Pharma Focus Asia - Issue 41

ISSUE 41

2020

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SUEZ

Solving the toughest water and process challenges Geert Verstraeten, General Manager, Analytical Instruments business and Sievers product line, SUEZ – Water Technologies & Solutions

Moving Ahead with Intelligent Virtual Clinical Trials Current Development and Future of Pharmaceutical 3D Printing

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Foreword Virtual Clinical Trials The new normal?

Across the world, one thing that has been a hot topic since the pandemic started is the arrival of a COVID-19 vaccine. COVID-19 led several pharma companies to pursue vaccine production with aggressive deadlines and a sense of urgency in developing and bringing to market.

People around the world have closely followed the vaccine candidates advancing each phase of clinical trials.

Impacted by the COVID-19 pandemic, many in-person activities have turned virtual for obvious reasons. A report published by Informa on Decentralised & Hybrid trials indicates that COVID-19 and the country-wise lockdowns have in fact resulted in increased use of decentralised / virtual trials.

Recent numbers point to an increase in funding for technology startups that provide virtual trial platforms powered by Artificial Intelligence (AI) and Machine Learning (ML). The advent of digital technologies paved the way for clinical research organisations conducting trials virtually. Virtual clinical trials make use of digital health technologies for information collection at every stage, thus helping improve patient recruitment and retention, which is a major challenge for traditional clinical trials, and monitor patient safety along with real-time data tracking and measurement. Over the past few years, there were attempts to decentralise clinical trials laying a path for continued experimentation and potential adoption in the long-run.

In 2011, Pfizer pioneered the virtual clinical trial model when it conducted a randomised trial using mobile phones and web-based technologies, in a bid to validate virtual, patient-centred approach to clinical research. Patient enrolment was a major issue for this study, but Pfizer published the results indicating this approach was safe and equally effective as a traditional trial. Pharma companies like Sanofi also took up this approach a few years later by partnering with technology companies,

albeit with limited success. Regulatory restrictions and various other reasons became a roadblock for companies to adopt virtual clinical trials on a wider scale.

The US Food and Drug Association (FDA) had early this year issued guidance on evaluating alternative assessment methods for clinical trials during public health emergencies. A recent update to the guidance suggests investigators consider alternative assessment methods for clinical trials, remote or virtual trials, while emphasising the need for patient safety. Adoption of virtual trials has been accelerated by the pandemic and it is worth noting that the shift to this has not been purely innovation-driven but rather a risk mitigation approach in the current global healthcare landscape.

With a focus on patient-centricity and increased use of digital health technologies for accurate data collection and real-time patient monitoring, benefits associated with virtual clinical trials outweigh the traditional model. But there’s little evidence to suggest the industry is in for a complete shift from conventional clinical trial approach. Clinical research and pharma organisations will do well to embrace hybrid models as the industry commits to bring about a meaningful change that benefits business and the global population at large.

This issue features an article by Ayaaz Khan, Global Head of Generics at Navitas Life Sciences, that revolves around how AI can play a key role in transformation of clinical trials into virtual mode for improved efficiency.

Prasanthi Sadhu Editor

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CONTENTS Solving the toughest water and process challenges

STRATEGY 06 Nanotechnology to Combat Covid-19

Joydip Sengupta, Department of Electronic Science, Jogesh Chandra Chaudhuri College (Affiliated to University of Calcutta)

Chaudhery Mustansar Hussain, Department of Chemistry and Environmental Science, New Jersey Institute of Technology

13 Pharma Trade Terms in Asia-Pacific

Time for a reset!

Brian D Smith, Principal Advisor, PragMedic

20 Health Canada New Validation Rules (Version 5.0)

For eCTD and non-eCTD Submissions

S D Devendra Raj, Senior Manager, Freyr Software solutions Private Limited

23 Vietnam

EU Pharma's strategic imperative

Aditya Agarwal, Principal, Roland Berger

32 Challenges and Solutions in HCP ELISA Development

The importance of reliable Host Cell Protein (HCP) monitoring during manufacturing of biopharmaceutical drugs

Martin Föge, Business Development Manager, BioGenes

RESEARCH & DEVELOPMENT 36 Formulating Haematopoietic Stem Cell Transplantation for Practitioners

A technology-based health service

S Dravida, Founder, CEO, Transcell Biologics

Lakshman Varanasi, Scientist, Instructor

CLINICAL TRIALS 44 Moving Ahead with Intelligent Virtual Clinical Trials

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Geert Verstraeten, General Manager, Analytical Instruments business and Sievers product line, SUEZ – Water Technologies & Solutions

Aditya Agarwal, Principal, Roland Berger

16 The Swiss Cheese Strategy

By copying the aviation industry, you can make sure your marketing strategy will fly

Ayaaz Hussain Khan, Global Head Generics, Navitas Life Sciences (a TAKE Solutions Enterprise)

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ISSUE 41 - 2020

COVER STORY

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MANUFACTURING 51 Continuous Manufacturing of Lipid-based Delivery Systems Using Melt Extrusion

Gautam Chauhan, Vivek Gupta* College of Pharmacy & Health Sciences, St. John’s University

56 Current Development and Future of Pharmaceutical 3D Printing

Yunong Yuan, Doctorate student, Sydney Pharmacy School

Lifeng Kang, School of Pharmacy, Faculty of Medicine and Health, University of Sydney

60 Novel Drug Delivery Systems

Industrial advancements

Farhan Jalees Ahmad, Professor, School of Pharmaceutical Education & Research, Jamia Hamdard

EXPERT TALK 64 Pharma Focus Asia Patient-centric Drug Delivery

Lonnie Barish, VP, Business development and marketing, Bora

John Ross, President, Metrics

Marc Brown, Chief Scientific Officer and Co-founder, MedPharm

SPECIAL FEATURES 39 BOOKS

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Advisory Board

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

EDITORIAL TEAM Debi Jones Grace Jones ART DIRECTOR M Abdul Hannan

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

PRODUCT MANAGER Jeff Kenney SENIOR PRODUCT ASSOCIATES Ben Johnson David Nelson John Milton Peter Thomas Sussane Vincent

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATE Veronica Wilson

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

CIRCULATION TEAM Naveen M Sam Smith SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam

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

Laurence Flint Pediatrician and Independent Consultant Greater New York City

HEAD-OPERATIONS S V Nageswara Rao

A member of

In Association with

Confederation of Indian Industry

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

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US

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STRATEGY

Nanotechnology

to Combat Covid-19 Rapid viral outbreaks caused great inconvenience to mankind, especially since the last decade.

The latest addition to the list is severe acute respiratory-related coronavirus 2 (SARSCoV-2) or more commonly Covid-19. As of 19 September 2020, this virus has a spread over 188 countries around the world, affected 30,500,368 people and caused 951,787 deaths.

Nanotechnology and nanomaterials have an impressive record against viruses and capable to address many critical healthcare challenges that originated from the coronavirus pandemic.

Joydip Sengupta, Department of Electronic Science, Jogesh Chandra Chaudhuri College (Affiliated to University of Calcutta) Chaudhery Mustansar Hussain, Department of Chemistry and Environmental Science, New Jersey Institute of Technology

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R

apid viral outbreaks have caused great inconvenience to mankind, especially since the last decade. The latest addition to the list is severe acute respiratory-related coronavirus 2 (SARS-CoV-2) or more commonly COVID-19 (Figure 1). As of 19 September, 2020, this virus has a spread over 188 countries around the world, affected 30,500,368 people and caused 951,787 deaths. Nanotechnology and nanomaterials have an impressive record against viruses and they can address many critical healthcare challenges that originated from the coronavirus pandemic.

Nanomaterials can play various roles for the treatment of COVID-19 via the production of the vaccine, development of rapid point of care detection platform,

STRATEGY

facilitate sustained release, improved antigen stability, and offer targeted delivery of an immunogen, besides it can also increase the period of antigen exposure (Figure 3). According to a World Health Organization (WHO) report dated 17 September 2020, there are 36 candidate vaccines in clinical evaluation and 146 candidate vaccines are in preclinical evaluation. Among these, 16 vaccines are nanotechnology-based, and they are summarised in Table 1. As the interactions between nanoparticles and the immune system are rapidly explored, it can be anticipated that nanotechnology will deliver quicker, safer and more effective vaccines in comparison to those synthesised using conventional approaches.

Figure 2: Schematic representation of the use of nanotechnology to combat Covid-19 (Reproduced with permission under CC BY 4.0 license) Figure 1: A) Schematic representation of SARSCoV-2 as a core-shell nanoparticle (B) TEM image of SARS-CoV-2 virions (Reproduced with permission under CC BY 4.0 license)

synthesis of viral disinfectants, therapeutic nanomedicine etc (Figure 2).

Regarding the development of the vaccine, a nanoparticle can be used as a nanocarrier to encapsulate the antigen payload to provide the required stability. Nanotechnology-based pathways also help to solve the challenges in vaccine delivery by guiding the vaccine to appropriate subcellular locations. There are many emerging nanotechnologies for the delivery of vaccines, for example, Moderna’s mRNA vaccine is based on a lipid nanoparticle platform and more such nanotechnology platforms including liposomes, cationic nanoemulsions, or polysaccharide particles are being used for guided delivery of mRNA based vaccines with improved stability. Moreover, nanotechnology-based vaccines can control premature degradation of antigens and

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Figure 3: Nanomedicine strategies for COVID-19 therapeutics and vaccine development (Reproduced with permission)

As of today, no vaccine has come in the market so currently there is a need for an inexpensive, rapid, pointof-care diagnostic test kit. A nanotechnology-based quick detection system has already been developed by Seo et al. using graphene-based Field-effect 8

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Transistor (FET) type biosensor (Figure 4). The sensor was synthesised by coating the graphene sheets of the FET with a specific antibody against SARSCoV-2 spike protein. The performance analysis was carried out employing nasopharyngeal swab specimens from

COVID-19 patients, cultured virus and antigen protein. The biosensor could detect the SARS-CoV-2 spike protein at concentrations of 100 fg/mL in clinical transport medium and 1 fg/mL in phosphate-buffered saline. Moitra et al. developed a colourimetric assay based

STRATEGY

on gold nanoparticles for the detection of Covid-19 with bare eyes. Gold nanoparticles capped with thiol-modified antisense oligonucleotides specific for N-gene of SARS-CoV-2 could diagnose positive COVID-19 cases within 10 min

NAME

from the isolated RNA samples. Qui et al. functionalised two-dimensional gold nanoislands with complementary DNA receptors and combined it with thermoplasmonic heat for insightful detection of the Covid-19 through

DEVELOPER

nucleic acid hybridisation with a lower detection limit of 0.22 pM. Shan et al. used a breath device comprised of a nanomaterial-based hybrid sensor array having multiplexed detection capabilities to detect disease-specific

METHOD / PLATFORM

Moderna coronavirus vaccine

National Institutes of Health (NIH) and Moderna (United States)

mRNA-based vaccine, which encodes the full-length of the spike (S) protein encapsulated in lipid nanoparticles

NVX-CoV2373

Novavax, Inc. (United States)

Virus-like nanoparticle, which contains SARS-CoV-2 S protein combined with adjuvant matrix –M

Ad5-nCoV

Cansino Biologics, Inc. (China)

Adenovirus 5 vector, which contains SARS-CoV-2 S nanoparticles produced in the baculovirus insect cell expression system

COVID-19 vaccine candidate

BioNTech/Fosun Pharma/Pfizer (Germany)

Lipid-based Nanoparticles (LNPs) combined with mRNA.

COVID-19 vaccine candidate

Viroclinics Xplore (Netherlands)

UQ`S molecular clamp technology, which locks the S protein conformation to mimic the protein found on the live virus

COVID-19 vaccine candidate

Ufovax, LLC (United States)

Virus-like particle with features of SARS-CoV-2 S protein protruding from a protein nanoparticle scaffold

COVID-19 vaccine candidate

Janssen Pharmaceuticals, Inc. (Belgium)

Recombinant vaccine using AdVac® technology, which is based on the development and production of adenovirus vectors (gene carriers) combined with the PER.C6® cell line

COVID-19 vaccine candidate

Translate Bio/Sanofi Pasteur (United States)

LNPs loading mRNA encoding functional proteins from SARS-CoV-2

DPX-COVID-19

IMV, Inc. (Canada)

LNPs formulated with DPX platform, containing peptides epitopes from SARS-CoV-2 S protein

COVID-19 vaccine candidate

CanSino Biologics/Precision NanoSystems (China/Canada)

LNPs combined with mRNA

COVID-19 vaccine candidate

Fudan University/Shanghai JiaoTong University/RNACure Biopharma (China)

LNPs loading mRNA encoding the receptor-binding domain of SARSCoV-2 S protein

COVID-19 vaccine candidate

Fudan University/Shanghai JiaoTong University/RNACure Biopharma (China)

LNPs loading mRNA that induces the formation of virus-like particles similar to native SARS-CoV-2 in the host

COVID-19 vaccine candidate

University of Tokyo/Daiichi-Sankyo (Japan)

LNPs combined with mRNA

COVID-19 vaccine candidate

BIOCAD (Russia)

LNPs formulated with recombinant vesicular stomatitis virus (rVSV) that expresses mRNA from SARS-CoV-2

COVID-19 vaccine candidate

St. Petersburg Scientific Research Institute of Vaccines and Serums (Russia)

LNPs formulated with recombinant S protein and other epitopes from SARS-CoV-2

COVID-19 vaccine candidate

LakePharma, Inc. (United States)

Recombinant vaccine containing COVID-19 S proteins created using CHO manufacturing platforms

Table 1: Nano-based vaccine candidates to prevent COVID-19 infection (Reproduced with permission under CC BY 4.0 license)

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Figure 4: SARS-CoV-2 detection scheme using FET (Reproduced with permission)

According to a World Health Organization (WHO) report dated 17 September 2020, there are 36 candidate vaccines in clinical evaluation and 146 candidate vaccines are in preclinical evaluation.

Among these, 16 vaccines are nanotechnology-based. biomarkers from exhaled breath, thereby enabling rapid and accurate diagnosis of Covid-19. Thus it can be believed that with the progress of time many more nanomaterial-based rapid diagnostic platforms will evolve to break the deadly transmission chain of the corona.

Coronavirus can be transmitted via various routes of (via cough or respiratory droplets, or biofluids), thus to combat the virus its dissemination must be prevented through disinfecting air, skin or surrounding surfaces.

As surface disinfectants, nanoparticles can be used because of their inherent

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Coronavirus & SARS-CoV & NANO Disinfectation

Virucide

11

Sterilization

5

Vaccine

Antiviral

13

Filter

11

15

19

4 Membrane

Biosensor

19 Detection

12 Coating

Figure 5: Distribution of patents related to SARS-CoV viruses within the ‘coronavirus and nano’ search (data obtained from ESPACENET) (Reproduced with permission under CC BY 4.0 license)

wide range antiviral activities, long stability and effectiveness at a lower dosage. Initial experiments revealed that silver nanocluster/silica compos-

ite coating had viricidal effects against SARS-CoV-2. Nanotech Surface, Italy has prepared a nanotechnology-based solution comprised of Titanium dioxide

STRATEGY

Regarding the development of therapeutic nanomedicine for COVID-19, no success is achieved till now but it could be envisioned that the feasible result comes out in near future. Another interesting aspect is many nanotechnology-based patents have been filed aiming at the prevention of Covid-19 (Figure 5). This

AUTHOR BIO

and silver which can act as surface disinfectant and surface will be selfsterilised for years. The silver nanoparticle is also used by Weinnovate Biosolutions, India and Defence Institute of Advanced Technology, India for the production of disinfectant to fight COVID 19 pandemic.

FN nano, USA synthesised titanium dioxide nanoparticles based photocatalytic coating to destroy COVID-19 residing on the surface upon exposure to light. Scientists of the Queensland University of Technology has developed biodegradable anti-pollution mask using breathable nanocellulose material which can remove particles smaller than 100 nanometers. Zhong et al. deposited superhydrophobic graphene on temperature-sensitive surgical masks which can sterilise the surface viruses under solar illumination for long-term usage. One of this kind of mask is already been commercialised by LIGC Applications Ltd., USA.

indicates the enormous application potential of nanotechnology to combat Covid-19. Finally, nanotechnology is a premium versatile tool which facilitates a variety of approaches and strategies that can contribute strongly to break the chain of transmission of this lethal infectious coronavirus disease.

Joydip Sengupta is an Assistant Professor in the Department of Electronic Science Jogesh Chandra Chaudhuri College (Affiliated to the University of Calcutta), Kolkata, WestBengal, India. His research area is mainly focused on Nanoscience and Nanotechnology with a special interest in carbon nanomaterials and his current research H-index is 10. Sengupta is the author of several research papers and book chapters published by Elsevier, Springer, Wiley, IOP etc.

Chaudhery Mustansar Hussain is an Adjunct Professor and Director of Labs at New Jersey Institute of Technology, Newark, New Jersey, USA. His research areas are Nanotechnology, Analytical Chemistry, Environment& Various Industries. Hussain is author of research papers and author and editor of several books with ELSEVIER, RSC, Springer, Wiley, etc.

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Pharma Trade Terms in Asia-Pacific Time for a reset!

Trade terms represent a significant and growing cost item generating low ROI for Pharma. Over-discounting has undermined the scientific value of branded drugs.

With change in prescription patterns, emergence of telemedicine and e-pharmacy, the time for Pharma to link trade terms with strategic objectives is now.

Aditya Agarwal, Principal, Roland Berger

T

rade terms represent a growing investment and cost item for most Pharma companies globally.

In Asia-Pacific (APAC), price pressures from limited healthcare budgets, and preference to generics under universal coverage have led to additional challenges widening gross to net investments made

by Pharma. In our surveys from last year,

~40 per cent of Pharma executives expect these investments to increase.

Additionally, with a new normal setting in post COVID, significant reduction in economic activity would eventually have an impact on pricing for innovative, originators and branded generics as seen post the global financial crisis in 2008 and Asian financial meltdown in 1997. Leading private hospitals are already looking at cash flow improvement through spend compression.

However instead of a gloomy scenario, significant shifts in the landscape will provide pharma companies

a one-time opportunity to reset trade terms:- 1) The rise of platforms, which enable greater direct response engagement with patients; most surveys predict that at least 50 per cent of APAC patients would use some form of digital health 2) Traditional Customers (pharmacies and hospitals) are likely to adjust to a new set of regulations, competitors (ePharmacy, TPA supported models, Telemed platforms) 3) Reformed patient expectations as patients age and become wellness-savvy.

New opportunities for pharma to invest and create a win-win with customers

Pharma companies have four clear opportunities to drive net revenue growth through effective trade terms and move away from traditional low performing discounts: Personalise patient programmes on platforms

Traditionally discount programmes to patients have lacked transparency and been slow to fully launch due to an offline approach and a strong dependency on traditional customers to introduce the programmes and share the benefits with patients. Especially for patients in the various emerging market of Asia, pharma

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STRATEGY

companies can now launch adherence and discount availment programmes directly with platforms. Traditional customers can be part of the programmes for dispensing and fulfilment as required.

While some companies started experimenting working with platforms as pilots, the risk of disturbing customer relations with hospitals and pharmacies hindered a full-scale launch.

Traditional customers now have an added incentive of being part of the platform play and hence the timing is right to expand engagement with platforms for pharma.

Reinvestment of fixed discounts into new avenues

Traditional customers are facing a whole new set of challenges with changing healthcare provider-patient habits and new regulations.

Help providers overcome operational challenges with telehealth: As providers continue to expand their presence in telehealth with a combination of offline and online initiatives, they are facing a multitude of obstacles of operational, culture, and the larger business model; For example, a key operational challenge is lack of visibility of patients due to low integration of data i.e. when a patient makes a Zoom video call with a doctor, the patient's details are not fully integrated into existing EMRs. Pharma could help to address some of the operational challenges, to help develop a deeper connection with patients for both providers and pharma themselves.

Support services for an uneven environment: Changes in prescription patterns and an overall uncertain environment leading to supply-demand balance issues. Trade marketers and sales leaders can offer to invest in these areas e.g. trend mapping, demand planning and reduce their fixed contractual discounts in lieu of support. A leading anti-ineffective player provided support to some key accounts through epidemiologists and modelling to help plan for different scenarios

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Additionally, pharma can be a true partner for providers on the evolving business model for digital health and remote care. Some prominent areas for strategic partnership include: Co-develop wellness initiatives: departing from traditional short-term discount programmes and awareness / screening initiatives, chronic players could develop annual wellness programmes with providers; payors too are keen on such partnerships. As a reference point, we recently worked with a leading chronic player on wellness initiative where they decided to partner with an insurance leader in China Expand outpatient outreach: Outpatient care is expected to be most disrupted for providers as per our recently released report, Future of Health – The rise of healthcare platform. An outpatient disruption could upend the demand models for Pharma as well: developing revenue growth plans with providers e.g. a specialty pharma company is helping hospitals with centralisation of oncology screening to help patients continue with follow-up without having to visit hospitals for screening.

Reinvent account relationship with companion product offerings

As patients pivot towards wellness and regulations allow for new models of care, partnerships across the value chain are likely to go mainstream. At the forefront, insurer driven products covering specific brands and disease areas (e.g. cardiology, oncology) are paramount. Further, ideas such as digital therapeutics in the capacity of companion offerings are being tried in some therapeutic areas including diabetes and neurology. Pharma companies can offer traditional customers an opportunity to exclusively participate in such offerings or even co-invest into the offering, for a limited time.

-Support Pharmacies with operations and targeted marketing

In markets like India and Philippines, where drug dispensing ratio of pharma-

cies is relatively higher than hospitals, the modifications to patient journeys with telehealth, reduced economic activity. and reduction in discreet spending by patients mean pharmacies might be looking at challenging gross margins; driving patient traffic back to stores through physical and virtual visits is already becoming a key priority. In this context, providing targeted marketing support and sharing some of the burden of the increased costs to serve due to express delivery models or the need to cater to short turnarounds by e-pharmacies, might create more lasting value for pharmacies. As a reference a Pharma company in China tagged customers through cloud platform, which helps pharmacies to fully understand customers and provides targeted marketing.

Offer flexibility in trade term lengths and negotiation cycles

Usually Pharma has followed an annual cycle of negotiating terms. Given the uncertainty, some parts of the contract could be open to shorter durations, thereby providing customers flexibility to demand for support as per business needs. This practice might not lead to an increase in net revenue immediately, but could bring a paradigm shift in how trade contracts are managed, providing Pharma larger control than before.

Shift in mindset and capabilities required for Pharma to take full advantage

Traditional approaches of governance and insights might fall short for Pharma to drive the highest ROI from these opportunities.

A few essential changes would be required: 1. Act local: quite often in APAC, trade terms for large Pharma companies are a result of global programmes. Given the very localised nature of the treatment protocol modifications now and changes introduced as per the evolving COVID-19 situation, local franchises should be provided a greater deal of freedom to manage terms.

STRATEGY

4. Deep investments in insights with an eye on the future: The key to manage the dynamism of the pandemic is to have a 360-degree view of various patient journeys from teleconsultation to dispensing / order fulfilment; and draw insights. The insights though do not always have to be a result of a sophisticated AI based tool but instead, Pharma companies may have to invest in periodical external benchmarks to stay competitive in terms of net price and co-create ideas with distributors and customers to identify data shifts. For example, a primary care player identified a few key territories in each market where its discounting is based on joint demand planning with wholesalers.

Trade terms are often seen as a 'Business-as-usual' topic of enabler functions but given their impact on operating profits and limited healthcare budgets, trade terms might be a key source of growth. Due to their sticky nature, the pandemic is a rare oppor-

tunity to transform the costs into new forms of investments. Usually established Pharma companies have focused significantly more on trade terms than innovative ones have, but in a scenario of reduced economic activity, innovative companies might have to strengthen trade relations to maximise launch effectiveness.

AUTHOR BIO

2. Embrace short-term adjustments to processes and governance: Quarterly calendars for pricing and trade reviews might have to hit a pause. Most organisations have a COVID-19 taskforce formally or informally defined. Trade term topics like changes in discount schemes and adjustment to rebate programmes as per changes in dispensing trends should be under the purview of this taskforce through an information loop. As the situation stabilises, the taskforce can determine the frequency of the programmes.

3. Reduce constraints of BU's and siloed P&L's: Managing terms and revenue growth is quite often driven by brand and BU's plans for an account, which are later rolled up to KAM or regional sales. While brand plans would have to remain the focus, innovation in trade terms will require for an institutional approach e.g. for co-developing a wellness solution, BD&L and market access functions might have better capabilities to develop partnerships across the value chain.

Aditya is a Principal with Roland Berger in Singapore. He is a core member of the Healthcare and Life Sciences practice, serving clients on a range of strategic and performance improvement issues. You may reach him at aditya.agarwal@rolandberger.com

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By copying the aviation industry, you can make sure your marketing strategy will fly In life sciences, such as pharma and medtech, marketing strategies often fail to deliver on their promises. This is because, to work effectively, 5 critical factors must align perfectly. Researchers refer to this as the swiss cheese model because it is like seeing through a cheese when all the holes must align. In this article, Professor Smith describes those five factors and how to manage their alignment to ensure that your strategy delivers what it promises.

Brian D Smith, Principal Advisor, PragMedic

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A

s you look at your newly-written marketing plan, you might want to reflect for a moment how much it resembles an airliner: it took a lot of effort to build, you want to be as sure as you can be that it will fly and not crash but once it takes off it is difficult to repair.

The biggest difference between a marketing strategy and an airliner is that, whilst air crashes are extremely rare, research shows that the majority of marketing strategies crash, in the sense that they

STRATEGY

do not deliver what they promise. How many marketing plans have you read that you would trust your life to?

It was these similarities and contrasts that led me to explore what lessons marketing strategists in the pharma, medtech and other life science industries could learn from the aviation industry.

The exemplary safety of air travel is a triumph of rigour and professionalism that has arisen out of many tragedies.

For decades, every disastrous air crash has initiated a thorough investigation.

From this has emerged the science of accident prevention, built on the finding that the large majority of accidents arise from a very few causes. Armed with this knowledge, I began to research what the major causes of marketing strategy failure in life science markets were. My findings were clearer than I expected and

they developed into a simple, practical process, analogous to the preflight checks performed before every flight, that pharma and medtech marketing professionals can and should use.

A first step: Finding your aircraft

Just as an aircraft technician will first ask “Which aircraft am I testing?”, it’s important to be clear what level of marketing strategy we are testing. My work didn’t concern high level strategies, such as which industry to be in or which disease area to enter. Nor was it concerned with tactical programmes, such as how to promote the product. Instead it concentrated on what is correctly called the Marketing Strategy, meaning that set of resource allocation decisions about which market segments to compete for and what value propositions to offer each

segment. Surprisingly, in many marketing plans this is not explicitly stated. You will get more value out of this article if you pause for a moment to write down what your own marketing strategy is in this what segment/what propositions format.

It is this clear, succinct marketing strategy statement that you should test.

Failure Factor 1: Market heterogeneity

When I spoke to those marketers whose strategies had not delivered on their promises, the most common thing I heard was “It did work but only for a minority of prescribers, patients and payers”. What this revealed was that many target markets are heterogenous mixtures of different needs and wants.

Successful strategies make sense of this heterogeneity and define their targets www.pharmafocusasia.com

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as groups whose behaviour is homogenous, since it is shaped by the same motivations. For example, if you target a disease category, say “uncontrolled severe asthma”, then the huge variety of patient behaviours, prescriber preferences and payer constraints within that category makes it very heterogenous.

Any single value proposition you make to that category may appeal to some of it but can never appeal to all of it. By contrast, if you target a segment defined as “adherent, motivated but uncontrolled severe asthma patients under innovative, engaged prescribers working in a permissive, value-oriented payer environment” then it is much more likely that the whole segment will behave and respond in the same way. Your marketing strategy will then have a much higher return on investment. In short, the reason many pharma marketing strategies fail is that their target is not a homogenous segment but rather a heterogenous category.

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lesson here is that marketing strategies fail when they compete head-on with larger rivals.

The lesson of marketing strategy failure is that strategies must anticipate market change and cannot hope to react to it.

change is laborious, such as modifying existing care pathways. This embedded market inertia is a powerful force and many marketing strategies in life science markets fail because they simply do not offer enough value to overcome it.

Failure Factor 2: Market inertia

Failure Factor 3: Competitive strength

The second theme to emerge from my interviews was “They liked what we offered, just not enough to change”. This exposed the simple fact that customers always have choice and compare your value proposition to their alternatives, including their current practice. And since, in medical settings, switching almost always has costs and risks, they will only adopt your offer if it is demonstrably better than that alternative. Successful strategies, therefore, offer a value proposition whose aggregate costs and benefits, be they clinical, economic or other, are clearly greater than the aggregate of the alternative. This may sound obvious, but recently published research shows that most pharma strategies make value propositions that are inferior or only marginally superior to the incumbent alternative.

Offering little or no reason to change and faced with the sometimes-significant costs and risks of changing, it is unsurprising that many prescribers, payers or patients display apathy towards new products. This is even more true when

After market heterogeneity and inertia, the third failure factor to emerge from my research was competitive intensity, otherwise known as the David and Goliath factor. In the words of one executive “The market leader was just too big.

They overwhelmed us”. This comment reveals the issue of competitive intensity, when your competitor enjoys an insuperable resource superiority over you.

My research revealed that, whilst this was a common cause of strategy failure, some “David” companies do find a way to kill their opposing “Goliath” in the same way as the biblical hero, by avoiding direct competition. By choosing to compete in a different segment and to compete with a different value proposition from their opponent, they largely nullify their opponent’s strength. These successful Davids focus on achieving a very high share of their target segment rather than a small share of their overall market. Almost always, this leads to a better return on investment than a lessfocussed, whole-market strategy. The

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Failure Factor 4: Competitive Intensity

The fourth failure factor described in my research interviews was when competitors had a particular strength that could not be overcome, such as brand loyalty, low cost or some clinical efficacy factor.

“We couldn’t get past their argument” was a typical cry of executives in this case. Again, there was an interesting contrast with those companies that had overcome their competitors’ “unbeatable” strength. Using the market heterogeneity mentioned in failure factor 1, these successful companies focus their resources into a market segment where their own strengths – for example, ease of use or low side effect profile – are important and where their own weaknesses – for example, their cost or their brand reputation – are less relevant. At the same time, they withdraw resources from market segments where their strengths are not appreciated and their weaknesses are important to patients, payers or professionals. By aligning their marketing strategy (remember: choice of target and value proposition!) so as to leverage their strengths and mitigate their weaknesses, these companies chose to fight the battles they were most likely to win.

By contrast, firms that did not seriously consider their own relative strengths and weaknesses inevitably found themselves fighting a battle in which they were at a disadvantage. Failure factor 4 therefore reveals that marketing strategies fail when they neglect to fully consider internal strengths and weaknesses.

Failure Factor 5: Market Movement

The fifth finding of my research was perhaps the saddest. Some executives told me “We did everything right, but the market moved”. This of course reveals the obvious truth that pharma and medtech companies operate in a world of rapid social and technological

STRATEGY

change. By contrast, regulation and technical complexity means that life sciences companies can rarely change quickly.

This means that our marketing strategies cannot afford to wait, see and then react to market change. Instead, it means that marketers must anticipate where their market is headed and design strategies to fit with tomorrow’s market, not yesterday’s. Again, the contrast between firms that did this and those that did not anticipate market change was informative. The latter focused on the ‘near’ market environment of customers and competitors, identifying only narrow and short-term changes in both. The former, anticipatory firms who futureproofed their strategy, looked wider to consider the ‘far’ market environment that, over time, shapes the market. This works because the ‘far’ environment of sociological, political, economic and technological trends ultimately and inexorably shapes the changes in the ‘near’ market environment. Hence the final lesson of marketing strategy failure is that strategies must anticipate market change and cannot hope to react to it.

The Swiss Cheese strategy

In addition to identifying the five factors that account for most marketing strategy failures, my research also identified a vitally important reason why it is harder to make a marketing strategy failure-proof than it is to make an airliner safe. Earlier work by Reason and other safety researchers finds that for a crash to happen, multiple errors must align.

For example, bad weather rarely causes an accident unless it is compounded by pilot error and mechanical failure. But the opposite is true in marketing strategy, which only succeeds if all five failure factors are avoided. In other words, for an air crash to happen usually needs multiple things to go wrong. For a marketing strategy to work, all five failure factors need to be understood and allowed for.

This discovery leads to the Swiss Cheese model of marketing strategy effectiveness, as shown in figure 1.

From Research into Practice

As useful as it is to identify these five failure factors, the real value of my research can be found in its practical application to the marketing strategy process. The detailed findings of the research, which space does not permit here, have led to the creation of a practical tool that allows marketing strategists to evaluate their own marketing strategy, identify exactly where it is at risk of failure and to correct those weaknesses before implementation. Using this Strategy Diagnostic tool, the pharma and medtech marketers can focus their improvement efforts onto the small number of issues that make the most difference. This novel and practical tool for pharma and medtech marketers is detailed in my book ‘Brand Therapy’ and you can also find a 20-minute overview of it on my YouTube channel.

When used by brand teams, it empowers them to objectively and systematically improve their marketing strategies and to evaluate competing strategy options.

Getting Professional

This research, and the Strategy Diagnostics tool that emerges from it, is a new and effective tool for marketing professionals in the life sciences industry. It gives marketing strategists an instrument for being more effective and more successful than their competitors. But in one sense the Strategy Diagnostics tool is old and established in our industry. As anyone who has worked in R&D, Clinical Trials or Manufacturing will tell you, professionals in those functions have used analogous tools for decades. By considering their own failures and mistakes, our colleagues in those functions have developed good practice tools and guidelines in such as GMP, GCP and GLP. Their highly-effective tools are one of the things that marks them out as professionals. It is a level of professionalism that their pharma and medtech marketing colleagues should aspire to and emulate.

AUTHOR BIO Brian D Smith is a world-recognised authority on the evolution of the life sciences industry. He welcomes comments and questions at brian.smith@pragmedic.com

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Health Canada New Validation Rules (Version 5.0) For eCTD and non-eCTD Submissions

The objective of this article is to provide validation updates of Health Canada. The Canadian Health Agency will be using the electronic Common Technical Document (eCTD) and non- electronic Common Technical Document (non-eCTD) validation rules version 5.0. The purpose of the updated validation rules is for the successful dispatch of the dossier to the Agency without any errors and warnings. Amendment to the validation rules for Health Canada is to help the sponsors to avoid submission rejection due to errors and warnings in the submissions and to avoid time consuming follow-ups. The errors detected by the Agency will be sent to the sponsors in a Zip format.

These amendments will come into effect for all Health Canada submissions from November 01, 2020. This article mainly focuses on file characters, size, type, document properties, naming conversion, metadata and XML elements that help in understanding the Agency requirements for dossier dispatch.

S D Devendra Raj, Senior Manager, Freyr Software solutions Private Limited

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H

ealth Canada is the Agency responsible for the wellbeing of the Canadians by ensuring high-quality health services and minimising the health risks.

Regulatory submissions for Health Canada can be done in both electronic Common Technical Document (eCTD) and nonelectronic Common Technical Document (non-eCTD) formats. However, they need to comply with the validation rules provided by the health authority to avoid rejections and follow-ups. Health Canada keeps amending these validation rules to assist the sponsors for the successful dispatch of the submissions.

The Agency will be using the recently updated version of validation rules (version 5.0) for eCTD and non-eCTD submissions effective from November 01, 2020. Upon submissions, the Agency will detect and notify the validation failures to the sponsors in a .zip format, which must be reviewed, corrected and resubmitted with the necessary modifications. Recent updates in the validation rules mainly focus on file characters, size, type, document properties, naming conversion, metadata and XML elements.

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Validation Rules - Classification

Health Canada eCTD and non-eCTD format updated validation rules (version 5.0) are broadly classified as: • General • Portable Document Format (PDF) Analysis • Referenced Files • XML Analysis • Regional • ICH Backbone • Study Tagging Files (STF) • Regulatory Enrolment Process Validation Criteria for Regulatory Submissions in the eCTD format GENERAL

This section mainly discusses the files (documents) and folders in the sequence of the submission. In a sequence folder structure, there should not be any empty files and subfolders present. Also, the files should be opened without any security access permission for the viewer. The file size should not exceed 200 MB for PDF and 100 MB for XPT documents, respectively. The sequence of the submission that is validated should be the highest in the application folder. A proper sequence lifecycle should be seen in the application folder. While validating the current sequence, the previous sequence should be made available; otherwise, the validation will throw errors. Word documents should be in the readable format and no password is allowed while submitting the dossier.

tion is allowed as per the ICH eCTD specification. The operational attribute of the files for the initial sequence should always be new.

REGIONAL

All the files should have only one file extension. The sequence number should be followed by subfolder M1 which in turn followed by subfolder ‘CA’. All the documents and leaf should have appropriate naming fulfilling the ICH eCTD criteria. The leaf title should not be left blank. The application number should start with the letter ‘e’ for all CA submissions. Replaced files should have identical content as referenced files.

The cover letter should not exceed more than three (3) pages. Node extensions in module 1 backbone (ca-regional. xml) are not allowed, except in 1.2.6 Authorization for Sharing Information, 1.2.7 - International Information and 1.6.1 - Comparative Bioavailability Information Also, the node extension title should not be left empty. No ‘append’ operation is allowed in Module 1.

ICH BACKBONE

Checksum type attribute should have MD5 value. Index and MD5 checksum files should exist. The utility folder should be present in M1. The number of leaves directly under a single node must not exceed 1000. The rule applies only to module 5 while using node extensions and also to leaves with operation attribute

PDF ANALYSIS

PDF documents should be in a readable format and should not be damaged.

Bookmarks and hyperlinks should be active, relative and should have a magnification setting of ‘Inherit Zoom.’ There should not be any password-protected documents. Document properties such as PDF version, page layout, magnification, fast web view should match ICH eCTD criteria.

Health Canada keeps amending these validation rules to assist the sponsors for the successful dispatch of the submissions.

‘new’. Do not mention strength values in the dosage form attribute in the sections 2.3.P, 3.2.P, 3.2.A.1 or 3.2.A.2. Any numeric value found in these attribute values will be reported as an error. If the strength value was already present in the previous sequence, the rule will not report an error for the current sequence. Leaf elements in 3.2.R Regional Information heading must be provided using node extensions. PDF files are not allowed as leaf elements directly under 3.2.R Regional Information heading.

STF

The value of the study-identifier/category/ study-id/title element must not be empty.

STF leaf element must reference another STF leaf upon append. Category information must be provided for certain STFs. Leaf references in the STFs should always target content files, not STFs. The STF study IDs should not be changed in the application life cycle. There should be only one file tag for each doc-content.

If Study Tagging Files (STFs) are used in the current validating sequence being validated, the node 5.3.7 must not be used. The Case Report Forms must be referenced from the STFs. The previous sequences present in the same dossier will not be checked. Leaf elements present in module 4 (except those in subsection 4.3), with an operation attribute ‘new,’ can use either node extensions, STFs or may be placed directly under the TOC sections. Leaf elements, with an operation attribute ‘new,’ in subsections 5.3.1, 5.3.2, 5.3.3, 5.3.4, 5.3.5 & 5.3.7 must use only node extensions or STFs. Although both node extensions and STFs are acceptable for study reports, only one or the other approach must be used consistently throughout the lifecycle of a leaf. Also, in a specific sequence, all leaf elements must use the same approach.

Validation Criteria for Regulatory Submissions in the non-eCTD Format

REFERENCED FILES

GENERAL

Referring to the other files (Hypertext Reference – HREF) within the applica-

All empty folders must be deleted before submitting the transaction to Health www.pharmafocusasia.com

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PDF ANALYSIS

Before submitting to Health Canada, ensure PDF documents are not password protected. The acceptable PDF versions are 1.4, 1.5, 1.6, and 1.7 and ensure the PDF documents are created using acceptable PDF versions. All the bookmarks must have only one assigned action that should open the destination page. The settings should be verified in the bookmark properties. Ensure that the PDF document does not include attachments/ portfolio documents. PDF documents exceeding 10 pages should have bookmarks except for literature references in sections 3.3, 4.3 & 5.4; and Health Canada application e-forms.

REFERENCED FILES

File path length character includes the file name, and the count starts at the application folder. The correct structure path for a non-eCTD transaction is x123456\m1.

Conclusion

Health Canada has updated the validation rules for Regulatory transactions submitted in the eCTD and non-eCTD formats. The purpose of the validation rules is to help sponsors in providing

AUTHOR BIO

Canada. Check the size of each file before submitting, to ensure it does not exceed the maximum file size limit (200 MB).

File extensions written in uppercase letters are not accepted and no manual change is allowed. The document should not have password protection and should be in a readable format.

a valid electronic transaction to Health Canada and reduce errors and followups. Sponsors can use a commercially available tool to validate their Regulatory transactions in eCTD and non-eCTD formats, before filing them to Health Canada. Health Canada validates each Regulatory transaction and if the errors are detected, a Validation Report describing the errors will be sent to the sponsor.

So, it is very important to file a submission to the Health Authority without any errors and warnings by complying with the ICH specifications and by validating the submissions which in turn results in approval of license to the product for marketing and human use.

Devendra is a competent professional with diverse experience in Regulatory affairs, Physiotherapy, Client relationship, operations, training/mentoring, team management and teaching. Devendra has Expertise in ensuring adherence to guidelines and requirements of different Regulatory authorities, quality systems and Regulatory compliance. Devendra has knowledge in medical and scientific literature search, and abstract writing as well.

High Containment Isolator for Micronization

))

1

This isolator reaches a Containment Performance Target (CPT) of 50ng/m3 and can host different sizes of jet mills to micronize down to a few microns.

2 The machine is fully automated with a centralized control system and HMI touchscreen panels.

3 For large production batches

all the 9 chambers are in use. For pilot batches, only a few chambers are used to minimize cost of operation and cleaning.

WWW.FPS-PHARMA.COM - INFO@FPS-PHARMA.COM

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Vietnam

EU Pharma's strategic imperative Vietnam's rising middle-class and increased modernisation of healthcare had already made it a key market for pharma. Now with the EU Vietnam FTA, winning in Vietnam is a strategic imperative for EU-Pharma. To be successful in Vietnam, EU pharma should consider a range of initiatives.

Aditya Agarwal, Principal, Roland Berger

V

ietnam is the European Union's (EU) second largest trading partner in ASEAN and close to 10 per cent of EU exports to Vietnam are pharma products. For various mid-tosmall sized EU pharma players, Vietnam has remained an alliance or a distributor led market. With increase in demand, positive economic prospects, increase in per capita healthcare spending and the boost of EVFTA, Vietnam is a strategic imperative for EU-Pharma.

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The time is ripe to prioritise Vietnam Growing demand and COVID dividend

Vietnam is one of the few economies in Asia which is expected to see a net growth in GDP per capita and income in 2020. It's enjoying a COVID dividend and leading cos across sectors, and is seeing Vietnam as a promising location for supply chain diversification. Healthcare spending in Vietnam is

expected to grow at nearly 6.5 per cent annually, with an encouraging sign that portion of public expenditure is rising faster. While traditionally, the market has seen strong growth in branded and unbranded generics, Vietnam lately has shown a higher appetite for patented

STRATEGY

products, driven by better affordability and improved market authorisation protocols. The pharma market is expected to see a stronger growth than the healthcare services market.

Other factors contributing to growing demand for pharma products is the rising middle-class, and ageing—it is expected that by 2038, 20 per cent of Vietnamese people will be over 60 years old.

ing other tools like cost plus method.

Government policy has also fostered a burgeoning health platform industry with several players emerging.

EU-Pharma can take advantage of these trends: exchange of information, engagement of the broader set of stakeholders is easier for them compared to their non-EU peers, due to the strengthening of trade relations between EU and Vietnam.

Modernisation of healthcare with new investments

EU-Vietnam FTA provides a clear boost

In addition to rising demand, a few factors are leading to increased modernisation of healthcare: A. Medical tourism: Vietnam has been positioning itself as a medical tourism destination. As per official statistics, nearly, 350,000 foreign visitors sought medical treatment last year. Treatments span the full range of medical services, with the most common choices of services including dental care, cosmetic surgery, cardiology intervention and fertility treatment.

Medical tourism plans, also call for driving increased modernisation and international standards for outpatient and emergency care services B. Privatisation: International and regional private players are keen to tap into the growth. Until recently, most of the healthcare services were provided by public hospitals. In the last few years though, public health stakeholders, have shown an interest in driving privatisation of healthcare to reduce fiscal pressures; this led to stake sales in public hospitals and, a positive outlook towards private financing and partnerships by public hospitals C. Increased sophistication of public players: Public players, especially leading educational institutions have been forming cross-border partnerships to increase industry know-how and improve the talent pool Similarly, beyond use of simple tools of external pricing referencing, pricing of the products in recent years has started includ-

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The real boost for further interest in Vietnam, though, comes from EVFTA. The recently auctioned FTA has 3 clear benefits for EU pharma players: Reduction of most tariffs and barriers, leading to a competitive positioning with pricing and affordability of drugs: about 70 per cent of the tariffs have been reduced, additionally some non-tariff barriers like direct pharma imports which was previously not allowed, is now permitted. EU investors are now allowed to establish a foreign invested enterprise to import pharmaceutical products and sell to local distributors or wholesalers EU FIEs would also have a specific exception that they can build their own warehouses. Post decree 55, FIEs were not permitted to own warehouses.

Increased market access under the national procurement schemes: Certain pharma bidding packages which were previously only open to local distributors and pharma players, shall now also be accessible by EU pharma.

These include marquee national tenders at Vietnam’s social insurance program, the Ministry of Health, the Hanoi and Ho Chi Minh City Department of Health, and 30+ hospitals. The share reserved for domestic suppliers/ producers will diminish over 15 years to a final share of 50 per cent.

Reduced requirements of local clinical trials: EU players can now selfconduct or manage trials in Vietnam; additionally, Vietnam will withdraw existing clinical trials requirements on

ethnicity which were not in line with international standards Faster market authorisation or longer patent protection by additional years if authorisation process crosses threshold Key considerations in Vietnam's Pharma market Hospital channel management:

Hospitals are a key dispensing channel facing a multitude of challenges - talent, budget and capacity. EU-pharma players, especially those which are mid-sized could go beyond the usual engagement techniques and adopt a solution driven approach to win share and advocacy, such an approach might have a higher return on investment rather than deploying a large sales force. Additionally, KOLs in Vietnam are looking for better content, and a targeted approach focusing on their needs; digitisation of HCP engagement provides a strong opportunity to address this.

Solution oriented approach: From outdated equipment to shortage of medical staff; from budget shortages to overcapacity – public hospitals are looking at solutions across the board.

Private hospitals too while benefiting from demand require help.

A leading private hospital CEO said, "Young qualified doctors often choose to work for public hospitals to get more clinical experience and opportunities to study abroad"; Led by MedTech players, a solution driven model has been working well with public and private hospitals. For example, a leading device player in clinical microbiology realised the lack of trained staff on advanced tests and set up an education program with public hospitals.

Due to long reimbursement cycles, hospitals are forced to manage working capital pro-actively, further accentuating the affordability challenge. Innovative financing of treatments, some already being piloted need to be launched at scale; private insurance players have

STRATEGY

Collaborating with distributors

With decree 54, FIEs had to rely and work closely with local distributors or work with regional ones to manage them.

While EVFTA allows for FIEs to establish warehouses, and participate in tenders, distributors would continue to play a pivotal role, especially for small to midsized players. FIEs will need support from

distributors on provincial tenders, engaging with KOLs and increasing footprint in new channels. While working with regional players is an option, regional players also rely on local players due to factors like reach, presence and regulations. Working with local distributors at least for a part of the portfolio is recommended, to increase local footprint and manage risks of decree 54. Local players though might lack some capabilities, hence collaborating with them or investing is a key strategic consideration. For example, one leading specialty pharma has been arranging for training to improve KAM capabilities of the distributor.

Bespoke models of distribution: Given the varying nature of distribution reach and capability, established pharma players in Vietnam, also tend to adopt bespoke distribution models.

For example: a multi-speciality player with generics and innovative drugs, has chosen 3 different models: Best of breed for vaccines: to distributors that have vaccine experience and adequate cold chain infrastructure Up-country agency: a distributor who holds the agency for its portfolio in up-country National distributors for prescription drugs: A national distributor who does not have reach in up-country region, but services for various distribution needs others for its prescription drugs

and reduced drug import hand-offs, EU-Pharma might be able to command a certain cost advantage which could be used for driving patient affordability or adherence.

Additional considerations

Government and policy shaping: Like other emerging markets, working closely with the government on policy shaping for new innovative treatments can prove to be valuable. Vietnam has been trying to reduce dependence on neighbouring markets for providing advanced treatments; EU-pharma should consider bringing knowledge from home markets and also facilitate exchange of ideas.

Impact investing: Vietnam has been seeing a surge in impact investments in education and healthcare.

EU-pharma could try to contribute and participate in these investments to develop the overall health ecosystem.

Setting up M&A's / JVs has been a proven way for various MNCs to enter the market, but EU-pharma could also set up a trading company to avail the benefits of EVFTA. Investors are required to obtain an import license along with other certifications, obtain proof of origin for EU pharmaceutical products. While several challenges in winning the market exist, starting now provides an opportunity to work with different stakeholders and shape the market.

Drug affordability

A large part of healthcare spending in Vietnam continues to be out of pocket.

While price regulations have ensured that prices are regulated and managed effectively, affordability of patients continues to be a challenge.

Decree 54, local trials and related protocols for working through additional layers for drug import, have led to an increase in compliance and drug supply costs, impacting competitiveness.Given the strong market access allowance through bidding packages, reduction in requirements for local trials

AUTHOR BIO

expressed a strong interest in developing companion products or indication specific offerings, as such products help with driving distribution for some of their core offerings.

During bidding and tenders, some of these unique offerings can be combined as value added services, to gain nonprice related advantages; With their strong experience of developed markets, EU-pharma could create a differentiated value proposition for its customers.

The four broad themes of solutions for hospitals which can be considered: i) infrastructure support; ii) financing (including working capital) support to enable better treatments; iii) training HCPs; iv) new treatment protocols and design of workflows Tailored KOL engagement: while KOLs have adopted digital engagement, a lot more is desired in terms of tailoring content for Vietnam. In a recent survey, nearly 60 per cent KOLs felt that they were not informed enough about the recent breakthrough drugs or indications, in their respective TA's. Further, KOLs expressed following expectations which were less visible to them: Latest information – Latest clinical trials – Other related topics like discovery, adverse events > Various information – Drug information (efficacy, side effects…)

– Other disease management > Timely and appropriate – Quick response to demands for information – Appropriate information according to treatment stage

Aditya is a Principal with Roland Berger in Singapore. He is a core member of the Healthcare and Life Sciences practice, serving clients on a range of strategic and performance improvement issues. You may reach him at aditya. agarwal@rolandberger.com

www.pharmafocusasia.com

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SUEZ

Solving the toughest water and process challenges Geert Verstraeten, General Manager, Analytical Instruments business and Sievers product line, SUEZ – Water Technologies & Solutions

What is your background in the industry?

I’m originally from Belgium and I studied to be a chemical engineer with a specialisation in biochemistry and biotechnology. When I started out, it was my goal to get into the biochemistry or biotechnology industry as a plant director but when I graduated from university, my first job was teaching chemistry, biology, and math. Teaching was a very good experience because it helped me to understand leadership. I realised how important it was to influence, motivate, and empower the students. I learned that this type of leadership role was a good fit for me so I decided to change my career path.

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I joined Analytical Instruments in 1999, as the European Sales Manager. At that time, it was part of IONICS*. I had several fantastic and inspirational mentors where I learned the ropes and started building the sales team. We had success in growing the business and I moved up the ranks. Analytical Instruments was acquired by GE and finally by SUEZ. I’ve been with the company for 21 years, so I must love it! The things that motivate me are still the same:making the world a cleaner place, environmental sustainability, and most importantly, developing our fantastic people.

STRATEGY

Geert Verstraeten is the General Manager for the Analytical Instruments business and Sievers* product line at SUEZ – Water Technologies & Solutions. Sievers is a market leader for ultra-pure water instrumentation in the life science, industrial & environmental industries.

A native of Belgium, Geert graduated from the University of Ghent as an Industrial Engineer in Chemistry. Geert began his tenure with Sievers instruments in 1999 and for over 21 years and now as part of SUEZ, has developed increasing responsibility holding roles in sales, service, marketing and management.

www.pharmafocusasia.com

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Sievers 500 RL

What does the Sievers product line represent?

When I think about Sievers, I think about innovation and being at the forefront of technology to help our customers. We really listen to our customers and find creative technical solutions to solve their issues.

This mindset comes from our heritage. Sievers has been a pioneer in the analytical instrumentation industry since introducing membrane conductometric Total Organic Carbon (TOC) detection technology to the market in 1993. Developing a better, faster and more efficient solution for our custom-

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ers was our goal then, and it is still our goal today.

The newest product in the Sievers portfolio is the best example of what Sievers represents. Using our expertise in compendia water testing, we have launched groundbreaking technology for endotoxin detection.

Launching the Sievers Eclipse* Bacterial Endotoxins Testing (BET) platform was driven by finding a better, faster solution to endotoxin testing. We listened carefully to our customers about their challenges using the 96-well plate.

We went back to the drawing board and developed a faster, simpler, and more environmentally sustainable solution.

All of those things working together are the reason we launched Eclipse and we’re very excited about the future of endotoxin testing.

Why is pharmaceutical water testing so important?

The global pharmaceutical industry has four fundamental parameters that are used to measure the chemical purity of water for production: conductivity, TOC, endotoxin, and bio-burden. Those parameters are used in a wide range of pharmaceutical applications and are highly regulated.

TOC, conductivity, and endotoxin are metrics that manufacturers must monitor

STRATEGY

to comply with regulations, but compliance is only the beginning. They also allow you to go beyond compliance and achieve optimisation, process understanding, and process control. When using accurate and reliable technology, TOC, conductivity, and endotoxin data are valuable tools that can help improve cGMP processes and product quality.

What are the trends for analytical instrumentation in the life sciences industry?

The pharmaceutical industry has always searched for ways to improve product quality. Water quality became a focus since it is a key input for product quality. As a result, the analytical instrumentation industry focused on improving TOC analysis in the laboratory. The industry measures TOC on the parts per billion, or ppb level. When measuring a drop of water in an Olympic sized swimming pool, accuracy is critical. In the past, the analytical instrumentation industry focused on improving the accuracy, precision, and robustness of TOC analysers.

Over time as instrument accuracy and precision continued to improve, the industry began focusing more on efficiency. Lab analysis required a huge amount of grab samples. The analysts were sampling, waiting for results and then finally analysing the results to report back to quality teams so they can release water. The time and resources to do the work also increased as regulations became stricter. How can a pharmaceutical facility improve efficiency? One of the ways is by increasing automation.

One of the key trends in the industry is moving from laboratory monitoring to online monitoring to save time, money, and human resources. Sievers technology is used in both laboratory and online environments. This like-for-like technology makes moving from lab to online easier. The transfer of technology and methodology allows for better and faster implementation when making the transition.

Why is online monitoring technology so important?

Laboratory-based testing requires human resource time for sampling and analysis while online TOC analysers report data in real time. Online monitoring means plant supervisors don’t need to wait to get results so companies can move faster.

The overall water monitoring process becomes more efficient.

Online water monitoring is becoming more and more important because the industry has realised it saves time and money, reduces errors, and improves product quality. Manufacturers can use the data to drive greater process understanding and process control.

The benefits of automation, process understanding and process control are outlined in the FDA’s guidance document on Process Analytical Technology (PAT). Online monitoring fits well within the framework for PAT.

It is our goal to partner with our customers to bring them to the next stage in their technology journey. That could be transitioning from lab to online water monitoring, RTRT, endotoxin, or online cleaning validation.

What is next for online monitoring?

The next evolution of online water monitoring for pharmaceutical grade water systems is facilitating Real Time Release Testing (RTRT). It is important to highlight that RTRT is not simply about installing an online TOC analyser.

RTRT means much more than having

access to data. It is only when the data is used to release the water, when the real improvements in speed, cost and efficiency begin.

The validation of instruments is important for RTRT. Without proper validation, the value of real-time data is lost. One should consider the underlying TOC technology and the extent to which it can be validated against quantitative ICHQ2 (R1) guidelines. This level of validation can only be achieved with an analyser, compared to sensor technology. Without comprehensive validation, how can you trust the data generated from the instruments?

SUEZ offers Validation Support Packages (VSPs) for Sievers instruments that make validation easy. This gives you the assurance that the data can stand up to close scrutiny. To use real-time data and PAT to its full potential, technology must be qualified, and methods must be validated per regulatory requirements.

ASTM E2656 is an important guidance document outlining the aspects of RTRT implementation. RTRT is a powerful tool to improve efficiency, reduce costs, save time, and stay compliant to regulations, but the technology and implementation play a key role.

What are the application trends in the life sciences industry?

Historically, TOC data was measured in purified water systems and it continues to be a critical parameter. One of the growing trends is using TOC and conductivity in Cleaning Validation processes. Cleaning validation is not new to the industry. However, companies are evaluating ways to make their cleaning validation processes more efficient to reduce equipment downtime.

TOC and conductivity have become important quality metrics for determining cleanliness of cGMP equipment. They also offer several benefits compared to product-specific methods such as HPLC. TOC and conductivity give a more holistic view of cleanliness

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S i e v e r s Te c h n o l o g y

compared to other methods that only measure specific components.

TOC methods are also easier to use than HPLC, allowing more people to be trained, and trained faster. Anyone can be taught to operate a TOC analyser.

The ease of use of TOC for cleaning validation allows organisations to manage human resources more efficiently, save time, and improve productivity.

understanding and control for cleaning validation programs. Using TOC data enables further cleaning validation process automation and has become the best practice. Cutting-edge online monitoring technology is here today.

The facilities that have not adopted TOC and conductivity for cleaning validation, and are not planning for the transition from lab to online, risk falling behind the competition.

What’s next for cleaning validation?

What’s the future for analytical instrumentation in the pharmaceutical industry?

Similarly to how the industry is advancing with water monitoring, the next trend in cleaning validation is moving from laboratory-based cleaning validation to Online Cleaning Validation. The FDA released its guidance document on PAT in 2004. Since then, we have seen the steady movement from lab to online water monitoring systems. We see the same trend in cleaning validation.

PAT lays the foundation for greater

The pharmaceutical industry is very demanding and forward-looking. We believe PAT is the future. PAT has been around for a while.It provides continuous process understanding, process control, and efficiency gains. Online analytical instrumentation technology and automation fit well with PAT and have clear, quantifiable benefits.

We at SUEZ focus on finding the most efficient solutions for our customers. Our vision is to focus on our customer’s needs and use our technology portfolio to help them. We started with improving TOC and conductivity instruments for the lab. Next, we added more support and services to those offerings to deliver more value.

Most recently, we expanded our portfolio to next-generation bacterial endotoxin testing.

Now, it is our goal to partner with our customers to bring them to the next stage in their technology journey.

That could be transitioning from lab to online water monitoring, RTRT, endotoxin, or online cleaning validation.

SUEZ is focused on bringing technical expertise to our customers. Our customers can trust us to be a partner and to deliver results they can count on. *Trademark of SUEZ; may be registered in one or more countries Advertorial

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190,000 READERS in pharma industry across the globe.

A leading brand name consisting of information with latest breakthroughs and trends in the industry, with huge subscriber database that leads you to best promotions in the market. uses on Strategy, Research & Development, Clinical Trials, Manufacturing, Information Technology. Available in online version. e-Book also available.

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Challenges and Solutions in HCP ELISA Development B The importance of reliable Host Cell Protein (HCP) monitoring during manufacturing of biopharmaceutical drugs In this article we will discuss regulatory recommendations concerning the determination of process-related impurities during biopharmaceutical drug manufacturing.

Furthermore, we suggest their implementation into the setup of a reliable Host Cell Protein (HCP) monitoring using Enzyme-linked Immunosorbent Assay (ELISA) during early and late stages and provide valuable insights into critical steps along the way of HCP ELISA setup.

Martin Fรถge, Business Development Manager, BioGenes

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iopharmaceutical drugs make up a large portion of global pharma sales, with 8 of the top 10 global drug blockbusters in 2019 being recombinant biopharmaceuticals.

Drug development is separable into five phases: i) Pre-clinical Phase, ii) Clinical Trials Phase I, iii) Clinical Trials Phase II, iv) Clinical Trials Phase III, and v) the Market Authorisation Application (MAA) followed by the Drug Launch, after all previous steps have been passed successfully. To ensure high-level patient safety during Clinical Trials and upon drug product release, a multitude of regulations have been authored by different regulatory bodies, such as the US FDA and the EMA. The MAA requires a profound overall assessment of potential risks and benefits, the so-called Critical Quality Attributes (CQA), which are included in the Common Technical Document (CTD). Host Cell Proteins (HCP) are one such CQA, they stem from the production cell line used for biological product manufacturing.

Defined as process-related drug impu-

STRATEGY

rities, HCP can negatively influence the quality, safety, and efficacy of a biological drug product. The HCP formation by such complex cellular production systems is influenced by a multitude of biotic and abiotic factors, which makes it hard to predict the HCP pattern of individual manufacturing processes. In particular, ICH Guidelines Q6B, Q8(R2) and Q11 define such impurities and address the need for the precise monitoring and the reduction of HCP during stepwise Downstream Processing (DSP), all the way down to low amounts. Although no precise values are specified, the common agreement is to reduce the HCP burden below 100 ppm in the final drug substance. Naturally, the accurate detection of HCP impurities in subsequent DSP samples down to the final drug substance heavily depends on the establishment of a reliable and robust method for HCP measurement. To achieve this, the use of multi-faceted HCP analysis methods is recommended. The EnzymeLinked Immunosorbent Assay (ELISA) is still considered the gold standard for HCP measurement, as it has advantages such as high speed, sensitivity and high throughput. Nevertheless, to overcome intrinsic limitations of individual methods for HCP quantitation, the implementation of orthogonal methods is strongly advised. This will be addressed below.

Selection of the Appropriate HCP ELISA

The HCP ELISA for HCP quantitation can be divided into three main formats: i) the commercial ELISA, also referred to

as generic HCP ELISA; ii) the platform (or multi-product) HCP ELISA; and iii) the process-specific HCP ELISA. While the generic HCP ELISA makes use of a broadly active antibody coverage approach which is specific only for the selected cell line of recombinant protein production, the latter two HCP ELISA formats are based on greater specificity towards the manufacturing and processing of particular biopharmaceuticals.

The answer to the question: “Which HCP ELISA is best to use during which phase of development of a drug candidate?� is not a clear dichotomous one, however there are common agreements for when the usage of the comprehensive HCP determination of either one or the other format is favoured. When discussing the advantages and disadvantages of each format, one needs to recall the previously-mentioned steps of drug development and all accompanied processes. During Phase I of clinical trials, the drug substance is required to be produced under GMP-grade manufacturing conditions at pilot scale volume and relies on proper technology transfer from pre-clinical process development, with putative changes in DSP still likely to happen. The drug substance used during Phase II of clinical trials has to be produced at larger volumes than the pilot-scale volume, using defined process parameter specifications, and thus meeting the requirements for high process robustness. By contrast, the drug substance used for testing in Phase III of clinical trials has to meet identical requirements as for continuous drug

production after marketing, providing at least three different batches of drug substance at production scale. For this phase of drug manufacturing, all of the processes need to be validated, including the use of analytical methods. If changes to manufacturing steps are carried out at this stage, process validation has to be repeated until a sufficient consistency is achieved. This also includes the monitoring of residual HCP impurities, which can technically vary in amount and composition when changes during manufacturing or DSP are introduced.

The common recommendation is therefore to rely on a broadly active generic HCP ELISA only during method development. When moving forward towards application for extended clinical trials in Phases II and III, the implementation of a process-specific HCP ELISA usually proves adequate for HCP monitoring, allowing the criteria for assay validation to be meet. The use of a platform HCP ELISA can be sufficient when manufacturing and DSP conditions and the principle nature of different biopharmaceuticals only vary in a small range without having major influence on the respective HCP pattern (see also Figure.

1). One aspect to factor in when being confronted with the decision of which HCP ELISA format to use for continuous HCP monitoring is the potential risk of limited antibody availability. While a commercial HCP ELISA might not be supplied constantly during the average life cycle of a biopharmaceutical, this risk can be significantly mitigated when choosing the development of a process-

Figure 1: Overview on different steps of drug development including downstream process development, and recommended use of HCP ELISA formats for HCP monitoring

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Figure 2: Schematic workflow including critical steps marked along the different phases of specific HCP ELISA development; DIGE = Difference Gel Electrophoresis, DS = drug substance, DSP = downstream process, IAC = Immunoaffinity Chromatography

specific HCP ELISA with a large-scale immunisation approach (see below).

Careful Functional Assay Design

The suitability of an HCP ELISA for HCP monitoring is usually determined by performance criteria, such as the assay’s sensitivity to detecting HCP trace amounts even in highly purified samples demonstrating the HCP logreduction over the various steps of DSP, the stringent dilution linearity, and a sufficient HCP-specific antibody coverage. In the following, critical aspects during specific HCP ELISA design are highlighted (see also Figure. 2).

One such factor is the selection of appropriate HCP mock material for polyconal antibody (pAb) generation.

Ideally, a great similarity in the HCP spectrum of both the HCP mock material and a process sample originating from recombinant drug substance (DS) production would indicate mock suitability for pAb generation. This can be analysed with Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis (SDS PAGE) using two-dimensional Difference Gel Electrophoresis technology (2D DIGE). Here, the HCP spot pattern of an early DSP sample is qualitatively compared to the pattern of a given mock sample. Also, HCP 34

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of low molecular weight (LMW) tend to be less immunogenic, and thus an underrepresentation of LMW-specific antibodies is frequently observed in standard HCP immunisation regimes.

A counterstrategy is the fractionation of the HCP prior to the immunisation of host animals, with both fractions in parallel. Furthermore, a differential pAb panel can be generated by employing two different host animal species (goat and rabbit) to be immunised, which allows for another level of selection. The HCP-specific immune response in indi-

vidual animals is monitored by ELISA titer determination and Western blotting. This also includes antiserum testing for cross-reactivity against the DS, in order to exclude false-positive HCP ELISA results during the process sample analysis. A preliminary ELISA then is set up with affinity-purified antibodies and its performance is evaluated based on the key parameters detailed above.

From this, the species which matches best the quality criteria is selected for extended immunisation and subsequent large-scale antibody purification.

Take Home Messages • Ensure HCP monitoring along the biopharmaceutical drug production process • Allow sufficient development time for a customised HCP ELISA assay • Use separate LMW HCP fraction for immunisation to tackle immunogenicity issues • Perform immunisation of two different species for optimal results • Consider methodological limitations and increase the reliability of your HCP coverage determination by applying orthogonal methods such as 2D Western blotting, IAC-2D DIGE and potential supplementary mass spectrometry

STRATEGY

The assessment of the suitability of an HCP ELISA for HCP monitoring includes the HCP-specific antibody coverage. This coverage analysis is performed to determine the ratio of HCP species that are successfully detected by the pAb, expressed as percentage HCP coverage. The traditional method is the 2D Western blot, using the HCP mock material and/or an early DSP sample. As mentioned above, the use of orthogonal approaches is advised. One such method involves the usage of Immunoaffinity Chromatography (IAC) with immobilised pAb, followed by 2D DIGE. The 2D DIGE comparison of the IAC eluate of the pAb-bound HCP fraction with the total HCP sample allows for the estimation of HCP coverage by the antibodies under non-denaturing conditions.

However, both analytical approaches come with inevitable methodological limitations. To achieve a scientifically sound estimation of the HCP coverage, the application of both methods for best reagent characterisation is strongly recommended. The completion of HCP ELISA set up includes optimisation with a focus on the titration of all reagent concentrations and incubation times, accompanied by an evaluation of assay specificity, accuracy and precision. This state-of-the-art HCP assay development includes the suggested use of both the HCP mock material and a relevant process sample during method optimisation. When factoring in the average developmental time for a process-specific HCP ELISA of at least 1.5 years, manufacturers of biopharmaceuticals are advised to begin planning for the introduction of reliable HCP monitoring assays during drug development as early as possible, in order to have a functional HCP ELISA at hand when assay validation is due. This also plays a role when a switch of manufacturer for continuous drug supply is considered. Taken together, the consideration of the critical steps mentioned here allows

for the implementation of robust and reproducible HCP monitoring during biological drug manufacturing.

Suggested Reading:

• Bracewell DG, Francis R, Smales CM. The future of host cell protein (HCP) identification during process development and manufacturing linked to a risk-based management for their control.

Biotechnol Bioeng. 2015;112(9):17271737. doi:10.1002/bit.25628 • Vanderlaan M, Zhu-Shimoni J, Lin S, Gunawan F, Waerner T, Van Cott KE. Experience with host cell protein impurities in biopharmaceuticals. Biotechnol Prog. 2018;34(4):828-837. doi:10.1002/ btpr.2640 • Zhu-Shimoni J, Yu C, Nishihara J, et al. Host cell protein testing by ELISAs and the use of orthogonal methods. Biotechnol Bioeng.2014;111(12):2367-2379.

doi:10.1002/bit.25327 • F. Wang, D. Richardson, and M. Shameem, “Host-Cell Protein Measurement and Control” BioPharm International 28 (6) 2015 • USP 39 Published General Chapter <1132> Residual Host Cell Protein Measurement in Biopharmaceuticals • ICH Guideline “Specifications: Test Proceedures and Acceptance Criteria for Biotechnological/Biological Products Q6B” (1999) • ICH Guideline “Pharmaceutical Development” Q8(R2) (2009) • ICH Guideline ”Development and Manufacture of Drug Substance (Chemical Entities and Biotechnological/Biological Entities)” Q11 (2012) • ICH Topic M 4 Q Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality (CPMP/ICH/2887/99) (2003)

AUTHOR BIO

Reagent Characterisation by Use of Orthogonal Methods for HCP ELISA Qualification

Martin Föge is a Business Development Manager at BioGenes in Berlin, Germany, since 2018. Here, he combines his scientific experiences with his knowledge on drug development and marketing.

Prior to his role at BioGenes, he completed a comprehensive training in Life Science Management, following his academic career including a Postdoctoral Position at University Clinics Jena and a research visit at Imperial College London. Martin holds a PhD in Microbiology from Friedrich Schiller University Jena, Germany.

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Formulating Haematopoietic Stem Cell Transplantation for Practitioners A technology-based health service

Transplantation is a medical procedure in which cells, or an organ, are extracted from one body and â&#x20AC;&#x2DC;fittedâ&#x20AC;&#x2122; elsewhere, either in the same body or in an altogether different one.

Transplanted entities could also be stem cells. Haematopoietic stem cell transplantation is a technological procedure intended for various ailments, genetic disorders or malignancies, and applied by Hemato-Oncologists at the point-of-care; the technology involves the handling of clinical-grade bioreagents/bio-components in closed systems.

The clinical presentation/aspect of the treatment could be designed as a comprehensive healthcare service model. Benefits of such a model would be wide-ranging and would include cost, ease-of-use, ease of access to high-end technology as translated to a medical procedure, and measurable treatment outcomes for the targeted medical condition, such as debilitating cancers, obtained from next-generation readouts.

S Dravida, Founder CEO, Transcell Biologics Lakshman Varanasi, Scientist, Instructor

T

ransplantation is a compelling need in India, and one that has few and very pricey providers mismatching the necessity. The frequency of occurrence of congenital or acquired blood disorders which can be treated by Haematopoietic Stem Cell Transplantations (HSCT, and sometimes termed Bone Marrow Transplant, or BMT) is sufficiently large for a viable corporate opportunity. Market research for these blood-related disorders in India indicates a rewarding market for HSCT treatment. The Asia-Pacific (APAC) and Latin-American markets hold the most

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promise for the bleeding/blood disorders disease indication. Their anticipated growth is due to steady increase in investments of local governments in improving access to healthcare, and the increasing tilt

by Big Pharma towards emerging econo-

mies. The blood cancer therapies market comprises leukaemia, multiple myeloma, and lymphoma; the first is further subdivided into Chronic Myeloid Leukaemia (CML), Acute Lymphocytic Leukaemia (ALL), Chronic Lymphocytic Leukaemia

RESEARCH & DEVELOPMENT

(CLL), and Acute Myeloid Leukaemia (AML). This market is anticipated to grow at a compound annual growth rate of 11 per cent year on year while the estimates from the footfall at different hospitals paint a similar picture.

The Indian Society for Blood and Marrow Transplantation maintains a registry of the stem cell transplantations done in India through its affiliate centres. The number of centres in India offering Bone Marrow Transplants (BMTs), also known as HSCTs, grew from 52 to 65 in 2016, and continue to increase at the rate of 10 per cent per year. 1878 transplants were made in 2016, as reported to the Indian Stem Cell Transplant Registry (ISCTR).

Among patients with aplastic anaemia, only 20- 30 per cent receive standard-ofcare treatment; which points to a larger need of HSCT procedure to be imparted.

There is therefore a large need for improving access to HSCTs in India (Kulkarni and George, 2019, Journal of Postgraduate Medicine). Data on disease prevalence is widely available, as is other census data in this regard. The leap from advancing clinical research, adoptions from the western medical technologies and practices to treatment centres in India, HSCT as a clinical procedure has been standardised and validated, has the sanction/ approval of the national medical agency, the ICMR Governmental guidelines. In the same pace, it is also believed that the new disease management strategies will evolve with home-grown scientific technological breakthroughs, R&D. The World Health Organization (WHO) in collaboration with the Worldwide Network for Blood and Marrow Transplantation (WBMT) monitors, coordinates, and recommends guidelines, standards for HSCT practice, all essential to harmonisation. Guidelines from the WHO state that regulation of transplantation at the national level is a governmentâ&#x20AC;&#x2122;s responsibility. The collection of accurate data on HSCTs and on relevant innovation and experience from responsible agencies worldwide, followed by its analysis and timely dissemination,

encourages establishment of uniform standards, best practices in this field. This will in turn automatically improve the packaging and clinical delivery of this critical treatment, enabling a vendor or technology provider to offer services to more than one market.

Post HSCT, survival in haematological disorders is linked to national macroeconomic indicators, one reason why the procedure must be optimised and delivered at cost. Organised support with financing the transplantation procedure would go a long way towards improving lifesaving access for a variety of haematological disorders. The disparity between GDP per capita and the cost of the HSCT is substantial while the government mediated financing in the form of a public-private partnership at national level such as the Aarogyasree scheme in India would go a long way towards improving life-saving access to a variety of haematological disorders. This would also incentivise the continued development of the technology and drive down its cost to be borne by the patient, and consequently make it affordable to the patient. Reimbursements will help the patient and the technology that will cause a proliferation of providers. A financing system for this technology, which is tailored to the Indian context, will benefit every stakeholder in its practice. While equitable and affordable healthcare is not easy to deliver, it need not remain a pipe dream in India forever. The larger concept of equitable and affordable healthcare as envisioned by the WHO in the Sustainable Developmental Goals 3.0 (SDG3.0) is applicable here too.

Myeloblasts with Auer rods seen in Acute Myeloid Leukemia (AML), advanced stage. Bone Marrow/ May-Grunwald Giemsa (MGG) stain.

Author: Paulo Henrique Orlandi Mourao.

The figure has been reproduced in the original format without any modifications. Use of this figure is governed by the Creative Commons Attribution-share Alike 3.0 Unported license.

India's first successful allogeneic bone marrow transplantation, i.e HSCT procedure, was done on 20th March 1983 at Tata Memorial Hospital, 37 years ago. Although HSCT is a procedure based on a simple principle, the outcome is now known to be dependent on a number of non-clinical technological factors: the sourcing of the biosample, the harvest and enrichment of the stem cell fraction from the biosample, stem cell yield, purity of the cellular fraction, the biosampleâ&#x20AC;&#x2122;s innate and process induced bioburden, product specifications and components, extraneous agents added to preserve the product until is transplantation, and product handling for clinical presentation, or HSCT; these factors can make or break the outcome. Also, these factors and their control constitute an integral part of the technology (and of any associated intellectual property). In order to best control these various variables and enable the best outcome, the technology provider should ideally (be a dedicated biotechnology company) provide services ranging from cell collection from donors to delivery at the point-of-care.

Biobanking facilities for haematopoietic stem cells can constitute a service in itself, and one that is of fundamental value in offering HSCT for immediate and tandem applications. The integrated banking cum transplantation procedure can, on the other hand, be offered as a package to the practitioner. (Biosamples are collected from bone marrow, or peripheral blood (after mobilisation from the bone marrow), or umbilical cord blood. For the autologous version of the procedure, stem cells are obtained from the patient in question (during remission); umbilical cord blood is not used here. The allogeneic HSCT procedure requires stem cells obtained from a matched donor who may be related to the patient. The authors believe that the ideal clientele for HSCT as a technological package are Haemato-Oncologists.

(Haemato-oncology pertains to the diagnoses and treatment of cancerous blood

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operated at the point-of-care, at a hospital or at the practitioner-designated technology provider’s facility opening up several working relationships between the stakeholders of HSCT technology practice.

“I have been actively monitoring the developments in the Healthcare industry around the world for nearly two decades and how it is facing the challenge of burgeoning cost of Healthcare. Healthcare budgets in advanced economies like the USA etc have reached unsustainable levels. The world needs very urgent reforms in the way pharma industry is providing solutions for major diseases like Cancers causing unsustainable burden on governments. The only way to drastically reduce healthcare costs is by introduction of advanced technologies like Stem Cell based treatments, Gene Editing, Personalized Medicine using Precision Medicine, Application of Artificial Intelligence and Machine Learning based Diagnostics and other such cutting edge technologies and innovation. India is uniquely positioned to adopt some of these advanced technologies and combined with its cost arbitrage deliver affordable healthcare to the world” says Mr Uday Chatterjee an angel investor in global med and biotech industry, representing a reputed global investment fund Indian Angel Network.

The benefits of advanced HSCTs in the form proposed, can be availed of not only by Indian nationals, but by patients worldwide. There are “those who AUTHOR BIO

disorders.) HSCTs are provided in India at BMT units in several reputed hospitals such as the Tata Memorial Hospital, Mumbai, the Christian Medical College, Vellore, Adiyar Cancer Centre, Madras, Apollo Speciality Hospital, Chennai, R&R Army Hospital, New Delhi, Gujarat Cancer & Research Institute, Ahmedabad. These units are known to continuously refine their facilities, techniques involved, and most often, the refinement is applied to making their services safer, more effective, and less expensive in the interest of the patients while the practising Hemato-Oncologists play a key role in the process.

The authors opine that if the Haemato-Oncologist is made the decision maker for both the patient and the centre where HSCT is offered, access to the technology, economies of the technology application in imparting HSCT works well popularising the cure option available. Neither the patient nor the treating centre will be at loss with this new service model where the practitioner is the user and client driving the demand sanctifying the very application with accountability of the transplant outcome, in control – An out of the box service model to offer HSCT with next generation benefits.

The HSCT procedure should be considered a medical technology for treating blood disorders as it is intended to improve the quality of healthcare at the point-of-care. The point-of-care refers to the physical location where the treatment is dispensed. The parts of the procedure that occur even before the encounter with the HSCT recipient have been unified, integrated, and take place inside a clinical-grade closed system made possible by recent advancements in the field bagging FDA approvals. The said steps include only the fractionation of the collected sample, isolation of the cellular population of interest, but not its customised formulation and ‘packaging’ for administration to the patient that involves human intervention. The system is portable, can be situated and

travel across international borders with the intention of receiving some form of treatment”, and many come to India.

Medical tourism in India has grown by leaps and bounds in the past decade into a US$ 9 billion industry in 2020, and is growing by 200 per cent. An increasingly large piece of this pie is for HSCT for blood -related disorders such as those mentioned above. The portion is likely to grow with an increase in the incidence of these diseases, and as hospitals in India continue to deliver. The foreign clientele comprises numerous nationalities, including Africa, and other Asian countries. A sizeable cohort of patients from Europe (Russia included), and the United States also visit every year. Cost, or the absence of analogous care in one’s native country, or both, is the primary driver of such tourism, for service that is on par, or nearly on par, with that in developed countries (Other determinants include to a lesser degree, culture, proximity, or perception of care). Here’s the point though that India has become a hub for medical tourists is not happenstance; it is the direct consequence of investment in training and technology, and supportive government policies. (It would be a shame if it were to squander this advantage.) All the more reason, then, for the design of a service model for HSCT, one that is appropriate to the Indian context and can benefit all. Technology is wealth- agnostic, and a lowering of the treatment cost of HSCTs will benefit people across the socio-economic continuum.

Subhadra Dravida is the Founder and CEO of Transcell Oncologics (www.transcellonco.science) that has developed a cell-based technology offered as point-of-care service to Hemato-Oncologists performing transplant (HSCT) procedures. She is a technocrat shaping new landscapes in the field of stem cell technology and it’s applications through Transcell. She can be contacted at suba.dravida@tran-scell.com Lakshman Varanasi is a Scientist, Instructor, Writer deeply interested in advancing research on catastrophic diseases. He has been involved in Oncology research for several years, and currently works as a Science Associate.

BOOKS

Controlled Drug Delivery: Volume 2 Clinical Applications (Routledge Revivals)

Surviving Cancer, COVID-19, and Disease: The Repurposed Drug Revolution

Author: Stephen D Bruck

Author: Justus R Hope

Year of Publishing: 2019

Year of Publishing: 2020

No. of Pages: 257

No. of Pages: 420

Description: Product Description: Published in 1983: Volume 2 deals with critical analyses of various test methodologies of polymeric implants, including their acute and chronic toxicological evaluation.

Description: Product Description: This book explains in easy-to-understand words the science behind repurposed drugs, commonly used pills already in your medicine cabinet that can kill cancer stem cells, the roots of cancer. Cancer stem cells are STIMULATED to REGROW and SPREAD and create resistance by standard treatments of chemotherapy, surgery, and radiation - THIS is the reason "cancers return and kill patients almost half the time." There are ways to stop cancer stem cells and he explains them in the book.

Controversial Statistical Issues in Clinical Trials Author: Shein-Chung Chow Year of Publishing: 2020 No. of Pages: 616

Description: The book focuses on issues occurring at various stages of clinical research and development, including early-phase clinical development (such as bioavailability/bioequivalence), bench-to-bedside translational research, and late-phase clinical development.

Numerous examples illustrate the impact of these issues on the evaluation of the safety and efficacy of the test treatment under investigation. The author also offers recommendations regarding possible resolutions of the problems.

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Analytical Testing for Pharmaceutical Industry in this Digital Age Joachim Weiss, Technical Director, Dionex Products, Thermo Fisher Scientific Other spokespersons Rich Youn, Senior Commercial Director, Commercial Operations, Asia Pacific and Japan (APJ) for Chromatography and Mass Spectrometry group, Thermo Fisher Scientific Ruby Ong, Senior Marketing Manager, Asia Pacific and Japan (APJ) for Chromatography and Mass Spectrometry group, Thermo Fisher Scientific Wai-Chi Man, Product Marketing Manager for Ion Chromatography, Thermo Fisher Scientific

What are the major trends shaping the developments of the pharmaceutical industry in Asia?

Rich Youn: As the hotbed of technological developments, Asia is riding the wave of global mega trends which include aging population, digitalisation, and the adoption of emerging technologies such as Artificial Intelligence (AI) and the Internet of Things (IoT).

These trends impact the pharmaceutical industry because as the population ages, we find that governments focus on making healthcare accessible, which in turns lead to lower drug prices. Ultimately, this brings pressure on the costs of drug production.

In the meantime, the global pharmaceutical industry is leveraging technologies towards Pharma 4.0 for connectivity, digitalisation and artificial intelligence in the development and manufacturing of pharmaceutical and biotechnology products.

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Would the global pandemic in 2020 impact the adoption of new technologies or the pharmaceutical industryâ&#x20AC;&#x2122;s transformation to Pharma 4.0?

Rich Youn: According to industry research firms, AI for the drug discovery and development market grew significantly due to the pandemic. The global AI for drug discovery and development market could reach US$4.81 billion by 2027 and attributed the rise in number of partnerships between AI providers and pharma and biotech companies to the development of drugs for treatment of patients affected from coronavirus as well as to helping scientists understand the protein structure of the virus, playing an integral role in drug design and accelerating vaccine technologies.

How does the pharmaceutical industryâ&#x20AC;&#x2122;s transformation to Pharma 4.0 impact companies like Thermo Fisher Scientific?

Rich Youn: Due to the pandemic, the world is expecting unprecedented progress from the scientific community.

Thermo Fisher Scientific is focused on driving innovations in technology that can help the scientific community to power discovery, improve productivity, and enable breakthroughs across a variety of applications.

Additionally, our team in the Asia Pacific Japan (APJ) region has been proactively making efforts to strengthen and empower a stronger and more knowledgeable community

of scientists, chemists, and laboratory professionals in Asia by facilitating knowledge sharing sessions.

Can you give an example of the knowledge sharing sessions? And why would the scientific community participate in these?

Rich Youn: Yes, for instance, Thermo Fisher Scientific had worked on virtual learning series and live video forums known as ‘Pharma 4.0: Transforming Pharmaceutical Manufacturing’ for participants from more than 12 locations across the APJ region. This series enabled them to meet with experts worldwide on pertinent issues such as regulatory and quality challenges, emerging technologies, and transformation to the laboratory of the future.

That series was in September 2020 while in June 2020, we held a successful virtual LCMS conference to empower learning for Asia’s lab professionals embarking on intelligence-driven mass spectrometry. In October, we held the Global Ion Chromatography Virtual Symposium for participants in Asia, Europe and the Americas.

For the scientific community such as laboratory professionals including scientists, researchers and chemists, they want to move science forward with confidence, scale research

and translate results faster and simpler than before.

More importantly, they want a new generation of intelligence-driven instruments and software that will enable them to acquire data more quickly and with greater accuracy than ever before.

It is imperative that we support their needs and desires to push the frontiers of science. Through knowledge sharing, we can work as one with the scientific community to progress for the greater good of society.

In 2020, we understand that Thermo Fisher Scientific celebrated 45 years of Ion Chromatography. Would you like to share with us the highlights of this milestone for the scientific community?

Ruby Ong: Ion chromatography is one of the most widely used separation techniques of analytical chemistry with applications in fields such as medicinal chemistry, water chemistry and materials science.

For ion analysis, nothing compares to the Thermo Scientific™ Dionex™ Ion Chromatography (IC) system. In 2020, the company marked 45 years of Thermo Scientific Dionex IC celebration with innovative technology. We are

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committed to ensuring that our IC systems continue to be future-ready, helping laboratory professionals be more productive, be safer with less chemical handling and maximise their resources.

The company’s key technological advancements for IC include: • Eluent Generation (EG) – Eluent generation is an electrolytic process that allows the production of high purity eluents for ion chromatography, and is a part of ReagentFree Ion Chromatography™ (RFIC™) • Reagent-free ion chromatography - Eliminate eluent preparation errors with RFIC. Using our Dual EG technology, lab professionals no longer have to manually prepare hydroxide and sodium acetate to analyse oligosaccharides • Hyphenated IC – Lab professionals can hyphenate ion chromatograph systems to gain an abundance of information instead of just using conductivity or amperometry as their IC detection. Hyphenate it with an inductively coupled plasma mass spectrometry (ICP-MS) to speciate transition metals to decipher toxic versus non-toxic; add an UV-Vis in serials to the IC in order to gain chromophoric information and sensitivity such as nitrate in high anionic content.

We understand that there is a special eBook on IC for readers of Pharma Focus Asia?

Ruby Ong: Yes, to commemorate the significance of this 45-year anniversary, we have a new eBook on IC authored by Joachim Weiss, PhD, Technical Director for Dionex Products at Thermo Fisher Scientific. Weiss is recognised as an international expert in analytical chemistry, and the 4th edition of his Handbook of Ion Chromatography was published in 2016. In 2015, he was awarded the Maria Sklodowska Curie Medal of the Polish Chemical Society for his achievements in separation science.

May we hear from Joachim Weiss more about this e-Book?

Joachim Weiss: Thank you for the opportunity to do this interview. Let me share my thinking behind this new IC eBook.

With the publication of Hamish Small’s legendary paper in Analytical Chemistry in 1975, 2020 marks the 45th anniversary of the introduction of Ion Chromatography. Over these four decades, ion chromatography has not only become the most dominant method in ion analysis, but also developed into a significant chromatographic technique within the field of separation science. While in its earliest embodiments, IC was focused primarily on the analysis of inorganic anions, today IC has an important role in the analysis of organic and inorganic anions and cations.

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Recently, I was looking for a comprehensive, but succinct, resource that explains the basics of ion chromatography. To my surprise, I did not find any compact source or comprehensive text on this subject, apart from my three-volume Handbook of Ion Chromatography that was published as a 4th edition in 2016. Since this is, by far, too detailed, I decided it was necessary to create such a document myself.

Therefore, I have developed an eBook, Basics of Ion Chromatography, for analytical chemists who are looking for an up-to-date introduction to ion chromatography, providing an overview on the major topics related to this expanding and increasingly important field of science.

Separation methods, stationary phases, and detection principles offered by Thermo Fisher Scientific as well as the most important application areas are covered. The eBook is not limited to methods for analysing inorganic anions and cations only, lab professionals will also find a compact description on modern carbohydrate and amino acid analyses as well as high-resolution separations of oligonucleotides and proteins.

On the topic of chromatography, you have over 30 years of experience in ion chromatography and 20 years of experience in the pharma industry, would you be able to provide insights on how lab professionals use IC for pharmaceutical impurity analyses?

Wai-Chi Man: In most pharmaceutical laboratories, IC is mostly used for salt screening for intermediates and drug substances. In recent years, we have seen more and more small polar impurities that affect the drug discovery process and drug safety. With newer technology, we are often competing with other techniques when we should be using multiple orthogonal methods to confirm the impurity.

IC is uniquely placed for small charged polar compounds for reproducible methods from research to manufacturing QC/QA laboratories. It can even analyse carbohydrates and amino acids without derivatisation.

Scan the QR Code or visit thermofisher.com/BasicsIC-eBook to download:

AUTHOR BIO Joachim Weiss is an international expert in analytical chemistry and is presently the International Technical Director for Dionex Products at Thermo Fisher Scientific. He is recognised as an international expert in Analytical Chemistry, especially in the field of Liquid/Ion Chromatography. For his achievements in separation science, Weiss was awarded the Maria Sklodowska Curie Medal of the Polish Chemical Society in 2015.

Recently we have seen how Nitrosamine has impacted the pharma Industry. To minimise the impact, at the final drug substance stage impurities such as nitrite and nitrate can be monitored routinely from starting material through to all the intermediate stages, using IC with conductivity detection.

Other break-down impurities, whether it is stability testing or process generated into small organic acids or amines can also be quantified by IC. Potential small toxic impurities such as hydrazine, cyanide, and many more charged species can be detected by IC to low ppb levels, especially using hyphenated techniques.

More commonly used as a hyphenated IC technique is conductivity with UV-Vis detection in series for high-low matrices. To enable confirmation of small unknown impurities Mass Spectrometry (MS) can be used with IC to elucidate retention and mass identification. IC-MS is extremely useful for genotoxins that are small, polar, and halogenated.

IC hyphenation of the elemental kind with an Inductively coupled plasma mass spectrometer (ICP-MS), often used for speciation for inorganic or organic species.

In challenging pharmaceutical impurity analysis, should lab professionals use IC and IC-MS? Wai-Chi Man: Most definitely. There are many challenges in pharmaceutical laboratories, from degradation to process impurities. From experience, there have been too many times that I have encountered those challenges. They usually come from a comment of “that doesn't look right”. It can be from a simple coating formed on the glass sample vial for the starting material to a mass imbalance at the final drug substance stage. Using the combination of IC and MS data, we can cover salt screening to unknown ionic impurities.

We have seen how MS has impacted liquid chromatography (LC) in the last few decades. LC-MS is now commonly used for troubleshooting and routine analysis. It is because LC-MS can reach low ppt levels to identify the impurity by mass and can be easily automated. In similar ways, IC is

also capable of the same performance but for charged ionic species. In many ways, IC uses ion exchange chemistry to elute its analytes using size-to-charge ratios. It provides good resolutions for the low mass size that usually ends up in the solvent front in LC or just not enough chromophore for UV-Vis detection. IC-MS detection can simplify some of the sample preparation as derivatisation to add chromophore or fluorescence is not required, with the combination of IC eluent, ion exchange column, and suppression technology to neutralise the background.

Lastly, can Thermo Fisher Scientific tell us more about the use of IC-MS in pharma QA/QC environments?

Joachim Weiss: Unlike liquid chromatography – mass spectrometry (LC-MS), which starts to find its way into QA/QC pharmaceuticals, ion chromatography – mass spectrometry (IC-MS) is currently not applied but under evaluation.

Since ion chromatography is part of liquid chromatography, I do not see any reason why IC-MS should not be applied in QA/QC in future. While for some IC applications in the pharmaceutical industry, such as the analysis of anionic and/or cationic counter ions, suppressed conductivity is the detection method of choice, I see the need for complementary detection methods such as MS when analysing organic acids.

Even utilising the most modern commercially available anion exchangers in the 4 µm format, baseline separations of small-molecular weight mono- as well as dicarboxylic acids from other anionic sample constituents (e.g., inorganic anions) are difficult, so that suppressed conductivity detection cannot be applied for an immaculate quantitation.

However, all these organic acids differ in nominal mass, so that a single quadrupole MS detector in SIM mode can be employed.

The latest generations of such MS detectors are very easy to use and robust, so that I do not see any obstacle for using them in a QA/QC environment. The same is true in the analysis of amines, another very important application for IC in the pharmaceutical industry. Here we have a very similar scenario: individual aliphatic amines or quaternary ammonium compounds can usually be separated from inorganic cations such as alkali and alkaline-earth metals, but if the sample contains a larger number of amines or the analytes are present in very disparate concentrations ratios partial co-elution are often observed. In such situations, IC-MS might serve as a welcome alternative for detection.

If you would like to connect with the Thermo Fisher Scientific experts, please email: CMD.APACMarketing@thermofisher.com Advertorial www.pharmafocusasia.com

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CLINICALTRIAL

Moving Ahead with Intelligent Virtual Clinical Trials Fuelled by the current COVID-19 pandemic, and the considerable volume of data generated during a clinical trial, Artificial intelligence (AI) has provided the much-needed impetus for transforming clinical trials into the virtual sphere for greater efficiency. From patient recruitment, protocol design, trial monitoring, to identifying the effect of blood thinners on virtual patients with irregular heartbeats, leveraging AI has helped life-saving drugs reach the market sooner.

Ayaaz Hussain Khan, Global Head Generics, Navitas Life Sciences (a TAKE Solutions Enterprise)

H

ealthcare today faces extraordinary challenges posed by the COVID-19 pandemic along with a rise in chronic disease burden worldwide, an aging population, and the growth of the middle-class Asian population. According to the World Health Organization (WHO 1), by 2020, an estimated three-quarters of all deaths globally would be due to chronic diseases. These stressors have helped facilitate innovations in conducting clinical trials in a bid to curb rising costs and reduce the time needed to conduct them. Simultaneously, there have been significant breakthroughs in science and technology, enabling intelligent clinical trial solutions.

A recent report by Researchand Markets stated that the global market

1. https://www.who.int/nutrition/topics/2_background/en/

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for e-Clinical Trial technologies 2, catalysed by the COVID-19 pandemic, is an estimated US$5.4 Billion(2020), with an expected rise to US$ 9.9 Billion by 2027. The U.S e-Clinical Trial Technologies market is at an estimated US$1.6 billion this year, while the market size in China is expected to be US$1.7 billion by the year 2027.

Among regional markets, China will be one of the fastest-growing, followed by Australia, India, and South Korea, with an estimated Asia-Pacific market value at US$1.1 Billion by 2027.

AI in Clinical Trials

Data provided by ClinicalTrials.gov shows that there was a reduction in the number 2. https://www.businesswire.com/news/ home/20200908005697/en/Global-e-ClinicalTrial-Technologies-Market-Trajectory-Analytics2012-2019-2020-2027---ResearchAndMarkets.com

of new trials between January and May 2020. Moreover, Michael Lauer from the US National Institutes of Health stated that nearly 80% of non-COVID trials 3 were either stopped or interrupted. Investigative sites had to resort to ingenuity and flexibility during the subsequent period of recovery from June to July, with prior investment on the right technology aiding in risk mitigation.

For instance, AI and machine learning (ML) platforms were leveraged by a global clinical research organisation to run six COVID-19 clinical trials using remote monitoring practices, while banking on vast experience and in-depth infectious disease expertise, that resulted in milestones reached ahead of time.

Furthermore, the advent of digital solutions in clinical trial management and conduct has improved transparency, with an onus on delivering better healthcare.

Consumers or patients have access to a wide range of information, and, with this dissemination of information, there is increased expectancy. This has initiated a need for rethinking clinical trials to maximise benefits. There has been a significant shift towards embracing the incredible advantages of data analytics, along with digital models of engagement, to forge clinical trials that cater to the current demands.

Significant strides in incorporating digital health solutions began a few years 3. https://www.thelancet.com/journals/lancet/article/ PIIS0140-6736(20)31787-6/fulltext

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ago, more as experimental solutions or as support for certain sections of clinical trials. Such investments have paved the way for hybrid clinical trials that are guiding forces for successful and efficiently run clinical trials.

Key steps in a virtual clinical trial

A virtual clinical trial harnesses the power of technology to improve patient recruitment, retention, collection of data, and analysis. They support efficient trials as they tap into digital technologies, like apps, monitoring devices, and online social engagement platforms to conduct each stage of the clinical trial. This includes enhanced support for recruitment, informed consent, patient counselling, measuring clinical endpoints, and in determining adverse reactions.

1) Patient recruitment: Clinical protocol development is the first step in a clinical trial. With the multitude of data sources, like imaging health, genomics, and patient-reported outcomes, there has been a shift in trial protocols to meet regulatory requirements. Multiple reasons

could hinder patient recruitment, including involving populations that are hard to reach, people with disabilities who cannot come to the trial centres, lack of awareness about the trials, and the financial burden on the study population if there is a need for frequent trips to the research centres.

Leveraging digital methods to facilitate recruitment has been in use since even before the current dictates of the pandemic. Encouragingly, such trends have been the reason for optimism, with clinical trial announcements popular over social media channels. Patients donâ&#x20AC;&#x2122;t have to travel to sites to sign up for the study; instead, they could send in e-consent forms. Technology reaches patients who would be most suitable for the study, ensuring that they participated with minimal travel to the site, significantly increasing patient participation and retention during clinical research studies. Such innovative solutions ensured that the first patient for a safety and efficacy trial for a COVID-19 drug product

was recruited within 26 days of the study being commissioned.

To ensure seamless collaboration, detailed and uniform training for effective management and use of digital tools for protocol adherence, recruitment, sample management, PD/Issue Handling, data entry and cleaning requirements, good source documentation, regulations etc., need to be provided.

2) Digital health data collection: After patients are recruited for a study, it is important to collect data during the clinical research study process. There are multiple ways to collect this data using digital tools. Demographic and medical health data, patient activity, and physiological parameters, patient-reported outcomes, along with images, can now be collected using electronic medical records, smartphones, or tablets.

There has been a dramatic shift towards digital monitoring and biomarkers. This refers to objective measures of behavioural, pathologic, physiologic, anatomic, social, and patient self-assessment, which can be obtained remotely

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CLINICALTRIAL

using digital technology and used as a means of evaluation. Examples of such technology include wearable activity trackers or phones with sensors to detect cardiogenic chest wall vibrations as a means of identifying heart failure or heart rhythm. Other examples include sensors to detect sweat for glucose, lactate, electrolytes, or sensors placed in braces to determine structural health markers for knee joint injury. Statistical analysis may be used to identify the effect of blood thinners on virtual patients with irregular heartbeats.

Digital technologies have also helped in collating data that couldnâ&#x20AC;&#x2122;t be collected through traditional means before. A case in point is the use of unique applications available in smartphones. Patients need to perform a set of tasks indicated in these apps, which is used to detect signs of Parkinsonâ&#x20AC;&#x2122;s.

Regulatory authorities have also been closely monitoring such advances in technology and data collection. The Food and Drug Administration (FDA) approved the use of the Apple watch in detecting heart rhythm abnormalities, like in atrial fibrillation, that use optical

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sensors for photoplethysmography and electrodes for electrocardiography. e-Source may be used as the primary source of patient data capture, except for informed consent form and laboratory data. The data from e-source may be synchronised with electronic data capture, so there is reduced data input required from sites.

3) Safety monitoring in virtual trials: The fast pace of digital technology movement into routine processes in a clinical trial has helped in significantly improving efficiency, reducing time and cost for sponsors. New tools are now being paired with traditional biomarker assessments to enhance safety and validation.

A considerable advantage of using digital tools in safety monitoring is that there is continuous data collection that can be used to detect infrequent events or even to identify situations that may not occur during a study visit. In a bid to better monitor clinical trials, artificial intelligence, and machine learningpowered digital platforms have been in use for many years to identify potential risks. Such platforms facilitate near realtime data insights that promote faster

detection of events and reporting, which has a considerable impact on clinical trial timelines and cost.

One of the critical factors in incorporating digital tools in virtual trials is meeting safety and regulatory standards.

4) Data Security: To develop intelligent clinical trials that do not require constant human monitoring but are dependent on advancements in technology, certain challenges need to be addressed. There is an increased need to tighten data security during collection, transmission, and analysis. There is a heightened risk of breach of data regarding the location that could affect the study participants.

To overcome this, the FDA has put forward specific guidelines, like conveying information collected by the digital tools to all stakeholders. Medical device certification has been developed as a measure to control data breach.

There is a need to understand the regulations that govern the use of data within specific geographical regions and the changes in rules that may exist in other areas. There is reduced dependency on physical sites in virtual trials, and

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6) Optimising trial methods: There are multiple ways in which virtual resources support clinical trials optimisation. A method of intervention optimisation, called micro-randomised trials, involves identifying factors like dose and timing that can be managed better using reminders. Such engagement strategies are best suited for patient recruitment, enrolling and retention. The personalisation of the clinical trial process helps in enhanced patient participation in clinical trials.

Optimisation of clinical trials can extend to other aspects of the trial as well. In time, it will help in building robust systems that greatly enhance the conduct of biomedical research.

The traditional clinical trials or the in-site system may not be effective during the current unprecedented times, however, the benefits of virtual clinical trials extend beyond the purview of the pandemic. There has been an increased dependency on innovative and intelligent solutions in managing clinical trials over the past two decades.

Societal interaction that has largely been based on face to face interaction is now slowly moving to the virtual space.

Though this transition has been slow in the clinical trial sphere, many tools are now being embraced to re-engineer clinical research. Robust methods to track the progress of clinical trials using AI powered platforms, or remote monitor-

AUTHOR BIO

patients may be enrolled from different cities or even countries. The rules that govern data collection, use, and inclusion in studies vary from one state to another and from one country to another. It is important to stay abreast of the latest in the field to ensure successful clinical research study outcomes.

The use of wearables and smartphones in data collection provides a continuous stream of information that is transferred to study investigators using web-based applications. This type of data transfer may be at risk of a security breach. The FDA is developing a risk-based approach in better regulating such third-party applications. Wearables provided by Apple and Fitbit have the necessary certificate as they follow the FDA's guidelines.

There have been warnings issued by the FDA against the use of certain insulin pumps and an implantable cardiac device as there were vulnerabilities in the pump that could result in tampering of the device by unauthorised people. The use of blockchain technology may be one potential solution to ensure data privacy and security. Though such vulnerabilities exist outside the clinical trial sphere, it is essential to use the right technology to ensure data security.

Virtual trials have a compelling advantage over traditional clinical trials when the technology is developed following guidelines.

5) Data analytics: Flexible, extensible, and scalable clinical trials can be carried out only with the support of effective data analysis. For example, an AI and ML powered platform enables study investigators to connect remotely and access data from clinical trials in near real-time. Such emerging technology helps automate processes and mapping data, with advanced analytic methods applied to manage multiple facets of clinical trials.

Such artificial intelligence and machine learning platforms help augment data extraction and in computational phenotyping that enhance efforts towards successful clinical trial outcomes.

ing using e-Source, with intelligent trial management using the trend output from such digital platforms have significantly elevated the conduct of clinical trials.

Large volumes of data from clinical trials can now be cleaned from the time of the first person enrolled in the study till the end of the study. Digital tools can also be used for periodic medical data review and to streamline clinical trials, with faster decisions taken on the drug development process.

Improved efficiencies throughout the clinical trial process will aid in reducing time and costs. The use of the right digital health solutions allowed rapid site activation within 20 days, faster recruitment of patients and comprehensive trial oversight for a safety and efficacy drug trial on moderate to severe COVID-19 patients.

The innumerable benefits when using digital tools to support clinical research reinforces the need to incorporate new forms of technology which act as critical enablers to achieve better coordination and in simplifying processes between the various stakeholders and ecosystems in a clinical trial.

Despite the current COVID-19 times of difficulty and uncertainty, clinical trial conduct experienced a ray of hope demonstrating real feasibility of virtual clinical trials. Virtual clinical trials have demonstrated the ability to improve access, reduce participation burdens, and enable the collection of robust and secure data, among other benefits with the support of digital tools.

To stay at the forefront of innovation, it is imperative that organisations understand critical healthcare needs, evaluate their capabilities and make necessary plans to deliver virtual clinical trials to patients.

Khan is an authority in the BA/BE domain of the generic drug industry. He brings with him a rich experience of conducting over 1000 Bioavailability/Bioequivalence studies. He is associated with Ecron Acunova (now under the banner of Navitas Life Sciences) for the past 10 years and is the Global Head of Generics. He has been a gold medallist in his academics.

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Why Cell and Gene Contract Manufacturers Must Embrace Digitisation?

Rachit Jain, Global Cell and Gene Lead Software, Kรถrber Business Area Pharma

The cell and gene industry is growing at a staggering 30 per cent CAGR and is estimated to reach US$14 bn by 2025. A number of cell, gene and stem cell therapy sponsors currently have novel drug substances and products and many rely on Contract Development Manufacturing Organizations (CDMO) to produce them with adherence to stringent regulatory cGMP conditions.

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Cell and gene manufacturing for both autologous (one to one) and allogenic (one to many) treatments face difficult issues such as: a complex supply chain, variability on patient and cellular level, cell expansion count and a tight scheduling of lot disposition process. This complexity affects quality, compliance and accountability in the entire vein-to-vein process for critically ill patients.

Electronic batch recording becomes vital

Cell and gene companies are emerging from years of laboratory scale development through preclinical tests and pivotal clinical trials to ultimately reaching

digitisation, automation and continuous improvement are reaping huge benefits. They have minimised the use of paper, automatised the calculations, sped the design of manufacturing batch records, reduced cGMP deviations and more quickly released manufacturing lots based on review by exception, which align with right first time initiatives.

Automated processes are a good starting point Cell therapy manufacturers rate manufacturing process stability and scalability as their top two considerations throughout clinical trials. They equally rank process variability, scale-up ease and reduced cycle time as motivation for automating both their manufacturing processes and supply chain. In this vein, a CDMO that is already a fully automated facility with EBR capability can help achieve these goals.

The detrimental impact of Sars-Cov-2 has challenged cell therapy sponsors with a stoppage of clinical trials and supply chain hurdles. In the manufacturing domain, both in-house and contract manufacturers have implemented strict guidelines to ensure employee safety. Manufacturers, who had embraced automation, quickly rebounded to get systems back online to meet delivery deadlines. In addition, they had a reduced risk of contamination as fewer hands touch paper or the final product, thereby drastically reducing the four-eyes-principle steps.

Cell therapy sponsors select CDMOs

FDA approval and commercialisation. Digital solutions such as a robust Electronic Batch Recording system (EBR) are vital. Given that the raw material for these processes are actual patient cells extracted in a clinic, a failed batch is devastating and could mean loss of a patientâ&#x20AC;&#x2122;s life. A failed batch due to poor paper record handling must be avoided at all costs.

A crucial component in reducing Cost of Goods Sold (COGS) in developing cell, gene and stem cell therapies is through increased efficiency of the manufacturing process. Automation provides a suitable option to address this challenge. Those manufacturers who have become early adopters of

Cell therapy sponsors have two options for how to manufacture: build an internal manufacturing capability or employ a CDMO/CMO. Investing in their own manufacturing facility would develop internal expertise, optimise processes, control manufacturing capacity, and potentially save money in the long run, if the drug commercialises.

However, utilising CDMOs/CMOs can help provide flexibility in capacity planning, reduce commitments to evolving technology platforms, and reduce initial investments. CDMOs/CMOs have existing cGMP facilities designed to comply with regulatory authorities. More importantly, they have a skilled workforce who can execute the process, manufacture the product and deliver it to hospitals and clinics. Some cell therapy sponsors employ a regional manufacturing model and use CDMOs/ CMOs to manufacture their products in various geographical regions. Concurrently, smaller scale

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sponsors are utilising co-working or collaborative spaces such as The Center for Breakthrough Innovation (King of Prussia, PA, USA) and the Cell and Gene Catapult (Stevenage, UK) for meeting their development and manufacturing needs.

Paper-based processes are inefficient and error-prone Sponsors’ demands are growing and complex, which have many CDMOs/CMOs pushing to become leaner and digital. To be agile enough to meet sponsor requirements of patient delivery deadlines and frequent schedule changes, an Electronic Batch Record solution should be a minimum prerequisite. Paper-based manufacturing systems are too slow and cumbersome in the cell therapy world. They lack the ease for tracking of data and continuous improvement.

For instance, given the volume of different manufacturing processes in the cell, gene and stem cell space, contract manufacturers must continuously manage customers’ work instructions and Standard Operating Procedures (SOPs) which change regularly. Operator training, manufacturing recipes and product specifications also vary and need to be updated frequently. Accurately and safely managing all of these changing documents via paper-based records is incredibly challenging and inefficient, with significant risk for harmful errors, delays and a lack of transparency.

In conclusion, CDMOs/CMOs must embrace digitisation. A cloud-hosted digital electronic batch records solution coupled with a flexible scheduling solution and integration to other supply chain and IT systems is the ‘need of the hour’ today. With an EBR, cell therapy sponsors can monitor the CDMO/CMO process right from their desk. The most important compliance parameters of chain of identity, chain of custody, chain of condition and limited time horizon for critically ill patients can be monitored right at one’s fingertips. Any events, delays or changes can be addressed immediately.

With some upfront initial effort, CDMOs/CMOs will save a lot of effort downstream when data is integrated across the enterprise and quality and production teams are relieved of an enormous documentation burden. Companies who have adopted EBR have reported an 83 per cent decrease in data input errors and more than 87 per cent decrease in review time after production completes by embracing the review by exception paradigm.

Rachit Jain is Global Cell and Gene Lead Software at Körber Business Area Pharma.

In his role, he is focused on helping clients build necessary digital ecosystems to support blockbuster individualised therapies (e.g. immunotherapy and regenerative therapies) to tackle rare diseases. Through his work in cell and gene and consulting, he has developed a unique understanding of the synergies between the software solutions of Körber Business Area Pharma and the challenges facing the cell and gene therapy industry today. Rachit has a background in Process Engineering and holds an MBA from an Ivy League Business School.

About Körber Körber is an international technology group with about 10,000 employees, more than 100 locations worldwide and a common goal: We turn entrepreneurial thinking into customer success and shape the technological change. In the Business Areas Digital, Pharma, Supply Chain, Tissue and Tobacco, we offer products, solutions and services that inspire.

At the Körber Business Area Pharma we are delivering the difference along the pharma value chain with our unique portfolio of integrated solutions. With our software solutions we help drug manufacturers to digitise their pharma, biotech and cell & gene factories. The software product Werum PAS-X MES is recognised as the world’s leading Manufacturing Execution System for the pharma & biotech industry. Our data analytics and AI solutions accelerate product commercialisation and uncover hidden business value. www.koerber-pharma.com Advertorial

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MANUFACTURING

Continuous Manufacturing of Lipid-based Delivery Systems Using Melt Extrusion Melt extrusion is a well-established pharmaceutical manufacturing technique for developing products with enhanced quality, low variability in less time.

This has led to exploring numerous lipids/surfactants processed using melt extrusion for added benefits such as higher scalability, versatility, ease of processing, content uniformity, and less wastage.

Gautam Chauhan, Vivek Gupta* College of Pharmacy & Health Sciences, St. John’s University

L

ipid-based Drug Delivery Systems (LBDDS) are well-established pharmaceutical delivery vehicles prepared by developing a stable dispersion of lipid/oil and aqueous phase with the help of surfactants and co-solvents, to reduce the interfacial tension between the two phases and create a stable biphasic system. There are few commercial-

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ised lipid-based products including Sandimmune® and Neroal® (Cyclosporine A). LBDDS have been majorly explored to improve the solubility of poorly watersoluble drugs with many inherent benefits such as sustained release, taste masking, and better swallowability. Other physiological benefits from LBDDS include biocompatibility, higher permeability,

avoiding first pass metabolism and enhanced bioavailability as they undergo digestion. In a study,Palin et al. demonstrated increased oral absorption of poorly water soluble drugs using LBDDS, as lipids provide most favourable conditions for lymphatic uptake and transport into systemic circulation.

Formulation of LBDDS was first developed by Mueller et al. as solid nanoparticles using precipitation technique by pouring hot microemulsion in cold water, following which several methods have been documented to prepare LBDDS, such as emulsification, ultrasonication, high pressure homogenisation, micro-fluidisation, etc. These techniques primarily involve melt mixing the lipid and poorly water-soluble drug to form a homogeneous lipid solution, further processed using surfactant and co-solvents to get a stable biphasic formulation.

Major components of LBDDS are lipids,

MANUFACTURING

surfactants and co-solvents, which are screened based on drug and formulation requirements. For instance in a study by Qazi et al., the drug release was modified using a combination of lipids and a faster drug release was observed for lipids with free hydroxyl groups such as Precirol®.

Surfactants are selected based on their Hydrophilic Lipophilic Balance (HLB value), characterised as water-soluble or -insoluble surfactants. Significance of surfactant’s HLB value has been well studied for modified release and for accommodating higher drug load. Finally, the co-solvents are added to the formulation for higher drug dissolution capacity and to facilitate better emulsification of the lipid inside the GI tract. Some of the common co-solvents used are propylene glycol, glycerin, etc. Based on their composition, the LBDDS are classified into four categories: Type-1 containing only oil/lipids without surfactants or co-solvents; Type-2 containing oil/ lipid with water-insoluble surfactant which form stable emulsions such as Self-emulsifying Drug Delivery Systems (SEDDS); Type-3 containing lipid/oil with water-soluble surfactants with more hydrophilic components which form Self-micro-emulsifying Drug Delivery Systems (SMEDDS) with lower particle size ranging from 50-200 nm; and Type-4 containing only hydrophilic surfactants and co-solvents which form a colloidal dispersion in contact with aqueous phase.

Once the composition of the lipid phase is optimised for drug accommodation, the preparation method is selected based on required formulation characteristics such as particle size, dispersity index, homogeneity, etc. Majority of preparation techniques involve high shear mixing and breaking the lipid droplets into smaller size, thus creating a homogeneous dispersion. These techniques include high frequency sonication, high pressure homogenisation, micro-fluidisation, high pressure atomisation (spray drying), etc. All these techniques have been used over the years and multiple drawbacks have been recognised such as

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degradation, polymorphic changes in the drug and excipients at high melt temperature, and residual aqueous phase affecting stability of the formulation. Continuous processing techniques like high-pressure homogenisation and micro-fluidisation contain small channels which may get blocked due to lipid accumulation in the system; while batch processing techniques such as sonication and homogenisation result in lower product yield. A study

by Opertiet al. demonstrated the yield value for sonication and homogenisation to be 25-50 ml per minute, which is insufficient for industrial scale-up.

Further, these techniques require high maintenance cost, more time consumption and tedious scale up from pilot to industrial scale. To address these technical problems, Hot Melt Extrusion (HME) can be used as a method of choice with continuous processing capability and large-scale output.

Hot Melt Extrusion

HME is a technique in which raw material is processed under high temperature and pressure with continuous mixing and shear force to give a uniformly dispersed product. In this process, the drug undergoes thermal transition and forms an amorphous dispersion with the carrier matrix. HME is a widely used technique to prepare formulations for

There is a lot of literature available for performing HME using solid polymers, but far less has been reported on extrusion of lipids.

poorly water-soluble drugs with higher entrapment efficacy, product quality and better process control. Since past one decade, HME has been widely used to prepare LBDDS including Solid Lipid Nanoparticles (SLN), nano-emulsions, nanostructured lipid carriers, lipid implants, etc.; as it provides additional benefits such as negligible heat exposure with short barrel residence time, avoiding formulation overheating/reheating, and continuous processing capabilities which save time, lower the cost of production and avoids batch-to-batch variability.

Hot melt extrusion is carried out using an extruder which comprises three major components. First, the feeding zone through which the material enters the extruder. Feeding zone is also used to control the feed rate which can affect the hardness, and sphericity of the extruded material (Figure 1A).

Feeding zone also comprises an inlet for adding aqueous solvent to the extrusion barrel. Second, the Barrel which is the main body of the extruder through which material passes from feeder to discharge unit. Based on barrel design, an extruder can be classified as singleand twin- screw extruder (Figure 1B).

Barrel is a heavy closed pack unit with separate heating blocks which can be adjusted to different temperatures based on the melt, transition and degradation temperature of the material. Finally, the screw assembly which consists of three types of screws, conveying screws for pushing the material forward, mixing screws arranged at different angles 0º and 90º for mixing the material forming homogeneous mixture, and discharge screw through which the final product is extruded out (Figure 1C). Other major parameters include screw speed which is adjusted based on feed rate and retention time. The screw elements are designed based on the formulation requirements, for instance, a greater number of mixing screws resulted in faster drug release; and higher dispersion was achieved by arranging mixing and conveying elements together.

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Figure 1: Schematic diagram of (a) twin-screw hot melt extruder and (b) single- and twin-screw extruder, (c) Screw arrangement/design with mixing- and conveying-elements/ screws.

Hot Melt Extrusion for Lipid Based Formulations

LBDDS have gained momentum over the last decade with development of highly versatile lipid excipients. For example, Compritol® 888 ATO can be used for controlled release, Precirol® ATO 5 has good coating properties, Gelucire® 50/13 can be used as a solubility enhancer, and stearic acid for pH dependent release(Table 1). Most of the lipids/oils are stable at high temperature thus making them suitable for melt extrusion for LBDDS preparation. Other advantages such as high scalability, solvent-free technique, low oxygen exposure, reduced process steps and time, give HME precedence over other melt techniques to prepare LBF. Several studies report comparative findings showing enhanced drug release for LBF prepared using HME compared to other techniques.

HME for LBF is performed by processing pre-mixed lipid and drug mixture through the extruder along with

other excipients. This process is carried out at pre-determined temperature based on thermal properties of the material which can be studied using Differential Scanning Calorimetry (DSC) for identifying the thermal behaviour of the material. Other parameters such as retention time depends on how long the material needs to be retained inside the barrel, which further determines the screw speed and feeding rate for the material. All these parameters are optimised and fixed for the pilot batch which can be easily scaled up to large scale manufacturing following simple transitional estimates avoiding wastage and ease of operation. As a reason, HME has been extensively used to prepare LBDDS, few of the examples will be discussed below: Solid Lipid Nanoparticles – As the name suggests these are spherical particles with an average size range of 100-1000 nanometers with an inner solid lipid core stabilised by surfactant/ emulsifiers on the surface. SLN can be

prepared using lipids with good coating properties such as Trimyristin, Glyceryl dibehenate, Stearic acid, Glyceryl distearate, etc. In a recent study, different parameters such as lipid/surfactant composition, screw speed, barrel temperature were studied and optimised for particle size <200 nm and >90 per cent drug entrapment.

Lipid based Granules – Lipid based granules can be prepared using thermoplastic binders such as polyethylene, hydroxypropyl cellulose, etc., which melt and form liquid bridges between the particles resulting in larger granules with size ranging from 0.2 – 4 mm. Granulation using HME has been performed with the advantages such as continuous processing, desired granule size, and modified drug release based on HLB value of the lipids as more hydrophilic lipids with higher HLB value resulted in faster water uptake and erosion.

Nanostructured Lipid Matrices – These lipid carrier systems are prepared using lipids with different fatty acids,

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thus forming an imperfect lipid matrix for drug accommodation. The extrusion of lipids is carried out at a processing temperature less than lipid melting point forming solid lipid matrices with drug release depending on the porosity of the solid matrix which can be adjusted by the processing temperature.

Protein Depot Delivery System – Protein depots are long term protein delivery systems for better patient compliance and safety. Lipids-based protein depot delivery matrices can be prepared using HME with enhanced protein stability and controlled release.

The release for protein depots can be adjusted using low and high melting temperature lipids, processed together to form a controlled release lipid-based protein depot delivery system.

Nano-structured Lipid Carriers (NLC) – NLCs contain a blend of solid

and liquid lipids which form a dispersed carrier system for drug delivery. These have added advantages over SLN, such as enhanced stability, improved drug loading capacity, and drug release flexibility. HME has been used to process selected lipids, cetyl palmitate and Labrafac to achieve better drug release for poorly water-soluble drugs. Further, NLC have been prepared for sustained release using pH-dependent release polymer HPMCAS. NLC prepared using lipids, Precirol®, carbuna wax, beeswax, etc. have been used for odor and taste masking.

Lipid Implants for Tumour Therapy – Most of the chemotherapeutic agents are lipophilic with very short half-life, thus making them good candidates for Lipid based implants. Recently, HME was used to prepare sustained release delivery of TRP2 peptide/oval-

Post-HME Processing of Lipid Based Carriers

The extruded lipid formulations may require further processing based on PHYSICAL STATE AT ROOM TEMPERATURE

MELTING POINT

Coating, Dual drug release, immediate release

Solid

62-86 ºC

Hydrogenated coco-glycerides, hydrogenated palm fat and oil, hydrogenated castor oil and hydrogenated rapeseed oil, hydrogenated cottonseed oil, hardened soybean oil

Implants, Immediate release, Controlled release (hardened cold extrusion)

Solid, Liquid

60-71 ºC

Polyoxylglycerides

Gelucire 48/16, Gelucire 50/13, Gelucire 44/14, Gelucire 39/01, Gelucire 43/01, Gelucire 50/02 and Compritol HD 5

Immediate release, Matrix forming agent, gelation agent,

Semi-solid, Liquid

33-65 ºC

Fatty acids

Myristic acid, Palmitic acid, Stearic acid, Behenic acid

Taste masking, Matrix forming agent, pH dependent release (stearic acid)

Solid (saturated fatty acid), Liquid (Unsaturated fatty acid)

60-90 ºC

Monoglycerides

Glyceryl monostearate, glyceryl monooleate, glycerol monolaurate

Immediate release, Matrix forming agent

Solid

55-90 ºC

Diacylglycerides

Glyceryl palmitostearate, and glyceryl dibehenate with 40–60% of diacylglycerides

Coating, controlled release, Taste masking,

Solid

50-80 ºC

Triglycerides

Trilaurin, trimyristin, tripalmitin (Dynasan 116), tristearin, tribehenin, triglyceride of long fatty acid

Controlled release (based on extrusion temperature)

Solid, Liquid

45-73 ºC

PEG fatty acid esters

PEG-6000

Pore forming agent, Solubility enhancer

Solid

58-63 ºC

Animal fats

Cow ghee

Sustained release

Solid

~ 80 ºC

LIPID CLASS

MATERIAL

APPLICATION

Waxes

Bees wax, carnauba wax, Paraffin wax

Oils and Fats

Table 1: List of Common Lipids and Their Characteristics

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bumin (OVA) for tumor therapy using lipids, Cholesterol (CHOL), soybean lecithin and Trimyristin (Dynasan 114).

Higher extrusion temperature resulted in smaller pore size in the implants resulting in release for over 200 days.

Lipid-based Vaccine Delivery Systems – Lipid based vaccine can be used to provide a sustained release for antigen which will decrease repeated dosing. Further, in case of mucosal delivery, lipids can provide mucosal immunity. Recently, lipid implants were prepared using a model antigen (OVA) for sustained antigen release. The release kinetics of the antigen was adjusted based on the lipid concentration.

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Conclusion

HME has been extensively used to process solid polymers such as hydroxy propyl methyl cellulose, polylactic acid, ethyl cellulose, polyvinylpyrrolidone, Polylactide-co-glycolide(PLGA), etc.

Therefore, there is a lot of literature available for performing HME using solid polymers, but far less has been reported

on extrusion of lipids. Hence, it is necessary to run pre-formulation studies for Lipids to understand their function and behavior for extrusion. LBDDS have a wide area of application ranging from modified release, taste masking, enhanced bioavailability, improved swallowability, etc.; combined with HME provides additional application-based advantages such as low product variability and high throughput. HME also facilitates other techniques such as milling, homogenisation, spheronisation, etc. which can

AUTHOR BIO

the final product requirements. These techniques include spheronisation for smooth surface and masking unpleasant taste and odor of the drug using spheroniser; probe sonication and High-pressure Homogeniser (HPH) for reducing the particle size and polydispersity index of the extruded emulsions. For instance, Bhagurkar et al. used probe sonication post HME to prepare nano-emulsion of uniform particle size ranging 12-15 nm. HPH and probe sonication both have been used as post extrusion techniques to prepare solid lipid nanoparticles with continuous manufacturing.

half page_Pharma Focus Asia - GelMA - Nov 2020_vectorized.indd 1

Gautam Chauhan is a Doctoral Student in pharmaceutical sciences with research interests in hot melt extrusion and 3D printed solid dosage forms.

be directly integrated with HME to set up a continuous platform for developing LBDDS. Further, process analytical technology such as infrared spectroscopy, UV/VIS, ultrasonic spectroscopy and Raman spectroscopy can be directly incorporated into the extruder offering real time process analysis which provide better control over the parameters and final product formulation.

References are available at www.pharmafocusasia.com

Vivek Gupta is an Assistant Professor of pharmaceutical sciences. His research focuses on developing novel non-invasive drug delivery systems for oral, pulmonary, and nasal routes of administration.

10/30/2020 2:46:40 PM

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Current Development and Future of Pharmaceutical 3D Printing

Additive Manufacturing (AM), also known as 3D printing, is a rapidly developing technology being explored in various sectors in pharmaceutical applications. The first 3D printed tablet was approved by US Food and Drug Administration (FDA) in 2015, which has created great interest in pharmaceutical 3D printing. This article exhibits the current 3D printing methods, as well as the advantages and disadvantages of this technology in new drug development and pharmacy practice.

The challenge and future direction of applying this technology has also been discussed.

Yunong Yuan Doctorate student, Sydney Pharmacy School Lifeng Kang School of Pharmacy, Faculty of Medicine and Health, University of Sydney

T

he worldâ&#x20AC;&#x2122;s first 3D printer was invented in the 1980s by using the method of stereolithography (SLA). After that, different types of 3D printers were gradually coming on the scene. The printing processes can be categorised into seven groups, according to the International Organisation for Standardisation (ISO)/ American Society for Testing and Materials (ASTM) 52900:2015 standard classify

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standard. They are (1) Binder Jetting (BJ); (2) Directed Energy Deposition (DED); (3) Material Extrusion (ME); (4) Material Jetting (MJ); (5) Powder Bed Fusion (PBF); (6) Sheet Lamination (SL) and (7) Vat1 Photopolymerisation (VP).Table 1 shows the basic principles, examples of suitable materials, advantages, and disadvantages of each of these seven systems.

The applications of 3D printing range from the integrated circuit to aviation, clothes to jewellery and foods to medicines. Recently, there has been a rapid rise in applying this new technology for pharmaceutical applications, e.g., to fabricate various dosage forms, such as tablets, capsules, transdermal Microneedle (MN) patches, suppositories, and implants. It has also been used to make novel drug testing systems, replicating complex biological structures in vitro. The selection of 3D printing methods depends on the requirement of printing materials. For pharmaceutical applications, the materials need to be biocompatible, stable, and possess appropriate mechanical strength.

Compared with traditional pharmaceutical manufacturing methods, 3D printing can offer product complexity, personalisation, and on-demand fabrication. First, 3D printing is an enabling tool to construct pharmaceutical products with complex geometries which can confer different drug release kinetics for different conditions. Second, it is useful to fabricate personalised medications, such as personalised dosing which are otherwise challenging to prepare with conventional methods. Third, 3D printing makes it possible for pharmacists fabricate the personalised preparations on the spot and dispense them to the patients. Lastly, 3D printing is cost effective for low-cost production of small quantities of medications, while conventional manufacturing methods are more suitable for mass production.

In this mini review, we summarised the most recent progress in pharmaceutical 3D printing published on academic journals, mainly in 2020.

Based on the current research, 3D printing has great potentials to change the current medical practice, especially in highly customised medications and the way medication is administered to patients.

Oral dosage forms

Rapid prototyping and optimisation of various printing parameters play a vital role in oral dosage forms design. Drug releasing rate from a pharmaceutical preparation could be controlled by selecting suitable material and / or structure for the 3D prints. For instance, instead of the commonly used thermoplastic materials, such as Polylactic Acid (PLA) or acrylonitrile butadiene styrene (ABS), hydrophilic pharmaceutical grade polymers such as Polyvinyl Pyrrolidone (PVP) can be used to print medicine with immediate release properties. Besides, the zero-order drug release profile may be achieved by creating a cylindrical tablet with dense outer regions and porous cores enabling high drug loading.

Clark et al. used an inkjet printer with ultraviolet light to make tablets containing carvedilol which has poor solubility in water. The printing ink consists of carvedilol, poly (ethylene glycol) diacrylate and vinyl-2-pyrrolidone. Tablets of different geometry (thin films, ring, mesh, and cylinder) were printed. It was shown that different release profiles can be obtained by varying the tablet geometry.

In another study, the drug ibuprofen was mixed with cellulose materials to form filaments for 3D printing. Printing parameters, such as shell thickness, layer height, and infill density were varied to print tablets with different properties.

The results showed that the tablets can be

customised according to the required dose and release rate. It was also demonstrated that Hot-melt Extrusion (HME) in tandem with Fused Deposition Modelling (FDM) printing offer a useful platform for the on-demand drug printing.

In addition to the new dosage forms with customised drug release profiles as mentioned above, AM could also be used to make dosage forms to improve the patientsâ&#x20AC;&#x2122; experience of taking medications.

For example, patients who suffer from dysphagia who have difficulty to take conventional tablets and/or capsules, can take orodispersible film, as an alternative. Orodispersible films are solid oral dosage forms which rapidly dissolve in mouth, which makes them recommended for patients with swallowing problems.

Utilisation of water-soluble polymers as a film forming materials are also beneficial to increase drug release, in addition to the printing process itself.

Lastly, tablets with various shapes were printed to cater to patientsâ&#x20AC;&#x2122; preferences. The printing filaments were prepared by mixing a polymer (hydroxypropyl cellulose), a plasticiser (mannitol) and a lubricant (magnesium stearate).

The mixture was extruded using a hot melt extruder to obtain the filaments for subsequent 3D printing using FDM method. Tablets of 10 different shapes were made, namely, disc, torus, sphere, tilted diamond, capsule, pentagon, heart, diamond, triangle and cube. While conventional capsule and disc shapes were acceptable, the torus shape was found to be a preferred novel shape, enabled by the 3D printing method.

Transdermal microneedle patches

Drug delivery through skin is another attractive approach in replace of taking orally. Patches with hundreds of Microneedles (MNs) can penetrate the skin to deliver drugs into the body.

Traditional manufacturing of these MN patches is complex and time-consuming.

With the 3D printing, the process can be simplified. In addition, by aiding of the 3D scanner and Computer-aided Design (CAD) software, the suitability www.pharmafocusasia.com

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CATEGORY BJ

BASIC PRINCIPLE A liquid bonding agent is selectively deposited to join powder materials

EXAMPLE TECHNOLOGY

ADVANTAGES

DISADVANTAGES

MATERIALS

• 3D inkjet technology

• Free of support

• Fragile parts with limited mechanical properties

• Polymers

• Design freedom • Large build volume • High print speed • Relatively low cost

DED

ME

• Composites • Metals • Hybrid

• Conflicts in surface quality and printing speed

• Metals

• Widespread use

• Vertical anisotropy

• Polymers

• Inexpensive

• Step-structured surface

• Hybrid

• High degree control of grain structure

Focused thermal energy is used to fuse materials by melting as they are being deposited

• Laser deposition • Plasma arc melting

• High-quality parts

Material is selectively dispensed through a nozzle or orifice

• Fused deposition modelling (FDM)/Fused Filament Fabrication (FFF)

• Electron beam

• May require postprocessing

• Ceramics

• Hybrid

• Excellent for repair applications

• Scalable

• Metals • Composites

• Fully functional • Large range of material options

MJ

Droplets of build material are selectively deposited

• 3D inkjet technology

• High accuracy

• Direct ink writing

• Low waste • High compatibility

• Support material is often required

• Polymers

• Conflicts in speed and resolution

• Campsites

• Ceramics • Hybrid • Biologicals

PBF

Thermal energy selectively fuses regions of a powder bed

• Electron beam melting (EBM)

• Relatively inexpensive

• Select Laser Sintering (SLS)

• Large range of material options

• Small footprint

• Conflicts in speed and quality

• Metals Ceramics

• High power required

• Polymers

• Powder residue

• Composites • Hybrid

SL

Sheets of material are bonded to form a part

• Laminated Object Manufacturing

• High speed • Low cost

• Ultrasound consolidation (UC) VP

Liquid photopolymer in a vat is selectively cured by light-activated polymerization

• Stereo Lithography (SLA)

• Vertical quality depends on adhesive used • Limited material use

• Excellent resolution and surface quality

• Polymers • Metals • Ceramics • Hybrids

• Limited materials

• Polymers

• Relatively expensive

• Ceramics

• Digital Light Processing

• Biologicals

Table 1: Basic principles, materials, advantages, disadvantages, typical build volumes and tool manufacturers of seven ASTM categories of Additive Manufacturing (AM)

and comfort can also be improved by tailoring the microneedle patches with specific shapes and sizes.

In one study, the 3D printed MN patches were designed for cisplatin delivery to treat skin tumours. The cisplatin was coated onto the MN shafts by using an inkjet printer. The coated MNs were applied onto skin to suppress tumour 58

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growth. In the animal testing, high animal survival rate was observed with the MN patch treatment.

Apart from normal MN patches, MNs with complex design can also be fabricated using 3D printing. For example, Han et al. designed a MN with bioinspired backward-facing curved barbs to enhance the ability for tissue adhesion,

for the MN patch to be firmly attached onto skin. This MN patch was fabricated

by UV photocuring. The results showed that the pull-out force of the bared MNs was significantly improved than that of non-barbed MNs. Lastly, MNs can be also printed on a curved surface to fit undulating surfaces.

Using a novel photocurable printing

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Drug testing systems

Apart from fabricating dosage forms, 3D printing can also be used to fabricate drug testing systems for new drug discovery applications. For example, transmucosal nasal drug delivery is a useful means to deliver drug into blood circulation.

Precise targeting of certain locations within the nasal cavity is important.

In one report, a nasal cavity replica was printed using synthetic polymers, to replicate the nasal cavity of a 33-yearold female patent. The nasal replicate was used to assess the spray deposition patterns within the 3D printed nasal cavity model, in order to obtain more efficient nasal sprays.

There are also reports on testing device for ocular drug delivery. For example, a platform was 3D-printed using nylon as the printing materials and was attached to the bottom of 6-well plates with cyanoacrylate glue.

The corneal tissue was placed onto the platform for organ culturing in vitro. It was demonstrated that in porcine tissue could maintain the corneal epithelium in the culture system. This organ culture system is potentially useful for ocular drug testing applications.

In another example, a paper-based analytical device was developed to screen herbal medicines for new drug discovery. The identification of bioactive compounds in traditional herbs has become an important approach to obtain novel therapeutic compound. Using the polycaprolactone-chitosan as the printing materials, biological probes were immobilised onto a microfluidic device generated by 3D printing. Then the device was used to screen active compounds in the water extracts of mulberry leaves and lotus leaves. The simple and low-cost

device provided a new approach to screen active compounds from natural sources.

Future directions and challenges

While 3D printing has made great progress in pharmaceutical applications, there are challenges hindering the printed products into the market and clinical practice.

First, it is difficult to amend the existing regulatory guidelines and standards to accommodate the 3D printed medicinal products, which are customised fora single subject. It is not feasible to conduct the traditional clinical trials, in testing many subjects. Until now, only limited AM products have been approved by the FDA. Second, material safety is another concern. There are various materials used for 3D printing, ranging from hydrogels, plastics, ceramics to metal.

Their intrinsic characteristics will affect the quality and safety of the printed product. During the printing process, the operating parameters, such as printing temperature, particle size, thermal stability, and mechanical properties also need to be considered. Besides, the choice of 3D printable materials is limited for a certain type of printing, which may limit its application. For instance, the materials used in vat photopolymerisation should have a photocurable functional group.

At the same time, the material should also have a safe profile.

AUTHOR BIO

ink, Lim et al. fabricated a curved MN patch with varying curvatures to simulate the specific portion of human facial contour using VAT printing method. It was shown that curved MNs complying with facial contours and delivered significantly more drug through skin, to reduce facial wrinkles.

Third, cost-effectiveness is another key point to go to market. In general, AM is more cost-effective than traditional manufacturing methods, to make small batches of tablets, capsules, liquids, and/ or customised products. To this end, AM could help to reduce the cost to provide personalised medications to the patients.

On the other hand, the use of 3D printing may prevent drug abuse potentially, by means of personalised medicine.

Finally, with the application of the 3D printing technology, the integration of multiple drugs in a single preparation is also possible. It will be useful for the patients who need to take multiple medicines and/or those who have difficulty in recognising various dosage forms of different colour, shape and sizes.

Taken together, the pharmaceutical application of 3D printing is still in its infancy. Based on the current research, 3D printing has great potentials to change the current medical practice, especially in highly customised medications and the way medication is administered to patients. With the rapid development of 3D printing in both the technology itself and the corresponding regulatory framework, it will become one of the indispensable tools in drug development and pharmacy practice in the future.

References are available at www.pharmafocusasia.com

Yunong Yuan is a doctorate student in Sydney Pharmacy School, studying 3D printing for cardiac tissue engineering. He uses both experimental and simulated methods to optimise the current additive manufacturing approaches to print replaceable cardiac tissues to treat cardiovascular diseases.

Lifeng Kang is a Senior Lecturer at the Sydney Pharmacy School.

His laboratory is focused on microscale technologies and 3D printing for drug delivery and tissue engineering applications.

Kang has published 3 books, 65 peer-reviewed papers, 79 abstracts and filed 7 patent applications (2 granted). His work has been published in premium academic journals such as Advanced Drug Delivery Review, Journal of Controlled release, Molecular Pharmaceutics, Biofabrication, Advanced Functional Materials, and Biomaterials Science.

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NOVEL DRUG DELIVERY SYSTEMS

Industrial advancements Development of an existing API molecule from an immediate release form to a novel delivery system can improve its performance in terms of Efficacy, Specificity, Safety and patient compliance. Its Importance is evident from the fact that Global â&#x20AC;&#x2DC;Novel Drug Delivery Systems Marketâ&#x20AC;&#x2122; 2020 is expected to grow at a CAGR of roughly 2.2 per cent over the next five years and will reach 30300 million USD in 2024, from 26500 million USD in 2019.

Farhan Jalees Ahmad, Professor, School of Pharmaceutical Education & Research, Jamia Hamdard

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C

onventional dosage forms and delivery systems present several challenges in treatment of diseases like poor bioavailability, high dose, frequent administration, systemic adverse effects, etc.

Also, increasing prevalence of chronic diseases, high demand for non-invasive administration of drugs, need for high bioavailability and targeted delivery of drugs for lesser side effects have paved the way for innovation in drug delivery systems. Therefore, pharmaceutical companies are focused on designing novel drug delivery systems to overcome the limitations of using conventional dosage forms. For this reason, novel drug delivery systems might be among the fastest expanding segments in the drug industry.

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Use of nanotechnology has further enhanced the importance of continuous improvisation and introduction of new delivery systems for administering active agents. Novel Drug Delivery Systems (NDDS) have played a crucial role in establishing nanomedicine over the conventional dosage forms. Therapies of several terminal diseases like cancer and immunodeficiency diseases where controlled and targeted therapy is required with minimum side effects. For these, smart nanocarrier-based systems have been used for better therapeutic action at the target site. Increased cost and timelines for developing new molecules has shifted the interests of the researchers to modify the routes of administration and drug delivering devices of existing molecules for better pharmacokinetic and therapeutic parameters. Industries are working majorly on advancements in administering drugs through patient friendly techniques including programmable, implanted devices, smartphone based solutions, lab-on-a-chip or microofluidic technology. All these techniques have increased the market share so much so that for the transdermal delivery systems alone, the market value is projected to have a Compound Annual Growth Rate (CAGR) of 4.3 per cent during 20202027. Presently amid the COVID-19 crisis, the global market for NDDS is projected to reach a market value of US$27.2 Billion by 2027 from US$7.7 Billion in the year 2020, growing at a CAGR of 19.7 per cent over the period 2020-2027. The industry for preparing nanoparticles, the key in the delivery systems, is projected to record 19 per cent CAGR and reach US$23.2 Billion in the coming years. This review focuses on the important NDDS that are extensively worked upon and account for a major share in the market today.

Nanocarriers

Nanocarriers have been actively used in developing drug delivery systems to overcome the limitations of conven-

tional systems. These are designed and programmed to acquire unique physical properties and functions to protect the drug from degradation inside the body, to selectively deliver it to the target area and to minimise systemic exposure and metabolism. These consist of an inert carrier, drug molecule and the conjugated targeting moiety. The controlled release of entrapped drug molecules allows maximum and accurate cellular uptake thereby having minimum side effects that is a prerequisite in the therapy of several diseases like cancer.

Nanocarriers generally comprise lipid systems (liposomes, micelles), Carbon Nanotubes (CNTs), metallic nanocarriers (iron oxide/gold nanoparticles), polymeric nanoparticles and dendrimers.

Apart from the pharmaceutical industry, food technology including nutraceuticals and cosmetic industry are the major market holders for the nanocarrier based NDDS. Table comprises the various industrial applications of nanocarriers.

Microfluidics mediated NDDS

Microfluidics technology has gained enormous popularity by manipulating liquids in the microscale channels.

Attributed to its precise drug delivery with flow control along with the use of minute quantities of samples, micro-

Novel drug delivery systems have always been the area of research interests.

With new technological advancements, researchindustry collaborations, introduction of new therapeutic platforms and emergence of diseases, it becomes inevitable to upgrade the commercial scale up ability.

fluidic systems have made targeted and controlled delivery possible in difficult areas like eye and brain. Drug delivery systems mediated through microfluidics are proving to be next generation delivery devices that could be designed to achieve maximum results using minimum active ingredients. They have been used in a wide range of applications like point-of-care testing, isolation, detection and analysis of biomolecules, etc.

The ability of microfluidics to undertake almost all the functions of the conventional methods is resulting in its expansion in the healthcare industry. In addition to this, technological advancements, increasing focus on data precision & accuracy, fast returns on investment, and faster testing & improved portability through microfluidic chip miniaturisation are contributing to the growth of the microfluidics industry.

The global microfluidics market is growing at a CAGR of 22.9 per cent and its worth is projected to reach three times in the next five years. Several factors are responsible for the rising demand of microfluidics in the healthcare sector like technological advancements, increasing point-of-care testing, increasing portability through miniature lab-on-a-chip technology, emergence of microfluidics based organ-on-a chip, 3D cell culture and increasing focus on precise data collection. These systems can simulate the microenvironments and are used as drug delivery systems with desired physicochemical characteristics.

The drug molecule can be immobilised to the microfluidic chip to reach the target site. Also a microfluidic system can be utilised to encapsulate multiple drugs in the same droplet. Khan et al. encapsulated ketoprofen and ranitidine HCl into a core-shell microparticle. Xi et al. developed another simple and economical method for encapsulation of two anticancer drugs using the fuidic nanoprecipitation system and PLGA polymer. Extensive research work is going in the field of production and targeting of nanoparticles to different

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organs of the body like transdermal, brain, ocular, etc. through microfluidic technology.

Martins et al. loaded efavirenz to a transferrin functionalised Poly (lacticco-glycolic) Acid (PLGA) nanoparticle complex, for targeting the BBB and treating HIV neuropathology. The use of microfluidics produced smaller particles, higher drug loading and association efficiency. Samaridou et al. designed RNA-loaded cationic nanocomplexes for nasal delivery to the brain. Modifying the microfluidic conditions enabled the rapid development of a scalable nanosystem with a uniform size and high association efficiency. Wang et al has presented a microfluidic system for transdermal delivery of very minute nanolitres volumes of drug solution in brief time pulses for neurological studies. Similarly, several studies have been done which use the microfluidic devices for drug delivery by forming nanoscale droplets or particles of the polymer and drug solution. They allow high throughput screening by using microwell arrays and multiplexed systems which is an important aspect for industrial application as industries encounter large numbers of parallel assays and samples.

Microfluidics industry is flourishing as it uses minimum samples and has a wide range of applications in the bioengineering sector.

Guided delivery systems

Development of less-invasive or noninvasive routes for the systemic delivery of drugs, including subcutaneous, buccal, oral, inhalational, transdermal and nasal routes have always been a field of research and development.

Global Non-Invasive Drug Delivery Devices Market is projected to a significant CAGR of 23.13 per cent during the period 2019-2025. Along with these conventional modes, different techniques have been innovated for targeted deliveries of the drug molecules through some guided medium. Diagnostic imaging agents including radio, ultra-sound

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NDDS for gene therapy The global market for gene therapy is estimated to grow to US$13.0 billion by 2024 from US$3.8 billion in 2019, at a CAGR of 27.8 per cent. This much growth is majorly driven by the high number of cancer and other target diseases, and the increasing funding for gene therapy research. Currently, microRNA (miRNA) and synthetic small interfering RNA (siRNA) loaded NPs have been greatly used in advancing target reach and therapeutic efficacy in several incurable diseases. They have shown a high therapeutic potential for gene therapy for a range of diseases, including genetic disorders, cancer, viral infections and autoimmune diseases.

Attributed to the technological advancements in genebased therapeutics, an increasing number of approved gene therapies as well as an expanding pipeline is expected. In this process, miRNA or siRNA can target any gene in the cell and then silences the targeted gene1. Various types of conjugated systems of drug and siRNA are employed to efficiently target the desired cellular structure. The gene delivery systems use viral or non-viral type vectors that show the desired cell specificity and are able to deliver an optimised amount of transgene expression to obtain the therapeutic effect. Sava et al loaded siRNA to chitosan nanoparticles to tone down the gene expression in Huntingtonâ&#x20AC;&#x2122;s disease through nasal administration. This system was designed to efficiently enter the brain and protect from degradation. Xia et al. conjugated selenium nanoparticles with siRNA for better therapeutic efficacy in hepatocellular carcinoma. Higher transfection efficiency, increased cytotoxicity to carcinoma cells and greater gene silencing ability was achieved. Mu et al developed the lipid-polymer hybrid nanoparticles for siRNA delivery to perform gene silencing in target cells. Extensive studies have been reported for siRNA delivery majorly for cancer treatment.

Gene therapy is looked upon as a hope to combat the most difficult diseases like cancer, Alzhiemer, HIV, etc. and has the potential to be developed as a novel method and system for desired gene silencing.

1, https://pubs.rsc.org/en/content/articlelanding/2016/tb/c6tb01462c#!divAbstract

and conventional magnetic contrast agents are engineered to deliver drugs as well as capture images of diseased organs. Novel therapeutic methods have emerged that use the guidance from outside to concentrate the drug molecules to the target tissues alongwith the real time imaging. This approach has been extensively studied to treat deadly diseases like tumours. These types of

guided systems have better reach to the target site and can efficiently deliver the drug moiety even through the barriers. Therapeutics crossing the blood brain barrier has always been a focus of research in studying neuropathological ailments. Various approaches have been studied for non-invasive guided delivery to the brain. Nose to brain delivery is one such approach in which

MANUFACTURING

NANOCARRIER

PHARMACEUTICAL

NEUTRACEUTICALS

COSMETICS

Liposome

Pain management, anticancer, molecular therapy, antibacterials

Antimicrobial peptides, curcumin, iron, tea polyphenols, stabilised food components

Vitamin E, skin care cream

CNTs

Scaffolds, pesticide analysis anticancer herbal drugs

As antimicrobial agents and increasing shelf life

Anti-aging and Hair coloring

Metallic nanoparticles

Magnetic drug targeting, magnetic hypothermia, photothermal therapy, chemotherapy drug delivery, gene therapy

Enzyme immobilisation, protein purification, and food analysis

Nano silver, titanium and zinc oxides

Polymeric nanoparticles

Intracellular targeting, oligonucleotides delivery, cancer chemotherapy, ocular delivery.

White tea, food preservation and encapsulation of bioactive molecules

Drug molecules in skincare products

6. Conclusion

Novel drug delivery systems have always been the area of research interests.

With new technological advancements, research-industry collaborations, introduction of new therapeutic platforms and emergence of diseases, it becomes inevitable to upgrade the commercial scale up ability. Therefore, the market is expanding and would account for a major share in the healthcare sector in the coming years. Nanotechnology has given a breakthrough in efficiently delivering the drug at the target site. Several types of nanocarrier systems for drug delivery have been explored that possess desired physicochemical properties and have been used for the treatment of several ailments. Apart from protecting the drug from the inside environment and degradation after administration, they are developed for controlled release

AUTHOR BIO

the nanocarriers are programmed to enter the brain via nasal administration.

Hasan et al have used weak electric currents to guide the liposomes through skin surface to improve the penetration of the encapsulated drug which otherwise had limited penetration due to the skin barrier.Nanoparticles conjugated with the ligands that could be detected in real time using fluorescent moieties can give the idea of the distribution of the drug. Nagaraju et al studied ligandbased drug delivery using nanoparticles in gastric cancer treatment. Another interesting NDDS guided externally is the Ultrasound (US)-triggered drug release. Major challenge in cancer chemotherapy is to enhance the amount of chemotherapeutic agents in the target tissues. Patrucco et al. used the US to stimulate the release of liposomal nanomedicine that is further monitored by using Magnetic Resonance Imaging (MRI). This type of technique generally needs co-administration of microbubbles with the ultrasound and resonates with the US frequency to pave the way for the drug release at the target site through formation of cavities. Tomitaka et al. have explored a new area of guided delivery. They engineered nanoparticles having iron oxide cores and plasmonic shells with gold branches. Strong magnetic and near-infrared stimulated nanocomplex systems gave image-guided drug delivery with a controllable drug release capacity.

at the target site. Microfluidics mediated NDDS have a major role to play in increasing high throughput screening in research and using minute volumes of samples hence, are majorly used in industrial scale. Challenges of using this technology are its complexity and high cost of development. For better reach to difficult targets like crossing blood brain barriers, external stimuli guided NDDS has made its niche in the industry. Also, treating the diseases right from their emergence i.e. the genes that control them has opened the way to use gene therapy extensively. There is still much research to perform in all these areas to overcome their limitations and establish the aims of NDDS i.e. maximum therapeutic effect with minimum toxicity.

References are available at www.pharmafocusasia.com Farhan Jalees Ahmad is currently a Professor, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India and is an internationally known researcher in the area of Pharmaceutical Sciences.

He continues to teach and leads a very productive research group which has been funded extensively by National and international funding agencies. The focus of his group has been in the area of Novel Drug Delivery System and He has two US patent, three PCTs and 20 Indian patents. With a total citation of 12059, H Index of 50 and i-10 index of 284, Professor Ahmad's work has been clearly well received by the scientific community.

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R OU ND TABLE

EXPERT TALK

Pharma Focus Asia Patient-centric Drug Delivery Contract manufacturing leaders offer their insight into drug delivery innovation and development.

Lonnie Barish, VP, Business development and marketing, Bora John Ross, President, Metrics Marc Brown, Chief Scientific Officer and Co-founder, MedPharm

Whatâ&#x20AC;&#x2122;s on the horizon for patientcentric drug delivery?

As more of the world reports better access to healthcare, the demand for safe effective therapeutics of all kinds will continue to escalate. This broad global acceptance of pharmaceutical based healthcare has accelerated the development of more sophisticated medications to treat the unmet needs of an increasing number of patients.

Conventionally, the market for all pharmaceuticals has been dominated

by North America, followed closely by Europe. However, with an increasingly ageing population and growing spending on healthcare per capita, demand for pharmaceuticals in the entire AsiaPacific region is expected to see rapid, significant growth for the foreseeable future.11 Asia Times reported in 2019 that the market for pharmaceuticals in China was set to reach US$161 billion, taking a 1. http://www.pharmabiz.com/NewsDetails. aspx?aid=121681&sid=21

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30 per cent share of the global market.

During the 2019 World Innovators Meet, Fu Xudong, senior vice-president of Bristol-Myers Squibb noted that China has emerged as worldâ&#x20AC;&#x2122;s second-largest pharmaceutical market, following the United States.2 Dose delivery in development

Oral Solid Dose (OSD) formulations continue to lead the market as a preferred dosage form. According to the US FDA Center for Drug Evaluation and Research (CDER), of the 38 small molecule drugs approved by the agency in 2019, 26 (68 per cent) were OSDs (19 tablets and 7 capsules).3 Demand for topical pharmaceuticals, another growing and patient centric drug delivery modality, is projected to reach US$129.8 billion by 2025 from US$95.2 billion in 2020, at a 2. https://asiatimes.com/2019/12/chinas-pharma-marketpoised-to-hit-us161-billion/ 3 https://www.fda.gov/about-fda/fda-organization/centerdrug-evaluation-and-research-cder

compound annual growth rate of 6.4 per cent during the forecast period.

MarketsandMarkets points out that growth in this market is being driven by the increasing prevalence of skin and soft tissue infections, eye diseases emergency treatments for burns.4 Pharmaceutical development and innovation is coming from both drug developers and their contract manufacturing partners. Pharma is relying more and more on external partners to deliver the solutions they need to deliver their formulations and explore the new modalities, personalised genetic therapeutics and chemistries being introduced.

To gain better insight into drug dose delivery technology trends Pharma Focus Asia invited leadership from three contract development and manufacturing organisations (CDMOs) serving the Asia-Pacific market for their input and perspectives on what is on the horizon for drug delivery.

4 https://www.marketsandmarkets.com/PressReleases/ topical-drug-delivery.asp

EXPERT TALK

Complex OSD systems for patient-centric dose control As more of the world reports better access to healthcare, the demand for therapeutics has seen a significant increase. This has prompted the development of medications to treat and/or cure more rare diseases, as well as further development and exploration of new modalities, genetic techniques, and chemistries to make better-performing drugs for more people.

Personalised medicine is a prominent trend in pharmaceutical development and is increasingly being applied in new and innovative ways. The techniques involved provide deep insight into different patient populations and the pharmacokinetic and pharmacodynamic effects of various drugs. As a result, health professionals can be more selective in their choice of pharmaceutical products for their patients, taking into consideration their efficacy in certain subsets of the population.

This growing trend is likely to prompt the development of even more complex but still functional drug forms. This includes the combination of APIs for related disease states and deploying them in bilayer/tri-layer tablets and more sophisticated combination products.

With patient groups responding well to oral medications that allow easy administration, require fewer doses to be effective, and reduce or eliminate unpleasant side effects, OSD delivery remains the most popular route for administering drugs.

Patient friendly OSD strategies

Drug developers looking to enhance patient dose compliance can explore and utilise these complex patient-friendly OSD strategies through two main avenues: 1. Fixed-dose Combinations (FDCs), modified release single-capsule forms 2. Multi-unit Particulate System (MUPS) tablet designs MUPS, a versatile technology combining proven pelletisation and tablet delivery modalities offers process efficiencies and by design, patient-friendly

attributes compared to capsules. This technology is not new but is growing in popularity to control dose frequency and side-effects.

This delivery allows new modified-release profiles and the dosing precision pharma needs for its advanced formulations and potent, combined APIs. It is essentially a successful method of getting multiple APIs to â&#x20AC;&#x2DC;play nice togetherâ&#x20AC;&#x2122; to create the complex but functional drug forms initiated by the push for personalised medicines.

As the demand for personalised/precision medicine grows it is evident these strategies will play an important role in developing the effective patientfriendly pharmaceuticals that society is demanding now to meet the future of healthcare.

LONNIE BARISH VP, Business development and marketing, Bora Lonnie Barish is the VP of Business Development and Marketing for Bora Pharmaceuticals USA. He is a seasoned Sales, Marketing, and Business Development Executive with over 25 years of experience in creating and managing Sales and Marketing teams. Lonnieâ&#x20AC;&#x2122;s strength lies in building solid relationships with his internal and external customers/ partners that create mutually beneficial opportunities. He has held senior sales roles at CMOs and CROs including ICON, AAIPharma, Cytovance and WellSpring.

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EXPERT TALK

Novel drugs need oral delivery to support patient-centric goals Highly potent novel OSD drugs have gained popularity. At Metrics, our seasoned scientists are experts in supporting clients with their highly potent active pharmaceutical ingredient (HPAPI) formulation and development projects. Our characterisation capabilities combined with key insights gained over many years of experience, ensure that the containment and handling practices of any HPAPI project remain aligned.

The demand for HPAPIs has increased mostly because of the rapidly expanding oncology sector. As technology evolves and more oncolytic therapeutics are conceptualised, many companies turn to CDMOs to develop and produce their HPAPI drug substance and drug products. Because of the complexity and hazards involved in producing these drugs it is often easier to outsource this process to a team with a trusted track record and the installed containment technologies to effectively handle these products.

Manufacturing HPAPIs in-house requires major investments in contained development, production facilities, equipment and trained personnel who are certified to handle potent compounds. There are also many regulatory restrictions involved in handling potent drugs due to their hazardous characteristics and risk to the environment, patients, and manufacturing personnel.

Whilst some pharma companies do have in-house HPAPI capabilities, they are often at commercial scale.

Yet, most contemporary needs for HPAPIs tend to be small batch sizes due to the specificity of the medication being produced. This means companies have had to partner with qualified outsourcing companies that are set up to handle smaller batches.

Key components in successful HPAPI operations

While there are a wide range of players now offering approaches to developing these drugs, not all CDMOs are equipped to properly handle HPAPIs. When looking for a partner, it is critical to first consider whether

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they have the proper equipment, facilities, and infrastructure to handle your HPAPI based on its known potency and health and safety hazards. Discuss the various risks associated with different unit operations and scales and be sure your CDMO can articulate a suitable plan to mitigate those risks and ensure they will be adequately addressed through the scale up process and commercialisation.

Engage development partners earlier for better patient centric delivery solutions

Asia, as well as pharmerging markets around the world are demanding more pharmaceuticals and more from pharmaceutical developers than ever before. All drugs, no matter what the route of administration, have to do more than ever. They have to be safe and effective and above all designed to suit the needs of the patient.

JOHN ROSS President, Metrics John Ross has more than 20 yearsâ&#x20AC;&#x2122; experience in the pharmaceutical industry across marketing and sales, manufacturing and distribution, global sourcing and supply chain.

Prior to joining Mayne Pharma, Mr. Ross was a Principal at Tunnell Consulting a leading US biotech and pharmaceutical consulting organisation. He has also held a number of leadership roles including Chief Operating Officer of Contract Pharmaceuticals Limited, a provider of outsourced third-party contract development, manufacturing and testing of pharmaceuticals.

EXPERT TALK

Topical formulations are inherently patient friendly Most of the pharmaceutical market is dominated by oral or intravenous dosage forms. For some drugs, these conventional options for delivery are not possible due to drug instability, inability to get the drug to the target site, or systemic side effects. As patient expectations continue to rise, so does the requirement for pharmaceutical companies to develop more ‘user- friendly’ dosage forms.

This includes those that positively impact their health while integrating seamlessly into their lifestyles. This is especially important with topical formulations as the cosmetic and aesthetic properties are a critical aspect as patient compliance is often driven by the ease of use and the application experience. At MedPharm, the end user’s opinions and preferences are crucial from the start and are incorporated into the target product profile we establish with our clients from the outset.

A major trend that has impacted drug dosage forms is the rise in the use of complex entities known as biologics.

These have brought their own challenges that has led to the need for new solutions in terms of packaging, analysis, delivery and stability. Research carried out with MedPharm’s experts challenges existing theories on topical delivery of these macromolecules and demonstrates that some aptamers can penetrate skin and remain active despite their large molecular weight (20k Daltons). This research offers hope for the discovery of new treatments for difficult-to-treat dermatological diseases.

There are multiple benefits associated with partnering with an expert for specialist dosage forms such as topical products for skin, eye, airways or mucosal membranes.

To facilitate optimum formulation development unique knowledge and experience are required, something that most development companies lack in-house. Specialist

contract developers like MedPharm possess an in-depth understanding of what it takes to get a product to market whether it is a new chemical entity, a re-purposed drug for a new indication, an OTC product or a generic. As a result, we expect to see a continued rise in outsourcing as the topical drug delivery market continues to advance.

MARC BROWN Chief Scientific Officer and Co-founder, MedPharm Marc Brown co-founded MedPharm in August 1999. He has been the guiding force behind all of MedPharm’s scientific developments and intellectual property. He has been Professor of Pharmaceutics in the School of Pharmacy, University of Hertfordshire since 2006 and has visiting/ honorary professorships at the Universities of Reading and King's College London. He has over 200 publications and 26 patents describing his work. His research interests lie mainly in drug delivery to the skin, nail and airways. To date, he has been involved in the pharmaceutical development of over 38 products that are now on the market in Europe, America and Japan. Prior to MedPharm he was an academic in the Pharmacy Department at KCL.

One thing all three contributors agree on is that the more complex the dose formulation or delivery mode, the more it makes sense to introduce it as early as possible to development partners. The efficient development of a safe, effective oral or topical medication hinges on so many things, but it is clear that if patient-centricity issues aren’t addressed it will likely never reach patients successfully.

References are available at www.pharmafocusasia.com www.pharmafocusasia.com

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STRATEGY

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MANUFACTURING BioGenes GmbH....................................................................................11 F. P. S. Food and Pharma Systems Srl...................................................22 Kรถrber Business Area Pharma.........................................................48-50 Rousselot..............................................................................................55 Syntegon...............................................................................................15 Valsteam ADCA Engineering.................................................................03

INFORMATION TECHNOLOGY Kรถrber Business Area Pharma.........................................................48-50

Eppendorf AG...................................................................................... IBC www.eppendorf.com/discover-the-flow F. P. S. Food and Pharma Systems Srl...................................................22 www.foodpharmasystems.com ILC Dover..............................................................................................05 www.ilcdover.com Kรถrber Business Area Pharma.........................................................48-50 www.koerber-pharma.com Rousselot..............................................................................................55 http://rousselot.com/biomedical Syntegon...............................................................................................15 www.syntegon.com Valsteam ADCA Engineering.................................................................03 www.valsteam.com ThermoFisher Scientific........................................................... IFC, 40-43 http://thermofisher.com/ICBold/ Turkish Cargo..................................................................................... OBC www.turkishcargo.com

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