence patient recruitment into clinical trials in Asia, each factor showcasing an area of clinical trial recruitment with the potential to lessen the patient burden and improve the overall experience. These were found to include: 1. Knowledge and Attitude: Several patients in the study said they had not heard of the term “clinical trial,” and many that had heard of the term were previously or currently enrolled in 28

P h a rm a F o c u s A s i a

ISSUE - 29 2017

one. This lack of familiarity would be a potential hurdle for recruiters, because patients would be less likely to seek out clinical trials if they had no concept of their existence. However, it turned out that 80 per cent of the participants asked for more information about clinical trials, showing that there is a desire for information, but inadequate means to obtain it. 2. Reasons to Join: This study highlighted the individual, medical and societal factors affecting the patient’s decision to participate in clinical trials. One deciding factor for some of the women in the study was how the study was introduced to them. The women preferred and were more trusting of

studies that were introduced to them by their doctors–highlighting the need for clinical trials to work with local institutions and within the local Asian community to target potential patients. 3. Relaying the Information: Another important take away from the study is that many participants said simpler language and visual aids, such as recordings and pictures should be used to relay the ICFs (Informed Consent Forms) and other information regarding clinical trials – including promotion of other clinical trials. Recruiters need to simplify the information and tailor it to audiences to make it easier for the patient to understand.

Clinical TriAls

Needs of Specific Markets: Getting the Word Out

Needs of Specific Markets: The Clinical Site

Investigator sites are critical to the success of any clinical trial. PAREXEL alone has value-driven partnerships with hundreds of clinical sites across the world, of which one in four sites are located in Asia, to support drug development for our clients’ investigational medicinal products. These sites, located in Japan, China, Korea, Taiwan, and in key countries throughout the rest of Asia, provide a means for patients to not only access innovative, new therapies, but have an improved clinical trial experience. Creating these partnerships in Asia is especially important for trial participation and diversity, as shown by the FDA in the 2015-2016 Global Participation in Clinical Trials Report where the majority of Asian trial participants in global studies were at non-US sites. Identifying the right sites isn’t easy. Data-driven feasibility is an approach to support site selection. Unfortunately, it is highly dependent on the robustness of the data being employed. For some

Local implementation of patient recruitment innovation requires knowledge of not only the challenges, but also the needs of the specific markets.

countries, historical data is sometimes scarce, depending on the indication or drug’s mechanism of action. This entails augmentation, which requires tailoring the approach to what is optimal in the specific country. In Japan and China, collaborating with Site Management Organisations (SMOs) that provide study nurse dispatch services to clinical sites has proven effective, in addition to other country-specific approaches. Needs of Specific Markets: Relaying the Information

Patient recruitment doesn’t end with identifying the patient, but requires the patient to consent to participate in the clinical trial. For the patient to give consent, they must first have a comprehensive understanding of the study. Some tools on the market try to make this information easily digestible with the use of animation to provide the patient with an overview of the study and related information – these tools are

A u t h o r BIO

The study conducted by BMC Women’s Health shows there is an opportunity to improve how we approach clinical trials. The industry is rapidly embracing patient centric methodologies, as a means to improve the patient experience, with the potential to improve recruitment rates, increase compliance with study procedures and reduce withdrawals. Increasingly technologies such as “web listening” are being employed to more accurately analyse the sentiment of patients and caregivers, as well as identify key influencers related to a specific indication. For Asia, this requires adapting technology for local languages, as well as differences in social media preferences. This approach allows companies to fine tune their approaches to provide valuable information about the disease, therapies, as well as the availability of clinical trials.

being actively used in China, Taiwan, Korea, and Japan. Such tools are often tailored culturally with voice overs in the local language and with animation that not only appeals to young children, but also adults and elderly patients, due to the ease of comprehension. There have already been increased trial consent rates, improved compliance /retention and shortened recruitment timelines in the studies where these tools have been implemented. An important factor is ensuring that the animation is culture agnostic and therefore acceptable in these very particular markets, and the simplicity of implementation is important to meet the needs of highly variable site environments. Reflections

Approaches for patient recruitment must have one thing in common: they must make things simpler for the patient. Participating in a clinical trial is filled with anxiety and uncertainties, especially coupled with existing challenges from the underlying disease. Reducing the anxiety and clinical trial burden are obvious steps to make things simpler for the patient. The industry has decades and decades of experience in running clinical trials. However, as treatments continue to evolve, there is a need to advance the way we run the clinical trials, to not only provide evidence of efficacy and safety, but to also gain further insights into how we can provide additional value for patients and investigator sites. Innovations in patient recruitment coupled with thoughtful local implementation are a step forward in our relentless pursuit to simplify the patient journey.

David Yoshii is the Senior Director for Global Site Solutions, covering feasibility, patient recruitment, site alliances, and other site related strategies for clients at PAREXEL International. His career spans over 20 years in drug development in various global leadership roles. He joined PAREXEL in 2011.

www.pharmafocusasia.com

Clinical Trails

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Clinical TriAls

Low Rates of Stroke and Major Bleeding with Rivaroxaban Confirmed by Global Study XANTUS pooled results study

Landmark global XANTUS real-world programme showed low rates of stroke and major bleeding of 0.9 per cent and 1.7 per cent per year respectively with rivaroxaban, generally consistent with Phase III Rocket AF trial. John Battersby, Medical Writer, Bridges Publishing Pte Ltd

esults of the pooled analysis of the global XANTUS realworld study programme were announced recently at the European Society of Cardiology (ESC) Congress in Barcelona, Spain. The study investigated the use of the non-vitamin K antagonist oral anticoagulant (NOAC) rivaroxaban for stroke prevention in patients with non-valvular Atrial Fibrillation (AF) (irregular heart beat). The study showed low rates of both stroke and major bleeding, including fatal intracranial (skull) bleeds in AF patients on XareltoÂŽ for stroke prevention. The majority (96.1 per cent) of the pooled XANTUS population did not experience stroke / systemic embolism, major

bleeding and all-cause death. This is generally consistent with the Phase III ROCKET AF trial and reaffirms the safety and efficacy of rivaroxaban in AF management. The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF. This pooled analysis combined real-world data from three prospective, single-arm, multi-centre studies across multiple regions, which together followed more than 11,000 patients from 47 countries: 1. XANTUS, the largest of the studies, which followed 6,784 patients from Canada, Israel and 10 countries across Europe. www.pharmafocusasia.com

Clinical TriAls

2. XANAP, the first Pan-Asian realworld study of rivaroxaban in AF stroke prevention, which followed 2,273 patients from 10 countries / territories in Asia (Hong Kong SAR, Indonesia, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, Vietnam and Pakistan). 3. XANTUS-EL which involved 2,101 patients from 17 countries in Eastern Europe, Middle East, Africa, and Latin America. Unmet Needs in Atrial Fibrillation (AF)

AF is a heart condition characterised by irregular heartbeats which increases the risk of stroke caused by blood clots by five-fold. Strokes due to AF are also more severe, causing disability in over 50 per cent of patients and generally worse outcomes than strokes due to other causes. The incidence of AF increases with age. The prevalence of AF is a global issue with the number of AF patients growing rapidly and expected to have doubled by 2050. AF is especially of concern in Asia due the regions rapidly ageing populations. It is estimated that by 2050, Asia will have 72 million AF patients, and 2.9 million among them will suffer from an AF-associated stroke. The good news is AF-related strokes can be prevented. However, there is still a significant number of AF patients in Asia not receiving optimal anticoagulant therapy for stroke prevention. Older anticoagulant therapy with Vitamin K Antagonist (VKAs) such as warfarin makes effective anticoagulation harder for patients and physicians due to its manifold food and drug interactions, regular blood monitoring requirements and risk of intracranial (skull) bleeding. These serious disadvantages cause VKAs to be under-used or under-dosed in AF stroke prevention, leaving patients unprotected. “NOACs like rivaroxaban can potentially address this medical challenge as they are at least as effective 32

P h a rm a F o c u s A s i a

ISSUE - 29 2017

as traditional warfarin therapy in preventing strokes in AF patients, but are easier to administer and carry a significantly lower risk of the lifethreatening intracranial bleeding,” said Professor John Camm, the Professor of Clinical Cardiology at St George’s University of London who presented the results at ESC. “While this has been well proven in clinical trials and real-world studies, the consistency of the combined data from the worldwide XANTUS programme adds significantly to our understanding on the safety of NOACs in AF patients, and gives physicians the confidence to prescribe rivaroxaban in daily clinical practice.”

The Studies

In the XANTUS pooled analysis, a total of 11,121 patients were enrolled into the three real-world studies and included in the analysis. Patients were from 47 countries in Western Europe / Canada/ Israel (47.5 per cent), Eastern Europe (23.2 per cent), East Asia (20.1per cent), the Middle East/Africa (6.2 per cent) and Latin America (3.0 per cent). The majority of patients (73.1per cent) initially received rivaroxaban 20mg once daily, while 25.1 per cent, 1.6 per cent and 0.2 per cent of patients received rivaroxaban 15mg once daily, 10mg once daily and other doses, respectively. There were differences in patient demographics,

Clinical TriAls

experience stroke / systemic embolism, major bleeding, and all-cause death.

The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF.

clinical characteristics as well as stroke and bleeding risks among the study regions. Patients with higher CHADS2 (stroke risk) or CHA2DS2-VASc (bleeding risk) scores at baseline were more likely to experience major bleeding, stroke /systemic embolism or death. Results from XANTUS pooled population showed low rates of both stroke and major bleeding with rivaroxaban at 0.9 per cent and 1.7per cent per year respectively, generally consistent with those in the ROCKET AF trial. Mean CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores for the pooled population were 2.0 and 3.5 respectively.

The findings were generally consistent across different regions and patient populations worldwide based on each of the individual studies. In XANAP, the Asian arm of XANTUS programme, the rates of both stroke and major bleeding were low at 1.7 per cent and 1.5 per cent respectively, generally consistent with Phase III ROCKET AF East Asia study and two other studies in the programme. CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores in XANAP were 2.3 and 3.7 respectively, higher than the mean scores of the XANTUS pooled population The majority (96.6 per cent) of patients on rivaroxaban in the study did not

About XANTUS Pooled Analysis

This is a pre-planned pooled analysis of the prospective, observational XANTUS, XANAP and XANTUS-EL studies of unselected patients with AF newly starting rivaroxaban for stroke prevention. Patients were followed for 1 year, at ~3-month intervals, or for ≥30 days after permanent discontinuation. Primary outcomes were major bleeding, Adverse Events (AEs) or Serious AEs (SAEs) and all-cause mortality. Secondary outcomes included symptomatic thromboembolic events and non-major bleeding. Treatment-emergent major outcomes were adjudicated by a central committee. 11,121 patients were included (Western Europe/Canada/ Israel: 47.5per cent; Eastern Europe: 23.2 per cent; East Asia: 20.1 per cent; Middle East and Africa: 6.2per cent; and Latin America: 3per cent). Of the patients 73.1per cent received rivaroxaban 20mg once daily (od) and 25.1per cent rivaroxaban 15mg (od); 72.4per cent had prior anticoagulation therapy. Mean age was 70.5 years and mean weight was 80.0kg.Co-morbidities included congestive heart failure (21.2per cent), hypertension (76.2per cent), diabetes mellitus (22.3per cent), prior stroke/non-central nervous system (CNS) systemic embolism (SE)/transient ischaemic attack (TIA; 21.3per cent) and prior myocardial infarction (MI; 8.9per cent). Rates of treatment-emergent major outcomes were: major bleeding 1.7 (1.5–2.0); all-cause mortality 1.9 (1.6–2.2); stroke/non-CNS SE 1.0 (0.8–1.2); stroke 0.9 (0.7–1.1). About XANAP

XANAPis the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia (Hong Kong SAR, Indonesia, South Korea, Malaysia, Philippines, www.pharmafocusasia.com

Clinical TriAls

P h a rm a F o c u s A s i a

ISSUE - 29 2017

XANAP is the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia.

Society of Cardiology (ESC). It is stated that NOACs offer better efficacy, safety and convenience compared with VKAs. NOACs are broadly preferable to VKAs in the vast majority of patients with AF. About Rivaroxaban

Rivaroxaban is the world’s most widely prescribed NOAC that has been prescribed to 31 million patients worldwide and more than 3 million patients in Asia-Pacific for the management of blood clots in seven distinct indications, including stroke prevention in AF. Rivaroxaban is also the most broadly indicated NOAC, approved for seven indications, protecting patients across more venous and arterial thromboembolic conditions than any other NOAC:

A u t h o r BIO

Singapore, Taiwan, Thailand, Vietnam and Pakistan) in routine clinical practice. All treatment and dosing decisions were at the discretion of the treating physicians and patients were followed up for one year or until 30 days after premature discontinuation. Bleeding events and major thromboembolic events were centrally adjudicated by an independent committee. At the end of the study, the majority (96.6 per cent) of patients on rivaroxaban did not experience stroke / systemic embolism, treatmentemergent major bleeding, and all-cause death. Overall, patients experienced treatment-emergent major bleeding at a rate of 1.5 per 100 patient-years (1.5 per cent per year); most of these major bleeds were treated using standard clinical measures. Rates of fatal bleeding were 0.2 per 100 patient-years 0.2 per cent per year). Critical organ bleeding occurred at a rate of 0.8 per 100 patient-years (0.8 per cent per year), which included intracranial bleeding at a rate of 0.7 per 100 patient-years (0.7 per cent per year). Stroke occurred at a rate of 1.7 per 100 patient-years (1.7per cent per year). The analyses from this study provide valuable insights on the usage of rivaroxaban by patients in Asia for non-valvular AF stroke prevention. “Strokes in AF patients are highly preventable. These robust findings further support rivaroxaban as a therapy of choice for stroke prevention in AF patients, with a low rate of major bleeding,” said Dr Foo Chuan Kit, Head of Medical Affairs of Bayer Pharmaceuticals Division for AsiaPacific. “By involving Asian patients in this worldwide programme, we offer valuable insights to help physicians in the region safely and effectively lower the risk of stroke in their AF patients.” Latest ESC Guidelines NOACs are recommended as first-line anticoagulants in the prevention of AF-associated stroke in the latest international guidelines for the management of AF by the European

John has been science and technical writer for many years and has focused on medical and healthcare issues for more than a decade. He has spent the last 20 years in South East Asia, mainly based in Singapore, working as a freelance journalist and media adviser to the pharmaceutical industry.

1.The prevention of stroke and systemic embolism in adult patients with non-valvular AF with one or more risk factors 2.The treatment of Deep Vein Thrombosis (DVT) in adults 3.The treatment of Pulmonary Embolism (PE) in adults 4.The prevention of recurrent DVT and PE in adults 5.The prevention of Venous Thromboembolism (VTE) in adult patients under going elective hip replacement surgery 6. The prevention of VTE in adult patients undergoing elective knee replacement surgery 7. The prevention of atherothrombotic events (cardiovascular death, myocardial infarction or stroke) after an Acute Coronary Syndrome (ACS) in adult patients with elevated cardiac biomarkers and no prior stroke or transient ischaemic attack when co-administered with acetylsalicylic acid (ASA) alone or with ASA plusclopidogrel or ticlopidine. While regulatory approvals may differ from country to country, across all indications, rivaroxaban is approved in more than 130 countries. References are available at www. pharmafocusasia.com

The International Medical Marketplace & Expo with Life Sciences & Pharmaceuticals Media Sponsors

IMMEXLS

Ingredients/ Packaging

To Attend/Exhibit go to www.ImmexLS.com or ian@immexls.com or(941)320-3216

www.ImmexLS.com

Pharmaceutical

Lifesciences &

and Expo with

Medical Marketplace

The International

Acquire New Business

October 23-24, 2018, Miami, Florida USA

Miami, Florida... The Gateway to Latin America, the Caribbean and the World

Make Valuable Connections

Clinical TriAls

Wearables in Clinical Trials

Where we are & where we are going As real world evidence becomes an integral part for many clinical trials, wearables allow for monitoring and data collection anywhere the patient is located â&#x20AC;&#x201C; freeing researchers of the location barrier of real world evidence. Xavier Flinois, President, PAREXEL Informatics

ith the demand for wearables and sensors in clinical trials on the rise, pharmaceutical companies are increasingly faced with the challenges of both rising costs and market saturation of similar drugs â&#x20AC;&#x201C; and that is where Clinical Research Organisations (CROs) come into play. From both a technology perspective and a processes perspective, CROs can leverage remote medical devices, unleashing an opportunity to collect novel endpoints and supplemental data that may improve the regulatory case. This also opens the door for CROs to make the case for reimbursement more 36

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Clinical TriAls

compelling, open up trial participation to a wider population and/or reduce site visits for patients who may not live close to an investigative site. Although medical devices like spirometers and activity monitors have been used in clinical trials for almost a decade, modern wearable technology is improving the patient experience and lessening the data management burden. Outdated spirometers or activity monitors had to be transported back to the clinical site, where the data was then transcribed into an Electronic Data Capture (EDC) system, and downloaded – a process prone to transcription and human errors. Now wearables are more scalable and allow clinical sites to digitally collect the information without transporting or transcribing. These updates improve both trial efficiency and data accuracy. Regulating Medical Devices

The use of medical devices for study endpoints has yet to receive regulatory guidance, but at a Drug Information Association Meeting in December 2016, the Federal Drug Administration (FDA) expressed cautious optimism that these devices could provide better and more timely insight into a patient’s health status. FDA speakers went so far as to say that researchers need not necessarily use medical devices with a 510(k) approval or CE stamp; consumer grade devices can be used as long as they are ‘fit for purpose.’ As regulators and drug companies accept the use of wearables, medical devices will play a more prominent role in clinical trial data collection, particularly in Phase II and III trials. Wearables by Phase: Phase I

With the initial influx of information gathering in Phase I, wearables fit well into the protocol of the early clinical stage. One instance of this was a trial that added remote sensors into Phase I. The objective of adding this technology was to both pilot the new sensors as well as to compare the sensor data to

Effective medical device use requires best-in-class medical, HEOR, biostatistics, logistics, technology and clinical trial conduct capabilities.

to receive large numbers of combination products for review as technological advances continue to merge product types and blur the historical lines of separation between FDA’s medical product centers, which are made up of the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH).”11 Wearables by Phase: Phase IV

the in-clinic data for a diabetes trial. With successful collaboration, the trial facilitators were able to produce a trial design that minimised the impact on the core protocol while maximising the number of devices. In all, six remote medical devices were added to the study –spirometer, blood pressure, pulse oximeter, blood glucose monitor, weight scale and activity monitor. Site and subject acceptance was high. It is expected that Sponsors developing new biologics where the benefit is best measured by sensors and/or where sensors provide valuable health status information to subjects, will begin piloting the applicable sensors in Phase I in parallel to their first in human clinical trials. Wearables by Phase: Phase II-III

Because of the lack of regulatory guidance, the validated use of specific mobile health devices to deliver primary endpoint data is expected over the next 12–24 months. In Phase II and III trials, clinical trial sponsors will likely use medical devices as exploratory endpoints to mature their understanding of the utility of sensorbased endpoints. For some disorders, medical devices will be used across all phases as combination products. According to the FDA, “Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. FDA expects

The growing demand for wearables in clinical trials is also being seen in Phase IV studies. The post-marketing demands and remote connectivity make wearables an ideal Phase IV component. Sponsors have the opportunity to make a strong case to regulators, especially in regard to why certain drugs should move to an over-the-counter status since the general population has the ability to use commonly available medical devices to either self-diagnose or monitor a particular health condition. Thanks to the maturation of this technology medical devices can now securely and wirelessly transfer data, increasing the integrity of clinical trial data. For example, once a reading is taken on a blood pressure monitor, that data is automatically downloaded to a hub (a device plugged into an electrical outlet). The patient then plugs in the hub once and takes his or her readings on the prescribed schedule. All of the data transfer is handled seamlessly and securely without the need for manual intervention – reducing the chance of human error. If the patient forgets to plug in the hub, the data is stored on the medical device until it’s plugged in. Alternatively, there is an option to securely transfer data via a companion app on a smartphone. What Else can Wearables Enable?

Medical devices offer a multitude of possibilities for researchers that go 1 “About Combination Products” - https://www.fda.gov/ CombinationProducts/AboutCombinationProducts

www.pharmafocusasia.com

Clinical TriAls

End-to-End Medical Device Components

It is critical that Sponsors leverage a medical device solution that securely and wirelessly transmits the data with the ability to store, visualise and alert from the big data time series data; however, the application of medical devices is not just a technology exercise. The performance of medical devices must be evaluated prior to use for study endpoints to understand if the device generates data within acceptable parameters and in comparison to the manufacturer's claims. 38

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Informed Consent Forms must be adapted for the collection of personal data and there are data storage and data transmission/re-use implications, particularly in the European Union. There are health economic and outcomes research considerations that must be taken into account to ensure that the associated endpoints are fit for purpose for regulatory submissions. Logistics also plays an important role on the front end, when devices are acquired, kitted and distributed to sites in a timely manner that accommodates the storage limitation at the sites. At the end of a trial, the devices need to be returned; cleansed or destroyed; and all data deleted from the device. Effective medical device use requires best-in-class medical, HEOR, biostatistics, logistics, technology and clinical trial conduct capabilities.

A u t h o r BIO

far beyond collecting blood pressure. Using the data collected from wearables, predictive analytics may allow medical devices to alert researchers of future medical events. The application of predictive analytics to connected medical device data may enable the identification of subjects who are who are not protocol compliant such that the sites can intervene to increase subject retention. A predictive analytics for sensor-based data will enable increased patient retention and safety. Wearables not only simplify data collection and improve patient safety; this technology allows for the advancement of international partnerships where multiple teams can be connected in real-time. Remote and in-clinic data can be “fused” together for sites and study teams to view side-by-side in Phase I-IV clinical trials. This takes away the barrier of geographic location for multiple sites working across the globe, and allowing this increased comparison of diverse data will increase the integrity of the results on an international scale. The value of wearables is not limited to trials sites. As Real World Evidence (RWE) becomes an integral part for many clinical trials, wearables allow for monitoring and data collection anywhere the patient is located – freeing researchers of the location barrier of RWE Wearables have created a structure where data collection is aboundary-free factor in clinical trial management.

Where does this Go Next?

So where can wearables take the industry? The shrinking size of medical devices and connected implantable device along with evolving technology will further enable the collection of novel and complementary data to support regulatory submissions and reimbursement. With experience and regulatory acceptance, the potential for connected medical devices is extraordinary. These devices have the potential to change the way clinical trials are conducted; to broaden participation in clinical trials at a time when subject recruitment is major barrier; to enable virtual trials; and to reduce clinical trial costs. The challenge today is not deciding on whether to use a mobile health device, but the effective integration into drug development programmes.

Xavier Flinois leads PAREXEL’s Informatics division, which provides innovative technology solutions to help optimise patient engagement, clinical and regulatory processes. He brings to PAREXEL more than 25 years of experience in technology and healthcare, including senior leadership positions with global companies in the clinical software, consulting and IT services areas.

$%!$& $"#%

www.pharmafocusasia.com

Research & Development

Merging Technology Transfer with Knowledge Translation Academic to industrial research

Technology transfer is not just limited to industries and R&D. A research scientist working in R&D may also work with universities. There are several examples of patent or product commercialisation happening in universities. This article focuses on how technology transfer can be coupled with knowledge translation. Vivek Dave, Sachdev Yadav, Harshavardhan ML Yadav, Isha Mehta Department of Pharmacy, Banasthali University

P h a rm a F o c u s A s i a

ISSUE - 29 2017

he government and research academics are increasingly aware of the relevance of their result to the industrial sector. The term knowledge translation was coined to represent proactive strategies to communicate research findings to those in a position to put the findings into practice. As it happens in most cases, the first consideration is given to market size. Simply put, it means that the market where we are supposed to market the product should be large enough to trade it in a very big volume. Moreover, it is very important to see weather

Research & Development

the intended result can be patentable or not, especially in the pharmaceutical industries. Technology transfer does not always involve a patentable invention, but also the transfer of the intact technology including copyrights, proficiency, and others. A good patent is that which cannot be overcome by any other universities; a weak patent will allow other universities or researchers to come up with good amendments on our idea leading to the problems of licensing. Some universities require employees and graduate students to report all inventions to the universities and, upon request, execute a formal assignment document. The Bayh Dole Act, a nonprofit organisational research and its documentation work that is closely concerned to the field, permits funding agencies to grant inventors requests to retain title, provided the universities have waived election of the title. However, if universities believe an invention is valuable, they will usually elect title, apply for patents, and then license the rights exclusively back to the inventors. This is the procedure usually followed in the case of inventors who obtain venture capital to form companies to develop their discoveries. However, a number of universities support their employees who wish to preserve the title to their inventions, and have sensible plans to ensure growth. Most universities also assert ownership over non patentable

materials created by their employees and recorded information generated by their employees. The quality of industry technology transfers is based on the student and industry relationships. The interaction with industry can also educate faculty and students with regard to salaries and working conditions in industry. Students learn that scientists in industry also publish. They learn that scientists in industry can spend less time raising funds for their labs than those in academia. It also has the potential for educating them with regard to the rewards of working in industry. This interaction can go a long way towards ridding industry of the stigma that has caused it recruitment problems in the past. Technology transfer can also provide funds for students and resources for enhancing programmes. They set some goals for preparing and distributing technology transfer guidelines which are shown in figure 1. The Bayh Dole Act Providing the Platform for Universities Technology Transfer

The Bayh Dole Act enacted on December 12, 1980 (The Patent & Trademark Act Amendments) (Public Law 96-517) created a uniform patent policy among federal agencies that fund research. Bayh-Dole enables small businesses and non-profit organisations,

Assisting students in commercialising their products

Making inventions available tp all consumers

Goals Revneu for the creator students

Defining Rights And Responsibilities

including universities, to retain title to materials and products they invent under federal funding. Subsequent amendments created uniform licensing guidelines and expanded the law to include all federally funded contractors (Public Law 98-620). The implementing regulations for Bayh-Dole are published at 37 CFR Part 401. Regulations Implementing Federal Patent and Licensing Policy Regarding ‘Rights to Inventions Made by Nonprofit Organisations, Universities and Small Business Firms’ are Codified at 37 Cfr Part 401. The Following Summarises the Significant Aspects of these Regulations

• The provisions apply to all inventions conceived or first actually reduced to practice in the performance of a federal grant, contract, or cooperative agreement. This is true even if the federal government is not the sole source of funding for either the conception or the reduction to practice. The provisions do not, however, apply to federal grants that are primarily for the training of students and postdoctoral scientists • The university has an obligation to disclose each new invention to the federal funding agency within two months after the inventor discloses it in writing to the universities • The decision whether or not to retain title to the invention must be made within two years after disclosing the invention to the agency. This time may be shortened, if, due to publication of research results or public use, the one-year US statutory patent bar has been set in motion. Under such circumstances, the universities must make an election at least sixty days before the end of the statutory period. If the university does not elect to retain title, the agency may take title to the invention • Upon election of title, the universities must file a patent application within one year, or prior to the end of any

Figure 1 Goals for preparing and distributing technology transfer guidelines www.pharmafocusasia.com

Research & Development

statutory period in which valid patent protection can be obtained in the US. The universities must, within ten months of the US filing, notify the agency whether it will file foreign patent applications. If the university does not intend to file foreign applications, the agency may then file on its own behalf in the name of the United States â&#x20AC;˘ Universities must include within the specification of the patent a

notification of government support of the invention and government rights in the invention â&#x20AC;˘ If the universities elect to retain title, the universities must provide the government, through a confirmatory license, a non-exclusive, non-transferable, irrevocable, paid-up right to practice or have practiced the invention on behalf of the US throughout the world

Documentations for Universities Technology transfer includes Inventor information:

Full college name that is mentioned on the certificates of inventor, name of college and institute, phone number of person and the institution, address for correspondence, age, sex etc. is to be mentioned in this column. Title of invention:

Selection out of column of the field your work belongs to. Like if it belongs to physical science, engineering, pharmaceuticals, or any other branch. Funding sources:

Name of department that is providing funding, like CDRI, CSIR, DBT, DST or any other funding agency that is providing funding to the said invention. Along with this account number grant number is to be mentioned. Did this invention utilise data or materials any biological products or population data if was in use. Dates of conception and public disclosure:

The date and mode of public disclosure is to be mentioned like on such date an oral disclosure or disclosure in research paper was made. Has the invention been reduced to practice YES or NO is to be mentioned. If yes, then it is to be provided with the information regarding the first successful operation of the invention that has been proved its advantages that distinguish it from prior technology. Describe the particular problem the invention seeks to solve. Describe how others have attempted to solve the problem and the limitations or deficiencies your invention

P h a rm a F o c u s A s i a

ISSUE - 29 2017

â&#x20AC;˘ The universities is obligated to have written agreement with its faculty and technical staff required disclosure and assignment of invention. Research Collaborations an Intangible Vagueness Simple Collaborations

Research partnerships sometimes have totally different meanings and there tends to be some degree of conceptual

Background research and prior art:

The researcher should describe all background research and prior art of related invention (novelty and non-obviousness of patent claims are judged against everything publicly known before the invention, as shown in earlier patents and other published material. This body of public knowledge is called prior art) for this researcher should disclose all the information like to give complete description of the invention. To describe the invention diagrams, graphs may be used. Attachments can also be made in order to check disclosure and information made on such. Describe in detail the novel features of your invention In support of the invention it must be describe that why invention is must and how novel the work is and what are its benefits to society. What are other forms of this invention or alternative uses or aspects of it? What has been done to demonstrate that your concept actually works, what is the current state of development? The stage of development is a critical question that both investors and companies asked in their evaluation of new technology. Indicate one of the following stages and include any supporting information (e.g. concept, early stage, bench prototype, industrial prototype, product, market.) What research plans do you have for further development of your invention. This column will indicate Future plan with that same invention if they are scheduled, or are in progress. And finally declaration is made signature that indicates all entries made by person was correct and he is responsible for all information. Sometime declaration is also made by both parties and every party is given a copy of same.

Research & Development

To improve a low rate of technology/IP commercialisation, universities and industry in India need to establish a close and intensive relationship and formulate strategies for achieving better technology transfer for mutual benefits.

Supporting or Assisting Students in Commercialising their Products

The guidelines help students to take care of each and every step while trying for technology transfer. Technology transfer is a complex subject, but its complexity may be reduced by following these guidelines and moving step-by-step for transfer purpose. Since students donâ&#x20AC;&#x2122;t have their own earnings to invest in such project, many government organisations provide funding to them. These include CSIR, DST, DBT, ICMR, DSIR etc. Students need send their filled up forms and a synopsis of their work and estimated results so that funding agencies can calculate the worthiness of the project. Making inventions available to all consumers is the next step. This is done through suitable advertising of the inventions. Defining rights and responsibilities are the major part of goals of technology transfer many collaborations are there, sometime like with faculty, or institute itself, so who will take care of which part is mandatory to clear.

vagueness one must be concerned about, especially in case of a review. For this purpose, a major type of intangible vagueness in research collaboration is easily seen with differences in level of analysis. The term research collaboration describes relationships between individuals as well as organisations. Many university researchers even go for co-authorship. For this reason, much of the published work focuses on co-authorship. By this definition, collaboration not just about on publishing articles, but articles that are more often concerned with technology development, software or patents and sometimes publication is not an objective. Collaboration does not require person-to-person interaction. Very large associations of specialists interact to produce research and publications and there are some cases where collaborators never meet or interact with each another. Knowledge and property focused collaborations

There are two different types of R&D output here, and they are very critical and relevant to this research collaboration. Knowledge is generally measured in terms of scientific and technical articles produced, cited and used. Increments to wealth are typically measured in terms of patents, new technology, new business start ups, www.pharmafocusasia.com

Research & Development

Discovery made by Universities

Disclosed to transfer technology office

Evaluations done by office / IP identification, Inventor Disclosure Form (IDF)

Patent applications

Market technology entrepreneurs

Negotiate licensing agreement and royalties

License technology

Used by existing firms

Used by new companies

Figure 2 Technology transfer procedure from universities to commercial market

P h a rm a F o c u s A s i a

ISSUE - 29 2017

and profits. In particular, most property-focused collaborations at some point have a knowledge focused phase or aspect. Most R&D collaboration are seen in private industry because most researchers are there working in these firms. The objectives and content of research in industry are very different from the universities, government or Nongovernmental Organisations (NGOs). In universities research, we examine two different research outputs: first, work focused on collaborations for expansion of knowledge and enhancing academic researchers, and second, work focused on collaborations dedicated, in order to producing economic value and wealth for the researchers. Faculty collaboration

A student and faculty working together goes beyond the standard for an undergraduate or graduate student at a university. The term must be defined in comparison to the usual level of support provided to all students within a department or discipline, and the definition may vary from one discipline to another. The determination must be made by the department or division head, subject to the affirmation of the dean. Collaboration may take to the form of a student assisting faculty with research or creative activities. It may take the form of students and faculty working together to develop an exhibit or production of works of art, outside of for credit courses. It does not include independent study courses taken for credit. It does not include work for pay or other compensation under the guidance of a faculty or staff person. The scientist discloses the invention to the university. Once the invention is disclosed, the technology transfer office evaluates the invention and decides whether

Research & Development

Research Phase:

Development Phase:

Commercialisation:

Researcher knowledge

Defining product

Testing by consumer

Methodology

Assessments

Billing & Material planning

Research findings

Co-development practices

Production & Capacity planning

Global knowledge

Implementation plan

Cost estimation

Adequate resources allocation

Reviewing IP status

Gathering consumer needs

Finalise marketing

Products specification

Impact

Producing prototype & test models

Patent

Figure 3 Knowledge transfer flow throw research, development and commercialisation phase www.pharmafocusasia.com

Research & Development

Faculty collaboration

Material support

Special situations

Figure 4 Ownership claimed by universities

or not to pursue acquiring a patent. The technology transfer office must consider the commercial potential of the invention, as well as prospective interest from the public or private sector. If the technology transfer office decides to invest in the invention, the next step is the patent application process. If the patent is awarded, the technology transfer office markets the technology to organisations and entrepreneurs. The goal of this marketing effort is to match the technology with an organisation or entrepreneur that who can best utilise the technology and provide opportunity for revenues to the universities. When a suitable partner is found, the university works with the organisation or entrepreneur to negotiate a licensing agreement. The licensing agreement typically includes a royalty to the university, an equity stake in the startup, or other such compensation. When an agreement is reached, the technology is officially licensed. In the final stage of the process, the organisation or entrepreneur adapts and uses the technology. The original invention typically undergoes extensive adaptation during the process to commercialisation. The university, 46

P h a rm a F o c u s A s i a

ISSUE - 29 2017

etc. In this phase all assessments are to be done and consumerâ&#x20AC;&#x2122;s needs are to be checked. A proper plan should be in place to work with for which implementations are necessary. At last the specifications of the products are to be given and various test models were prepared. From there it directly enters the commercialisation phase where testing is done by consumers, and finally when good feedback is seen from users, the production is planned along with all billings of productions and materials. Intellectual property is reviewed once again and final impact is seen if everything is fine with it, it is finally filed for a patent. Ownership Claim of Student and Universities

and sometimes the inventing scientist, might continue to be involved with the organisation or entrepreneur to help develop the technology or to maintain the licensing agreement. Different Phases of Knowledge Transfer from Universities / Academics Institute to Market

Knowledge transfer flows throw research, development and commercialisation phase in universities as described in figure 3. The transfer process of knowledge is done in three steps: research phase, development phase, and commercialisation. Research phase further includes researcher knowledge, methodology, research findings, and global knowledge. Here, the developer first collects knowledge about the product or technology they want to work on. Then they develop proper and validated methods for the establishment of technology transfer, and to mention all validated tests and their references and then at the end it is subjected to known people by the mode of papers. Next comes the development phase where first step is to introduce the product by defining all its benefits, side effects

The advent of heightened interest around the issue of ownership of the intellectual property rights of what is created, invented or discovered by students has created a much more complex situation on the part of students, faculty and providers of sponsorship and case studies. Universities respect the long standing tradition that students own their academic work. The university does not claim ownership of such intellectual property. There are some common point focus ownership claim as showed in figure 4. When the university provides material support beyond the standard for student research, including academic credit and non-credit work, intellectual property will be owned by the universities. If work is done by faculty collaboration, when there is collaboration between a student and universities faculty or staff to create works as part of research or development activities, intellectual property will be owned by the universities. In special situations the certain courses or special projects where students are presented with the opportunity to participate in projects or activities, the ownership of any resulting intellectual property

Research & Development

must be assigned either to the universities or to a sponsoring entity as a condition of the student's participation

A u t h o r BIO Vivek Dave received his Ph.D in Pharmaceutics from Banasthali University, India. Since 2008 in academics he has accumulated substantial knowledge on technology transfer and novel drug delivery system which is shared in publication and seminars all over the world.

Conclusion

Technology plays a crucial role for creating market growth. Academic institutions or universities act as a cradle for innovations, new ideas and knowledge creation. In India, academic institutions and universities suffer from a low rate of technology /IP commercialisation. To improve this rate universities and industry need to establish a close and intensive relationship and formulate strategies for achieving better technology transfer for mutual benefits. For this, enhancing technology transfers by giving a chance to universities is an appreciable step. Universities may follow government guidelines or have their own, but they are supposed to follow the Bayh Dole Act. These guidelines are of great significance in order to make technology transfer convenient and help to eliminate dark sides of the practice.

Sachdev Yadav has earned his Ph.D in Pharmacology from Banasthali University, India. Since 2003 he has been instrumental in both industry and academics.

Harshavardhan ML Yadav, B.A.LL.B (RMLNLU), LL.M in IPR (NUSRL), NET-JRF. Since 2015 working as Assistant Professor (Law) at Jamnalal Bajaj School of Legal studies, Banasthali University.

Isha Mehta has completed M.Pharm, in Pharmaceutics from Banasthali University, India My area of interest is technology transfer. Basically my main aim to put my knowledge to the advancement of drug technology and make it affordable and reachable to each one of us.

References are available at www. pharmafocusasia.com

((Isolator for R&D and QC laboratories

))

maximum performance for your needs It works with sterile products either toxic or non-toxic, granting the highest safety

level. It is designed for the containment of potent powdered compounds during various functions and process steps involved with injectable formulations and filling.

www.foodpharmasystems.com

info@foodpharmasystems.com

Ph +39 031 543429

at: 52 H FPS Visit - stand 4 C21 A d W n ta IW CPh India - s I CPh

It is designed as a complete development laboratory containing the balance, magnetic stirrer, mixer, homogenizer, centrifuge and area for hand filling.

systems: (( ContainmentSafety and Control ))

www.pharmafocusasia.com

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Research & Development

CREATING THE PERFECT CAPSULE Choosing the right shell excipient for your formulation challenges This article outlines the key challenges facing soft and hard capsule formulation and focuses on the importance of choosing the right excipient to optimise the delivery of Active Pharmaceutical Ingredients (APIs). It also explains why gelatin is the excipient of choice for pharmaceutical manufacturers, and highlights the advantages and disadvantages of the latest alternatives developed. Bjorn Vergauwen, Principal Scientist, Rousselot

s the pharmaceutical market expands and new technologies and actives are adopted, selecting the right excipient is essential to achieve optimum performance and functionality in pharmaceutical formulations and in particular in capsules, todays’ consumer preferred dosage form. The global markets for empty hard and soft capsules are expected to grow significantly and reach annual revenues of US$2.13 billion and US$755 million respectively by 2022. According to FDA documentation, over the past five years, about 12 per cent of all US prescription based (Rx) and over-the-counter (OTC) pharmaceutical products were dosed with hard capsules. On the other hand, the popularity of soft gels shows no signs of slowing down, mainly due to their use in nutraceutical markets and added value in difficult

Rxformulations, including very low dose APIs(<3 mg), potent compounds, hormones and cytotoxic compounds (safe handling), oxygen-labile APIs, and especially poorly soluble or poorly permeable APIs. In the article that follows, the performance of different capsule shell excipients—the market leader gelatin; hydroxypropylmethyl cellulose (in short hypromellose, or HPMC) and pullulan for hard capsule manufacturing; and modified starch for soft capsule—will be reviewed in the context of the latest industry requirements, namely clean label, technical performance, operational effectiveness and safety. Favoured for its high functional capabilities, gelatin has been used in both hard and soft capsules in the pharmaceutical and nutraceutical www.pharmafocusasia.com

Research & Development

industries for over 100 years. The first capsules were manufactured with gelatin in 1834 and, for decades, it has been the safe and only choice. The first commercially feasible gelatin alternative entered the market in 2001, a soft gel shell alternative made of a blend of modified starches (hydroxypropyl starch) and carrageenans. Soon after, hard gelatin capsule alternatives were commercialized, using HPMC as the main shell ingredient. First generation HPMC used carrageenans or gellan gum, differently from the more recently commercialised second generation HPMC capsules that do not require a gelling aid. The Clean Label Requirements

The natural trend keeps gaining momentum and, originally associated with the food industry, it has expanded to capsule manufacturing, with the nutraceutical market leading the way. Innova Market Insights even considers it as the number one trend in 2017.Clean label is a nonregulated term, but is widely accepted as â&#x20AC;&#x2DC;containing recognisable ingredientsâ&#x20AC;&#x2122;, the absence of artificial or chemical ingredients, and the addition of sustainable and naturally sourced ingredients. Surprisingly, people often mistakenly associate clean label with vegetarian origin, although products of plant origin could have been extensively chemically processed and lose their clean label status. Of the excipients reviewed in this article, only gelatin meets the natural and clean label trend as outlined above. Gelatin is a recognisable and sustainable ingredient. Pullulan (and carrageen an used as gelling aid), are brought to market essentially undistinguishable from the form that is present in nature and therefore carry an e-number in the European Union (EU). HPMC for hard capsules, and modified starch for soft capsules, on the other hand, undergo a heavy chemical process to produce capsules with a synthetic base. Obtained from felled and shredded trees (HPMC), or corn crops (modified starch) and partially etherified with methyl and/or propyl groups, these 50

P h a rm a F o c u s A s i a

ISSUE - 29 2017

ingredients are classified as additives and aree-number labelled in the EU. Technical Performance API release/dissolution

In capsule-dosed medicines formulated for immediate release, capsule opening time represents the most important parameter to evaluate effectiveness. With the exception of enteric capsules, the sooner the capsule opens in the stomach, the sooner the API becomes available for absorption by the body. The functional properties and dosing of excipients play a key role in dissolution time. With respect to hard shells, gelatin and pullulan capsules represent the best options and exhibit similar in vitro dissolutions profiles, when HPMC capsules show vendor-to vendor variability. HPMC capsules can open unpredictably depending on the gelling aid used, with 50 per cent release ranging from 24 minutes to more than two hours, and should, therefore, be avoided to formulate pharmaceutical grade medicines, except if aiming to achieve gastro-resistance. Crosslinking

In a cross linking reaction, two or more molecules are joined by a covalent bond, resulting in an increase in molecular weight. Affecting the cross linked polymerâ&#x20AC;&#x2122;s solubility, cross linking might also have an impact on capsule opening time, and ultimately bioavailability. Proteins in general crosslink in the presence of certain aldehydes. Being

a protein, gelatin is more likely to this phenomenon in contrast to the polysaccharides HPMC, pullulan and modified starches. However, high quality pharmaceutical excipients and active ingredients are free of aldehyde contaminations, which is why cross linking is usually not an issue with Rx and OTC gelatin capsules. Oxygen and water vapour permeability

To meet the formulation needs of APIs with complex stability profiles, capsules generally represent the safest choice. However, oxygen permeability differs significantly amongst the commercially used capsule shell ingredients. For instance, gelatin and pullulan hard shells display equivalent, low oxygen permeability, while first and second generation HPMC capsule shells permit oxygen transfer up to 50 times faster. When oxygen-sensitive compounds are encapsulated into HPMC capsules, it is recommended to include an antioxidant in the fill formulation or to package the capsule product into an oxygen-resistant configuration, such as a blister package with aluminium foil. Soft gels offer the safest choice for formulating oxygen sensitive APIs because of the absence of ahead space. Water vapour interplays differently with the capsule types examined. Pullulan is the most hygroscopic translating in an unwanted perceived tackiness when holding pullulan capsules for 30 seconds or more. HPMC capsule shells have a

Research & Development

Cost efficiency

Considering the overall cost of manufacture, raw materials for first generation HPMC capsules cost approximately four times more than gelatin, while manufacturing costs are three times as much. In addition, supplying the raw materials for HPMC accounts for 50-60 per cent of the total production costs, while this is only 45-50 per cent in the case of gelatin hard capsule production. Atleast 40 per cent less raw material is required to manufacture a batch of hard gelatin capsules, as compared to production with HPMC. Safety first

Figure 1 Rousselot internal study, R&D Expertise Center Ghent, May 2017. Dissolution profiles showing the mean percentage of riboflavin released from gelatin, HPMC capsules vendor to vendor variation HPM generation), and pullulan/ gelling aid capsules in 0.1 M HCl buffer at pH 1.2, 37 Â°C, 75 rpm, 1 h.Bars represent SD, n = 3.

three-fold lower average moisture content than hard pullulan and gelatin capsule shells, and are therefore thought to be the logical choice to formulate moisture sensitive APIs. However, studies have been unsuccessful to demonstrate this proposed benefit. Operational Effectiveness

While capsules offer manufacturing advantages over other dosage forms, there are still several factors to consider when determining operational effectiveness.

adapted machines featuring thermo regulated pins. Likewise, machine modifications (e.g. melt-extrusion devices as an alternative to spreader boxes) are generally required to tailor the rotary die process to the use of soft shell alternative ingredients (modified starch/carrageenans). The manufacture of thin HPMC and pullulan films usually involves slightly longer manufacturing times and results in higher weights and increased weight variation of the finished products.

Weight variations

The thermo-reversible properties of gelatin allow a high level of machinability, as only a single shell ingredient is required for use with dipping pin machines (hard capsules) or rotary die encapsulation machines (soft gels). The manufacture of first generation HPMC capsules and pullulan capsules instead requires secondary gelling agents to meet the viscosity requirements of the dipping pin moulding production process. Second generation HPMC hard capsule production does not employ the standard dipping pins equipment to manufacture hard gelatin capsules, but requires

Pullulan capsules are somewhat more weight-stable than HPMC capsules, which vary substantially. Gelatin capsules offer the most reliable weight stability profile of all tested types of hard capsules.

A u t h o r BIO

Machinability

In the highly regulated pharmaceutical industry, gelatinâ&#x20AC;&#x2122;s standardised production process remains a guarantee for high quality. Moreover, the gelatin production process does not fall under the European Commission Seveso Directive for the prevention and control of chemical plant accidents, unlike the manufacturing process of many other pharmaceutical ingredients, such as HPMC or modified starch. Conclusion

The latest technologies and developments in the capsule industry have led to the introduction of new shell ingredients to the market. In the face of increasing demand for safe and clean label products, rising costs and the importance of operational effectiveness, sophisticated fill formulations and stringent regulatory pressures, gelatin offers a futureproof solution to meet these capsule challenges. References are available at www. pharmafocusasia.com

Bjorn Vergauwen is Principal Scientist at Rousselot. He currently coordinates R&D projects aimed at unlocking the unmet potential of gelatin. His main expertise relates to the biophysical and biochemical principles underpinning gelatinâ&#x20AC;&#x2122;s behavior in food and pharma applications and to its use in pharmaceutical dosage forms. Dr. Vergauwen has a PhD in biochemistry from Ghent University, Belgium. Before joining Rousselot in 2014, he had several missions as Post-Doctoral Researcher at Ghent University where he conducted research in enzymology and structural biology for 17 years.

www.pharmafocusasia.com

Manufacturing

The Rise in Sterile Manufacturing A focus on containment

Containment is key during aseptic processing and this has led to the development of new transfer methods that are both enclosed and minimise the requirement for operator intervention. In this article, author discusses modern containment methods and the advent of split butterly valve technology to improve production processes. Christian Dunne, Global Product Manager, ChargePoint Technology

ontainment is key during aseptic processing and this has led to the development of new transfer methods that are both enclosed and minimise the requirement for operator intervention. In this article, Christian Dunne, global product manager of AseptiSafeÂŽ at ChargePoint Technology discusses modern containment methods and the advent of split butterfly valve (SBV) technology to improve production processes. Industry Outlook

The world market for contract pharma manufacturing is expected to reach US$79.24bn in 2019 rising from US$54.54bn in 2013, with strong revenue expansion predicted up to 2025. The sterile contract manufacturing sector has experienced steady growth over the past five years with the contract manufacturing of injectables leading the sectorâ&#x20AC;&#x2122;s growth since 2011. There are a number of key factors that influence the sterile market. By the end of 2024, the cancer segment is projected to reach close to US$100bn in value, expanding at a CAGR of

6.5 per cent. Revenue from the cancer segment in the global sterile injectable drugs market is expected to increase 1.7X by the end of 2024compared to that in 2016. In addition, the antibiotics market was valued at US$39.8mn in 2015 and is expected to witness a CAGR of 4.0 per cent to 2025. Global demand and the growth in specific markets, including oncology, have supported the continuous growth of the biopharma market. Consequently this is driving the need for increased development of Antibody Drug Conjugates (ADCs) in an industry that is also seeing a rise in conventional drug manufacturing using high potency active pharmaceutical 52

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Manufacturing

ingredients (HPAPI)s. This is also driving the need for high potency handling capabilities, particularly highcontainment manufacturing facilities. With the global active pharmaceutical ingredients market expected to reach US$213.97bn by 2021 from US$157.95bn in 2016, it is growing at a CAGR of 6.3 per cent. The factors driving market growth include increasing incidence of chronic diseases, rising prevalence of cancer, technological advancements in API manufacturing, growing importance of generics, rapidly increasing geriatric population and increasing uptake of biopharmaceuticals. The transfer of Active Pharmaceutical Ingredients (APIs) must be carried out correctly during high potency and aseptic processing to ensure highest quality of the product and complete sterility of the manufacturing processes. Containment strategies are an important component of manufacturing facilities to address these risks and adhere to the strict safety requirements associated with processing these types of products. Traditional Methods and Challenges

There are many challenges involved in ensuring product sterility, including operator handling and the need to invest in containment equipment to protect the product from external contaminants which could come from the operator or the surrounding environment. It is, therefore, important to ensure that solutions are implemented to counter potential risks posed by human intervention. Regulations and standards for clean room environments have gone some way to alleviating and managing the risks. Ranging from grade A to grade D, there are various approaches associated with each grade, from closed to open handling of a sterile product. In a grade A environment, less than one Colony Forming Unit (CFU) is allowable meaning there is no contamination. The market has also already witnessed some diversification with

technologies that can help minimise the risks associated with potent compounds, including isolators, Restricted Access Barrier Systems (RABS) and SBVs that are now in use to safeguard drug products throughout the manufacturing process. Closed transfers, such as the use of SBV, limit manual intervention, reducing the risk of cross contamination, and create a dust free environment to ensure operator safety. New design technologies to remove the risk of airborne exposure have been pivotal in achieving high containment. Isolators

Isolators are an arrangement of physical barriers that provide an enclosed working space that is detached from the surrounding environment. Operators perform tasks through half-suits or glove ports, enabling manipulation to be undertaken within the space from outside the enclosure without compromising integrity. Due to the high-performance requirements for these enclosures, integrated pressure decay tests have become the norm during start up and prior to any bio decontamination phase, with the leak of the chamber being a key factor in the classification of the device. A limitation of isolators is that they can create difficulties in transferring

materials in and out of the cabinet. This can require a docking isolator to be connected and its interior sanitised before materials can be transferred. The qualification ofH202 (hydrogen peroxide) vapour systems in isolators can also be difficult. As a result, there is a need to suspend everything within the cabinet to remove any hidden surfaces. RABS

The RABS approach offers increased flexibility for operators to interact with the process outside of the sealed area by putting a physical barrier between operators and production areas. To allow a more limited barrier to be permissible, RABS must be set-up in high-class, generally ISO 7 clean rooms. RABS contribute distinct advantages by enabling operators to maintain a distance from the process, while allowing the enclosure to be opened if significant intervention is required. In comparison to isolators, RABS can ensure faster start-up times and improve the ease of changeover while also allowing for more operational flexibility and lower validation expenditure. Although isolators do offer the advantage of higher integrity chambers for a more robust closed solution. Many pharmaceutical companies are finding that the use of aseptic SBV technology integrated to either the www.pharmafocusasia.com

Manufacturing

Figure 1 Operation process with text

SBV Technology

Manufacturers can benefit greatly from aseptic SBV technology by its closed handling method that enables Sterility Assurance Levels (SAL) and reduces the need for operator intervention. It also reduces the need for cleaning and validating large areas which consequently leads to minimal downtime, while also increasing flow and yield from product transfers. The technology provides a safe method for product transfer from one container, process vessel, isolator or RABS to another part of the process to ensure complete sterility of the transfer. The unique design of the aseptic SBV enables decontamination to take place in a closed environment. Once sealed, a gap is created between the discs and hydrogen peroxide gas is flushed through this enclosure to decontaminate the space. The process of validation is done in the same manner as that of an isolator or RABS with the use of chemical indicators to ensure full coverage of the enclosure is obtained and to ensure a validated SAL of 10-6has been achieved. Processing time varies between four and 30 minutes depending on the gassing system utilised. This is extremely fast when compared to a conventional airlock or isolator techniques which could be in the region of four to six hours. SBV can also contribute considerable cost savings in comparison to traditional approaches, being as much as three to five times cheaper than alternative methods. The advent of sealed transfers using SBV has enabled the downgrading of the external environment as it creates an internal grade environment of its own due to the integrity of the approach. By making it possible to downgrade the surrounding clean room level, this technique has the potential to transform the environment in which drug products are manufactured. This in turn delivers cost savings and process improvements due to the less restrictive operating requirements. 54

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Conclusion

The containment market is continuing to grow rapidly, driven by increasing substance potency, regulation and market dynamics such as the growth in biopharmaceuticals. Key benefit to advanced aseptic processing includes the complete elimination and control of all sources of impurities, and perhaps most importantly, those generated from human intervention. The selection of an appropriate barrier containment technique will be dependent on several factors and choosing the right contamination control platform requires considerable research into what a product needs for an effective process design. References are available at www.pharmafocusasia.com A u t h o r BIO

isolator or RABS for the transfer of material in or out of the enclosure is a complementary technique which works together to achieve the required sterility assurance.

Christian Dunne is the Global Product Manager for ChargePoint Technology for the Aseptic range of products. Over the past 15 years, Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries in the form of high containment and aseptic process solutions. For the past four years, Christian has been working with ChargePoint Technology on the advancement of its split butterfly range of solutions in the aseptic and containment fields, handling high potent/ sterile powders and small-scale components, where both product and operator protection are paramount. Christian is an active member of ISPE and PHSS.

CANTEL MEDICAL ĂŶƚĞů DĞĚŝĐĂů ƐŝĂͬWĂĐŝĮ Đ WƚĞ >ƚĚ ƐŝĂ͗ ʞ ƐŝĂ͗ ΀нϲϱ΁ ϲϮϮϳͲϵϲϵϴ &Žƌ ŵŽƌĞ ŝŶĨŽƌŵĂƟ ŽŶ ĞŵĂŝů ƵƐ Ăƚ ŝŶĨŽΛΛĐĂŶƚĞůŵĞĚŝĐĂů͘ĐŽŵ͘ƐŐ Žƌ ǀŝƐŝƚ www.mcpur.com

Change for the Better Datwylerâ&#x20AC;&#x2122;s approach

The Indian pharmaceutical market for years has been a growing market and will continue to do so by all projections. Rahul Dev, Vice President India at the global industrial supplier Datwyler underlines the importance of the Indian market for the company: â&#x20AC;&#x153;The Indian market is quite a substantial market share for Datwyler. With the newly extended facility, based on the First Line manufacturing standard, we will supply even more customers in the Indian and global market. We are currently supplying the top ten of Indian pharmaceutical companies and global players

P h a rm a F o c u s A s i A a

ISSUE - 29 2017

in India. We invest in growth and believe it is one of the core strengths of the Indian market.â&#x20AC;? Datwyler manufactures components and container closures for glass vials, syringes, and pre-filled syringes in a clean room manufacturing environment. Yearly, about 4 billion of those components are manufactured in the Indian facility and exported to the US, European and South-East Asian market. The production volumes are to increase with the extension of the current facility in Pune. Rahul Dev sees the trend for high-end pharmaceuticals for the whole Indian

market. Currently, the market has the highest number of USFDA approvals and with more companies buying from Indian manufacturers, this development will continue. Datwyler will invest substantial amounts in new facilities that are to be opened in the future, furthering the manufacturing of components of the Omni Flex family, a state-of-the-art coating technique, particularly for components for parenterals. By the end of 2017, the facility will be running at a 90 per cent capacity. Currently, Datwyler employs over 400 people in India and with the new facility the number will increase to 500 approximately. The employees, from shop floor to managers, are from India of which the majority is from the villages around the facility in Pune. The commitment to the region and the employees is also shown in the social and environmental involvement. Datwyler supports and maintains a school in Kesurdi. Growth does always also mean change â&#x20AC;&#x201C; and with Datwylerâ&#x20AC;&#x2122;s help it is change for the better.

Advertorial www.pharmafocusasia.com

Information Technology

Take a Pass on the 3pm Samples Innovation in laboratory informatics technology is eliminating the battle for scientists with late afternoon sample analysis requests. Steve Madden, Software Product Manager Mass Spectrometry, Agilent Technologies

one are the days when chemists would wait patiently for paper reports on their particular sample results to be sent to them. The introduction of informatics technology brought with it results that can be delivered by email and uploaded through a central system or stored in the cloud, so that they could be presented quickly and 58

P h a rm a F o c u s A s i a

ISSUE - 29 2017

allow for timely decision making. Advances in laboratory informatics technology have changed, and continue to change, the way in which laboratories gather and interpret actionable information. Todayâ&#x20AC;&#x2122;s laboratories are looking for informatics technology that are easyto-use, speed up their work, and deliver accurate results.

The use of modern informatics technology means that scientists no longer have to battle with sample analysis requests that come in at 3p.m., working hours of overtime to pull the information together. In the past, sample research information would take a substantial amount of time to analyse and, with respect to pharma, therefore risk slowing

Information Technology

down the drug pipeline. Today, scientists are able to access the information that they are seeking within minutes. What are Labs Looking for?

Laboratories want a data system that is easy to use, that speeds up their workflow and guarantees confidence in its results. Designed from the ground up to make mass spec analysis easier from tuning to a final report, Agilent’s MassHunter Software delivers just that. One of the innovations Agilent offers in its software suite is the MassHunterWalkup software . This program makes it easy for non-MS experts to use a mass spectrometry to get the answers they need to make decisions. Many core labs are currently setting up Walkup systems so that they are able to share results directly with the user a few hours after a sample has been inserted into the auto sampler. This is a real success for many labs as it removes the burden of setting up and organising in-house analysis. This provides an “ATM” type of function for non-software users, removing the long wait for analytical results to come through. Many companies work under a core lab model which means that they have dedicated laboratories within their facility and that they hire MS experts who are responsible for conducting the analysis. Within this model there is the ongoing risk that analysis will back up and cause chemists to have to wait a long time to get their results — subsequently delaying further decisions down the line. Currently we are seeing many core laboratories setting up these types of high-throughput informatics systems such as MassHunterWalkup so that a chemist with a newly created sample can walk in, put it into an autosampler, fill in a few fields with information and hit ‘Go’. Within a few hours they will receive an email with their analytical results. Pharmaceutical laboratories want answers fast, but they also want a

Innovation in laboratory informatics technology has completely transformed the way modern scientists work, so much so that in today’s laboratory a 3p.m. sample request is met with timely, reliable and accessible results instead of hours of overtime.

simple process through which to get them. Suppose you are a scientist synthesising a new compound, then you need to confirm an answer before making a decision on your next steps. If it takes two to three weeks to get the result it is difficult to move forward. Often this means you will either work on something else or assume that the work you are conducting is going well, and continue to work on it without knowing the outcome of the results. When this happens, and the results differ to what you had predicted, all the time spent and invested in the sample has been wasted. In addition to the MassHunterWalkup software offering, Agilent also has a personalised quantitative analysis called “Quant-My-Way”. The software is a set of tools designed to assist the user in exposing only the capabilities of interest so that you can create your own tailored, streamlined version of MassHunter Quantitative Analysis for each specific assay. This allows the customer to modify the information to see exactly what they want to see. Using this tailored model to create result reports that contain specific information of interest reduces the time required to find the answers you need. As well as wanting answers faster, pharmaceutical laboratories need

confidence in the reliability of their results. In protein therapeutics, there are several ways to characterise the attributes of a new biomolecule. A ‘bottom up’ approach will take the protein, chop up it up with specific enzymes and then analyse each peptide. You can then put the information together in order to confirm the sequence and determine the identity and location of Post Translational Modifications (PTMs). MassHunter BioConfirm is software for the analysis of biopharmaceutical samples. Agilent has just introduced a new algorithm for this peptide mapping workflow. Using the MS/ MS data from an LC/Q-TOF, which is much more specific and informationrich than MS-only data, it is able to rapidly identify peptide sequences and PTMs. This allows the calculation of the overall coverage of the protein as well as the locations of the PTMs on the sequence. Visual Assets Provide Answers

However, it is not enough to just get lists and lists of new data – humans are visual animals which need excellent visualisations to rapidly assess new information and make decisions. The peptide mapping results are displayed on a new Sequence Coverage Map, which clearly outlines which parts of the sequence are confirmed, as well as whether the evidence is from MS/MS or MS-only data. It is possible to load multiple data files into the Sequence Coverage Map to get a cumulative coverage, e.g. from a multiple enzyme digest or Agilent’s Iterative MS/MS mode that digs deeper into the sample with each subsequent MS/MS run. Agilent’s MassHunter VistaFlux software, which is used in pharma research through to drug discovery, is another example of an innovation in lab informatics that is changing the way scientists work. VistaFlux helps scientists map metabolic pathways and then visualise them in different ways. It can be used to test hypotheses on the Mechanism of Action (MOA) of new www.pharmafocusasia.com

Information Technology

And how does informatics technology play into this? Agilent recently launched an MS/MS library (the Extractables & Leachables PCDL ) that helps pharmaceutical companies determine if any E&L compounds are present in the products they are supplying to patients as a result of the materials they are produced and packaged in. The ability to recognise this contamination gives these companies the opportunity to prevent them. The library is used with other parts of the MassHunter suite for fast and accurate results. Innovation in laboratory informatics technology has completely transformed the way modern scientists work, so much so that in today’s laboratory a 3p.m. sample request is met with timely, reliable and accessible results instead of hours of overtime. A u t h o r BIO

drugs and has recently been applied in the development of a new diabetes treatment by a major pharmaceutical company. This software tells the user over time what is occurring on the pathways through insights from algorithms, which transform into visual results that are easily discerned. These visualisations of the results create an efficient, time-saving working environment for all users. Maximising the Opportunities in Laboratory Informatics

Pharmaceutical companies need to be able to ensure the safety of its products. This requires rigour for every aspect of their product’s development and use– from drug development through to the packaging used to contain the drug itself. To ensure this, biopharma companies are transitioning to the production of protein therapeutics with Single Use Technologies (SUT) such as plastic disposable bioreactors, membrane absorbers, media bags, bioprocess containers, disposable mixers, and samplers. However, it is very important that no unwanted compounds leach out of the plastics that might be delivered inadvertently to patients. Similarly, the packaging materials, containers and recipients might also contaminate a small molecule pharmaceutical product. 60

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Steve has significant experience in chemical analysis, chemometrics and bioinformatics. Prior to his current role, Steve worked in software R&D and support. Today, he manages the marketing of Agilent’s MassHunter qualitative software. This portfolio embraces customers’ needs in a wide variety of markets including pharmaceutical, biopharmaceutical, and chemical analysis.

www.pharmafocusasia.com

More than

190,000 READERS in pharma industry across the globe.

We Brand the Future. We create DiďŹ&#x20AC;erence.

Hard-copy Subscriptions: Email: info@pharmafocusasia.com Tel: +91 40 4961 4567 Media Contact: Email: advertise@pharmafocusasia.com Tel: +91 40 4961 4567 61

P h a rm a F o c u s A s i a

ISSUE - 29 2017

HannanDesignStudio.com

Frequently preferred pharma magazine, a leading brand name, a source of information with latest breakthroughs and trends in the industry, with huge subscriber database that leads you to the best promotions in the market. Focuses on Strategy, Research & Development, Clinical Trials, Manufacturing, Information Technology. Available in online version.

Books

Transforming Big Pharma: Assessing the Strategic Alternatives

The Future of Pharma: Evolutionary Threats and Opportunities

Pharmaceutical Statistics Second Edition

Author: John Ansell

Author: Brian D Smith

Year of Publishing: 2016

Author: P Srinivasa Babu, P Seshagiri Rao, TE Gopala Krishna Murty

No. of Pages: 284

No. of Pages: 214

Year of Publishing: 2016

Description: In Transforming Big Pharma John Ansell addresses critically how strategy works in the pharmaceutical industry. The long-standing dearth of new products has led to a growing shortfall in revenues. Ansell assesses the wide range of alternative strategies big pharma companies have been pursuing in recent years in attempting to overcome this. He shows that there is sound evidence to expect the recent upturn in the number of new products reaching the market to go on to greater heights. Chapters assess the complex trends in attrition rates, show how rife spectacular sales underestimation in the industry remains, and explain how conventional wisdom on the chances of product profitability also seriously undersells the industry.

Description: The Future of Pharma examines the causes of the industry's potential decline and offers a convincing and rigorous analysis of the options open to it. What emerges is a landscape defined, on the one hand, by the changing marketplace of mass-market consumers, institutional healthcare systems and wealthy individuals; and on the other by the alternate sources of commercial value - innovative therapies; super-efficient processes, supply chains and operations; and closer customer relations and increasingly tailored health services. The challenges to the pharmaceutical industry now and in the medium and long-term are very significant. Brian Smith's highly readable research findings are a wake-up call and a first step forward for anyone concerned with the future of the industry; whether executive, customer, policymaker or investor.

No. of Pages: 602

P h a rm a F o c u s A s i a

ISSUE - 29 2017

Description: Books covering pharmaceutical sciences combined with statistics are not available in the market. To overcome this setback, this book is authored in a detailed and easy to understand manner incorporating the updated information containing the following features. • Syllabus prescribed for B. Pharm & M. Pharm students is covered in detail • The application of pharmaceutical statistics to research and clinical evaluation • Prime importance is given to the creation of tables and graphs • Data presentation, inferential tests such as parametric and nonparametric methods, regression and correlation factors are presented lucidly • The importance of ANOVA in statistical designs used in pharmaceutical research • Introduction of elementary concepts of the design and analysis of factorial designs • Optimization techniques with suitable examples • The important designs and their applications predominantly used in controlled clinical studies • Application of statistics in quality control.

Drug Wars: How Big Pharma Raises Prices and Keeps Generics off the Market

Author: Mahendra Rai, Ranjita Shegokar

Starting Out in the Pharma Industry: Essential Knowledge for Life Scientists: Volume 1

Year of Publishing: 2017

Author: C F Harrison

Year of Publishing: 2017

No. of Pages: 493

Year of Publishing: 2017

No. of Pages: 159

Description: Completely dedicated to the biomedical applications of metal nanoparticles, this book covers the different toxicity problems found in healthcare situations and also provides comprehensive info on the use of metal nanoparticles in treating various diseases. Metal Nanoparticles in Pharma is the first edited volume to set up the discussion for a clinical setting and to target a pharmaceutical audience of academic and industry-based researchers.

No. of Pages: 122

Author: Robin Feldman, Evan Frondorf

Description: While the shockingly high prices of prescription drugs continue to dominate the news, the strategies used by pharmaceutical companies to prevent generic competition are poorly understood, even by the lawmakers responsible for regulating them. In this groundbreaking work, Robin Feldman and Evan Frondorf illuminate the inner workings of the pharmaceutical market and show how drug companies twist health policy to achieve goals contrary to the public interest. In highly engaging prose, they offer specific examples of how generic competition has been stifled for years, with costs climbing into the billions and everyday consumers paying the price. Drug Wars is a guide to the current landscape, a roadmap for reform, and a warning of what is to come. It should be read by policymakers, academics, patients, and anyone else concerned with the soaring costs of prescription drugs.

Metal Nanoparticles in Pharma

Description: This book explains the many complexities of the pharmaceutical industry: the processes, the expectations, the skills you need to know and the careers you can enter all laid out in an informative and jargon-free manner. For those who have started or want to start in the pharmaceutical industry, this book is a vital resource. What does it include? - An introduction to the entire drug development and manufacturing process. We examine how a drug goes from chemical entity to a final pharmaceutical; how drug batches are made, checked, and released to the market; we look at the marketing process, pharmacovigilance, and how processes change over time. - Industry expectations. We look at the knowledge you should learn during the first few weeks and months, attributes you should be cultivating, and how to work effectively with your manager. - Industry skills you need to succeed.

www.pharmafocusasia.com

Products & Services Company.........................................................Page No.

Company.........................................................Page No.

STRATEGY Dätwyler Schweiz AG............................................... 56-57

CLINICAL TRIALS ALLTUB Group.............................................................. 39

Ethiopian Cargo............................................................ 23

IMMEXLS....................................................................... 35

EtihadCargo.................................................................. 11 Emirates SkyCargo..................................................... IBC F.P.S. Food and Pharma Systems Srl........................... 47 MENA............................................................................ 25 Phillips-Medisize Switzerland.................................. 12-17 Turkish Cargo............................................................ OBC RESEARCH & DEVELOPMENT Cantel Medical.............................................................. 55

MANUFACTURING Akzo Nobel Chemicals (India) Ltd.............................. IFC Cantel Medical.............................................................. 55 Dätwyler Schweiz AG............................................... 56-57 Phillips-Medisize Switzerland.................................. 12-17 Turkish Cargo............................................................ OBC Valsteam ADCA Engineering........................................ 03 Vetter Pharma............................................................... 05

F.P.S. Food and Pharma Systems Srl........................... 47 IMMEXLS....................................................................... 35 Phillips-Medisize Switzerland.................................. 12-17

Suppliers Guide Company.........................................................Page No.

Company.........................................................Page No.

ALLTUB Group........................................................39 www.alltub.com

F.P.S. Food and Pharma Systems Srl.....................47 www.foodpharmasystems.com

Akzo Nobel Chemicals (India) Ltd........................ IFC www.kromasil.com

IMMEXLS.................................................................35 www.immexls.com

Cantel Medical........................................................55 www.mcpur.com

Phillips-Medisize Switzerland........................... 12-17 www.phillipsmedisize.com

Dätwyler Schweiz AG........................................ 56-57 www.datwyler.com

MENA......................................................................25 www.pharmamanufacturingmena.com

Ethiopian Cargo......................................................23 www.ethiopianairlines.com/cargo

Turkish Cargo......................................................OBC www.turkishcargo.com

Etihad Cargo...........................................................11 www.etihadcargo.com

Valsteam ADCA Engineering..................................03 www.valsteam.com

Emirates SkyCargo...............................................IBC www.skycargo.com

Vetter Pharma.........................................................05 www.vetter-pharma.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it. 1.IFC: Inside Front Cover 2.IBC: Inside Back Cover 3.OBC: Outside Back Cover