Pharma Focus Asia - Issue 39

ISSUE 39

2020

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Head of Sales, APAC

DELIVERING A COMPLETE SOLUTION TO CUSTOMERS

COVID-19 Pandemic Risk assessment and future control Virus Outbreak Impact on pharma industry

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Foreword Treating COVID-19 Global pharma makes early strides The COVID-19 pandemic hit industries across the globe as countries adopted various measures that included travel restrictions, border closures to imposing nationwide lockdown, in a bid to contain or slowdown the spread of virus. Almost six months after the novel corona virus was first diagnosed in China, the number of patients, currently standing at 6 million, continues to soar along with number of reported deaths.

COVID-19 patients are admitted with varying conditions, and there is no one-size-fits-all approach or one medicine to treat them. Healthcare organisations have been testing the use of various anti-viral drugs to treat patients based on their symptoms. Transfusions with convalescent plasma is understood to be a safe approach in treating COVID patients, according to doctors at John Hopkins University. Early results from countries like China suggested improvement in patients administered with hydroxychloroquine or chloroquine, used primarily to treat malaria.

However, recent studies published by the Lancet journal have raised concerns of hydroxychloroquine increased in-hospital patient mortality.

All said and done, emergence of a drug can help deliver positive results in treating patients.

As countries brace to overcome this pandemic, pharma majors, scientists and governments have been speeding efforts to come up with a potential vaccine for COVID-19. According to clinicaltrials.gov, more than 1,900 studies are underway, and several companies have already ventured into clinical trials and early tests to determine vaccines are safe. Large pharma companies such as AstraZeneca, Pfizer have announced plans to produce and make available tens of millions of

doses by mid-to-late 2020. Gilead Sciences has obtained approval to use Remdesivir, its antiviral drug, in emergency, in India, U.S. and South Korea, after showing moderate signs of improvement in COVID-19 patients over a five-day course. However, there was no major improvement in patients who received the drug for 10 days.

While efforts are on to test and get vaccines ready for treatment, scientists have notably warned that any rush to fast-track clinical trials could prove counter-productive and result in a catastrophe.

Another challenge facing the global pharma industry is responding to the supply chain disruptions causing vulnerabilities in patient treatment during a pandemic. For the pharmaceutical supply chain, major challenge lies in China being at the centre for both demand and supply. The current situation has presented an opportunity to the Indian pharma industry to become a preferred alternate hub for manufacturing APIs and intermediates.

Companies will do well to relook at their supply chain strategies, focus on risk management in a bid to build resilience to overcome challenges.

The latest issue of our magazine contains articles revolving around COVID-19, its impact on the pharma industry, the need to focus on risk assessment and future control of pandemics and how this presents an opportunity for Indian pharma to become more self-reliant.

Prasanthi Sadhu Editor

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CONTENTS MANUFACTURING

COVID-19

40 Biologics Reshaping Pharmaceutical Market

Prasanthi Polamreddy, Scientific Manager, Excelra Knowledge Solutions Pvt Ltd.

48 Finding a Path to Global End-to-End Labelling

Christophe Djaouani, EVP Regulated Industries, SDL

STRATEGY 06 COVID-19 Pandemic

Risk assessment and future control

Sakshi Nanda, Surabhi Johari* School of Biosciences Institute of Management Studies University Courses

12 COVID-19

From a challenge to an opportunity for Indian pharma to become selfreliant

Sharada Prasanna Swain, Associate Professor, Medicinal Chemistry, National Institute of Pharmaceutical Education and Research

V Ravichandiran, Director, National Institute of Pharmaceutical Education and Research

16 Virus Outbreak

Impact on pharma industry

Dhruv Kumar, Associate Professor, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh

51 Sustainable Packaging

Pharma to take care of the planet

Maria Ferrante, Senior Director, Marketing and Communications PMMI

54 Next Generation Biorepositories for Transformative Medicine S Dravida, Founder CEO, Transcell Biologics

V Vellanki, Intern, Transcell Biolife

Aman Iqbal, Scientist, Healthcare Entrepreneur

58 SBV Technology and Eradicating the Risk of Contamination in Aseptic Manufacturing

Christian Dunne, Global Product Manager, ChargePoint Technology

64 Biosimilars in The Public Health Sector

Measures to promote the use

Josep M Guiu Segura, Pharmacy department, Catalan Health and Social Care Consortium

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RESEARCH & DEVELOPMENT 22 Integrative Associative Classification for Cancer Biomarker Discovery

Ong Huey Fang, Lecturer, School of Information Technology Monash University

32 Intelligent Nanomaterials in Pharmaceutical Analysis

A vision of future

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Rßstem Keçili, Anadolu University Yunus Emre Vocational School of Health Services, Department of Medical Services and Techniques

Chaudhery Ghazanfar Hussain, Research Scholar, Computer science and Technology, Dept. of Education Lahore

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

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ISSUE 39 - 2020

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Advisory Board

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

EDITORIAL TEAM Debi Jones Grace Jones ART DIRECTOR M Abdul Hannan

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

PRODUCT MANAGER Jeff Kenney

Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

SENIOR PRODUCT ASSOCIATES David Nelson Peter Thomas Sussane Vincent

Frank Jaeger Regional Sales Manager, AbbVie, US

PRODUCT ASSOCIATES John Milton

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

CIRCULATION TEAM Naveen M 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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The products and services advertised are not endorsed by or connected with the publisher or its associates. The editorial opinions expressed in this publication are those of individual authors and not necessarily those of the publisher or of its associates.

Copies of Pharma Focus Asia can be purchased at the indicated cover prices. For bulk order reprints minimum order required is 500 copies, POA.

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

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STRATEGY

COVID-19 PANDEMIC RISK ASSESSMENT AND FUTURE CONTROL The latest COVID-19 disease outbreak caused by novel corona virus, which is now officially known as SARS-CoV- 2 extreme acute respiratory syndrome, is a global public health pandemic. While the COVID-19 outbreak in Wuhan, China, was in December 2019, it spread to over 100 countries.

This disease spread to more than 100 nations with more than 14, 50,343 confirmed cases, and more than confirmed 83,568 fatalities worldwide till 8 April 2020. However, as a consequence of the mandatory isolations / quarantines millions of people were affected by this disease. If COVID19 is not efficiently regulated the spread of the virus, may potentially pose significant challenges to global health systems and have far-reaching consequences in the world economy.

Sakshi Nanda, Surabhi Johari* School of Biosciences Institute of Management Studies University Courses

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here is a widespread panic around the world about COVID-19, caused by the novel Coronavirus. In late December 2019, China health Officials reported an outbreak of pneumonia of unknown origin in Wuhan, Hubei province. The World Health Organisation (WHO) originally called this disease "Novel Coronavirus-infected Pneumonia (NCIP) and this novel coronavirus was provisionally named 2019nCoV. Novel, because it is new to humans, meaning that this specific virus is one that we have never seen before. The disease is potentially a case of zoonotic transmission that may occur through contact and

COVID-19

TNFÎą Interleukin

Fever

Macrophages Interleukin

SARS-CoV2 Entry into Alveoli Difficulty in breathing due to fluid accumulation SARS-CoV2 ACE Interaction

Systemic inflammatory Response Syndrome (SIRS)

ENTRY INTO LUNGS

BLOOD PRESSURE

BLOOD VOLUME

PERFUSION

MULTI SYSTEM ORGAN FAILURE (MSOF) Figure: 1

respiratory route. Arrival of COVID19 is disturbing as the human body lacks immunity against this virus, combined with its ability to spread and its relative lethality. The virus is spreading globally at an alarming late since its discovery and has been causing thousands of deaths and subsequently having an impact on our health systems and as well as economy.

After China, it has spread subsequently to 37 other countries including Italy, United States, Japan, South Korea, Australia, Iran, France and India. The outbreak was declared as Pandemic and Public Health Emergency of International Concern on 11 March 2020, by WHO. As of 20 April 2020, there have been 2,319,066 confirmed cases of Corona spreading across 213 countries.

The incubation period of COVID19 is assessed to be between 2 and 14 days, meaning the symptoms appear to develop within 14 days after coming in contact with someone with confirmed coronavirus. COVID-19 is mainly transmitted through droplets generated when an infected person coughs, sneezes, or exhales. Also, these droplets are too heavy to hang in the air, and quickly fall on floors or surfaces and one can be infected by breathing in the virus if he comes in proximity of someone who has COVID-19, or by touching a contaminated surface and then your eyes, nose or mouth and Corona viruses

can also spread by aerosolisation as well.

Clinical presentations of COVID-19 range from no symptoms (asymptomatic) to severe pneumonia. COVID-19 patients primarily show symptoms of fever, fatigue or myalgias and dry cough.

Patients with severe illness may develop dyspnea and hypoxemia within a week after onset of the disease, which may quickly progress to acute respiratory distress syndrome (ARDS) or end-organ failure. Though majority of cases (almost 80per cent) are milder respiratory infections and pneumonias and the severe illness and death is more common among the elderly or the individuals with other comorbidities like diabetes, hypertension, smoking history, weak immune system or pre-existing lung disease. (Figure: 1)

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STRATEGY

will be provided to the citizens, while maintaining stringent safety norms.

Similarities and Differences between COVID-19, MERS and SARS

SARS, MERS and COVID-19 are viral respiratory infections and belong to the common genome of a virus. Research has shown that SARS-CoV and MERSCoV originated in bats, and it is likely that SARS-CoV-2 did as well. SARSCoV then spread from infected civets to people, while MERS-CoV spreads from infected camels to people. However, the scientists are trying to determine how SARS-CoV-2 spread from an animal reservoir to people. The reproductive transmission number for COVID-19 is estimated by WHO is between range of 2 to 2.5 which is higher than SARS (1.7 to 1.9) and MERS (<1), clearly indicating that it has higher potential to spread. However, the fatality rate of novel coronavirus infection is estimated to be 2.3, which is lower than SARS (9.5 per cent) and much lower than MERS (34.4 per cent).

Control measures by health system and governments

Countries around the world were in a state of panic about the spread and are still concerned that the magnitude of this pandemic cannot be taken lightly. India too took up the control measures as directed by WHO guidelines, first and foremost step taken up was traveler screening at airports, in order to curtail the geographic spread of infection. But it was effective for short mean incubation period. For larger incubation periods, travelerrs will not show symptoms. They will be healthy enough to travel and it becomes difficult to detect. Hence, a containment plan which mentions about non pharmaceutical intervention was declared.

‘Quarantine’ and ‘Isolation’ were the important contents of the containment plan. Quarantine refers to separation of individuals who are not yet ill but have been exposed to COVID-19 and thus have a potential to become ill. Isolation refers to separation of

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The reproductive transmission number for COVID-19 is estimated by WHO is between range of 2 to 2.5 which is higher than SARS (1.7 to 1.9) and MERS (<1), clearly indicating that it has higher potential to spread.

individuals who are ill, suspected, or confirmed COVID-19 cases. Doctors and nurses were provided with online training on management of COVID-19 patients. Tele- consultation facility was provided to ensure that all COVID19 patients should get uniform clinical care. Quarantine Facilities were set up. A meticulous surveillance system in line with contract tracing enabled to track the individuals who tried to avoid the surveillance and didn’t follow the quarantine measures.

Social Distancing measures were implemented to mitigate the impact and interrupt the human to human transmission chain as it can reduce the intensity of the spread and slow down the increase in the number of cases thereby helping the Healthcare system to prepare and cope with influx of the patients. Also, restrictions on mass gatherings were imposed in order to contain the virus. Social distancing at work places, measures for closure of schools and sanitisation of areas to limit the spread of transmission were adopted.

Lockdown was declared nationwide on 25 March 2020 in order to contain the spread and flatten the curve. But it was assured that all daily essentials

Diagnostics and Drug Management

The diagnostic tests for COVID-19 include molecular tests and serology tests. Detection is done by using two approaches- Whole Genome Sequencing and Real-Time Reverse Transcriptase PCR (RT-PCR). In earlier days of the outbreak, Sequencing was used for early documentation of this novel virus and its discovery and isolation. Currently, nearly all diagnostic testing is being done using RT-PCR. Abbott Testing kit known as ID NOW COVID was launched as game changer since it can deliver positive results in as little as five minutes and negative results within 13 minutes Various companies worldwide are manufacturing the coronavirus diagnostic test kits, which includes Glenmark Diagnostics, Cepheid, Bio fire Diagnostics, Meridian Biosciences.

In India too Mylab became the first company to launch diagnostic kits. SD Biosensor and Altona Diagnostics in India have also got the approval for the same. The test is done on respiratory samples — nasopharyngeal and throat swab.

Currently, no antiviral medication is recommended, and treatment is directed at relieving the symptoms.

Clinical management includes prevention of infection, control measures and supportive care, which includes supplemental oxygen therapy and ventilatory support system when required. NSAIDS like ibuprofen are being used currently for symptomatic reliefs. Zinc, Vitamin D and Vitamin C studies have shown to reduce the length of viral infections and respiratory and lung inflammations.

The idea behind treating the symptoms is to prolong the patient’s life and help him to develop his immunity system and remove the infection. Though specific treatment for COVID-19 is still not yet available, but the positive aspect is that drugs are being tested and

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susceptible or at risk of catching COVID-19. This is also called as “Convalescent Sera.” Or the Plasma Therapy. Plasma Therapy has shown some positive results recently in treating the patients of COVID-19. Another method of treatment under study is blocking the part of the immune system which is reacting highly to the COVIDinfection.

Risk factors and challenges

The sad part is that this new Coronavirus appears to spread much faster than SARS. So, a virus that spreads easily presents a huge Public Health Challenge in designing a system that can efficiently contain it. Also, the primary risk assessment based on its epidemiological characteristics is that everyone is susceptible, and it is still not known about neutralizing and developing the immunity post infection. Individuals at higher risk for severe disease and death include old age individuals and those with underlying conditions of diabetes, hypertension, chronic respiratory illness and cancer.

Understanding the COV infection among healthcare workers is one more aspect to be considered in risk assessment. It is important for not only the

characterisation of viral transmission but also for preventing the future infection in healthcare workers and reducing the secondary infection in the health care setups. According to an estimate, India has a shortage of about 6 lakh doctors and near about 20 lakh nurses, and an even bigger number of supporting medical staff. This means losing even a single doctor or nurse or any supporting staff, due to lack of protective equipment or not following the standard operating procedure (SOP) in handling COVID-19 cases is a cost that India cannot afford to bear. Another risk factor that cannot be ignored is that a seasonal cycle to the Coronavirus epidemic is possible meaning that there is risk factor of ramping up the corona infection again from severe weather and climate change. Also, due to lockdown and people staying inside the houses there has come evidences of decreased level of Vitamin D deficiency and this can further reduce the immunity of the body and the person is at high risk of catching respiratory infections.

Despite India's proactive and swift move to contain this COVID-19 steps, there have been challenges in its way of fighting corona. Key concerns are the country's high population density,

Sakshi Nanda is an HR professional with 3 years of industry experience. She is graduate in Pharmaceutical Sciences and Masters in Human Resources. Currently she is working as a freelance writer for magazines and journals.

AUTHOR BIO

clinical trials are giving results. The WHO announced it has helped to launch four “mega trials'' against COVID-19 and these trials are focusing on drugs that can directly block SARS-CoV-2 – the virus strain that causes coronavirus COVID-19, from replicating inside the lungs. Some of the main drugs on whose trial we are looking forward are Remdesivir, Lopinavir/ Ritonavir, Chloroquine and Hydroxychloroquine.

Remdesivir is an intravenous antiviral drug which is under study and has shown some positive changes in COVID-19 patients, but large trials are still needed. Combination of Lopinavir and Ritonavir is currently used to treat multiple sclerosis, thereby enhancing the body’s natural defense system against COVID-19. Chloroquine and Hydroxychloroquine can block the viruses and prevent infection, but still large trials are needed in collaboration with WHO. The studies have demonstrated that chloroquine phosphate inhibits SARS-CoV-2 and there have been studies to show that hydroxychloroquine sulfate inhibits SARSCoV-2 in vitro. Among those treated for COVID-19, Azithromycin is also believed to relieve the symptoms. In parallel to this, the combination of hydroxychloroquine and azithromycin had been evaluated in invitro studies on SARS-CoV-2 infected cells and showed that there was a considerable synergy of these two products if they are used at doses which are suitable in doses required for human body. As per Monash university study in Australia, a single dose of Ivermectin can stop the growth of Corona virus growth in cell culture within two days and has been suggested for clinical trials.

Two other kinds of treatments are also being explored in trials and these work in a different way. The first is passive immunization- that is the transfer or the transfusion of protective antibodies from someone who has recovered from COVID-19 to someone who is

Surabhi Johari is a Professor at Institute of Management Studies University Courses Ghaziabad. She has gained her expertise in various molecular modeling techniques utilized for Computer-Aided Drug Design. She is working on multiple drug discovery projects with interdisciplinary teams of structural biologist, medicinal chemist, pharmacologist and physicians.

COVID-19

of sanitation and an adequate sewage disposal system is also coming up a hurdle to contain the virus.

Future control

COVID-19 is not the first, nor will it be the last among rapidly spreading pandemics of high impact to cause health disruption and deaths. Pandemics are emerging at higher frequency and it is becoming difficult to contain because of population growth, economic integration, urbanisation, migration, climate changes and faster travels. A comprehensive strategy, including surveillance, diagnostics, clinical treatment, research, and development of vaccines and drugs, is urgently needed to win the battle against COVID-19 and other infectious diseases. The good part is that only after a few weeks of the discovery and isolation of SARS-CoV2, vaccine development started by scientists across the world. But failure is possible. There is no sure shot guarantee that a vaccine

will develop within a short time period and even if it gets developed, it has to go under test for safety and efficiency.

Artificial Intelligence and Data analytics can play an important role in modern genome sequencing methods. There is a need to create artificial intelligence (AI) programs and make it available to scientists to improve healthcare vastly. A greater understanding of these phenomena can empower the community to respond far more rapidly to such viral attacks. This approach can help to recognise any deviations before it reaches epidemic proportions. Global cooperation, collaboration and investment are necessary to ensure a safer future. We need to implement a multi-sectoral dimensional approach in managing the problem of global pandemic diseases that includes governments, industry, financial systems, academia, international organisations and civil society, everyone having responsibilities towards building a global public health security.

FPS is pleased to announce the launch of a new innovating solution for swabbing, that will ensure the absolute safety of operators and patients:

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overburdened public health system, high prevalence of non-communicable diseases (NCDs), a smaller number of testing laboratories, and inadequate number of hospital beds, ventilators and ICU facilities. The absence of widespread testing is causing actual count to appear “statistically invisible”. Laboratory diagnostic capacity weakness at national and community levels of the Healthcare System in India can greatly reduce the effectiveness of outbreak containment. Hence, timely and accurate laboratory testing of specimens from cases under investigation is an essential part of the management of COVID-19. Social distancing in a densely populated Indian population is coming up as a risk factor. The houses in slum areas of India are so congested that people cannot follow social distance norms as recommended by the doctors. In Mumbai, seventy-one people have tested positive for coronavirus in Dharavi, Asia’s biggest slum. Lack

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Maximum protection to the patient and the healthcare staff carrying out the test because of the “physical”” barrier it creates between both which eliminates any risk of contact/contagion.

Maximum reduction/elimination of contamination risks for the collected samples but also for the environment thanks to a safe system for removing the samples from the cabin withe a continuous liner.

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COVID-19

FROM A CHALLENGE TO AN OPPORTUNITY FOR INDIAN PHARMA TO BECOME SELF-RELIANT The COVID-19 pandemic has affected people of more than 200 countries, with more than 4200 thousands people infected and about 300 thousands deaths are confirmed worldwide. There is no specific drug which can cure the disease. Only supportive care is available. Many companies have started clinical trial of existing antiviral drugs against COVID-19.

Gileadâ&#x20AC;&#x2122;s Remdesivir has got approval for treatment of COVID-19 patients. Fujifilmâ&#x20AC;&#x2122;s Favipiravir is also recommended by Tokyo for treatment of COVID-19.

Sharada Prasanna Swain, Associate Professor, Medicinal Chemistry, National Institute of Pharmaceutical Education and Research V Ravichandiran, Director, National Institute of Pharmaceutical Education and Research

C

hina and India are the leading players in bulk drugs, and manufacture more than 40 per cent of global bulk drug. China is the largest bulk drug supplier in world, and India is second. As reported by ministry of commerce, India exported drugs formulation and biologicals of 12.9billion USD in 2017-18, which increased to 14.4billion USD in 2018-19 (11.46% increase). At the same time, India also imported bulk drugs/intermediates of 2.9billion USD in 2017-2018, and it increased to 3.5billion USD in 2018-2019 (18.95% increase).

Similarly, India imported organic chemicals of 14.2billion USD in 2018-2019, which is 14.66% higher than previous year (12.4billion USD). This signifies that though India is self-reliant on drugs formulation, it is dependent on other countries for many APIs and intermedi-

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ates. The import is also increasing each year. The current situation is inhibiting the supply of those intermediates/APIs, which are procured from abroad as there is lock down. This may affect supply of finished dosage forms of those APIs. To avoid these unwanted situations and to get uninterrupted supply of essential medicines, India is planning to become self-dependent. Currently, the key starting materials (KSM) of many drugs are being procured from abroad, as they are available at competitive price. This has led to shut down of many Indian small and medium chemical industries. Indian government has already decided to set up pharma parks in different places in India. The state governments of Punjab and Tamil Nadu are also in the process of setting pharma parks in their respective states. This will act as an incentive

and encourage pharmaceutical industries to manufacture KSM and API in India.

This will also be advantageous for fine chemical industries, as huge amount of organic chemicals is being imported every year. The major concern will be competing with foreign companies in cost. The Indian government is preparing a list of 38 essential APIs where India needs to be self-dependent. So, these API should be manufactured in India which also includes production of intermediates and other organic chemicals used for these API syntheses.

India has more than 1200 US FDA approved API manufacturing units.

There are large talent pools in the field of organic chemistry. There are also international level universities and research institutes which are actively involved in organic chemistry research. Indian bulk drug industries have the expertise of developing process for synthesis of complex molecules. The major concern is to be cost-competitive. The key factors for reduction of cost could be scientific advancement, economic or government support and new strategies for business (industrial symbiosis and cluster manufacturing). The new process development involves different synthetic route scouting, optimisation / fine tuning of process, technology transfer along with manufacturing chemists. Generally, different new synthetic route design and feasibility studies are done by experienced organic chemists. Then comes optimisation of process by process chemists. Parameters like yield, impurity profile and solvent selection are done during this process.

Then a team including process chemist, production chemist, and chemical engineers facilitate the technology transfer of new process.

Indian companies have excellent expertise and skill in process optimisation and technology transfer. But, scientific knowledge or technological advancement in new synthetic route design is highly essential. This includes development of new scalable synthetic transformation, reactions with high atom economy, new

COVID-19

Indian companies have excellent expertise and skill in process optimisation and technology transfer. But, scientific knowledge or technological advancement in new synthetic route design is highly essential.

Franco Malerba initiated the conception of a sectoral innovation system. This system helps to study the interaction mechanism of the technology, organisation and institution which occurred in the process of innovation from the perspective of the sectoral system.

This framework involves three parts: knowledge base, actor and networks, and institutions. The knowledge refers to the specific science and technology of a sectoral innovation activity. The actors refer to industries and non-business organisations. Industries are the key instigators of innovation, involved in the whole process such as production, sale, and application of new technology. The non-business organisations are universities and research institutions, which support the innovation and technology diffusion, and promote the integration and complementarity of knowledge, skill, and specialisation. These actors share knowledge, and interconnect through various methods of cooperation,

AUTHOR BIO

technologies like flow chemistry, etc.

Pharmaceutical industries can enhance these kinds of research by collaborating with research institutes and universities.

The government’s plans to establish mega bulk drug (API) parks where benefits can be availed by using common facilities for pollution control, effluent treatment or solvent recovery, water supply etc. can be useful for containing costs. Such mega parks will also provide clearances for plants with minimum interface and other various facilities.

The process should be designed in such a way that chemicals can be used in cascade: they can not only be recycled, but also reused. Industrial symbiosis is a form of bringing companies together in innovative collaborations, and finding ways to use the waste from one as raw material for another. Hence, through ‘industrial symbiosis,’ spent chemicals from one industrial process can become feedstock for another. For example, Ferric Chloride (FeCl3), the by-product of steel pickling in Hydrochloric acid (HCl), will be useful for water treatment processes.

This will lead to massive emissionscutting, reduction in chemical waste and cost-saving process. This is a timeconsuming process. This may not give immediate financial benefit to industries.

Here, the collaboration between industry and leading research institutions are highly desired.

A manufacturing cluster makes business easier and cost-efficient. It is an interconnected system of like-minded businesses in a centralised location, allowing industries to benefit from collective growth. Clusters create an environment with good communication which allows industries to bridge gaps and generate a more efficient ecosystem for design, production, and distribution. There are different frameworks for designing clusters. In ‘Sectoral innovation system and cluster’, innovation capability is one of the focus parameters. Pharmaceuticals is a research-based sector. So, more improvement of innovation capability will help rather than simple analytical framework.

competition, exchange, and communication, which materialise the network of the sectoral innovation system.

While moving for successful pharmaceutical clusters, any undesired effects should be taken care for the sake of sustainable growth. Instead focussing only on tier-I cities, the industries may look into tier-II and tier-III cities for lower labour and manufacturing cost. As China and South Korea are facing the rising labour cost, the same problem will also arise in India 10 years from now. The rate of pollution is also another key factor to be controlled. The development of high atom economy processes, and efficient effluent treatment and waste disposal can help in this regard. Many starting materials for API synthesis are harvested from nature rather than organic synthesis. India may not have enough natural resources, which prompts use of technologies like ‘hydroponic’ to grow medicinal plants and increase production. Inorganic metals like copper, zinc, nickel, etc., are classical catalysts in several organic reactions.

Mostly, these are imported from abroad.

African countries’ natural resources could be a good source of cheap and continuous supply of these inorganic metals.

In summary, the necessity of continuous supply of intermediates, medicines under this pandemic situation has prompted Indian pharmaceutical industries, and government to start efficient plans to be self-reliant. The action plan and effect will be visible in the very near future.

Sharada Prasanna Swain is an Associate Professor in medicinal chemistry at National Institute of Pharmaceutical Education and Research-Kolkata. He has broad experience in industrial research in new process development for API (Dr. Reddy’s Lab Ltd), and new non-immunosuppressive anticancer agent (SPS-7) development for prostate cancer (preclinical is under progress).

V Ravichandiran is Director of National Institute of Pharmaceutical Education and Research-Kolkata. He is Member Scientific Advisory Board in Central Council for Research in Ayurvedic Sciences (CCRAS), Ministry of AYUSH, Govt. of India.

He has 26 years Professional and research experience in field of Pharmacy, Drug discovery, and Natural products.

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FPS SWAB TESTING STATION Performs the swab for COVID-19

FPS is an Italian company specialised in the design and manufacture of micronisation solutions and containment & isolation systems for the production of active pharmaceutical ingredients; it is mainly addressed to chemical, pharmaceutical and cosmetic companies all over the world. Eighteen years after its foundation, FPS today has three plants: a legal and administrative office in Como, a production plant in Fiorenzuola d'Arda and a commercial office in Philadelphia (US).

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The pride and joy of the company is the R&D and Test Centre, recently implemented where three ISO8 clean rooms are available dedicated to the execution of technical micronisation tests for small quantities up to large batches. It is also available a wide range of mills with special configurations for performing dedicated tests and an isolator where it is possible to perform technical tests on highly active products.

With more than 1,200 systems in operation worldwide for handling pharmaceutical substances, FPS presents itself on the market as an international company, extremely flexible and able to adapt to the customer's needs.

During this difficult period, FPS always operating and try to contribute to improve the critical health situation. FPS drew on its vast experience designing similar systems to achieve the best ergonomics, FPS has chosen to concentrate all its efforts on the realisation of these "swab isolators" in a short time, maintaining the high standards of safety and quality.

Inspired by the Korean hospital of Yangji in Seoul idea, FPS has designed and realised the first prototype of Swab Testing Station (STS) to perform the swab for COVID-19 on a high number of potentially infected patients in a few minutes and in total safety, both for the operator and the patient.

The cabins are easily transportable and, once positioned in strategic points, as hospitals entrances, pharmacies, neighbourhoods, squares, public spaces..., it is composed by 2 cabins: while one is used for swabbing the other can be sanitised, and it will allow operatives to perform till 10 swabs in one hour.

The Swab Testing Station (STS) is made by two separated working cabins. Each cabin has side walls in transparent plastic complete with 2 flanges for gloves installed for safe execution of activities inside the cabin from the outside. Glove flanges are provided with a system for safe glove change from the outside of the cabin. The glove support system allows to install many different types of gloves commonly available on the market.

The construction of the structure uses specific technologies adopted for stainless steel in the pharmaceutical industry. The seals for the front and side panels are made of silicon. The back-swinging door has static gaskets to provide a good seal.

A “continuous liner” system is installed on the side wall for the samples to be collected outside.

The cabin is provided with an upper technical area where both the components necessary for the operation and the instruments for control are installed. The technical area is easily accessible for maintenance activities.

The system works under a small negative pressure with the surrounding environment. In this configuration the volume of air escaping the cabin will be extremely minimal. Operators will be allowed to access the internal volume easily and comfortably for the repeated execution of the testing activities.

Each cabin is equipped with pre-filters for inlet air (G4 or a similar) and a HEPA filter to ensure that the cabin air is safe to be released in the environment.

The outlet HEPA filters shall be of the type used in clean rooms. They are inserted in the upper technical area and fixed by an appropriate system.

It's possible to install an automatic sanitisation system is proposed to eliminate the need for the physical presence of any operator in the cabins.

FPS supports the final users and maintenance workers with dedicated training, also by remote connection.

Mr Carlo Corsini, the owner, says: “I’m proud of our team for working together and putting their technical skills at the service of public health on such short notice, working with enthusiasm despite the difficult period we’re all going through".

For more information: www.fps-pharma.com Advertorial www.pharmafocusasia.com

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STRATEGY

VIRUS OUTBREAK

IMPACT ON PHARMA INDUSTRY Though the viral outbreak is not common but it happens time to time ie.

Ebola, Swine Flu, SARS and most recent COVID-19 outbreak. Because of the pandemic outbreak of COVID-19 and global lockdown, the demand and supply of pharma industry has significantly affected due to the shortage of manpower and resources in pharma industry. This kind of viral outbreak negatively regulate the pharma industry which affect the world economy.

Dhruv Kumar, Associate Professor, Amity Institute of Molecular Medicine and Stem Cell Research, Amity University Uttar Pradesh, India

V

iral outbreaks are not new to the world. Before COVID-19, we had other outbreaks such as Ebola in 2014-2016, Swine Flu (H1N1) in 2009, and Severe Acute Respiratory Syndrome (SARS) outbreak in 2009-2010. But the COVID-19 outbreak became a pandemic, and broke the record of all viral outbreak in past 100 years, forcing the World Health Organization (WHO) to declare health emergency globally. Most of the affected countries have declared global lockdown as a consequence of the high rate of transmission of the Novel Coronavirus Disease (COVID19). In recent weeks, 30 per cent to 40 per cent new cases have been reported in European countries and in USA alone. Whereas, some countries like

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China, Singapore, Israel, and South Korea are effectively managing and the incidence of new cases have sharply declined. Some countries like India, Pakistan, Russia, Turkey are experiencing controlled rise in new cases in last few weeks. Other parts of the world are also experiencing the exponential rise in new cases. Initially the coronavirus affected the Asian markets largely, but now it has become the global issue.

The aggressive virus control strategies of China and low case load in India has somehow stabilised the coronavirus infection as compared to the rest of the world, mainly USA and European countries. This global lockdown has significantly affected key industries such as oil, industry, and pharma.

This is not a completely new experi-

ence for the pharma industry. In last few weeks, the public-private partnership has promoted pharma industries around the globe to work in association with Government agencies to solve the COVID-19 issues. This public-private partnership to fight against COVID19 is supporting the development of new therapeutic approaches, vaccines development, medical equipment development, and personal protective equipment (PPE) development.

As reported by the Association of the British Pharmaceutical Industry, several pharma companies are working on the development of vaccines, therapeutic development, and repurposing of drugs which are already FDA approved for other diseases like Ebola and HIV against SARS-CoV-2.

COVID-19 The aggressive virus control strategies of China and low case load in India has somehow stabilised the coronavirus infection as compared to the rest of the world, mainly USA and European countries.

pharmaceutical ingredients (APIs) made from them. APIs are used in antibiotics, vitamins and other essential medicines, and are heavily sourced from China and India. These APIs include mainly aspirin, amoxicillin, paracetamol, azithromycin, ofloxacin, metronidazole, HIV drugs lopinavir and ritonavir, vitamins such as B1, B6, B12 and E, female reproductive hormone progesterone etc.. The main reason of restriction of export of selected medicine was to prevent the domestic shortage of those pharma products in their home country.

Most of the big pharma industry are working only from 10 per cent to 30 per cent of their capacity, which has hampered the demand and supply of pharma products globally. The United States is the largest consumer of pharmaceutical product and the restriction in supply of those medicines has hugely impacted the American healthcare systems. In this scarceness, countries like the USA and European countries are planning to bring back the production of hundreds of medicines back to their own house. Though, several countries have resumed their manufacturing of the pharma products, the major concern is

AUTHOR BIO

Some companies have identified potential compounds against SARSCoV-2 and donated compounds with the potential to treat coronavirus patients for emergency use and clinical trials. As per the data available on ClinicalTrials.gov, there are 902 studies found for SARS-CoV-2/COVID-19, which are currently under consideration for the clinical trials. Several antiviral drugs (ritonavir, remdesivir, favipiravir, umifenovir, triazavirin, sofosbuvir etc.,) antimalarial drugs (chloroquine and hydroxychloroquine), immunomodulators (tocilizumab, adalimumab, eculizumab, sarilumab, ixekizumab, fingolimod, meplazumab, camrelizumab etc.), and other cell- (mesenchymal stem cells (MSCs)) and plasma-based therapies are currently under trial. Pharma companies are taking different approaches in vaccine, therapeutics, and diagnostics development for COVID-19. Pharma companies such as Gilead Lifesciences, Cipla, Glenmark, Dr. Reddys etc., are exploring ways to use existing technologies that provide the ability to rapidly upscale production once a potential vaccine candidate and therapeutic drugs are identified against COVID-19.

In the current situation, pharma and healthcare systems are being put under significant pressure to fulfil the demand of medical equipment, PPE, vaccines, generic medicines and other hospital-related supplies in the critical situation of global lockdown. India is the largest producer of generic medicine and vaccines which require raw materials mainly from China. The global lockdown has already affected the demand and supply of the medicine, and related products due to the shortage of manpower and resources in pharma industry. Now, after five months of COVID-19 outbreak and thousands of deaths, most of the pharma companies in India and China resumed their production lines, but the major concern is countries like India have restricted the export of dozens of medicines; and China has restricted export of active

interruption in product delivery. The huge restrictions on population movements across the world makes distribution and delivery a huge problem. Even if the manufacturing of an APIs in one country goes well, it has to be moved to another dominion to be processed into a final product. In this incredibly fluid situation, the pharma industry needs to constantly monitor these issues and assess their possible impact for the immediate future as well as long term impact. The industry must think around corners and anticipate problems before they become larger immediate issues. Businesses should revaluate their contracts and plan strategies to minimise the big losses because of this outbreak.

In view of the present situation of COVID-19, the social distancing approach has emerged as one of the best ways to control the spread. But the question is, how long can this go on? In this current scenario, the proper utilisation of the pharma products and health-related medical resources is very important. The very important thing is supply comes after demand.When people stay safely and healthy, there is no need to take extra medicine and extra medical care.

So, in this scenario, the load on pharma industries will be minimised. While drug shortages due to COVID-19 are so far limited and expected to remain in the short-term, if the pandemic continues then stockpiles of pharmaceuticals, APIs and other chemicals may decrease, resulting in short-term shortages of several pharma products. Further complications come from distribution, particularly with population movement restrictions around the globe. A number of pharma companies are already in huge loss in last few months because of COVID-19.

After completion of B.Sc in Chemistry(Hons) from Banaras Hindu University (BHU), India and M.Sc in Bioinformatics from the University of Allahabad, I completed PhD from the School of Biotechnology at University of Bologna (UNIBO), Italy. I have received postdoctoral training from the School of Medicine at University of Kansas Medical Center, USA. Currently, my lab works on Molecular Medicine, Drug Designing, Drug Development, Translational Cancer Research and Bioinformatics.

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DELIVERING A COMPLETE SOLUTION TO CUSTOMERS Lonza is a company that designs, develops and manufactures a wide range of dosage forms for the pharmaceutical, consumer health and nutrition industries. We currently have more than 4,000 customers in over 100 countries. In the APAC region, we operate from eight sites in Sydney, Hong Kong, Mumbai, Bangkok, Jakarta, Suzhou, Delhi and Sagamihara.

Deepak Sood, Head of Sales, APAC

What is your role at Lonza and how long have you worked there?

I joined Lonza in January 2018 as the commercial director for the organisation’s Capsule Delivery Solutions team. In July 2019, I became Head of Sales in the Asia Pacific region for our innovative capsules in the Capsule Delivery Solutions portfolio. Then in early April 2020, I assumed responsibility for the APAC business as head of Lonza’s newly formed business unit for Capsules & Health Ingredients. I’m also currently Lonza’s Managing Director for India.

What are the latest trends in the pharmaceutical industry, particularly in the APAC region?

A notable trend in the APAC region is that the market for traditional medicines remains as strong as the market for western chemical API driven pharma products. As a result, we’re dealing with significant differences in regulatory and quality demands as well as supporting different approaches to brand marketing – for example, the nutrition market is very focused on green label and animal-free products at the moment, whereas for pharma this is less of a focus.

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The region is also very fragmented and while we have strong and growing presence across the entire APAC region, the competitive landscape varies from country-to-country. In addition, there are further nuances in each market where the number of manufacturers, pricing, attitude to quality and the accessibility of various markets by pharma manufacturers all play a part in partner selection. As more western companies look towards the APAC region for services in the coming years, we’re likely to see this fragmentation lessen as the focus on quality increases. This is cyclical as it is not that long since manufacturing moved to the west, however, increasing growth in the APAC region and higher quality products becoming readily available for patients and consumers is making it an attractive prospect for customers once more.

A lot of our focus has been in the US and EU over recent years as these markets have been responsible for most of the innovation in the pharma and biopharma sectors. The APAC region is still very much relied upon to deliver traditional hard gelatin capsules so there are significant opportunities to introduce innovative products that deliver additional value.

Where are you seeing the most demand for products?

Lonza’s Capsugel® range of capsules is one of the most diverse portfolios ranging from plant based HPMC (Hydroxy Propyl Methyl Cellulose) capsules to hard gelatin capsules.

The Asia Pacific market is still very heavily driven by the hard gelatin capsule market, with over 90% of Lonza’s manufacturing volume within the region remaining in this area currently.

This is typically driven by western chemical API-based medicines. If we look at the traditional medicines market in India, the most common products

AUTHOR BIO

Deepak Sood, Head of sales, APAC and Managing Director for Lonza in India. Deepak has over 30 years of industry experience in India & Asia Pacific in the pharma and healthcare space. He has a deep understanding of various business segments and has wide contacts in the Indian healthcare and chemical industries. Deepak has been actively involved in setting up greenfield and brownfield (capacity expansion) projects. His career achievements are a reflection of strong leadership skills and a proven track record in sales, R&D, pilot plant operations, business development, strategic planning and operations including P&L management.

are immunity supplements which are available in a range of dosage forms including powders and syrups, meaning at the moment there is a very limited share for capsules. This may in part be due to the animal derived polymer of traditional gelatin capsules which is problematic in a country where roughly a third of its population are vegetarian.

There are a few trends which may alter this dynamic in coming years. Firstly, the current drug development pipeline is heavily focused on oncology and where the dosage form is a capsule, developers are opting for HPMC products. These are a more robust capsule and are strong delivery vehicle for highly specialised APIs – both of which are vital for highvalue oncological drugs. There will be a challenge when it comes to volume as these products will not be typical block-

buster mass-market therapies but very specific, targeted therapies.

There is scope for hygroscopic APIs currently on the market to move into HPMC capsules and we are working with various customers to show them the advantages of our Vcaps ® Plus products, for example its known pH dissolution performance. In general, we anticipate that there will be a movement to such capsules, but it will be gradual.

On the nutrition and nutraceutical side of the market, there is a huge push towards both sustainability and vegetarian products. Brand owners want to market their products with ‘Green Label’ claims to meet consumer demand and as a result there is a huge movement towards non-animal based capsules where provenance can be proven.

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This is a very fast-growing market for us at the moment, particularly in the APAC region.

Are there any major challenges?

We have two major challenges at the moment.

First is capacity – such is the demand for Capsugel® products that we are always working at a very high utilisation rate - that sometimes means our lead times can be longer than some of our competitors. However, we are continuously investing in our facilities to expand and ensure we can continue to cater for customer demand.

Second is cost – Capsugel® products are quality-centric and we focus on developing and using robust, validated processes to ensure the quality of our capsules is at the highest standard, in addition our processes and vendor qualification criteria is uniform across all our manufacturing sites to ensure consistency. Some of our competitors can undercut our prices by developing ‘minimum viable products’ that only just satisfy regulatory requirements but offer no value to brand owners or patients beyond that. Lonza’s offering is very different in this sense as quality is something that we pride ourselves on and it is the added value of our team’s expertise and ongoing support that really makes the difference for our customers.

How do you see the APAC pharma landscape developing over the next five years?

As cost pressures increase in western markets, more and more companies will look to the East to support their manufacturing needs. 15 years ago, there was a very strong resistance to Indian APIs in western markets, now if you look at the United States, Indianmade APIs and generics are growing in

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Lonza’s Capsugel® range of capsules is one of the most diverse portfolios ranging from plant-based HPMC (Hydroxy Propyl Methyl Cellulose) to hard gelatin capsules.

popularity as they are more cost effective than those provided by competitors which manufacture domestically.

In addition, a lot of Lonza’s customers in India are manufacturing finished formulations and supplying them to the developed markets, for example some of the largest suppliers of paracetamol in the UK are manufacturers from India.

This dynamic is showing a steady, sustained move of manufacturing to the APAC region. There is a gap in the excipients supply market which will need to be filled in the coming years to ensure a long-term shift to manufacturing in the region can be sustained – given the scale of the opportunity, I’ve no doubt this will happen.

How can Lonza support companies during this transition?

The pharma industry will always be a highly regulated market, and this poses a challenge for customers – switching a capsule over is not just about changing manufacturing processes. To convert a new capsule, or to qualify an alternate supplier for a particular molecule can be a very painfully slow process due to the regulations and it requires changes to be made to the dossier. The timeline can be anywhere from two years to three years.

It also demands a lot of investment in terms of internal resources and capex from customers to develop an alternate vendor and ensure proper onboarding.

Adding to this is the increased interest from regulators such as the FDA and

the EMA that is peaked when process changes occur.

From our customers’ perspective, if everything is working with their current supplier, why should they change? This works well for when it comes to retention as there are never any problems with our products, but when it comes to securing new business it can be a challenge.

Our approach to knowledge sharing and the support of our regulatory teams are two of the key enablers that help us overcome these challenges. We work hard to become knowledge partners to our customers, not merely a transactional dealer for them and that's how we drive the value. Our efforts around HPMC capsules are indicative of these efforts. We are conducting a significant number of seminars and bridging knowledge gaps for our customers so they can understand the value of HPMC capsules and start considering whether they can convert some of their hard gelatin volumes.

Rather than just support functions, we have regulatory experts in key geographic markets who have experience with local bodies and can provide additional consultancy to the customer. We have an advantage over our competition in terms of geographic flexibility because we have a physical presence in most major markets – especially in the APAC region where we have sites in China, Japan, Indonesia and India. Importantly, we can support our partners when they look to enter new markets – we have access to western markets and knowledge partners around the globe who can provide insight into the regulatory compliance requirements of most countries.

Lastly, Lonza also offers Lonza EngineTM equipment and we have seen high uptake of the filling machine in the APAC region usually combined with our Capsugel® capsules as well.

This means we can deliver a complete solution to our customers.

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STRATEGY & DEVELOPMENT RESEARCH

INTEGRATIVE ASSOCIATIVE CLASSIFICATION FOR CANCER BIOMARKER DISCOVERY Integrative analysis of microarray data with prior biological knowledge is a promising approach to discover reliable and accurate cancer biomarkers. Associative classification is widely used in data mining and has great potential in cancer biomarker discovery for identifying associated genes with interpretable biological information.

Ong Huey Fang, Lecturer, School of Information Technology, Monash University

B

iomarkers or biological markers cover a wide range of substances that can be measured from body tissues, cells, blood or fluid. For instance, a cell expresses genes when they are required for biological processes, and the measurement of gene expressions under different physiological conditions provide essential clues of gene functions. Therefore, biomarkers play essential roles in understanding complex biological mechanisms, as well as in diagnosis, prognosis and

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treatment of diseases, such as cancer.

The desirable characteristics for ideal cancer biomarkers are non-invasive, low cost, simple to perform, discriminative, informative and produce high accuracy, sensitivity and specificity in clinical applications. Nevertheless, having these ideal characteristics remain as challenges in cancer biomarker discovery. Low specificity is the situation when a test yields false-positive results, causing unnecessary anxiety and treatment to a patient. While,

low sensitivity is the situation when a test yields false-negative results, which cause a false sense of security to a patient. Figure 1 shows the possible applications of cancer biomarkers and their respective role.

Biomarker discovery is the process of identifying and measuring the intrinsic features of high-throughput molecular profiling data, such as microarray data, or also known as gene expression data.

Microarray data analysis is a powerful preclinical exploratory study for discov-

Screening

Diagnosis

Staging

Prognosis

Prediction

Monitoring

Detect a cancer at its early stage, when there are no symptoms

Identify a cancer from its signs and symptoms

Determine the extent a cancer has spread within the body

Assess possible outcomes of a cancer, such as chances of survival, responses to treatment, and the likelihood of recurrence

Predict responses to different treatments

Monitor cancer recurrence and therapeutic responses

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RESEARCH & DEVELOPMENT

ering potentially useful biomarkers.

A microarray is an ordered collection of biological materials printed onto a small solid substrate such as membrane and glass slide. The common type of array is DNA microarray, which is a glass slide with thousands of spots or probes. Each fixed spot contains identical DNA molecules that correspond to a gene.

Microarray data is used to analyse gene expressions within a single sample or to compare gene expressions in two different cell types or tissue samples, such as between healthy (normal condition) and diseased tissues (test condition). Small in size with a large number of genes, microarray has become an indispensable tool to assay the expression levels up to thousands of genes simultaneously in a single experiment.

Some of the well-known microarray platforms include AffymetrixGeneChip, Agilent, and Illumina Bead Chip. Although a microarrayâ&#x20AC;&#x2122;s platform design is subject to include only known genes, it is still considered less biased compared to other high-throughput technologies. Besides, it could provide hints about functional relationships and interactions among genes. Its sensitivity allows detection on very low expressions of mRNA. Examples of microarray-based biomarkers that have been approved for clinical tests include MammaPrint, Roche AmpliChip, Rotterdam Signature, ColoPrint, and NuvoSelect. Despite these promising applications, microarray-based biomarkers are not widely used by either organisation issuing clinical guidelines or expert panels. Remaining challenges that need to be addressed in microarray data analysis are such as cost of development, false-positive errors, data quality, data qualification and interpretation. Besides, lacking organised and integrated resources have worsened the situation.

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RESEARCH & DEVELOPMENT

MICROARRAY DATASET

DATA TRANSFORMATION

GENE SELECTION

CLASSIFICATION

PERFORMANCE EVALUATION

Figure 2.The generic flow for microarray data classification Data mining provides a wide range of methodologies and tools in microarray data analysis to uncover novel cancer biomarkers and to understand the underlying genetic causes of cancer diseases. Its capability to cope with high-dimensional data make it more preferable compared to conventional statistical methods. Typical microarray data analysis with data mining techniques includes gene selection, classification and association rule mining.

The main goal of microarray data classification is to build an efficient and effective classifier that is capable of differentiating gene expression profiles for accurate disease diagnosis or prediction. However, due to a large number of genes and small samples size, traditional statistical and classification techniques are not able to deal with it efficiently, leading to false-positive and overfitting problems, as well as reducing the accuracy and speed of classifiers.

Therefore, gene selection, or also known as feature selection, is an essential task for microarray data classification to identify differentially expressed genes

Along with that, Associative Classification (AC) has gained popularity in microarray studies to classify data and to uncover to discover interesting biological relationships from large microarray datasets. Such information is indeed important to extract relevant gene markers, which in turn can create more reliable and accurate cancer diagnosis.

AC is a hybrid approach that integrates both classification and Association Rule Mining (ARM). In data mining, ARM is also known as association analysis or frequent pattern mining. ARM is widely used in businesses to predict customer purchasing behaviours called market

GENERATE CARS Discretisation

Rule Reneration

BUILD CLASSIFIER USING CARS Pruning

Figure 3. The block diagram of an associative classification framework

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basket analysis. It works by analysing customer transactions to identify frequently co-occurred items. The same idea can be applied to analyse the human genome, which contains about 20,000 to 30,000 of genes as interacting items. Classification based on associations approach aims to identify a subset of rules, known as Class Associative Rules (CARs), whose consequent are restricted only to target class labels.

The classifiers built by existing ACs had proven to produce better accuracy and could improve the understandability and reasoning of a problem. With the assumption that a good classification resulted from a good biomarker identification or the other way round, our study attempts to achieve this goal by using the AC approach. The common strategy in AC is to decompose a problem into two major tasks, as shown in Figure 3. The first task is to generate a complete set of CARs that satisfy userdefined values, such as minimum support and minimum confidence. The second task is to build a classifier based on the strongest CARs

and to reduce dimensionality by removing irrelevant, redundant and noisy data. The k-nearest neighbours, naĂŻve bayes, logistic regression and support vector machine are popular classification algorithms used for microarray data classification. These classifiers have shown good performances when combined with suitable gene selection.

Figure 2 presents the generic flow for microarray data classification.

Rule Selection

Training

Testing

RESEARCH & DEVELOPMENT

The problem of mining microarray data with AC can be described more formally. Let T = {t1, t2, …, tm} be a dataset or transaction database that contains all transactions. Let G = {g1, g2, …, gn} be the set of all items found in T, and let C = {c1, c2, …, ck} be the set of class labels. Each transaction ti consists of a set of items X, which has been labelled with a class y, such that X G and y C. In other words, a transaction represents a set of expressed genes for a sample or patient, and a transaction database includes all gene expressions recorded from a microarray experiment.

Below are the definitions for some of the terms in AC: • Transaction database:Figure 4 (a) illustrates an example of a microarray data matrix with relative gene expression values. The genes are treated as items, while the array of samples are treated as transactions. As the microarray data consists of continuous attributes, it needs to be discretised and treated as categorical attributes. Figure 4 (b) shows an example of microarray data that had been discretised into a binary matrix. In discretisation, a certain cutoff value is applied, where an expression value that is above the cutoff value is considered highly expressed and is assigned a value of 1. Otherwise, it is considered highly repressed and is assigned a value of 0.

Discretised microarray data matrix can be further transformed to a transaction table, as shown in Figure 4 (c).

• Item: An item is an attribute-value pair of the form (gi, v), where gi G is an attribute taking a value, v, such as an expression value. In certain cases, an attribute can also take multiple values.

• Itemset: An itemsetX, where X G is a set of zero or more items. A k-itemset is an itemset that contains k items, such as {Gene A, Gene C, Gene D} is a 3-itemset.

• Class Associative Rule: A class associative rule is an implication expression of form X y, where X G, y C, and G C = . The left-hand side itemset is known as the antecedent,

Figure 4. (a) Microarray data matrix with gene expression levels, (b) Microarray data matrix discretised into binary notation, and (c) Transaction table of a microarray data

while the right-hand side itemset is known as the consequent. The consequent of a CAR must be an itemset with a single item from the class label of set C. X and y are non-overlapping item sets.

• Support: The support of a CAR, X y is defined as the percentage of transactions in the database that contain X and is associated with class y, which is supp(X Y) = count(X y) / count(X). Support is an important indicator to show the frequency of occurrence for a rule. Non-frequent rules that did not satisfy user-defined

minimum support can be pruned out as their occurrence could be simply due to chance.

• Confidence: The confidence of a CAR, X y is the percentage of transactions in database that contain X also contain class y, which is conf(X Y) = count(X Y) / count(X). Confidence indicates the predictability and reliability for a rule. Therefore, rules that did not satisfy user-defined minimum confidence can be pruned out.

In the past few years, there are also efforts directed toward knowledge-driven or

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RESEARCH & DEVELOPMENT

Transcriptomic (e.g. microarry)

Genomic

Metabolomics

(e.g. gene ontology)

(e.g. KEGG Pathway)

Proteomic

(e.g. protein-protein interaction)

Data Integration

Integrated data from different sources

Biomarker Selection

Ranked rules with candidate biomarkers

Optimisation

Xlssificatin to select strong biomarkers

Evaluation

Predictability, Reproduciility and Interpretability

Figure 5. An integrative analysis framework with associative classification

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integrative analysis, which combines microarray data with other data sources, such as prior biological knowledge. An integrative analysis in data mining means to combine heterogeneous data, information and knowledge for the generation of higher-level knowledge and new testable hypotheses.

An integrated system of multiple types of high-throughput functional genomic data is expected to facilitate fast, accurate, systematic identification and prediction of highly complex biological data. To achieve that, sophisticated computational and analytical methods are needed to overcome current challenges by increasing the sensitivity and specificity in high-throughput data. Diverse genomic data such as gene ontologies, protein-protein interactions and KEGG pathways are integrated by computational methods to create new integrated data with functional relationships between genes. These integrated data can then be used for microarray data classification, and evaluation is done using cross-validation or using a test set of labelled data.

Figure 5 presents the proposed integrative analysis framework for the integration of heterogeneous biological data (e.g. transcriptomic, genomic, proteomic, and metabolomics data), with the processing components of data integration, biomarker selection, optimisation, and evaluation. An associative classification algorithm is adopted to generate the desired number of association rules with the highest support that meet minimum confidence. Several modifications are introduced for mining informative association rules from both microarray and biological transaction tables. With the framework, the top-k CARs generated from different target classes of microarray transaction tables were integrated,

RESEARCH & DEVELOPMENT

and a new ranking algorithm was applied to select a set of strong rules that contain potential biomarker genes that can discriminate classes. An interestingness measurement is proposed to rank the CARs, where the interestingness for a rule is the sum of the information-content from three observations, namely the average information gain, average classification accuracy and modified enrichment score. The most top-ranked class associative rule is considered the most informative rule with the lowest interestingness score, and its genes are considered the most informative genes. Gene subsets are generated from the informative genes of the top-ranked rules, and only the most informative gene subset inputted for the training of classifiers. The best gene subset is the set of genes that can achieve the highest predictive accuracy with less number of genes. The evaluation of the selected biomarkers is based on their predictability, reproducibility and interpretability performances. Also, results

obtained were evaluated and compared with other existing methods to determine whether the research problem is resolved or not.

The proposed framework had been tested on four UCI datasets and eight microarray datasets of colorectal and breast cancers. In comparison with other existing methods, it outperformed in terms of classification accuracy and Area Under the Curve (AUC), as well as showing significant reproducibility and interpretability results. These promising results have proven that the proposed

method is capable of identifying potential genes, which can be further investigated as biomarkers for specific cancer diseases. The experimental results can be found in the paper Informative top-k class associative rule for cancer biomarker discovery on microarray data. For future works, multi-platform microarray data can be integrated into the same integrative analysis to produce more reliable and accurate biomarker discovery.

Moreover, an improved AC method can be introduced to increase the efficiency of rule mining.

AUTHOR BIO Ong Huey Fang is specialised in Intelligent Computing. Her interests are in AI, bioinformatics, and software engineering. Her recent research centres on using intelligent techniques to identify cancer biomarkers through omics data. She has also worked on intelligent systems related to ML, speech recognition, gesture recognition, and AR.

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TOC for Cleaning Validation Getting started…

Rohit Chakravorty, Lead Application Specialist, SUEZ - Water Technologies & Solutions Michelle Neumeyer, Life Sciences Product Applications Specialist, SUEZ - Water Technologies & Solutions

1. What are some of the advantages of the various analytical methods for cleaning validation?

Analytical methods for cleaning validation can be broadly classified into two categories: specific and non-specific methods.

Specific Methods: Analytical methods that provide information about (or quantitate) only a specific ingredient in the formulation, commonly the active pharmaceutical ingredient (API).

• The key advantage is that these methods provide quantitative information about the target analyte.

• Examples of non-specific methods include

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chromatographic methods (HPLC, UPLC, GC), spectroscopic methods (MS, UV-visible, atomic absorption), electrophoresis methods, ELISA, etc.

• However, with ever changing regulatory requirements, the specific methods listed above do not achieve the most comprehensive and compliant monitoring program. The global regulations are now expecting cleaning validation to encompass data inclusive of all potential contaminants, not just the API. Active ingredient, excipients, degradants, cleaning agents and detergents should be included as part of a monitoring program.

• Specific methods should be used where the risk to the product is moderate to low and when

it is not feasible to perform visual inspection and non-specific testing.

Non-Specific Methods: Analytical methods that provide information about (or quantitate) the entire formulation.

• The key advantage is that these methods give a quantitative value of the entire formulation, degradants, and cleaning agents combined for a more comprehensive understanding of cleanliness.

• Examples of specific methods include total organic carbon (TOC), conductivity, gravimetric, pH, etc. TOC and conductivity are the most common non-specific methods deployed for cleaning validation, verification, and monitoring.

• Non-specific methods like TOC have more sensitive limits of detection (LOD) as compared to specific methods like HPLC. TOC provides greater sensitivity while also capturing a complete picture of the cleaning process. TOC analysis is suitable for high to low risk products.

2. What are the risks of only measuring API in a cleaning validation program?

API is a very small part of the entire formulation and doesn’t necessarily equate to the most toxic or hardest to clean. Thus, measuring something that is only 1/10th or 1/15th of total ingredient present inside the production equipment is a big risk. Excipients and degradants can be left undetected when using a specific method.

If the active ingredient is degraded during the cleaning process, it is quite difficult to quantify the API using specific methods. For example, degradants may have different properties than the intact API and may not elute with the same profile, thus going undetected. With non-specific methods such as TOC, degradants would be detected and quantified.

3. For manufacturers currently using a product-specific method for cleaning validation, such as HPLC, what are the steps needed to transition to TOC? First, a feasibility study is required for the compounds of interest to determine appropriate recovery using TOC analysis. This is to ensure that TOC is suitable for performing cleaning validation with these compounds of interest. Next, TOC should be qualified as a method per USP <1225> or ICH Q2(R1) quantitative method validation guidelines. Finally, product limits should be converted to TOC limits

and the recovery factor should be considered. SUEZ offers numerous resources to ensure successful implementation of these steps.

4. How difficult is method development for TOC for cleaning validation, particularly related to calculating Maximum Allowable Carryover (MAC) and determining worstcase residues?

Method development is straightforward with Sievers TOC Analyzers. Acid and oxidiser flow rates need to be determined depending on the sample concentration. If concentrations are unknown, there is no need to worry – the Sievers Autoreagent feature is designed to use the correct acid and oxidiser flow rates based on sample matrix. This adds a few additional minutes to the process but is still faster than conventional specific methods.

Nothing changes for determining worst-case compounds and performing MAC calculations. The only additional step is multiplying the final limit by the % carbon of the worst-case compound to obtain a TOC acceptance criteria.

SUEZ Applications Specialists are experienced in guiding customers in successful transitions from HPLC to TOC for cleaning validation. Support may include help with TOC limit calculations and optimising protocols for soluble and insoluble API.

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5. Can TOC be used to detect compounds that are insoluble in water?

Using TOC requires an aqueous sample solution. That being said, many compounds that are considered hard to solubilise or even insoluble can be detected by TOC with suitable method development. Introducing heat, agitation, or adjusting the pH of a sample can greatly increase the solubility of a compound so that it can be readily detected using TOC analysis.

As a part of method development, it is essential to demonstrate proper recovery of these compounds by running protocols to demonstrate linear recovery.

6. What types of detergents or cleaning agents can be detected using TOC? TOC is commonly used to detect trace residues from many detergents and cleaning agents including those with acidic, alkaline, or oxidative matrices. TOC and conductivity may also be used together to analyse cleaning agents that exhibit both a conductivity and TOC response for better understanding of both the ionic and organic cleanliness. In a study conducted in the SUEZ Applications Laboratory, CIP 100, CIP 200, alkaline and neutral detergents, sterilant sporicidal agents, and quaternary ammonium cleaners were analysed using Sievers TOC Analysers. These all exhibited linear recoveries using several concentrations, establishing the suitability of TOC for detecting residual cleaning agents and detergents.

7. When using TOC for cleaning validation, how fast can manufactures obtain data and make decisions for equipment release?

It depends on how the analysis is being performed.

Traditional grab sampling and laboratory analyses can be time consuming and take days to release equipment. At-line, wherein a portable analyser is in close proximity to the process, can reduce workflow and laboratory delays, allowing for equipment release within minutes. Online analysis with Sievers TOC, wherein an analyser is directly integrated with the process, allows for real-time data and real-time equipment release. Analysis itself takes a couple of minutes for each sample in standard mode. For processes with time constraints or in the case of profiling a cleaning process, Turbo mode can be used to gather data faster. Turbo mode gives a data point every four seconds, allowing for huge efficiency gains in a cleaning validation program.

Rohit Chakravorty is the Lead Application Specialist with SUEZ - Water Technologies & Solutions responsible for providing application support in India, SAARC and ASEAN region for the Sievers product line and TOC applications, notably in cleaning validation and real time release testing (RTRT) of pharmaceutical water.

Prior to joining SUEZ, Rohit was an Application Specialist with Sysmex and a Research Assistant at Sun Pharmaceutical in India. Rohit holds a Masters in Biotechnology (Gold Medalist) from Padmashree Dr. D.Y.Patil University in India.

Michelle Neumeyer is the Life Sciences Product Applications Specialist for the Sievers line of analytical instruments at SUEZ - Water Technologies & Solutions. Previously, Michelle has worked in Quality at Novartis and AstraZeneca, ensuring compliant water systems, test methods and instrumentation. Michelle has a B.A. from University of Colorado, Boulder in Molecular, Cellular and Developmental Biology.

8. What are some of the greatest efficiency gains manufacturers can achieve with TOC for cleaning validation?

TOC enables manufacturers to deploy Process Analytical Technology (PAT) for a cleaning validation program.

Using at-line or online technology for cleaning validation greatly increases the efficiencies of a monitoring program. Not only are data and equipment released in real-time, but time spent on sampling, analysis, and human error investigations are greatly reduced using PAT applications. Furthermore, TOC can aid in optimisation of the cleaning process itself. Using TOC data, the amount of water, detergents, and time may be reduced based on process profiling capabilities of online cleaning validation deployment. Finally, as mentioned in the previous question, obtaining data every four seconds with Turbo mode can significantly aid in process optimisation.

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Intelligent Nanomaterials in Pharmaceutical Analysis A vision of future

Materials in nano-scale appeared as one of the phenomenal and unique materials to the modern world due to their excellent features such as high surface area, small size, high stability, high reactivity and versatile chemistry for the surface functionalisation. The physicochemical features of these materials in the range between 1 and 100 nm are completely different compared to the same materials at macroscale. These unique and great characteristics of intelligent nanomaterials make them sexcellent candidates for pharmaceutical analysis which basically determines the quality of pharmaceutical products through analytical chemistry. In this review paper, intelligent nanomaterials and their applications in pharmaceutical analysis is discussed. Innovative techniques for the application of intelligent nanomaterials in the analysis of pharmaceutical compounds in terms of various economic drawbacks, safety and health concerns of nanomaterials and life cycle assessment within pharma industry are also described.

Finally, the drawbacks, challenges and new opportunities for the future design and development of intelligent nanomaterials for pharmaceutical analysis are discussed..

Rßstem Keçili, Anadolu University Yunus Emre Vocational School of Health Services, Department of Medical Services and Techniques Chaudhery Ghazanfar Hussain, Research Scholar, Computer science and Technology, Dept. of Education Lahore Chaudhery Mustansar Hussain, Department of Chemistry and Environmental Science, New Jersey Institute of Technology

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N

anotechnology has brought a revolution in the area of medicine and an exponential development was reported in the nanotechnology related-patents for the pharmaceutical applications in the past twenty years. The pharmaceutical companies are deeply focused on the nanotechnology to overcome the drawbacks and find out the solutions for the challenges in the production of pharmaceutical compounds and come up with safe, cheap and highly sensitive approaches and techniques for drug development. The tools in nanotechnology are adding great value to the existing commercial products thereby providing new opportunities in the various segments of R&D in pharmaceutical companies.

On the other side, process development refers to both design and synthesis of pharmaceutical compounds, their intermediates, and the development of the efficient analytical techniques for diagnostic applications. A miniaturised automation platform provides the design and development of efficient high-throughput synthetic routes for the drug discovery or synthesis processes. The studies for break-

RESEARCH & DEVELOPMENT

distinct physical, chemical and biological features were designed and developed for the successful applications in the pharma industry.

2. Intelligent nanomaterials

through pharmaceuticals require facile and fast synthesis of complex compounds and testing of their biological activities but the availability of short supply of substrate molecules is a limitation. This limitation can be overcome by applying the miniaturisation approach. In this approach, the idea is to do scale synthesis using high precision nanoliter robotics (i.e. hundreds of a reaction could be carried out in a single day using as little as 0.02 milligrams of material per reaction).

The rapid and sensitive identification of synthesised pharmaceutical compounds is very crucial during the preclinical development process. In the preformulation stage, the availability of the compound is scarce and thus, development of formulation should be performed in the very low quantities of the target pharmaceutical compound. Therefore, nanosuspension formulations were found to be valuable at the screening step.

Nanotechnology addresses these issues by designing and applying of intelligent nanomaterial-based drug delivery systems which are capable of achieving enhanced biopharmaceutical features by altering the

biopharmaceutical and pharmacokinetics features of the target pharmaceutical compound. Various nanomaterials such as polymeric nanoparticles, liposomes, nanoemulsions, micelles and dendrimers can be successfully used as nanodrug delivery systems (Figure1). With the innovative nanoscience and nanotechnologybased approaches, nanomaterials having different functionalities, shapes and

The intelligent nanomaterials exhibit biomimetic features since they can change their unique features that enables them to be applied in drug delivery and selfhealing materials. The examples include the application of intelligent polymeric nanomaterials as artificial muscles that can contract and return to original shape when short-circuited. These can replicate muscular action and can have strong visual effects.

One of latest interesting and promising research field is the designing and development of intelligent nanomaterials whose structure and chemical features are responsive to the biocatalytic action of natural enzymes. Enzymes play a crucial role in all metabolic and biological processes and their deregulation is a feature of many diseases. Therefore, the intelligent nanomaterials can efficiently sense these enzymes in the physiological environment and behave as an effective and promising tool for therapeutic and diagnostic applications. Various examples of enzyme responsive- intelligent nanomaterials are polymeric nanomaterials, phospholipids and inorganic nano-

POINT-OF-CARE DIAGNOSTICS

HIGH RESOLUTION MRI & MULTIPLE IMAGING MODALITIES

LAB-ON-CHIP NANODEVICES

BIONANOSENSORS

Figure 1. Nanotechnology-based tools for personalised medicine (Reproduced with the permisson from)

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materials. Functional Mesoporous Silica Nanoparticles (MSNs) were successfully designed and prepared by using alkoxysilane tether, ι-cyclodextrin and multifunctional peptides to target tumor cells and decrease the side effects of Doxorubicin (DOX) which is an antitumor drug. The multifunctional peptides were composed of the cell-penetrating peptide of seven arginine (R7) sequence, an enzyme-cleavable peptide of GFLG and a tumor-targeting peptide of RGDS. When MSNs loaded with DOX are incubated with tumor cells and normal cells, the nanoparticles could efficiently target tumor cells through the specific interactions between RGDS and integrins receptor ιvβ3 overexpressed on tumor cells, followed by penetrating cell membrane with the aid of R7 sequence.

Once DOX-loaded silica nanoparticles penetrate into the cellular membrane, the antitumor drug DOX is quickly

released because of the breakage of GFLG peptide cleaved by cathepsin B, resulting in increased antitumor activity. This effective enzyme-responsive nanoparticle based-drug delivery system exhibit an excellent potential in the area of nanomedicine (Figure 2).

3. Applications of intelligent nanomaterials 3.1. Applications of electrochemical sensors-based on intelligent nanomaterials

Electrochemical techniques have found many applications in various areas. This is because they are costeffective and are capable of carrying out in-situ and real-time studies .

Over the past four decades, there has been increased demand in the area of electrochemical methods that have

A RGD recepter Cathepsin B enzme

B

MSN

RGDS

a-CD

Rs

DOX

GFLG

Cathepsin B enzme

Targeting site

Tumor Cell

C

E D Lysosome

Dead cell

F Figure 2.The schematic representation of the (A) functionalisation procedure of the MSNs. (B) MSNs loaded with DOX under physiological conditions. (C) RGDS-targeted to the tumor cell. (D) Endocytosis into a specific tumor cell.

(E) Cathepsin Benzyme-triggered drug release in the cytoplasm. (F) Apoptosis of the tumor cell. (Reproduced with permission from [5])

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capability to detect low concentrations of the analytes. The analyte recognition is among the major processes involved in any sensor system. Additionally, the increased demand is as a result of their speed, portability, specificity and low cost. Selectivity and sensitivity are important paramaters for the electrochemical sensors. Surface modification of electrodes in electrochemical sensors by immobilisation of recognition components is an efficient approach to obtain a high binding of target compound with good selectivity and good response. The surface modification of electrodes in the design and preparation of electrochemical sensors has firstly been reported by Itaya and Bard in 1978. Since then, a lot of studies on the design and development of electrochemical sensors in different application areas have been published.

Graphene-based electrochemical sensors have received a great deal of attention due to their great ability for the sensitive detection of organic compounds.

The high surface area renders enhanced the process of electron transfer enabling a highly attractive support for the incorporation of nanoparticles. In an interesting work carried out by Biris et al., gold nanoparticles were successfully embedded in the graphene sheets. The platinum electrode was then modified with the prepared graphene-based nanocomposite for the sensitive detection of adenine, one of the DNA bases. In their study, the authors concluded that the kinetics of the interfacial charge transfer on the platinum electrode surface modified with graphene lead to an increase in the electrochemical oxidation of the target compound adenine.

In another study, Zhang and colleagues reported the preparation of a graphene based-electrochemical sensor for the efficient detection of acetaminophen in pharmaceutical tablet samples. In their study, reduced graphene oxide was doped with phosphorus and then coated on the surface of glassy carbon electrode. The prepared electrochemical sensor displayed

RESEARCH & DEVELOPMENT

excellent sensitivity and selectivity towards acetaminophen in pharmaceutical tablet samples. The sensor response was linear in the concentration range from 1.5 ÂľM to 120 ÂľM. The detection limit was achieved as 0.36 ÂľM. 3.2. Separation applications of intelligent nanomaterials

Gold nanoparticles were successfully applied in the Capillary Electrophoresis (CE)-based analysis due to the improved separation resolutions. These nanoparticles also behave as a pseudo-stationary phase in the existence of poly (ethylene oxide) (PEO) for the efficient separation of double-stranded DNA. The interaction between PEO and DNA molecule is increased in the existence of nanoparticles thereby enhancing the sieving ability of PEO without any change in its viscosity. The separation of acidic and basic proteins using a capillary filled with surfactant capped gold nanoparticles were also reported along with great separation efficiencies towards various target compounds. A facile approach was developed and demonstrated for the fabrication of highly effective separation columns coated with octadecylaminecapped gold nanoparticles for open tubular capillary GC. Monodispersed silica nanotubes having desired size and shape were designed and successfully prepared by using template-assisted synthesis approach. These developed nanotubes have inner voids which can be filled with various compounds varying from large protein molecules to small molecules and the inner and outer surfaces of the nanotube can be efficiently functionalised.

One of the interesting applications of the nanotubes is the intelligent nanophase extractor for the efficient removal of small compounds from the solution.

Because the outer surface of the nanotubes exhibits hydrophilic feature and inner surface shows hydrophobic behaviour, these nanomaterials are promising candidates for the efficient extraction of the lipophilic compounds from the aque-

ous samples. The nanotube functionalised with antibody enables an ultimate extraction selectivity. The antibody produced against the drug, 4-[3-(4-fluorophenyl)2-hydroxy-1-[1,2,4]-triazol-1-yl-propyl]benzonitrile(FTB) selectively binds to the RS enantiomer and the Fab fragments of the antibody are immobilised on the inner and outer surfaces of the silica nanotubes.

3.3. Clinical applications of intelligent nanomaterials

Among various applications of intelligent nanomaterials, the most promising applications are in the area of biomedical sciences. These interesting applications have crucial effects on the human health since these nanomaterials are targeted towards the diagnostic techniques for disease which are fast and low-cost. To decrease the side effects and increase the therapeutic effects, the pharmaceutical compounds should be selectively targeted at the disease site and accumulate for a prolonged time in the body. Drug release refers to the design and development of efficient approaches, techniques and formulations required to transport any pharmaceutical compound safely within the body in order to obtain the efficient therapeutic effects. In this regard, intelligent nanomaterial based-drug release systems have opened new opportunities in the area of medicine. Intelligent nanomaterial based-drug release systems accumulate and binds specifically to the disease target with controlled release behaviour. The careful design and preparation of these nanomaterials as effective drug carriers should address various key issues such as biodegradability and biocompatibility, high stability at physiological pH values, excellent drug loading capacity without any toxicity and industrial production of these nanomaterials in large-scale for clinical applications.

The stimuli responsive intelligent drug release systems deliver the drug at specific tissues in the systematic administration.

These do not freely extravasate during the blood circulation and are released at the

targets where the nanocarriers accumulate by active or passive targeting strategy.

An immunoassay is a biochemical technique which is efficiently applied for detection concentrations of a small macromolecule in a sample solution by using an antigen or an antibody.

In this approach, the key issue is to obtain a measurable signal in response to a binding effect. Screen-printed electrodes have attracted great attention as immunosensors because of their unique features such as miniaturised dimension, low cost and facile fabrication and large-scale production. A single drop of sample i.e only a few microliters of a sample solution is used to conduct all the immunological stages thereby decreasing the consumption of the reagents. Screen-printed electrodes can be successfully coated with nanoparticles that increase the sensitivity of these electrodes. In an interesting study, a screen-printed electrode was modified with silver nanoparticles and effectively applied for the preliminary screening of cystic fibrosis that is a common genetic disease caused by the autosomal recessive gene known as the cystic fibrosis transmembrane conductance regulator gene. It affects multiple organs such as lungs and intestines which causes the irregular transport of chloride and sodium ions across the epithelial cells.

It has been reported that the oxidation of silver is sensitive to concentration of chloride ions. Sweat chloride levels are important for the effective diagnosis of cystic fibrosis. A layer of silver nanoparticles is deposited on the working electrode and anodically stripped off to generate silver cations. The anodic stripping voltammetry of silver nanoparticles yields a single silver oxidation peak in the absence of chloride ions whereas two voltammetry stripping peaks (one for AgCl and other for the oxidation of Ag to Ag(I) ions) are obtained observed in the existence of chloride ions. The silver chloride peak is used for the quantitative determination of chloride concentration.

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On the other hand, Parkinson’s disease and Alzheimer’s disease are the most common neurodegenerative diseases which affected 1.6 per cent of the world population, and around twentysix million people, respectively. This has posed a growing challenge for the patients, clinicians, caregivers and society. The current treatment approaches rely on the clinical symptoms of the diseases and therefore the efficient diagnostic techniques depend on the proficiency of the treating physician. Nanoparticle-basedsensor systems are successfully applied to distinguish groups of Parkinson’s and Alzheimer’s disease patients from a healthy control group. The diagnostic approach relies on the identification of patterns of volatile organic compounds in the exhaled breath. The disease-related changes in the blood chemistry may be transmitted to the alveolar exhaled breath through the lungs even in the initial stages of the disease. The nanoparticle-based sensor

undergoes fast and reversible changes in electrical resistance on being exposed to characteristic volatile organic compounds.

Thus, breath prints can be the basis for the design and fabrication of facile, low-cost, non-invasive biomarker using nanoparticle-based sensor systems.

3.4. Spectroscopic applications of intelligent nanomaterials

Silver nanoparticles show great Surface Plasmon Resonance (SPR) behaviour and thus, they are capable of ultra-sensitive analysis down to single molecule level in surface enhanced Raman scattering (SERS). However, various crucial parameters should be considered when silver nanoparticles are used. These factors are the analytes/probes in direct contact with the surface of silver nanoparticles can lead to an interference in the spectroscopic analysis, the mechanism of SPR mediated chemical reactions is complex because the dual functions of silver nano-

particles, silver is easily oxidised under ambient conditions that leads to reduce in plasmonic enhancement. The silver nanoparticles can efficiently be integrated with graphene to increase their plasmonic performance. Shell isolated silver were reported to display excellent plasmonic features with high stability even after 16 months of storage. The silver nanoparticles also have the advantage of achieving Raman signals with great quality and can be further expanded to surface-enhanced fluorescence that is efficiently used for the sensing and biological imaging applications.

3.5. Pharmaceutical applications of intelligent nanomaterials

Hydrogel-forming polysaccharides attracted great interest in the design and preparation of silver nanoparticles having different sizes and morphologies. Polysaccharide-based hydrogels are effective and intelligent materials

Various pharmaceutical applications of intelligent nanomaterials are shown in Table 1.

Type of nanomaterial

Features

Applications

Reference

Polymeric nanoparticles

Biodegradable, Biocompatible, provides complete drug protection.

Great carrier for controlled and sustained drug delivery

(49,50)

Quantum dots

Semi-conducting, bright fluorescence, high photo-stability.

Long term multiple colour imaging of liver cells, labeling of breast cancer marker, imaging of cells and tissues.

(51,52)

Carbon nanotubes

High mechanical strength and excellent electrical features.

Gene delivery, peptide delivery.

(53)

Dendrimers

Highly branched and monodispersed polymer system.

Controlled and targeted delivery of bioactive compounds.

(54)

Metallic nanoparticles

High surface area, stable, non-toxic.

Drug and gene delivery, sensitive diagnostic assays, radiotherapy.

(55)

Micelles

High drug entrapment, payload, stability.

Targeted active and passive drug delivery, diagnostic value.

(56,57)

Liposomes

Biocompatible, versatile, easy functionalisation.

Active drug and gene delivery, delivery of proteins and peptides.

(58,59)

Iron oxide nanoparticles

Superparamagnetic

Magnetic resonance imaging (MRI) and intracellular monitoring.

(6,61)

Silica nanoparticles

Silanised and coated with oligonucleotide.

Nanobiosensor for trace analysis, detection of DNA, destruction of tumor by binding to malignant tumor cells.

(62,63)

Table 1. Various pharmaceutical applications of intelligent nanomaterials

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that are extensively applied in pharmaceuticals, cosmetics and daily life.

Hydrogels were successfully employed as templating or capping agents for the preparation of silver nanoparticles.

One of the potential hydrogel forming polysaccharide is glucuronoxylan. It has been efficiently used as a carrier for the targeted release of various pharmaceutical compounds because of its pH responsive on-off switching feature. The synthesis of Silver nanoparticles was carried out by using glucuronoxylan at alleviated temperature via diffuse sunlight assisted green technique. Intelligent nanomaterials composed of glucuronoxylan and silver nanoparticles are also successfully used in wound healing dressings. The hydrogel layer does not allow the bandage to fix in the wound area because of the moisture. Thus, patient compliance can be achieved by developing such types of bandages. The mechanism of wounds is based on the collagen content and tensile strength of epithelium tissues. The fast wound healing tendency is because of the cross-linking of the collagen fibers.

On the other hand, diabetes is one of the major health problem in the world that shows an alarming increase.

Approximately 25 per cent of patients are at elevated risk of developing foot complications which is also called ‘diabetic foot ulcer’. In patients with diabetic foot ulcer, the process of wound healing is impaired.

Various methods have been applied for the treatment of diabetic foot ulcer. But, these methods have some limitations.

With the fast progress in the area of nanomedicine, nanoparticles exhibited remarkable results in wound healing processes. The achieved results indicated that diabetic foot ulcer displayed a good response when Fe2O3 nanoparticles are used. (Table 1) In summary, intelligent nanomaterials can be successfully used in many pharmaceutical applications. These applications are dependent on the surface modifications of the nanomaterial, their size and interactions with different target compounds.

4. Commercialisation of nanomaterial-based pharmaceutical products

Nanomaterials are extensively used in various industrial fields and among these fields, pharmaceutical industry is an emerging at a very fast pace. The global nanomedicine market is driven by emerging innovative approaches and techniques for drug release, different healthcare applications, and low-cost therapies.

The nanomedicine area has revolutionised the current diagnostic techniques for diseases. The global nanomedicine market is categorised into diagnostic imaging, drug release, vaccines, regenerative medicine and implants etc. The global nanomedicine market accounted for US$111,912 million in 2016, and is expected to reach US$261,063 million by 2023.

With the rapid progress in nanotechnology and nanoscience, National Institute of Health (NIH) promoted a National Nanotechnology Initiative (NNI) programme in 2000 to promote the nanoscience-based studies in health science. Extensive funding from the government stimulated the launch of interdisciplinary studies. With novel approaches in nanomedicine, the area of nanoscience was rapidly adapted by researchers in pharma industry to create ‘nanopharmaceuticals’. In 2016, the size of the nanomedicine market in the world was estimated to be US$138.8 billion. The existence of 40 per cent pharmaceutical products in phase II of clinical development is anticipated to be commercialised over the next decade (https://www.grandviewresearch.com/ industry-analysis/nanomedicine-market).

4.1. Economical drawbacks Nanomedicine has a crucial role in efficient diagnosis and treatment of diseases across the entire healthcare spectrum. However, size of the market, economic value, and fields of application remain unclear. The European Scientific Foundation (ESF) identified 5 main fields of nanomedicine including analytical tools, nanoimaging, nanomaterials and

nanodevices, novel therapeutic and drug release systems, clinical, regulatory and toxicological issues. According to the authorities, there are no scientific hurdles which can block the entry of nanomedicine products in the market since most of the techniques and approaches are now in the mature state. However, there seem to be external parameters (i.e. availability of capital, technology transfer management universities, intellectual property landscape and regulatory issues etc.) which hinder the commercialisation of nanomedicine.

For it to succeed, the cooperation of main pharmaceutical and medical device companies is needed since these have the means to finance clinical trials of diagnostic devices and new pharmaceutical compounds. Though researchers claim that the technologies are fruitful for the commercialisation but representatives from the pharmaceutical companies caution that the technologies are not mature enough so that investments can be provided. Therefore, this lead to very slow uptake of any biotechnology by the pharmaceutical companies. Therefore, these companies wait for the cutting-edge technology which has the potential to move ahead with financial investment.

4.2. Safety and health issues of nanomaterials

With the rapid advancements in nanotechnology, the design and production of engineered nanomaterials dramatically increases as well as incidental nanomaterials. Despite the excellent properties and many great applications of the nanomaterials, there are still some questions, challenges, drawbacks, and concerns about the potential influences of the nanomaterials on the natural environment and human health. The toxicity of the nanomaterials is one of the crucial concerns. Most of the nanomaterials will end up in the environment (air, water and soil). Because many of nanomaterials are not biodegradable, they may remain in the environment for a long time. Biological organisms such as micro-

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Pharmaceuticals

Environment

Health care

Sustainable development Figure 3.The schematic depiction of the interconnected view of sustainable development (Reproduced with permission from)

organisms, plants and animals could take up nanomaterials in the ecosystems and bring nanomaterials into the food chain. For example, nanoparticles can easily enter human body via respiratory system. Once nanoparticles enter the bloodstream after passing through the respiratory system, they can accumulate in the certain regions of the different organs. Therefore, the negative impacts due to the nanomaterials on human health should be carefully evaluated. For this purpose, a new field called â&#x20AC;&#x153;nanoecotoxicologyâ&#x20AC;? is gaining public attention. Furthermore, future applications of engineered nanomaterials are highly promising. Therefore, efforts and evaluations for the safety of nanomaterials on the environment and animal health will continue to be a research priority.

Consequently, sophisticated statistical understanding and methodologies is carefully needed in the designing of toxicity studies and in analysing toxicity data. Prior to the use of nanomaterials especially for in vivo biological applications, various important physiological factors (i.e. distribution, absorption and

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toxicity) of these nanomaterials should be considered and carefully evaluated according to the international regulatory guidelines which are still under development.

5. Modern society and sustainable analysis of pharmaceuticals

Pharma companies are increasingly imparting a lot of importance on becoming more sustainable by developing pharmaceutical compounds which have same medicinal value but show less negative effect on the environment. The design, development and applications surrounding the pharmaceuticals play a crucial role in minimising their negative effects on the environment and increasing the sustainability of the healthcare. The progresses in the various areas of medicine including personalised medicine, drug design, targeted drug delivery, medical genetics, formulations and worldwide initiatives such as medications management and pharmaceutical care are bringing sustainability in quality health care close to reality. The schematic depiction of the interconnected view of sustainable

development is shown in Figure 3. As can be seen from the figure, the sustainable development is divided into 3 categories including pharmaceuticals, environment, and health care. These categories are interconnected with each other and thus this model view of the sustainable development has a conceptual simplicity in terms of sustainable analysis of pharmaceutical compounds. The categorisation of the effetcs on human society based on these three categories makes the analysis facile and straightforward. When pharmaceuticals, environment and health care are balanced, they provide the sustainable development of the human society.

With the fast research advancements in the field of intelligent nanomaterials and nanobiotechnology, the current pharma industry mainly focuses on the inventing medicines, specially nanomedicines to allow patients to live longer, healthier and more productive lives. The pharma industry is committed to bring key nanomedicines to patients with minimum environmental effects. In the past years, the pharma companies paid great attention towards the improvement of productivity and quality, reduction in waste and control on both production process and R&D researches. These are not only driven by considerations in decreasing of production costs but also enhancing awareness of sustainability.

6. Conclusions

Intelligent nanomaterials have gained great attention from many researchers since they display unique properties such as high physical and chemical stability, versatile chemistry for the functionalisation and high surface area. The chemical features of intelligent nanomaterials in the scale between 1 and 100 nm are completely different compared to the materials in micro- and macroscale. At present, the opportunity of intelligent nanomaterials in pharmaceutical applications at industrial scale seems to be still growing at lower levels of its ability. In addition, it is expected that the use of intelligent nanomaterials in the pharma-

RESEARCH & DEVELOPMENT

reported in the literature. However, novel techniques and technologies applied for the production of intelligent nanomaterial-based products in pharmaceutical industry are still under development and more efforts are needed to produce low-

AUTHOR BIO

ceutical industry will play a crucial role in next-generation pharmaceutical technologies and devices in the near future.

The main objective of the modern research is to close the gap between the scientific laboratory research and practical applications in industry. Most of the research on the design and development of novel intelligent nanomaterials in the pharmaceutical analysis is carried is limited to lab scale in literature.

Therefore, the studies on development of intelligent nanomaterials on a commercial scale are strongly recommended. In conclusion, commercialisation of nanotechnology-based innovative products is very important and needs enough investments from pharmaceutical and medical device corporations. In addition, optimistic approaches and methodologies are needed to motivate policy makers to design the applications of intelligent nanomaterials in sustainable systems.

Many successful pharmaceutical applications of intelligent nanomaterials were

cost and effective products before these intelligent nanomaterial-based pharmaceutical products are commercially available in the market.

References are available at www. pharmafocusasia.com

Chaudhery Ghazanfar Hussain is a Research Scholar inComputer Science and Technology, Department ofEducation, Punjab, Pakistan .His key areas of research are Data Science, Computer Networks,Environmental Modeling and Industrial development.

He is author of monographs on software technology. He is a true IT professional and affiliated with several companies.

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

Rüstem Keçili is currently an Associate Professor at the Yunus Emre Vocational School of Health Services, Anadolu University, Turkey. He worked as a researcher at MIP Technologies AB, Sweden, and was a visiting researcher at the University of Manchester, UK. His professional background covers nanomaterials, molecularly imprinted polymers and chromatography.

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BIOLOGICS RESHAPING PHARMACEUTICAL MARKET The Biotherapeutics market has gained substantial attention and evolved as a profit-making segment of the pharma industry for a decade. This article sheds light on how next-generation proteins are reshaping the market and talk about innovative strategies that pharma companies are thinking of to cut down the developmental cost incurred for producing a safe and efficacious biotherapeutic product and improvising patient experience.

Prasanthi Polamreddy, Scientific Manager Excelra Knowledge Solutions Pvt Ltd.

T

he biotherapeutics market is booming. Currently, annual growth rate of biologics is double that of conventional pharma and is forecasted to grow rapidly. Increase in incidence of chronic diseases like cancer, diabetes, autoimmune diseases, genetic conditionsâ&#x20AC;Śetc and acceptance of biotherapeutics because of their high efficacy and safety are some of the major factors driving the biopharmaceutical market. Also, biologics gained edge in diseases that could not be successfully targeted by small molecule drugs especially oncology indications and autoimmune ailments. And today biotherapeutics industry moved one more step ahead and invested in the development of next generation biologics which forms the current era. However, despite the considerable demand, high cost associ-

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ated with biotherapeutics restricts market growth.

Evolution of biotherapeutics

Since the launch of breakthrough therapeutic drug â&#x20AC;&#x201C; Insulin (enzyme replacement therapy) in 1982, the growth potential of biologics has been promising. In its early days, this industry faced some serious concerns. Despite vast challenges in its path, this industry evolved as multibilliondollar market and today 7 of the top 10 bestselling drugs are biologics. Many innovative therapies were launched till date and comprise vaccines, enzymes-based therapies, cell therapies, gene therapies, immunotherapies, peptides and protein products. Monoclonal antibodies (mAbs) revolutionised the biotherapeutics market and rose to leading position among the other biologic products.

Antibody drug conjugates

The increased scale of demand for effective biologics, especially monoclonal antibodies and continuous efforts to improvise the therapeutic potential led to advancement of protein engineering technologies which further fuelled the development of next generation biologics. These next generation biologics are characterised by longer half-life and low immunogenicity and comprise antibody drug conjugates (ADCs), bi-specific and multi-specific antibodies, fusion proteins, engineered cells and antibody-like proteins (ALPs). ADCs are one of the lucrative classes of engineered proteins and were proven to be effective in combating cancer, especially haematological malignancies and breast cancer. Though the side effect profile of ADCs is comparable to that of chemotherapeutics, it has not dampened their development and rather intensified ADC R&D. Currently there are almost 600 clinical trials focused on ADCs of which 40 trials are evaluating ADC and check point inhibitor combinations in oncology indications.

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Fusion Proteins

Another promising class of next generation biologics comprises therapeutic fusion proteins. Fusion protein product is obtained by genetically fusing two protein domains encoded by two different genes and hence exhibits multiple functional properties. There exist several categories of fusion proteins depending on the type of proteins that were fused. One of the predominant types among these fusion proteins is the Fc-fusion protein where Fc fragment of IgG is fused with protein or peptide. And the first fusion protein to get FDA approval is the Fc-fusion protein (Etanercept (Enbrel) in 1998).

Since then many Fc-fusion proteins have been approved in the major markets of USA, Europe and Japan and include Abatacept (Orencia), Belapacept (Nulojix), Aflibercept (Eylea), Rilonacept (Arcalyst), Romiplostim (Nplate), Dulaglutide (Trulicity), Albiglutide, Efmoroctocog alfa (Elocta), Asfotase alfa (Strensiq).

Apart from Fc-fusion proteins, some of

the other types of fusion proteins (where a protein has been linked to either peptide/ kinase/toxin/cytokine/antibody fragments/ albumin/transferrin/blood factors) have been successful in the market. Given the commercial success as evidenced by many approved therapies of this class, it is very likely that fusion proteins would emerge as promising therapies in the years to come.

Bispecific antibodies

Fusion proteins were also designed to interact with two or multiple target proteins and exhibiting bi- and multifunctional characteristics. Bispecific antibodies (bsAbs) hold great promise as therapy and swiftly expanding with more potential for commercial success. Targeting two antigens at a time with bsAbs was not a very new concept and was highlighted with the approval of catumaxomab. In Spite of considerable side effects associated with this therapy, the spark was retained and created surge in R&D and investment and these continuous efforts resulted in

the approval of two therapies- blinatumomab (binds to CD3 on T cells and the CD19 antigen on tumour cells) and emicizumab (binds to the FIXa and FX zymogen). Currently, almost 85 bsAbs are in the clinical developmental pipeline and among these 86% are targeted for oncology indications (AMG 420, REGN1979 and XmAb14045) reflecting a considerable interest in their development as cancer therapy. Though a good number are in the early phase of clinical development pipeline these are yet to be proved as commercially viable.

Gene therapies

Gene therapies are another class of biologics witnessing success in the market and expected to grow tremendously in the near future. Despite the many obstacles and failures in the initial phases, gene therapies have seen huge progress in the recent past and are being used to target life threatening disease like cancers and nerve degenerative diseases. Since the

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approval of first gene therapy in 1990 for ADA-SCID (Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency), ~10 therapies did hit the global markets. Luxurna, developed

by Spark Therapeutics is the first human gene therapy approved in US (in 2017) for Retinal dystrophy. In the same year, first CAR-T therapy developed by Novartis (KYMRIAH) received the approval and Kite Pharma’s YESCARTA was approved shortly thereafter. CAR-T therapies generated by engineering T-cells revolutionised the cell and gene therapy research and continue to receive a good amount of investment in the R&D perspective. These therapies marked a milestone in this new field and generated an enormous amount of interest among academia, research institutes and pharma companies. Currently a good number of CAR-T therapeutic leads are in mid- to late stage of clinical development and this field is poised for success soon. Next generation gene therapies based on CRISPR platform also hold great promise and poised to grow impact biotherapeutics market significantly.

Currently, hundreds of therapies are in clinical development and this growing popularity can be correlated with considerable increase in capital investment to fund research activities.

Phage therapy, though sounding new is perhaps a century old concept. In phage therapy a bacteriophage will be used to kill bacteria and hold huge promise in tackling antibiotic resistance. Currently there are no approved therapies in healthcare, but seems things are moving in the direction of success and might become more common soon.

Challenges with biotherapeutics

However, biologics do have disadvantages. (a) Their inherent structural complexity increases the developmental time and cost (b) Their high molecular weight and complex structures impede them from crossing the cell membrane and targeting intracellular molecules (c) Complex mechanism of action (d) formulation challenges like aggregation and degra-

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Advancement of protein engineering technologies has steered in unprecedented opportunities to develop safe and efficacious biotherapeutics.

dation (e) Limited delivery mechanisms.

Most of the biologics should be administered intravenously and this requires multiple hospital visits life-long in case of chronic conditions and is cost intensive (f) complex manufacturing and characterisation processes. As biologics are produced from live cells, selection of right cells and cell cultivation conditions hugely impact the production of the quality product with good yield. And characterisation of biologics is difficult compared to small molecules (g) cell expansion (required numbers) being bottleneck for cell therapies (h) clinical testing is associated with huge financial burden.

Innovations in the field

Biopharmaceutical companies are also thinking of ways to maximise the therapeutic window of biologics and harness novel manufacturing processes, formulation and delivery device technologies to ensure production of quality and stable product, to make the product more affordable and improvise the experience of patients. Genentech has developed a second generation anti-CD20 Ab (Gazyva) by glycol-engineering Fc region of original anti-CD20 Ab (Rituximab) to enhance Fc gamma receptor IIIA binding which is essential for cytotoxicity functionality.

Gazyva was the first glycol-engineered

antibody to get FDA approval and this drug was also granted break-through designation. Genentech’s Trastuzumab (Herceptin), in intravenous form had been approved in 1998 and is considered as breakthrough drug for treatment of HER2+ breast cancer. Later, with an objective to improve patients compliance, Genentech developed subcutaneous form of drug (Herceptin Hylecta) which received FDA approval in 2019.

The safety of subcutaneous form of the drug is comparable to that of intravenous form. Takeda is also presently evaluating the efficacy and safety of a new subcutaneous formulation of monoclonal antibody vedolizumab (Entyvio) in adults with moderate to severely active Ulcerative colitis (UC) or Crohn's disease (CD) which is currently being administered intravenously. Formulating biologics into oral dosage forms will significantly reduce the delivery cost. But, whether gastric pH, gastric enzymes and epithelial cells lining the gastrointestinal tract would help the orally administer biologic product in achieving the required bioavailability is a critical factor to be considered. Because these challenges were observed with the oral form of insulin. This further led to the development of inhaled insulin therapy by Pfizer which was approved by FDA in 2006. Another innovation that comes in this direction is the RaniPill™capsule developed by Rani Therapeutics. Delivery of drugs through this robotic pill was equivalent to injections in pre-clinical and human trials are underway.

Other paths that researchers are looking for consideration are, using wearable drug delivery devices as a solution.

FDA approval of Pushtronex™ system (on-body infusor with prefilled cartridge) for Repatha (Evolocumab), a hands-free device designed to provide 420 mg of Repatha in a single dose is another milestone in the course. But, will success of Pushtronex™ system boost the innovation in this angle? Given increased volume of data and increasing importance of artificial intelligence which is being embraced by all other industries, pharma companies which

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thrive on innovation are also thinking of adopting this technology to decrease developmental costs and increase success rates. Leveraging artificial intelligence for predicting the right parameters and conditions required for bioprocessing and thereby bring down the developmental costs and producing high quality product is something which biotherapeutics industry is contemplating on. In context of cell therapies where obtainment of relevant number of cells with viability, potency and safety is currently challenging, use of analytical technologies might create a new wave in manufacturing of cell therapies.

Artificial intelligence would also hold great promise in early drug discovery phase more predominantly target identification which is crucial for success rate of therapeutic products. Would artificial intelligence become magic bullet in biologics manufacturing? All biotherapeutics are produced from living cells, majorly CHO cells and hence sensitive to manufacturing processes. Giant biologic manufacturers

are looking for alternatives to mammalian cells so as to decrease the production cost and increase product quantity. Biogen in collaboration with Bill & Melinda Gates Foundation and MIT Center for Biomedical Innovation have engineered eight alternative hosts including fungal, algae, and trypanosome systems for the production of full-length mAbs. Future vision

Finally, advancement of protein engineering technologies has steered in unprecedented opportunities to develop safe and efficacious biotherapeutics. Investment of huge efforts on optimising existing

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therapies to make drug targeting better, enhancing functionality and improvising patient experience through new formulation and drug delivery devices suggest prominent swift towards biotherapeutics market in the years to come. Also, changes in the FDA regulations (removed a rule under Section 610.21 of the FDA code) implemented recently pertaining to biologics would further boost the approval rates for biotherapeutic products. Hence, with this advancement in technology and increased investment on innovation, biotherapeutics products will continue to enrich medicinal armoury and make a foot print in the near future.

References are available at www.pharmafocusasia.com

AUTHOR BIO Prasanthi Polamreddy is a pharma professional with over 10 yearsâ&#x20AC;&#x2122; experience in standardizing and analyzing pharmacological data, computational drug discovery, and development of pharma competitive intelligence reports. She currently works with Excelra Knowledge Solutions Pvt Ltd as a scientific manager.

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TISSUE ENGINEERING Choosing low-endotoxin gelatins for cell cultures Barbara Vanhoecke, Innovation Manager Biomedical, Rousselot

Tissue engineering involves the creation of functional constructs for therapeutic purposes that restore or improve damaged tissues or whole organs in patients.

The process requires three essential components: an appropriate three-dimensional scaffold to support transplantation and growth of cells; cells, which can

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be reparative cells, that are able to form a functional matrix; and biologically active molecules, such as cytokines and growth factors that promote the formation of the desired tissue type.

One of the preferred methods to build the scaffold is with the use of hydrogels, polymer-based substances with a high water content that replicate

the characteristics of the extracellular matrix. As a natural, well-known ingredient, gelatin holds a huge potential in tissue engineering and gelatin-based hydrogels are a popular choice thanks to their biocompatibility and biodegradability.

In the following interview, Barbara Vanhoecke, Innovation Manager Biomedical at Rousselot, explores the value of low-endotoxin X-Pure gelatins already in early stage research and developments in field of tissue engineering, which might eventually go into the clinic with a strong safety profile.

1, What are the current challenges for tissue engineering?

Despite the significant investment in scientific research, the scalability and the undeniable potential, there are only a few current clinical applications of tissue engineering and even for those commercial success has been difficult to achieve. One of the primary challenges is the lack of a unified regulatory approach, as the fast-moving and complex nature of the industry outpaces the ability of regulatory frameworks to keep up.

But there are also a number of biological challenges. Before implantation the host cells are expanded and grown in tissue culture. Implanting scaffolds populated by these tissuegrown host cells is challenged by the generally low survival in vivo of the host cells. Another major challenge is revascularisation of implanted tissues/organs at the human scale. Moreover, there are major risks associated with tissue engineering due to potential tumorigenicity, immunogenicity and rejection of the graft. However, by using biomaterials that closely mimic the body’s own matrix and by avoiding unnecessary immune responses these risks can be greatly minimised. Further, it is critical that the biomaterial used to replicate the

functions of the body’s extracellular matrix provides the appropriate molecular and mechanical signals needed for the cells to achieve the necessary growth, migration and differentiation.

To generate new, functional and compatible tissue in the transplanted cellular scaffold, low-endotoxin gelatin can provide a favourable environment for cell growth and be used to create hydrogels with the precise characteristics required such as mechanical strength. Since it naturally contains arginine– glycine–aspartic acid (RGD) peptide sequences, gelatin provides attachment sites for cells, which facilitates well-defined mechanical and biological signalling.

2. Why is it important to monitor and regulate endotoxin levels for tissue engineering?

A type of pyrogen (i.e. a substance that induces fever when released into the bloodstream), endotoxins are a component of the exterior cell wall of Gram-negative bacteria. While they do not directly harm any tissue, they can initiate a strong immune response by human immune cells as an indicator for the presence of bacteria. However, they can also trigger other cell types, like stem cells and endothelial cells. Actually, any cell type containing the toll-like receptor-4

Barbara Vanhoecke holds a PhD in Medical Sciences as well as a Master in Biochemistry. She joined Rousselot in 2017 and is now Innovation Manager Biomedical working in particular on the X-Pure range. Barbara Vanhoecke has published two patent applications and is author/co-author of more than 40 scientific papers.

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is sensitive to these molecules and can therefore be affected in some way. Depending on the concentration and exposure time, endotoxins can negatively impact cellular activity in terms of growth, morphology, differentiation, inflammation and protein expression even at very low levels (<100ng/ml). In stem, immune and endothelial cells specifically, using lowpyrogen gelatin as biomaterial for scaffolds helps to minimise the risks of both immunogenicity and potentially tumorigenicity of the transplanted hydrogel.

When it comes to immunogenicity, it is important to use highly purified biomaterials for the construction of the scaffold. Contamination with elevated levels of endotoxins and other pyrogens creates unwanted immune reactions once implanted in the patient, effectively risking failure of the implant and endangering the patient’s health. Similarly, since (chronic) inflammation can transform cells and induce tumor growth, the use of extra pure biomaterials might also help avoiding deregulated cell growth and thus tumorigenic constructs.

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3. What are the benefits of using low endotoxin gelatin in hydrogels?

Gelatin’s biocompatibility and tunable mechanical properties are two essential characteristics in the development of hydrogels.

During the gelation process many parameters, such as temperature, can be changed or controlled in order to achieve the hydrogel structure of interest.

Adequate mechanical strength, for example, can be obtained by modifying the crosslinking degree. Also, countless combinations with other molecules (APIs, other biomaterials) are possible with gelatin-based hydrogels.

These properties, combined with its high purity, make low endotoxin gelatin an ideal material for biomedical applications. To qualify the benefits of using low endotoxin gelatins in cellular hydrogels, a study carried out in collaboration between Rousselot and the University Medical Center of Utrecht set out to assess the effect of endotoxins contained in hydrogels on differentiation of mesenchymal stem cells (MSCs) and peripheral blood mononuclear cells (PBMCs). Improved differentiation of MSCs into chondrocytes was seen after 28 days of culturing in a X-Pure low endotoxin gelatin hydrogel, compared to a non-purified gelatin. Also, a reduced inflammatory response of PBMCs was observed when cultured on top of a low endotoxin gelatin hydrogel as evaluated by measuring TNFalpha and CCL-2 release in the culture medium after 3 days of culturing.

X-Pure’s potential in endotoxin-sensitive cell cultures was also highlighted by a second study carried out in collaboration with Ghent University. A comparison on the viability of immune cells (THP-s) in a 10% X-Pure gelatin solution versus MatriGelTM showed a significantly improved cell survival in X-Pure after 3 days of culture. This study highlights the potential of X-Pure as a valid and improved alternative to MatriGel for endotoxin-sensitive cell cultures, as it also represents a solution to the batch to batch variation and the overload of growth factors associated with MatriGel. Interestingly, gelatin hydrogels devoid from endotoxins can also be used for storage or transport of endotoxin-sensitive cells, as they significantly improve their survival. Preliminary results of a study carried out in collaboration with Ghent University showed that the addition of 10% X-Pure gelatin to the medium significantly improved viability of endothelial cells after 3 days of storage at 4°C, even in absence of serum, and was significantly better compared to non-purified gelatin.

4. What else should hydrogel manufacturers look for when choosing low-endotoxin gelatin?

Among the several factors to be taken into consideration to evaluate low endotoxin gelatins, other pyrogenic activity in the biomaterial used is the first that comes to mind.

These other non-endotoxin pyrogens can also trigger an adverse immune response in the human body and cause an anaphylactic shock. Associating low endotoxin levels to low pyrogenic activity can be a dangerous assumption, as the LAL assay, commonly used to measure endotoxin contamination, does not measure non-endotoxin related pyrogenic activity.

The results of Rousselot’s latest purity testing show that the full X-Pure portfolio consisting of both type A and B gelatins (hydrolysed and non-hydrolysed), can be produced and delivered pyrogen-free. This is important since there are no type A gelatins today on the market that are free from pyrogens. For some applications however, such as for the use of gelatin nanoparticles in drug delivery systems, the selection of type of gelatin is very important to get the desired release profile of each compound.

The quality, safety and compliance of excipients can’t be overlooked either. It’s important to partner with a supplier committed to consistently deliver

ingredients of the highest quality, compliant with the international standards as well as fully traceable and extensively tested.

In such an evolving field, collaborative partnerships with suppliers can be an invaluable source of formulation, technical and R&D support.

This is why Rousselot works in close partnership with its customers to co-develop new products and applications.

5. What other exciting applications is X-Pure suitable for?

Highly purified gelatins hold an enormous untapped potential in several emerging application areas.

Exciting uses come from the 3D bioprinting sector, for example, where again low endotoxin gelatin can reduce the risk of tissue rejection.

XPure’s low immunogenicity also represents an opportunity to advance innovation in wound dressing applications, as minimising pro-inflammatory stimuli could reduce the risk of sustained inflammation.

Furthermore, the fields of biomolecule and drug delivery are increasingly turning to ultrapure gelatin to prepare injectable micro- and submicron particles as well as colloidal gels that comply with the highest regulation and quality standards Advertorial www.pharmafocusasia.com

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FINDING A PATH TO GLOBAL END-TO-END LABELLING

As health authoritiesâ&#x20AC;&#x2122; local requirements evolve and their quality expectations increase, many companies are often faced with difficult choices when it comes to developing a multilingual regulatory labeling infrastructure that is scalable, cost efficient and future-proof. This article will discuss the various methodologies, strategies, and resources that can be implemented to enable effective end-to-end labeling.

Christophe Djaouani, EVP Regulated Industries, SDL

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perating in one of the most demanding and highly regulated environments, pharmaceutical companies face the constant challenge of managing medicinal product information for regulatory labelling submissions that comply with regional and national agency requirements.

High standards demanded by regulatory agencies during the submissions process â&#x20AC;&#x201C; which varies by country â&#x20AC;&#x201C; puts enormous pressure on firms to ensure that the filings are effectively coordinated between the central team and local affiliates and that every element of their application is flawless.

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The approval process is a long and arduous journey and keeping product information up-to-date in multiple languages requires mobilising many resources centrally and locally. Local regulatory affairs stakeholders may outsource or be directly involved in the translation, review and formatting process. This constant handling of the documentation can cause inconsistencies and quality issues and, most importantly, limit the time to be allocated to main regulatory activities.

As regional and national authorities' requirements evolve and their quality expectations increase, many companies

are faced with difficult choices when it comes to developing a multilingual regulatory labelling infrastructure that is scalable, cost efficient and future-proof.

To maximise global reach and reduce time to market, pharmaceutical companies should consider employing new technologies to enhance compliance of their product information with regional and national regulatory filing requirements in multiple languages and geographies.

Label management is complex, spanning the entire lifecycle of a medicinal product, and has global and regional implications. Those involved in label

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management – from creation through to implementation – work with crossfunctional disciplines within the organisation, e.g. pharmacovigilance, regulatory affairs, medical affairs, and supply chain. It is also one of the most common areas of critical inspection findings by the governing regulatory authorities.

Typical inspection failures include failure to identify and submit safety variations, delays in submitting variations, and failure to implement updated reference safety information following variation approval. Taking into consideration the variation in country-specific regulations, translation requirements and local functions compound these challenges. Pharmaceutical companies have invested heavily in personnel and disparate technologies to manage the end-to-end (E2E) labelling process; however, facing increasing complexity, inherent legacy systems and processes, pharmaceuticals are faced with a significant obstacle to improve this overall process.

The following barriers to making E2E labelling a reality are the most commonly cited: • Organisational change management: Most stakeholders span the entire organisation and have grown accustomed to working in Microsoft Word and managing information at the file level.

• Siloed technologies: The extremely wide array of systems (RIM, ERP, tracking, etc.) involved across the labelling process, the lack of integration between them and the many manual steps push the boundaries of any centralisation exercise.

• No single source-of-truth: Ensuring that the entire organisation, regardless of geographic location, use current approved content in their local submission remains a challenge.

• Organising complex global regulations: Every country follows very specific guidelines when it comes to labelling format and content.

• Submission delays: Managing new drug registrations, variations, extensions to deadlines, and compliance requirements across multiple markets is a signifi-

cant challenge. Launching or updating product information simultaneously in multiple countries poses yet another challenge.

• Legacy products and filings: Most organisations retain a wide portfolio of legacy products that were placed in local markets years ago with minimal visibility into these off-patent filings.

• Fragmented collaboration: Ineffective content review and collaboration can jeopardise registrations and submissions.

This is particularly crucial for organisations with teams located globally.

With the number of co-development, - licensing and – commercialisation agreements on the rise, most biopharma companies are looking to significantly increase their ability to share labelling content globally.

Furthermore, as these organisations are embracing new cloud-based solutions as their authoritative source of content across their entire ecosystem, a structured and global approach to content, or even to data, becomes more of a reality. www.pharmafocusasia.com

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Companies follow vastly different paths when it comes to their digitalisation journey and contending with the reality of their global regulatory labelling infrastructure, a controlled and focused step-by-step approach will help establish the necessary foundations for a future E2E labelling model.

Regulatory Content Management Model ORCHESTRATION

Assembly

Workflow

Modular and Structured “Intelligent” Content

Cloud Assimilation

Interconnectivity between systems (CCMS, TMS, RIM, ERP, etc.) and other data repositories remains the single most important element in any E2E labelling initiative. As such, ensuring that all these technologies are designed with ease of integration in mind will determine the long-term viability of your model.

Furthermore, this will prove even more crucial as the biopharma industry further transitions from a content-based to a data-based regulatory content management model. (Figure 1) Translation Management System (TMS)

Helping biopharma companies evolve their current translation process to one where translation activities are streamlined and automated represents the single

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Multi-Channel Delivery

Headless Delivery

CONTENT HUB

Content Store

Neural Semantics

Content Synthesis

Collaboration Tools

Translation

INTEGRATIONS ERP

ECM

Other

RIM

Figure 1. Regulatory Content Management Model largest opportunity for the industry with the lowest overall risk. By centralising translation requirements into a single cloud-based system, companies can decrease time-to-market and costs, while preserving data integrity and increasing visibility and traceability of their activities on a global scale.

Technology will play an essential role in any E2E labelling initiative but it is not a silver bullet. If there is lack of process standardisation then

AUTHOR BIO

By leveraging a structured approach to the creation of new labelling content, biopharma companies will be in a position to access a single repository for labelling documents while minimising rework and duplicate information entry.

Additionally, with component content management systems (CCMS) providing a “Word-like” authoring environment and focusing on new labelling content first, the negative impact associated with change management and legacy labelling content conversion is minimal. This highly targeted approach would also help further support and validate a compelling ROI, especially when linked to new standards set forth by the regulators, such as the identification of medicinal products (IDMP) ISO standards.

PRESENTATION

implementing technology is not going to achieve the desired results. While ensuring that your various systems are interconnected is crucial, one should look at taking advantage of the deployment of these systems to further drive process harmonisation and ease the collaboration between the central team and local affiliates. An organisation can reduce its risk by selecting a part of the process that has defined controls and limited exposure. Risk could be minimised further by developing an approach to efficiently manage translations for a select number of countries or in a given geographic region. Once the model is viable and generates a clear ROI, it will form the basis to further support global expansion.

Christophe Djaouani is EVP of Regulated Industries at SDL, an intelligent language and content company. Beginning his career in the multilingual communications field in 1998, Christophe has used his 18+ years of industry experience to drive SDL’s regulated industries strategy, building a team of highlyskilled experts to respond to client needs with ground-breaking solutions.

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Sustainable Packaging

Pharma to take care of the planet With the global sustainable packaging market estimated at US$220 billion in 2018 and projected to reach US$280 billion by 2025, sustainability has become an important part of the overall brand image story for many pharmaceutical companies.

Maria Ferrante, Senior Director, Marketing and Communications, PMMI

T

he top five drivers of this move to sustainability, according to the Packaging Sustainability: A Changing Landscape report from PMMI, The Association for Packaging and Processing Technologies, include brand perception, competitive pressure, environmental advocates, top-down company culture and good stewards of the planet.

While a major focus for many, nearly two out of three brand owners participating in the PMMI report cited added cost as the top reason their sustainable packaging initiatives have slowed.

While the package is a vital part of any sustainability strategy, how the prod-

uct gets into the package also warrants consideration. Solutions such as integrated monitoring and more flexible machinery can aid pharmaceutical manufacturers in improving the sustainability of their packaging operations through improvements in areas such as packaging material loss and overall equipment effectiveness (OEE). With sustainability an important driver, Changes in materials and packaging formats to improve these efforts has an impact on machinery and operations.

Technology advances are also driving efficiency, which, in turn, will assist with sustainability efforts. Industry 4.0 will

utilise automation, robotics and artificial intelligence to increase the efficiency of packaging operations. These advances will enable the identification of problems before they occur, reducing material waste and product loss.

The PMMI report outlines five top functional machine improvements that have the greatest impact on manufacturing operations when moving to more sustainable packaging: • Reliability: Machines need to reliably handle a wide range of substrates, sizes and shapes. When making adjustments on any part of the machine, there should be an indicator that signals achievement of accurate parameters.

• Flexibility: Equipment must account for material variances as the trend of lightweighting continues to grow.

Machines need to be flexible enough to account for variations in material thickness and maintain throughput, pass inspection and minimise rejection rates. In general, new machines need to be easier to use, service and clean.

• Automated changeover: There needs to be more precise settings for automatic changeover to achieve greater accuracy when moving from product to product, which could include material or size changes. Strive to standardise and simplify changeover procedures.

• Cleanability: Cleanability is a top-of-mind concern for machine

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considerations, particularly in pharmaceutical manufacturing. Manufacturers desire machines that utilise less water and fewer chemicals while still meeting hygienic standards. â&#x20AC;˘ Sensor feedback: To achieve a complete sustainability profile for a machine, and consequently a package, improved inline sensors are needed to monitor scrap levels, alert for predictive and preventative maintenance, track quality control, measure yield, track energy and water used and monitor temperature, time and pressure.

When looking at operations and the machine improvements needed, pharmaceutical manufacturers need to decide whether it is beneficial to buy new equipment or modify existing equipment.

This decision depends on many factors in their drive toward sustainable packaging.

Pharmaceutical companies are the least likely to make machine modifications due to strict validation requirements.

They are looking for new machines to fill, index, cap and seal, as well as robotic and automated solutions for end-of-line.

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Another consideration is the type of packaging operation as different packaging functions have different challenges.

For example, in thermoforming processes, substrates have different melting points and do not flow the same, causing performance issues when forming trays. Monomaterials, touted for their recyclability, are gaining attention, but sealing can be a problem at higher speeds. Sealing can also be a challenge when filling varied shapes and sizes; using more sustainable materials may mean a stronger seal is required.

Most (67 per cent) of manufacturers experience and expect machine issues when introducing new materials.

For pharmaceutical manufacturers, the biggest challenge is the requirement of equipment validation with each package change. Additionally, manufacturers require highly reliable data collection from sensor feedback to measure sustainability goals. Sealing and closing during filling can be a problem with thinner films, and conveying lighter gauge materials can often cause jams. In some

instances, manufacturers are moving from hot glue to ultrasonic sealing to reduce waste.

Despite these challenges, 53 per cent of manufacturers are evaluating or implementing new materials to be more sustainable. Some of the material innovations reported include barrier layers that are recyclable, new substances to extend shelf life, plant-based material that is renewable, 100 per cent recyclable mono-materials with barrier properties and affordable bio-based alternatives that are biodegradable and compostable.

On the packaging materials side, the industry is working towards developing materials that offer the right combination of being fully sustainable, affordable and protective while maintaining shelf aesthetics. Report participants indicated they are looking for ideal characteristics such as cost-effective, scalable manufacturing, globally available, robust and protective and efficient to ship.

According to a GlobalWebIndex survey, 59 per cent of consumers way they would pay more for eco-friendly packaging.

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On a global level, over 450 partner companies, led by the Ellen MacArthur Foundation in collaboration with the UN Environment Program, have entered into a global commitment to achieve a clear set of sustainability goals by 2025.

One of the UN Sustainable Development Goals for packaging includes working towards 100 per cent reusable, recyclable, or compostable plastic packaging by 2025. They acknowledge using recycled content is essential.

When working to achieve sustainability goals, pharmaceutical manufacturers should consider identifying material alternatives that offer equal or less costs, use fewer resources and produce less waste. In addition, it is important to implement operational changes that bring equal or improved quality. When making changes, focus on cultural changes that will have a measurable impact as well as allocate enough resources to address sustainability aggressively. In order to ensure buy-in throughout an organisation, install company-wide recognition of the importance of sustainability.

When looking to develop a more sustainable package, PMMI’s report outlines some key guidelines that can help: • Too much reduction: Reducing the packaging too much can result in damage to the product inside, increasing overall costs and harming brand perception.

• Consider all sustainable factors of your material: For example, paper typically takes much more water and energy to produce than plastic. While it might be easier to recycle, it may be less sustainable overall when examining the larger picture.

• Durability: Material made from recycled product is not as durable and gets less so after each round of recycling.

The increased cost and decreased overall durability mean that recycled material is not right for every product.

• Origin: If using recycled content, the origin of the material is necessary. according to ISO standard 11-607.

Newer, renewable packaging materials, including plant-based and bio-based packaging options, can create a circular economy and are being explored by more than one in four participants in PMMI’s report. One vitamin and supplements manufacturer reports implementing an initiative to add sustainable packaging to their products. When looking at these materials, manufacturers need to consider factors such as how fast the new materials can run, the material’s limiting effect on machine flexibility and possible machine modifications. That said, the global market for bioplastics is predicted to grow by more than 15 per cent over the next five years. Currently, 45 per cent of all bioplastics are produced in Asia and 20 per cent in the EU. The EU share is expected to climb 30 per cent by 2024.

With one of the UN Sustainable Development Goals centering around reuse business models as a preferred “inner loop” and reducing the need for single-use plastic packaging, over one in three brand owners participating in the PMMI report are implementing reuse, return or refill options. One vitamin/supplements producer reported exploring a program to return packages through distributors, providing a reward or benefit for returns. A global leader in healthcare products has created product recycling for hospitals and a returnable program for vision care products.

These types of returnable packaging programmes warrant careful consideration as they require more labor, stringent cleaning, dedicated infrastructure, cost justification, robust packaging and more consumer involvement.

PMMI’s report highlights the fact that the key to successful sustainability initiatives takes teamwork from packaging engineers and product developers.

Reducing packaging’s impact on the environment is a way to build brand loyalty and connect with customers. The quest for a more sustainable package has thrown open the doors to innovation and companies are thinking beyond traditional approaches to develop innovative and novel solutions to improve the sustainability of their packaging.

Additionally, true sustainability takes consumer cooperation. One of the UN Sustainability Development Goals is to commit to achieving the vision via collaboration with the private sector. Of the participants in the PMMI report, over half (52 per cent) agree that consumers need better education to understand sustainability and what it really means for packaging design and costs.

The next generation of consumers will demand less material in packaging, and companies need to look at their entire sustainability equation. According to a GlobalWebIndex survey, 59 per cent of consumers way they would pay more for eco-friendly packaging.

As the sustainability initiative grows, it is more important than ever that pharmaceutical manufacturers stay abreast of the latest developments.

Register and learn more at www.packexpointernational.com

AUTHOR BIO

Maria Ferrante is Senior Director, Marketing and Communications for PMMI, The Association for Packaging and Processing Technologies and the producer of the PACK EXPO Portfolio of trade shows. Ferrante is an award-winning writer/ editor who has been covering the packaging industry for over 25 years.

www.pharmafocusasia.com

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Next Generation Biorepositories for Transformative Medicine A biorepository is a biobank that collects, processes, stores, and distributes biological materials to support future scientific investigation.

Next generation biobanks with in-built capacities to store clinical grade biosamples, derived therapy grade cells, donor or patient’s clinical data, acquired cellular sequence data are forecast to lead in offering biobank derived transformative medicine. The biobanking industry’s future looks bright with deep entry barriers owing to the intellectual property surrounding the applications – A new order of the ages.

S Dravida, Founder CEO, Transcell Biologics V Vellanki, Intern, Transcell Biolife Aman Iqbal, Scientist, Healthcare Entrepreneur

F

or centuries naturalist collected and curated various flora and fauna from around the world with the idea that these collections would provide important information about natural world. Biobanking was started with a similar purpose like collection of biospecimen as an inventory to be utilised for scientific research. The modern era of biobanking can be traced to have originated during the Cold War by anthropologists who had begun to collect and store blood and tissue samples from indigenous communities. They collected the samples fixated on the fact that these samples contained vital clues about genetic ancestry and human evolution. Biobanking in it’s various forms is an activity involving the collection of biospecimen and associated data and their storage for differing lengths of time before use. In some cases, biospecimens are immediately used, but in others, they're stored typically for the term of a specified project or in perpetuity until the materials are declared to be of little value with applications.

The field of biobanking has further changed over the past thirty years. It went from predominantly university-based repositories that were developed for research needs of specific projects into institutional and government supported repositories, commercial biorepositories, population-based, disease-oriented biobanks and lastly, virtual biobanks. The information related to stored biospecimen have increased in complexity from basics data sets like date of collection, disease diagnosis, to extensive information sets like phenotype, clinical history, genomics, proteomics of the biosample.

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Cryopreservation technology

Cryopreservation is a procedure that preserves organelles, cells, tissues, other biological materials by cooling to very low temperatures (-20 deg C and more).

Viable tissues, derived stem cells, cells which have great potential for use in clinical research, medical applications, cannot be stored viable just by cooling or freezing for a long time as ice crystal formation gives osmotic shock causing membrane damage during freezing and thawing leading to cell death. The use of cryoprotective agents and temperature control equipment are necessary evils for the successful cryopreservation of cells or tissues to retain viability intended for applications. The methods and variety of cryoprotectants used in cryopreservation of biological samples may vary depending on the type of biosample and type of utility for which the biosample is cryopreserved giving room for intellectual property and technical knowhow in this space.

Freezing of biological material is a preclinical step that determines heterogeneity and decentralisation of biobanking.

Storing temperature conditions at the time of collection and during maintenance are pre-analytical features affecting basic data heterogeneity. Presently, the standard temperature for storage of tissues and cells are between − 80 °C and − 150 °C (recommend liquid nitrogen, in particular the vapour phase stage (−150 °C) over the liquid phase (−196 °C)) while ultra-low temperatures preserve the integrity of proteins, DNA, RNA, and cellular components.

Biobank residing data sets

Collection of stem cells and tissues derived from samples present an enormous data source. Besides analysing cellspecific genotypes that can be used for cell-based therapies (described later), there is also the opportunity to carry out whole genome sequencing for each individual sample. Depending on the background of the individual, one can get a very good sense of the genetic

makeup of others from the same background giving rise to a genetic pool that will allow for the development of genotypic specific personalised medicine as described later. When you take the individual tissues and grow them into 3D organoids, one can screen a library of drugs (small molecules and biologics) giving rise to genotypic and phenotypic specific drug combinations personalised for each individual. Now imagine taking every single tissue from the biobank, growing it into 3D organoids and carrying out ultra-high throughput screening can provide us terra bytes of data that allows us to aid our understanding of complex epigenetic-genetic interplay to develop precision medicine.

Large scale biospecimen banking in conjunction with highly annotated clinical data for each biospecimen is crucial to identifying optimal patient demographics, therapeutic approaches for specific patient subgroups, and laying the foundation for novel discoveries based on interrogation of the big data derived from this approach. However, to protect patient identity and confidentiality it is necessary to de-identify the biospecimen. This task can be accomplished via a Clinical Data Warehouse (CDW) using bar codes linked to patient Medical Record Numbers (MRNs), and MRNs linked to patient Electronic Medical Records (EMR). The biobank itself remains blind to patient identity but is able to access patient medical records and demographics. Biospecimen, if collected and stored properly, may be used for both therapy and research. That is, large samples such as cord blood or adipose tissue may be later removed and used for patient treatment. However, if multiple small aliquots of the specimen are also stored those “bullets” can be used for research and interrogative purposes to determine patient qualifications for trials and improved outcomes from such trials, along with providing specimens for research interrogation that produces big data that can be the source of novel discoveries and additional therapies.

Preserving all the way

With incredible advancements in the technologies to do with collection and storage of human samples to obtain important results in the field of medical research, today one can collect, store, preserve tissues, stem cells, cells, DNA, proteins, subcellular components for ever, retrieve whenever needed integrating standard procedures for the coordination of sample collection and usage.

Cell lines

The history of cell line biobanking started with generation of the HeLa cell line in 1951 at Johns Hopkins Hospital. The HeLa cell line is used worldwide in research laboratories as it offers an optimal and stable model system for in vitro research experiments while scientific results have been gained with vital advantages for global health like the development of polio vaccines.

The evolution of cell line biobanks highlights the importance of standardising technical procedures; data reproducibility in medical research. Major cell line repositories include: Japanese Cancer Research Resources Bank, ATCC (USA), Leibniz-Institute DSMZ, European Collection of Cell Cultures, Korean Cell Line Bank.

Specimen/Tissues

The first specimen biobanks started as university-based repositories with attached hospitals and research institutes for specific research projects. They were established by clinical researchers with access to patient populations that took advantage of the availability of ‘left over’ aliquots or biosamples that were going to be discarded were stored for either immediate or future use. Automated sample processing, the dawn of World Wide Web revolutionised the management use specimen from biobanks eventually. One such success story in utilising specimen from biobanks is the development of trastuzumab antibody (Herceptin), one of the drugs effectively used to treat specific subtypes of breast cancer.

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Stem cell biobanking

In multicellular organisms like humans, stem cells are undifferentiated cells that can differentiate into various types of cells and self-renew. They are found in embryos, foetus and adults with different properties in each. They are named as: Embryonic stem cells, Fetal stem cells, Hematopoietic stem cells, Mesenchymal stem cells, Tissue specific stem cells, Induced Pluripotent stem cells. There are five known types of sources to harvest stem cells: 1. Biopsy 2. Biological discards 3. Embryos 4. Foetus 5. Cadaver.

Cord Blood biobanking for Hematopoietic stem cells; Peripheral blood/Bone marrow banking for both Hematopoietic and Mesenchymal stem cells; Amniotic/Cord tissue banking for Mesenchymal stem cells; Tissue banking for derived epithelial stem cells, endothelial stem cells; induced pluripotent stem cell banking are some of the popular concepts. These concepts are regulated operating entities to do with collection, processing, cryopreserving and retrieving the stem cell units from the repositories for applications. Before the advent of stem cell biobanking concept that allows partial or complete evaluation of the genome, epigenome, transcriptome, metabolome, and proteome components of the biospecimen stored, and Formalin-Fixed Paraffin Embedded (FFPE) tissue was the specimen usually collected in biobanking databases were used in research programs. The â&#x20AC;&#x153;next generationâ&#x20AC;? era has exposed several disadvantages in the use of FFPE tissue for molecular/genetics and protein studies paving way to cryoprotectants used cryopreserved tissues for better-quality of the derived components that includes cells for clinical applications like clinical trials and cell therapies.

Biobanked Stem cells for cell therapies/regenerative medicine (Autologous and Allogenic):

Stem cells have the remarkable potential to be developed into many different cell

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types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. One of the key orthologous applications of biobanking is the opportunity to harvest stem cells for regenerative medicine. Research in the last couple of decades have allowed researchers around the world to transform mouse stem cells into variety of human cells like neurons, skin cells for grafting, and many more.

Stem Cell Therapy (SCT) is the treatment of various disorders, non-serious to life threatening, by using stem cells.

These stem cells can be procured from a lot of different sources and used to potentially treat more than 80 disorders, including neuromuscular and degenerative disorders.

Hematopoietic disorders (e.g. leukaemia, thalassemia, aplastic anemia, MDS, sickle cell anemia, storage disorders etc.) affect the bone marrow and manifest with various systemic complications. Stem cells from a donor (either from cord blood or bone marrow) are known to reconstitute the defective bone marrow and permanently overcome the disorder.

Degenerative disorders arise from degeneration or wear and tear of bone, cartilage, muscle, fat or any other tissue, cell or organ. This could occur due to a variety of reasons, but it's normally the process known as ageing, or 'getting old' that is the biggest cause. The disorders have a slow and insidious onset but once contracted, can be long-standing, pain-staking and lifelong. These disorders can affect any organ of the body.

The common degenerative disorders are diabetes, osteoarthritis, stroke, chronic renal failure, congestive cardiac failure, myocardial infarction, Alzheimer's disease, Parkinson's disease etc.

Although stem cells are often used in therapy immediately upon isolation, in many circumstances the stem and progenitor cells will be harvested, processed and banked frozen until a later time. Biobanking is a convenient alternative to same-day therapeutic use, in that it allows for patient recovery (e.g., from liposuction or surgery), provides time to identify the best treatment options, and may allow for multiple interventions without additional patient inconvenience or risk.

Biobanking can be advantageous in both the autologous and allogeneic settings, to reduce costs, to personalise therapies if needed, and to reduce patient inconvenience. In the autologous setting the collection and banking of biospecimen can inconvenience the patient only once, with multiple aliquots being set aside for future use. The biospecimen can be collected when the patient is at their youngest and healthiest, so that the cells are most optimal for use in therapy at any time in future. In addition, it reduces the concerns about disease transmission and immune rejection. In the allogeneic setting it can permit selection of the most ideal biospecimen donor when personalised therapies are not needed. Young and healthy donors free of disease or other medical issues can be utilised, biospecimen expanded into hundreds if not thousands of therapeutic aliquots, and then placed at various banking sites around the country (or world) where they can be immediately available when needed. Creation of large autologous biospecimen banks (e.g., cord blood banks) can also permit clinical trial tailoring to specific patients with certain diseases or indications that shortens time to treatment, rapidly fills patient recruitment quotas and increases the probability of positive treatment outcomes.

Biobanked Stem cells for precision medicine and predicting health signatures

Human specimens and derived cells with associated clinical and phenotype data make it possible to analyse

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Biobanked Stem cells in drug discovery

The evolution and heterogeneity of biosamples composing the biobanks go hand in hand with the development of highly sensitive, high-throughput methods in discovery and development of new drugs or re-purposing drugs utilising the phenotypically responsive platforms derived out of stored biosamples — Phenotype--based drug discovery— A next generation approach. The complexity of the molecular patterns of diseases provides multiple opportunities for targeted therapeutic intervention, tailored to suit the particular characteristics of the disease. Developing and evaluating such novel therapies demands access to well designed and structured collections of biosamples and derived selective components.

Therefore, harmonising biobanking procedures to develop innovative solutions supporting biobank’s operability directed to developing new drugs effectively reaching out to the largest possible number of patients is one of the next gen scenarios.

Biobanked Stem cells in Standard Care

Hematopoietic Stem cell Transplantations (HSCT) is regulated as Standard Care in practising treatments for blood and blood

related disorders worldwide while blood stem cells are harvested from clinical sources like cord blood, bone marrow and peripheral blood. Autologous, Allogenic and tandem transplantations are part of Standard Care while cryopreserving the harvested and formulated stem cells is a necessary component in imparting HSCT highlighting the role of Biobank in Standard Care.

Blood biobanking

Blood is known as one of the most common biospecimens with utility well established. It is collected in sterile tubes containing preservatives or additives specific to application and blood fraction need (serum, plasma, white blood cells, red cells). The optimal temperature for blood component storage varies between low (− 20 °C) and ultra-low temperature (− 80 °C) for short- and long-term, respectively for maintaining the integrity and stability of every blood component.

DNA/RNA banking

Fresh frozen tissue is found to be ideal specimen for DNA/RNA extraction as genetic material is reduced or degraded in FFPE tissue due to cross-links between nucleic acids induced by formalin and the time interval between tissue resection and fixation. Molecular analysis is majorly dependent on the collection/ extraction/storage modalities of DNA and RNA molecules. DNA is more stable than RNA and is preserved at −80 °C for longer periods.

AUTHOR BIO

large cohorts with large-scale genome sequencing leading to the identification of several novel molecular alterations in cancer, and tumour subtypes are classified according to distinct genomic alterations, letting a precision medicine approach for patient care.

Likewise, cryopreserved donor or patient’s biosample derived cell specific genotypes analysed provide predictive health signatures of an individual which is different from diagnostics. Biobank derived predictive health signatures are more authentic with associated data points to offer the services related to the donor/patient’s life style to prevent or prolong the contraction.

Genomic biobanks and meta-analysis of genomic data promises to reveal the genetic underpinnings of health and disease. Data sets associated with biobanks can aid in the building of country and population specific health programs either to prevent or combat epidemics and pandemics.

As the field of biobanking evolves in the coming decade, it is impossible to ignore bioethics and compliance associated with it. The intent is to protect the donors or patients from disclosures of their personal health information.

Every country/geography sets standards and regulations in order to ensure privacy and security dealing with data residing in biobanks.

The progress of individual in relation to translational medicine will be an unsolved issue of conceptual interpretation of the human genome data, modern research in chemical biology, molecular, cell biology, biotechnology and other allied branches impossible without biobanking and using different types of biological materials. Establishing functional dynamic biobanks of the human material should be connected with the need of solving a range of social, medical and humanitarian issues.

Transformative medicine that starts and ends with patients is known as the future of global healthcare while Biobanks can step up to transformational role in offering predictive diagnostics, personalized medicine — a one stop hub from womb-to-tomb offering transformative medicine.

S Dravida is the Founder CEO of Transcell Biologics (www. transcellbio.science). She is a Technocrat innovating new vistas in the fields of adult stem cell technologies and commercialization.

V Vellanki is pursuing B.S Finance and Economics at Penn State University. He is an Intern at Transcell Biolife (www.transcell.in) a next gen biobank with a vision to become an epicenter offering transformative medicine in Asia Aman Iqbal is a Scientist and Healthcare entrepreneur. He is a technology and healthcare visionary, and is passionate about the role of data in automating various industries including healthcare.

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SBV Technology and Eradicating the Risk of Contamination in Aseptic Manufacturing (Figure:1)

Containment is key during aseptic processing and this has led to the development of new transfer methods that are both enclosed and minimise the requirement for operator intervention.

In this article, the author discusses modern containment methods and the advent of split butterly valve technology to improve production processes..

Christian Dunne, Global Product Manager ChargePoint Technology

Introduction

The global CMO Market is growing at a CAGR of 12â&#x20AC;&#x201C;13 per cent between 2018 and 2022. The growth is attributed to increased outsourcing of generic drugs

by Big Pharma companies. Additionally, medium and small pharma and biopharma companies, who do not possess adequate infrastructure, will also outsource, thereby driving the market.

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Presently, non-sterile drug manufacturing dominates the global CMO market.

However, the sterile manufacturing market is expected to grow at a higher rate (15 per cent) than the non-sterile market (9 per cent) thru 2022.

Aseptic Processing

Manufacturing environments contain many potential sources of contamina-

tion which present significant hazards during the manufacturing of biopharma products. Itâ&#x20AC;&#x2122;s important for firms to ensure successful containment to prevent endotoxins, microorganisms or particles entering the manufacturing environment as this could put patient safety at risk.

Equipment, materials, and people within the manufacturing environment can all offer potential sources of

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contamination if not suitably controlled.

In response to this need we have seen multiple technologies starting to be developed, intended to allow the safe and sterile transfer of sterile APIs, biologics and biosimilars during processing.

Isolators and Restricted Access Barrier Systems (RABS) have become commonplace technologies used to meet these needs in recent years.

Regardless, both of these solutions have their drawbacks. Isolators are typically challenging when it comes to transferring materials in and out of the chamber and this can cause productivity delays during the startup and shut off processes. Furthermore, RABS offer lower integrity chambers and this solution also requires sterilisation or manual cleaning processes such as Steaming in Place (SIP) between uses and this has increased time pressures which can cause delays.

Aseptic SBV enables decontamination to take place in a closed environment.

Once sealed, a gap is created between the two discs and Hydrogen Peroxide (H2O2) gas can then be flushed through this enclosure which decontaminates the space. Chemical Indicators (CIs) are used to validate and reassure the users that full coverage of the enclosure has been achieved. Biological Indicators (BIs) are then used to ensure a 99.9999 per cent,

A Contract Development and Manufacturing Organisation (CDMO) specialising in blow-fill-seal technology required a sterile solution for transferring drug substance during aseptic production. Its capabilities extend well beyond manufacturing, with an in-house development team specialising in all aspects of bringing a product to market - from lab scale batches, regulatory filings, scale-up, manufacturing and distribution.

not a possibility.

The entire process needed to be performed under strict aseptic conditions, in order to remove the need to upgrade the whole room from a grade C cleanroom to grade A or introduce an over pressurised grade-A area around the point of fill.

Conventionally RABs and isolators would have been favoured in this situation due to the benefits which include enhanced sterility assurance. However, these both require a high initial and longterm capital investment and also require significant footprint within a facility so the company decided to search for a solution that was more appropriate to their application.

Challenge

Application

The CDMO was looking to solve the issue of charging sterile drug substance into a mixing tank. This is a common problem with all aseptically prepared products.

It was imperative to the process to sustain sterile conditions whilst docking a vessel to the container and then moving solid drug substance to form liquid. The product was sterile filtered as it was passed through the filler to become a completely dissolved liquid. However, in this application, the product being delivered to the filler was a suspension and so this was

An aseptic bio-valve product was selected to overcome these aforementioned shortfalls, providing a fully sealed powder transfer attached to the inlet port of the vessel. This valve can be pre-steam sterilised alongside the vessel, unlike traditional conventional connections incl SBVs (see illustration 1a/b). Once connected, it removes any contamination that might have come from the environmental surroundings thanks to the mating faces of the transfer being fully controlled and validated (see illustration 2a/b). (Figure:2) (Figure:3)

also known as a 6-log reduction in bacterial spores has been achieved.(Figure:1) Case study Sterile API Addition to a Mixing Vessel

Dock SIP Cap illustration 1a

SIP through Cap â&#x20AC;&#x201C; Pre-Sterilising Active & Vessel illustration 1b

(Figure:2)

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The bio valve creates a sealed chamber between the passive and active sections and when these two halves are docked, the sealed compartment is then bio decontaminated with Vaporised Hydrogen Peroxide (VHP).

Illustration 2a

Illustration 2b

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(Figure:3)

This process thereby removes any biological contamination to a validated 6-log reduction.

Furthermore, once fully mated, the discs can be opened which allows the product to be transferred from transfer container to vessel, free from the risk of contamination. This allowed the process to be performed with enormous cost and production benefits and still within a grade C space, although the process needed to be fully validated first to ensure that the initial expected benefits could be confirmed.

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Validation

Acceptance criteria for the cycle included: All CI strips used in the cycle must have changed colour.

The positive control BI must demonstrate growth.

At least one BI from each location must not demonstrate growth. change was analysed to confirm that even vapor distribution has taken place. The BIs were then relocated to a Spordex culture media and placed in an incubator (between 55-60OC. They were then kept under observation for seven days and analysed for potential microbial growth).

Once the cycle was developed it was then performed three times to form the Performance Qualification (PQ) for this element of the process. Multiple media runs were performed prior to validation in order to fully validate the system and proving successful, these were then carried forward with three media runs at PQ. The sterile hold achieved greater than 10 days with product transferred to the container and with the bio valve positioned in the closed interlocked location. The sterile hold period was achieved for the passive section (product in transfer container) for 48 hours.

Conclusion

The installation is now fully operational.

As well as benefiting from low capital equipment cost, a smaller footprint and improved installation, the CDMO can

Parameter/Phase

Dehumidification

Conditioning

Decontamination

Aeration

Time, hh:mm

00:10

00:00

00:06

00:25

Airflow, SCFM

16

N/A

9

16

Injection rate, g/min

N/A

N/A

4.0

N/A

Humidity, mg/L

2.3

N/A

N/A

N/A

now boast improved sterility assurance, a greater ease of use for operators, and low maintenance which has certainly improved the CDMOâ&#x20AC;&#x2122;s process.

As the requirements of complex APIs continue to evolve, it will become increasingly important for technologies in the sector to be agile in order to adapt to new demands and changing customer needs.

AUTHOR BIO

Firstly, microbiological validation must take place. This produces a validated decontamination cycle which enables the H2O2 gassing phase. Following this, there follows four phases which the generator will run to ensure that a fully validated gassing cycle is achieved every time.

Firstly, itâ&#x20AC;&#x2122;s important to condition the chamber to reduce the humidity and provide an ideal condition for biological kill. Following this dehumidifying step, the VHP is introduced to the chamber gradually for increased decontamination.

The VHP concentration is then maintained in order to deactivate any microbiological activity within the chamber.

Finally, once biological decontamination is completed, the VHP is removed from the system so that no harmful levels of residue are left. Typically, the acceptance level is 1ppm although in this instance 0.4ppm was the achieved level. The CDMO used a lower residue limit to ensure they had a robust system with no chance of contamination of the product due to gas residue.

The complete decontamination cycle can take as little as four minutes. For this particular application, the process was only being performed once a day and to ensure a robust cycle was produced, additional time was added to each of the critical phases, ensuring that decontamination was confirmed, and gas was aerated from the system. This resulted in a 41minute full cycle. (Table:1) Primary cycles employed Cis to control H2O2 distribution. When acceptable CI levels were achieved BIs were introduced to confirm full decontamination was attained. Once both the BIs and CIs were collected, their colour

Christian Dunne is the global product manager at ChargePoint Technology for the sterile containment solutions. For the past 20 years Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries to overcome high potency containment and aseptic processing challenges.

His technical expertise spans high containment isolators, grade A (ISO5) sampling & dispensing facilities, together with R&D and production filling line restricted access barrier systems (RABS) and isolators.

(Table:1) www.pharmafocusasia.com

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Meeting the Logistics Needs of Asia Pacificâ&#x20AC;&#x2122;s Growing Clinical Trials Karen Reddington, President, Asia Pacific, FedEx Express

A growing middle class and aging population has fueled the ascent of the Asia Pacific region in the global healthcare industry. Now the pharmaceutical sector is responding by tapping more patients in the region for new drug development trials.

Asia Pacific has advantages that makes it attractive for clinical trials: access to a ready and diverse patient pool, lower recruitment costs and favorable policies.

The focus of clinical trial researchers is now shifting from developed markets of Japan, Australia, South Korea, Singapore towards emerging economies like Thailand, China, the Philippines and Vietnam. Local regulatory frameworks are course-correcting to keep pace with the industryâ&#x20AC;&#x2122;s development.

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New markets, familiar logistical challenges

In the nearly 20 countries involved in clinical trials in the region, the sites are moving away from the first and second tier cities to smaller ones and remote locations. This poses obvious logistical challenges beyond just connectivity or understanding local provincial customs and regulations. Reliable transit times are essential to ensure irreplaceable patient samples that are delivered in the right condition and on time. Cold chain packing solutions and dry ice deliveries are required, plus robust contingency management to navigate unexpected obstacles. The ability for logistics companies to address these chal-

lenges, while at the same time offering cost competitiveness and delivering a high level of service to the pharma customers, is critical.

FedEx is one organisation that is working to achieve this by combining its core network transportation capabilities with specific value-added elements for pharma customers. Its Clinical Express solution for time and temperature sensitive samples is designed to assist laboratories, Contract Research Organizations (CROs) and pharma companies in the overall logistics management of their clinical trials.

Local solutions for market-specific needs FedEx has also come up with some market-specific solutions. For example, site investigators in Japan require on-site support and adherence to stringent protocols while performing pick-ups from clinical trial logistics providers. To meet this need, it has built a team of 500 trained and certified drivers pre-approved for entry into hospitals. These drivers provide specialised white glove services from samples packing to document preparation, which are unique to Japan.

Sites in Australia require the flexibility to order packaging supplies at the time of booking, instead of ordering supplies in advance. So, FedEx set up a dedicated Customer Service desk to manage these requests and a fleet of 300 drivers to bring packaging supplies and dry ice to the sites during pick-up.

Medical trials in Japan and Korea are dominated by small to mid-sized local pharma players, who require local drug storage centers. In late 2019, FedEx Life Science Center (LSC) in Shinkiba, Japan underwent a major upgrade to serve the complex logistics needs of its pharma customers and contract research organizations (CROs). This facility now features smarter storage systems for keeping clinical trial test drugs or Investigational Medicinal Product (IMPs) in bulk rather than shipping them individually, saving more cost and clearance time. LSC is able to provide economies of scale, making it an important value-added service to customers.

Expertise and innovative technology at the core

The demand for global cold chain logistics is set to grow more than 10% CAGR over the next five years . Logistics service providers are innovating to improve reliability. Solutions like the FedEx Medpak VioC shipper box are made from high-grade Vacuum Insulated Material (VIP) fitted with Phase Change

Karen Reddington is president of the Asia Pacific Division of FedEx Express, the world’s largest express transportation company.

Material (PCM) that can maintain temperatures between 2 to 8°C for up to 96 hours. The VIP boxes and PCM panels are reusable, making them cost effective and environmentally friendly. In case of delays during transit, there are storage facilities that allow these packages to ‘hibernate’ temporarily while maintaining their temperature integrity. This solution can be coupled with FedEx proprietary technology SenseAware®, a near real-time monitoring device which tracks temperature during the journey of the shipment. It can record other key variables including humidity, light exposure, shock events and other environmental factors that could impact the shipments As we enter the third decade of the century, global health issues continue to remain a hot topic.

Pharmaceutical professionals have higher demands of their time as they tackle even greater challenges.

By continuing to offer the right support and services to this industry, experienced logistics providers will be able to help in driving vital growth in the years to come.

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BIOSIMILARS IN THE PUBLIC HEALTH SECTOR Measures to promote the use The promotion, impulse, and sustainability of the use of biosimilar medicines in the public health sector require a variety of strategies. Incentives should be designed for prescribers and health institutions that consider the needs of the referring doctors and health professionals who are treating the patient, as well as the objectives of the health centre or institution.

Josep M Guiu Segura, Pharmacy Department Catalan Health and Social Care Consortium

T

he promotion, impulse, and sustainability of the use of biosimilar medicines in the public health sector require a variety of strategies. Incentives should be designed for prescribers and health institutions that consider the needs of the referring doctors

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and health professionals who are treating the patient, as well as the objectives of the health centre or institution.

Healthcare systems in many countries provide universal health coverage, which entails a high impact on health system budgets from therapeutic deci-

sions. Sustainability demands that clinical judgments be balanced in part by budget restraints. In this light, biosimilars drugs are announced to contribute to the sustainability of healthcare systems so that present and future patients are properly treated, while original biologics value is

MANUFACTURING

unchallenged. Because the introduction of biosimilars is a cost-effective alternative, the delay in their incorporation implies a lost opportunity in terms of medicine expenses savings for the public health systems. Stakeholders also acknowledge that the advantages of biosimilars are more than budgetary, as their introduction enhances the dynamism and competitiveness of the pharmaceutical market. . However, without determined healthy competition policies, or incentives for use, the promise of biosimilars could not come about.

Therefore, health administrations actions are needed to prevent withdrawal of biosimilars from the global and local marketplace. Measures to encourage switching in patients who are clinically stable, initiate naĂŻve patients, enable biosimilars procurement, educate key stakeholders, and many others are being adopted in many countries.

In a time of rapidly increasing of healthcare expenditure, there is an urgent need to bring on drug cost savings while maintaining care quality and clinical effectiveness. Biosimilars are consistent with this concept and comprise an important instrument for making medicines more accessible. However, to have maximal impact, it is essential that biosimilars are accepted by healthcare professionals and patients and that healthcare systems are responsive to biosimilar drugs uptake. Education on, and trust in, the regulatory framework pathway for these drugs will play an important part. A higher global alignment in the regulatory requirements and decision making at the global level would likely increase confidence in biosimilars and enable simplified development programs. A consistent approach to biosimilar approval would consider existing regional differences in regulations, as well as ensuring that the concept of â&#x20AC;&#x2DC;head-to- headâ&#x20AC;&#x2122; biosimilarity at the core of guidelines from the European Medicines Agency (EMA) or the Food and Drugs Agency (FDA) and World Health Organization WHO were preserved. Moreover, global adoption of

Value-added services could eventually play an important element in the longterm sustainability of biosimilar markets and embed valuable solutions to patient needs in the tendering procedures.

guidelines that have shown to be successful could accelerate the approval processes and advance in patient care.

Biosimilars are quality products that are fundamentally equal in pharmacological properties and administered under identical conditions for the same indications. Approval requirements for biosimilars also guarantee equal quality that is indistinguishable in structure, function, and clinical characteristics from the original. So, best value appears to be a reasonable approach to procurement design. However, value may have various implicit meanings, which in terms of healthcare should always be patient addressed.

After several years of biosimilars already in the market, a wide clinical experience with biosimilars serves as validation, revealing the rigorous guidelines for biosimilar development from drug agencies like the EMA or the FDA. Actually, the EMA regulatory framework have been acknowledged by other agencies and institutes, such as the US FDA and the WHO. Because registered biosimilars and reference biologics are counted practically equal, prescribing of biosimilars could be admissible based on the clinical experience acquired via biosimilar launches in Europe and past undertakings on generics.

Biosimilars are typically launched at discounted prices compared to reference biologics, often leading to a drop in the cost of the biologic treatments overall.

This discount pricing allows to free up resources without reducing g quality of care, granting a net positive effect on healthcare sustainability. Increased patient access to biological therapies is also one of the beneficial effects of biologic treatments affordability.

Additionally, the redistributed funds may be used to improve other healthcare services, upgrade technology equipment or innovative medicines, or consider initiating a biological therapy at earlier stages of a given disease, conceivably modifying long-term treatment approaches.

The analysis of patient registries with more data through greater biologic treatments access will help figure the longterm effects of biosimilars on disease progression.

The exhaustive structural and functional analysis of reference products required by manufacturers of biosimilars have enlarged the understanding of molecular and functional properties of original biologics. Also, biosimilar commercialisation eases the risk of shortages with the availability of more medicinal versions of the biologic drug, which is a major concern for pharmacists and healthcare authorities.

On the other hand, biosimilar development is also linked to pharmaceutical innovation, despite there is not research generated in new molecules. To provide a competitive advantage and a response to commercial threats posed by biosimilars, manufacturers of reference biologics may seek new molecules or improve the existing pharmaceutical products.

The innovation though the improvement on the drug administration, such as subcutaneous formulations of rituximab and trastuzumab, were likely urged by the challenge of approval of the intravenous biosimilar formulations.

The manufacturing process of a biosimilar is also a source of innovation. Compared with the reference

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products, more batch-to-batch consistency is provided by new production methods also involving innovative in-process control analytic techniques.

This technological innovations in production may improve the production system for many other biologics.

Maintaining the clinical effectiveness of the original, manufacturers may claim for higher stability formulations, less immunogenicity products, or easier and more comfortable ways of delivery.

Moreover, biosimilar marketing has also entailed innovations in legal provisions for updating and improving the legal framework of biologics taking biosimilars into consideration.

Pharmaceutical innovation is a must and is certainly fostered by biosimilars.

A key aspect of biosimilars is enhanced marketplace competition. In this situation, reference products manufacturers offer lower prices to biosimilar levels; and in the absence of economic leverage, prescription of reference biologics tend to prevail. In some occasions, market shares of reference products may even be extended through large discounts.

Such actions are barriers to the penetration of biosimilars in the market and may discourage investments in other country markets. In Europe, the legislation enforces a healthy competition, prohibiting some anticompetitive practices to preserve incentives for biosimilar launch.

To keep a healthy competition, many institutions advocate for pro-biosimilar policies or at least the adoption of active measures and sustainable pricing.

Given the known preferences for reference biologics and the distorted perceptions of benefits and risks linked to biosimilars, these measures are necessary. If pharmaceutical companies were to withdraw from the biosimilar market, the great opportunity for savings in the health system already mentioned would be lost.

Barriers to the adoption of biosimilars The overall assessment of biosimilars by health professionals is positive, but in practice some barriers have been identi-

fied in their prescription practice such as lack of trust, a discouraging financing system, research collaborations with the reference manufacturer, greater logistical complexity for the hospital pharmacy, or perception of low difference in net price.

Other important issues are the uncertainty about biosimilar interchangeability and switching, since these concepts are not properly understood nor legally established.

Interchangeability is a property of the drug, which is based on proven therapeutic equivalence, and switching is the exchange between two interchangeable products during the treatment without the express consent of the prescriber, usually performed by the pharmacist.

Switching is one of the most debated issues and with greatest disagreement, where some scientific societies argue that the decision of switching a biologic drug should be indicated by the prescriber, after consent of the patient and making a clinical monitoring.

However, the use of biosimilars is generally allowed or recommended at

Proper strategies to improve the adoption of biosimilars Information and training to ensure stakeholders collaboration

This training should be addressed to all agents involved: prescribers, pharmacists, payers, patients.

Switching procedures

Availability of a switching procedure in the organization and guides.

Gain sharing

Sharing the savings with the teams or hospitals involved in its application

Biosimilar quotas

These quotas can be linked to incentives or penalties in the management arrangements.

Follow-up records of patients

To provide data on the own patients’ safety and effectiveness records.

Promoting innovation

To encourage manufacturers of reference biological medicines and biosimilar medicines to continue innovating through pricing and tendering criteria

Figure: 1

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the beginning of the drug treatment. But switching is commonly not allowed in a treatment already initiated in a patient with an optimal sustained response.

Consequently, the interchangeability of the reference medicines to the biosimilars implies some legal and pharmacological aspects. The FDA requires evidence-based studies on switching from a reference drug to a biosimilar, in terms of effectiveness and safety, to consider a drug as ‘interchangeable’, an issue that is not addressed by the EMA. However, the interchangeability has been left to EU member states to regulate. The FDA, on the other hand, is entitled to consider a biosimilar as interchangeable and several USA states have approved laws that allow pharmacists to perform the switching.

Despite this regulation, no biosimilar has yet been designated as ‘interchangeable’ by the FDA. Many studies support switching to biosimilars, even promoted by some health authorities and governments.

However, automatic substitution is prohibited in many countries. Clinical

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evidence is weaker when it comes to switch between biosimilars, but long clinical experience in experienced countries does not provide unexpected drug warnings.

There have been important changes in the recommendations of the scientific societies that have led to significantly progress with the biosimilar confidence, although most of them are still reluctant to automatic substitution.

Health policies are required to encourage biosimilar promotion and implementation, stimulate their use and build trust in prescribers, pharmacists and patients. Some policies have left the market run itself, and other times, promotion has been ‘only for naïve patients.’ On the other hand, some economic incentives could lead to unethical situations, and initiatives that are not supported or agreed by healthcare professionals may not progress.

The nocebo effect can compromise the benefit of biosimilars. In patients where drugs have been switched for a non-medical reason, treatment discontinuations may be higher than if they had continued with the same medicine.

Although is not a problem related to drug efficacy, safety or immunogenicity, it could affect adherence and increase medical visits. (Figure:01) Bottom-up strategies, based on consensus between professionals, should be the preferred strategy for health authorities, as well as the consensus recommending of scientific societies and therapy guidelines for the use of biosimilars.

Procurement as a leverage for biosimilar promotion

There are different tendering practices for biologics and biosimilars across the world, with price dominating decision-making and little evidence for consideration of value-added services when awarding contracts.

Value-added services could eventually play an important element in the longterm sustainability of biosimilar markets and embed valuable solutions to patient needs in the tendering procedures.

Consideration of such value-added services could improve the long-term viability of biosimilars, as procurement would not be only based largely on cost. It has also the potential to provide benefits for patients and healthcare providers that are routinely available in order to obtain improved health outcomes.

However, there is not a standardised approach with the awarding criteria through the different tenders. Biosimilar manufacturers therefore deal with different challenges with each tender. These differences in services can also enhance a segmented market and promote competitiveness beyond price.

Tendering invites are mainly only accessible from a regional or national health-authority perspective. What’s more, information about the outcomes of procurement processes and details of successful bids are neither not readily accessible. In consequence, there is a need for increased transparency on biosimilar tendering between procurement organisations in the criteria included and applied for consideration of value-added services in tendering for biosimilars.

References are available at www.pharmafocusasia.com

AUTHOR BIO

Josep M Guiu Segura is a Hospital pharmacist. He is currently Head of pharmacotherapy at the Catalan Health and Social Care Consortium in Barcelona, Spain.

He is also adjunct lecturer of Clinical Pharmacy and Pharmacotherapy at the Faculty of Pharmacy and Food Sciences of the University of Barcelona. Since 2018, he is Vice-president for the European Region of the Hospital Pharmacy Section of FIP.

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PRODUCTS & SERVICES Company........................................................................Page No.

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

STRATEGY

CLINICAL TRIALS

Cantel Medical............................................................................ IFC

Hoong-A Corporation...................................................................09

Datwyler........................................................................................05

Quantys Clinical Pvt. Ltd...............................................................41

Hoong-A Corporation...................................................................09 Turkish Cargo............................................................................OBC

Rousselot................................................................................ 43-47 MANUFACTURING BioGenes GmbH...........................................................................39

RESEARCH & DEVELOPMENT

Cantel Medical............................................................................ IFC

BioGenes GmbH...........................................................................39

F. P. S. Food and Pharma Systems Srl............................. 11, 14-15

F. P. S. Food and Pharma Systems Srl............................. 11, 14-15

Hoong-A Corporation...................................................................09

Quantys Clinical Pvt. Ltd...............................................................41 SUEZ Water Technologies.............................................. IBC, 28-30 Syntegon.......................................................................................27

Rousselot................................................................................ 43-47 SUEZ Water Technologies.............................................. IBC, 28-30 Syntegon.......................................................................................27 Valsteam ADCA Engineering........................................................03

SUPPLIERS GUIDE Company........................................................................Page No.

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

BioGenes GmbH........................................................................ 39 www.biogenes.de

Quantys Clinical Pvt. Ltd............................................................ 41 www.quantysclinical.com

Cantel Medical......................................................................... IFC www.cantelmedical.com

Rousselot..............................................................................43-47 www.rousselot.com

Datwyler..................................................................................... 05 www.datwyler.com

SUEZ Water Technologies............................................IBC. 28-30 www.suezwatertechnologies.com/sievers

FedEx Express......................................................................62-63 www.fedex.com/sg/healthcare/index.html

Syntegon.................................................................................... 27 www.syntegon.com

F. P. S. Food and Pharma Systems Srl...........................11, 14-15 www.foodpharmasystems.com

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

Hoong-A Corporation................................................................ 09 www.ha1511.com

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

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1.IFC: Inside Front Cover, 2.IBC: Inside Back Cover, 3.OBC: Outside Back Cover

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