ISSUE 38
2020
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PATIENT ENROLMENT Doing it the phygital way Natural Intelligence True AI is a distant promise for marketers The Cyber-Physical Security of Pharmaceutical Manufacturing Processes
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Foreword Patient Enrolment Doing it the physical+digital way Clinical trials are imperative for testing drugs and therapies, advancing the science of care, and coming up with an effective treatment approach to enhance outcomes for patients. A major challenge that organisations engaged in clinical trials is patient enrolment and retention. According to Forte Research, a meagre 7 out of 100 known patients complete a trial successfully, while 18per cent of patients end up dropping out of the trial at various stages. There are several barriers that contribute to the persistently low rates of trial participation and dropouts and these include refusal to comply, financial, logistical concerns, lack of resources for both clinicians and patients. Digital disruption and artificial intelligence (AI) have powered the industry through every stage of drug development. AI has the potential to bring down clinical trial cycle time while enhancing the costs of productivity and improving outcomes. Leveraging predictive analytics and AI models can help increase the pace of understanding diseases, identifying patients and investigators for a new clinical study. A well-established digital infrastructure powered with AI algorithms paves way for continuous streaming of clinical data. This data can be aggregated, stored and managed for future requirements. When data is captured electronically, it minimises human errors and helps the investigators integrate with their databases seamlessly. A Deloitte report on the impact of AI on the biopharma value chain indicates that traditional approach to clinical development offers a 10 per cent success rate and rightly observes that it’s time for a transformation in clinical trials for increasing productivity. Biopharma companies have notably been able to access to real-world data, but with not much fruition due to lack of
skills and technologies for effective utilisation of the data. The Randomised Controlled Trials (RCT) approach was primarily designed for test massmarket drugs and continues to be the standard to validate the efficacy and safety of new drugs. As pharmaceutical companies continue their efforts to gather real-world data and evidence for providing value-based outcomes, patient engagement becomes a critical. Patient-centricity helps obtain real-time data. In order to move in this direction, all the key stakeholders will have to begin focusing on the patients’ needs and preferences. Also, the sponsors ought to develop open communication channels to share information with patient and seek perspectives, which would help engage patients and retain them throughout study. Digital has the potential to transform clinical development by reducing clinical cycle times, making clinical trials more cost-effective and drug development more productive. Biopharma companies would do well to partner with technology firms in deploying effective digital strategies for clinical development. The cover story of this issue talks about challenges around patient enrolment and retention for clinical trials. In this article, the author throws light on how technology can help bridge the digital world with physical to provide unique interactive experience for patients
Prasanthi Sadhu Editor
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STRATEGY 06 Natural Intelligence True AI is a distant promise for marketers
Brian D Smith, Principal Advisor, Pragmedic
RESEARCH & DEVELOPMENT
COVER STORY
CONTENTS
12 Ocular Drug Delivery Perspective Current challenges and opportunities
Reshal Suri, Pursuing PhD, Pharmaceutics, Jamia Hamdard
Sarwar Beg, Assistant Professor, Department of Pharmaceutics School of Pharmaceutical Education and Research Jamia Hamdard
Kanchan Kohli, Head, Department of Pharmaceutics School of Pharmaceutical Education and Research Jamia Hamdard
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Doing it the phygital way R B Smarta Chairman & MD, Interlink Marketing Consultancy Pvt. Ltd.
20 Multi-faceted Gateways for Drug Repurposing Need for an integrative approach
Saraswathy GR, Associate Professor, Department of Pharmacy Practice, Faculty of Pharmacy, Head of Pharmacological Modelling and Simulation Centre, Ramaiah University of Applied Sciences
V Lakshmi Prasanna Marise, Assistant Professor, Department of Pharmacy Practice, Faculty of Pharmacy, Member of Pharmacological Modelling and Simulation Centre Ramaiah University of Applied Sciences
34 Clinical Trials in a Petri Dish Closer to reality
Hema Sree, Doctoral Research Student Pharmacological Modelling and Simulation Centre Ramaiah University of Applied Sciences
Mamatha K, Assistant Professor, Department of Pharmacy Practice, Faculty of Pharmacy, Head of Pharmacological Modelling and Simulation Centre, Ramaiah University of Applied Sciences
MANUFACTURING
Rachana R Pai, Faculty of Pharmacy Ramaiah University of Applied Sciences
Swarna Mariam Jos, Faculty of Pharmacy Ramaiah University of Applied Sciences
46 Emerging Technologies for Particle Engineering Dilip M Parikh, President, DPharma Group Inc.
26 Nano-Based Drug Delivery Road towards cancer therapy management Dhruv Kumar, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University
30 Advanced Computational Drug Discovery Tools Through user friendly web servers
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CLINICAL TRIALS
Antonio J Banegas-Luna, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Universidad Católica San Antonio de Murcia (UCAM)
Maria Paredes-Ramos, PhD student, Metals in Environment and Medicine (METMED), Physical Chemistry Department,Universidad edaCoruña(UDC)
Marién M Moreno, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Universidad Católica San Antonio de Murcia (UCAM)
Josefina M Vegara-Meseguer, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Higher Polytechnic School, Universidad Católica San Antonio de Murcia (UCAM)
Horacio Pérez-Sánchez, Principal Investigator, Bioinformatics and High Performance Computing Research Group (BIO-HPC) Universidad Católica San Antonio de Murcia (UCAM)
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Subhadra Dravida, CEO, Transcell Oncologics
52 Intraperitoneal Sustained - Release Chemotherapy for Refractory Ovarian Cancer Smrithi Padmakumar, Post-Doctoral Researcher Department of Pharmaceutical Sciences School of Pharmacy Northeastern University
Deepthy Menon, Professor, Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences
Mansoor Amiji, Professor, Pharmaceutical Sciences, and Professor, Chemical Engineering, Northeastern University
INFORMATION TECHNOLOGY 57 The cyber-physical security of pharmaceutical manufacturing processes
Ravendra Singh, Engineering Research Center for Structured Organic Particulate Systems (ERC-SOPS), Department of Chemical and Biochemical Engineering, Rutgers The State University of New Jersey
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Advisory Board
EDITOR Prasanthi Sadhu Alan S Louie Research Director, Life Sciences IDC Health Insights, USA
EDITORIAL TEAM Debi Jones Grace Jones ART DIRECTOR M Abdul Hannan
Christopher-Paul Milne Director, Research and Research Associate Professor Tufts Center for the Study of Drug Development, US
PRODUCT MANAGER Jeff Kenney
Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA
SENIOR PRODUCT ASSOCIATES David Nelson Peter Thomas Sussane Vincent
Frank Jaeger Regional Sales Manager, AbbVie, US
PRODUCT ASSOCIATES Austin Paul Jessie Vincent 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
Kenneth I Kaitin Professor of Medicine and Director Tufts Center for the Study of Drug Development Tufts University School of Medicine, US
SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam HEAD-OPERATIONS S V Nageswara Rao
Laurence Flint Pediatrician and Independent Consultant Greater New York City
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Neil J Campbell Chairman, CEO and Founder Celios Corporation, USA Phil Kaminsky Professor, Executive Associate Dean, College of Engineering, Ph.D. Northwestern University, Industrial Engineering and the Management Sciences, USA
Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US
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STRATEGY
Natural Intelligence
True AI is a distant promise for marketers Despite all the current hype, Artificial Intelligence (AI) is in its infancy in the commercial part of the pharma value chain. Its benefits are in the distance and, for the foreseeable future, available only to special cases where there is lots of freely available data to work with. And this focus on AI can blind us to the hugely valuable resource that almost all life science companies have at their fingertips, their Natural Intelligence. Natural Intelligence (NI) is the ability to take the information we already have and synthesise it to create compelling and commercially valuable market insight on which to build our strategy. Brian D Smith, Principal Advisor, Pragmedic
D
espite the hype, the routine use of AI in marketing in the life sciences is a long way away. Much of what is sold as AI is, in fact, just old-fashioned analytics that, whilst useful, is not novel. True AI is already making some contribution in areas such
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as drug discovery, where it can be applied to large data sets. But in marketing, where the problems are sociological rather than technological, and data are often Superfluous comma hysteria around AI is more of a distraction than a benefit. In particular, the bubble around AI often
draws attention away from the value that can be added without big data, massive processing power or expensive consultants. For most marketers in pharma and medtech, there is a more practical approach. Millions of years of evolution have gifted life science marketers with
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STRATEGY
FOUR STEPS OF DEDUCTIVE INTELLIGENCE 1. Identify some critical assumption upon which your strategy depends but for which you do not have strong evidence 2. Create a conflicting pair of hypotheses from that assumption (see example) 3. Use readily available data to test the hypotheses 4. Depending on which hypothesis is supported, either confirm, revise or refute your critical assumption Figure 1
the best information processors in the universe. It is sitting between our ears, if we know how to use it. My research work concerns how life science companies are evolving, with a particular interest in their commercial models. My observations of how the best life science companies approach strategic marketing planning reveals that the best results come from the application not of novel techniques but from what we might instead call NI. There seem to be three broad approaches to the use of NI in marketing. These are easily applied, using existing or readily available information, and they provide enormously valuable insights to guide strategy and create competitive advantage. Their simplicity might make them seem obvious to you but they are not used by most life science marketers and they are a source of relative competitive advantage. Consider the examples below and how you might apply them to your strategic marketing planning. Deductive intelligence
Deductive intelligence is the bedrock of the physical and natural sciences, but life science marketers make relatively little use of it. It involves four steps (Figure 1). For example, you might strongly believe that your sales are suffering because of the high price of your product, relative to a competitor. Acting on this assumption might require price discounting or the costs of enhancing the product. Before
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you do so, develop a pair of conflicting hypotheses from your strongly held assumption. For example: H0 If price is an issue, market share should be the same or similar in all sales regions H1 If price is not the issue, market share should vary significantly between sales regions These hypotheses can of course be tested by looking at regional sales data. If market share is reduced evenly across regions, then your assumption about price is probably, although not necessarily, correct. If however market share is low in some regions and high in others,then you should consider another explanation, such as sales team skills or customer segmentation varying by region. If the hypothesis testing leads to another belief, then that can be tested in the same way. In either case, using deductive intelligence
to test assumptions means plans are built on better information. Abductive intelligence
Abductive intelligence Is especially useful for ‘seeing the wood for the trees’ problems. It has six steps (Figure 2). For example, you might want to understand why the uptake of an innovative product is slower than expected. You and your colleagues may have a number of alternative explanations ranging from price, to performance to slow customer decision making. Based on those untested explanations, it is relatively easy to carry out, for example, interviews with a representative set of customers. Importantly, the interview questions should be open (“Tell me about how you decide to adopt new products like X”) not closed (“Is the price putting you off adopting X?”). You can then develop a categorisation scheme based on the alternative explanations. For example, you might categorise all mentions of price concern as ‘price problems’ and all mentions around internal discussions as ‘Internal decision making’. Analysing the interviews to see which categories are found in the data, you can look for emerging themes, such as how often price is mentioned directly or indirectly, or how often different aspects of internal politics are mentioned. You can then assess the strength and frequency of themes and use that to decide which of the alternative explanations seems to best fit with the emergent themes.
SIX STEPS OF ABDUCTIVE INTELLIGENCE 1. Consider a business issue that is especially important to you 2. Develop several alternative explanations for that business issue 3. Gather qualitative data that relates to the issue 4. Develop thematic categories from the alternative explanations 5. Perform thematic analysis on the data 6. Select whichever alternative explanation best fits the thematic analysis Figure 2
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EIGHT STEPS TO INDUCTIVE INTELLIGENCE 1. Consider a business issue that is especially important to you 2. Gather qualitative data that relates to the issue 3. Read the data carefully to get a sense of what themes it contains 4. Develop thematic categories from that reading 5. Perform thematic analysis on the data 6. Add any new thematic categories that emerge during categorisation 7. Repeat the thematic analysis until the data is fully categorised 8. Use the thematic analysis to develop an understanding of the business issue Figure 3
One of the putative explanations may emerge as very well supported, or more than one explanation might contribute to the slow uptake of the product. Whatever the case, the outcome informs how you might resolve the business issue and accelerate uptake. Inductive intelligence
Inductive intelligence is used to generate completely new information, rather than test what we think we know. It has some similarities with abductive intelligence but has 8 steps (Figure 3). For example, you might want to understand why patient adherence to a treatment regime is so poor but have no clear idea why this might be. Without hypothesising or suggesting explanations, you could carry out, for example, interviews with a patients, prescribers and carers. Again, the interview questions should be open (‘Tell me about taking your medicine’) not closed (‘Are the injections putting you off taking your medicine?’). Then, and again without hypothesising or trying to think of alternative explanations, you can read and re-read the interviews several times. From this reading, several explanations of non-adherence emerge and these can be used as categories, as in abductive intelligence. The interviews are then analysed for phrases using the emergent categories.
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However, as this analysis takes be added place, new categories might emerge and added to the analysis framework. The interviews should be repeatedly analysed until most of the interview transcript is categorised with either the original or newly emergent categories and no possible explanation of non-adherence is left uncategorised. The strongest and most frequent of these categories then leads to one or more explanations of the business issue, in this case non-adherence, even when none was initially apparent. This new explanation informs how patient adherence, and therefore outcomes, might be improved. Thinking tools
As the philosopher Daniel Dennett put it, a carpenter can’t do much woodwork without woodworking tools and we can’t do much thinking without thinking tools. In the same way, a life science
marketer can’t make strong strategy without these three strategic thinking methods. The three methods are both alternatives and complements. Each has their own place in the process for understanding the business situation but they can also be used together. Deductive intelligence is especially useful when one begins with an unsupported belief and wants to get to a stronger, more supported planning assumption. It is the alternative to acting on “gut feel” and reducing the strategic marketing plan to an expensive experiment. Abductive intelligence comes into play when the there is disagreement in the team and several alternative views are competing to drive the strategy. It is the alternative to allowing the loudest voice or most powerful person dictate the strategy. Inductive intelligence is at its best in new situations or when the team does not have much experience of the market. It is the alternative to assuming that this market behaves like other, more familiar markets when there is no evidence that it does. And of course the three kinds of intelligence are complementary. For example, inductive intelligence might generate multiple explanations of, say, the mental algorithm that prescribers use to choose what to prescribe. These can be narrowed down by abductive intelligence to the most likely explanation. The final, most likely, explanation can then be tested using deductive intelligence. The end result is that natural intelligence, usually using existing or readily available data, produces knowledge that is a better foundation for strategic marketing planning. This means that the strategic plan has a higher probability of meeting its goals, which is, ultimately, the test of a marketing strategy. AUTHOR BIO Brian D Smith is a world-recognised authority on the evolution of the life sciences industry. He welcomes comments and questions at brian. smith@pragmedic.com
RESEARCH & DEVELOPMENT
OCULAR DRUG DELIVERY PERSPECTIVE CURRENT CHALLENGES AND OPPORTUNITIES
Efficient drug delivery to eye remains a major challenge for the pharmaceutical researchers worldwide due to the number of barriers offered by this sensitive organ namely, static barriers dynamic barriers and metabolic barriers. Bypassing these barriers to reach the target site is the key to optimal therapeutic effect of ocular drugs. As the anatomy and physiology of each barrier is unique the ways to bypass them should also be different. This review summarises the various challenges and newer trends in the ocular drug delivery. Reshal Suri, Pursuing PhD, Pharmaceutics, Jamia Hamdard Sarwar Beg, Assistant Professor, Department of Pharmaceutics School of Pharmaceutical Education and Research, Jamia Hamdard Kanchan Kohli, Head, Department of Pharmaceutics School of Pharmaceutical Education and Research, Jamia Hamdard
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A
s per the estimation of a Forbes analysis (2013), around US$5 billion is spent by large pharmaceutical companiesfor a single drug approval. Despite immense increase in the research expenditure and number of compounds in the development phase, the rate of approval of these compounds is fairly less due to the lack of drug efficacy. This innovation drought is also a major concern of ophthalmic care
RESEARCH & DEVELOPMENT
market. Though anti-VEGF therapies in wet AMD and Xalatan (latanoprost) for glaucoma have been a breakthrough discovery, yet effective and tolerable treatments are not available for a large number of ocular diseases. Expiry of patents in addition to failure of new proprietary drugs launch indicates significant impact of generics on the therapeutics market. Even though new drugs have high market potential, stringent regulatory requirements pose hurdles at late stage of clinical development. Therefore, fine-tuning and improvement of existing products is highly desired rather than the development of a whole new class of ophthalmic drugs. To achieve this, knowledge about pathophysiology of ocular diseases and limitations of current therapies is the need of hour but before that a thorough understanding about the anatomy and physiology of eye is crucial to design and develop an effective/safe dosage form. The unique environment of eye can offer major barrier to drug delivery. This review summarises various challenges and opportunities in ophthalmic drug delivery.
Current challenges in ocular delivery Unique ocular environment:
A significant challenge faced by the formulators and research scientists worldwide is bypassing the protective barriers of the eye without causing any damage to the ocular tissues. These static (biological), dynamic and metabolic barriers result in poor bioavailability of topically administered drugs (Figure 1). Also, high efficiency of the blood-retinal barrier (BRB) makes it difficult for the therapeutics to reach the posterior segment which is compromised in retinal degenerative disorders. Maintaining therapeutic drug concentration over prolonged periods in the eye is yet another challenge. Furthermore, the disorders of lacrimal secretion and treatment of lacrimal gland are still not so explored areas. The presence of melanin in uvea and retinal pigmented epithelium (RPE) also lowers the pharmacological activity of the therapeutic agent, necessitating the administration of higher amount of doses. Figure 1
Choice of route of administration:
Though topical route is a non-invasive and highly patient compliant route, nasolacrimal drainage, high tear dilution, efux pump and the corneal barrier limits the drug bioavailability. Additionally, it is inefficient for the disorders of the posterior segment. Intravitreal route on the other hand is suitable for posterior segment drug delivery but is invasive in nature with many complications (vitreous haemorrhage, retinal detachment, and endophthalmitis). Alternative route like Periocular is favuorable for controlled drug delivery for a long period of time but presence of retinal pigment epithelium offers an obstacle. Systemic route of drug delivery has good patient acceptance but encounters the blood-ocular barriers and the need of high dosing resulting in systemic toxicity often makes it unsuitable. Physicochemical drug properties:
Certain drug properties such as lipophilicity, molecular weight, molecular size and shape, charge, solubility, and degree of ionisation significantly influence the
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RESEARCH & DEVELOPMENT
• Startified corneal epithelium
• Tear turnover
• Corneal stroma
• Reflex blinking
• Sclera
• Nasolacrimal drainage
• Conjuctiva Static Barriers
Metabollic Barriers
• Phasel I & II enzymes • Efflux Pumps
Dynamic Barriers
Intraocular Environment • Blood-aqueous Barrier (BAB) • Blood-retina Barrier (BRB)
Figure 1: Fundamental ocular barriers as a major challenge for ocular delivery of the drugs (adapted with permission from Suri et al. 2009);
route and rate of permeation across the ocular membranes. Therefore, amphipathic nature of the molecule is desired for permeation through the ocular layers. Predictive animal models:
Animal models that more accurately simulate human ocular disease gives better drug efficacy results, define model therapeutic mechanisms of action and suggest optimal target receptor in a cost-effective manner before the expensive clinical trials are carried on. Due to the lack of availability of suitable animal models, selection of drug for clinical investigations and further human disease study is often limited. A greater challenge is posed in case of diseases like Thyroid Eye Disease which is resistant to modelling in animals1. Overlapping clinical resemblance of diseases:
It has been observed that due to superficial clinical resemblance, a number of conditions are grouped together which are a result of different etiological process and thus demand different therapeutic strategies. For example, in ocular inflammatory diseases, many forms of uveitis are ‘lumped together’ in the same clinical trial that require different outcome measures, may be due to poorly defined
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disease phenotype, poor understanding of pathogenesis or lack of clear diagnostic markers etc. Moreover, if the investigators increase the size of trial, due to the low ‘signal-noise’ ratio the chances to identify a successful treatment decrease1. Prediction of Outcome measures:
Outcome measures, mostly non-invasive like visual acuity, or intraocular pressure that have good patient acceptability and early detection, are key factor for ophthalmic studies. The problem occurs when outcome measures are subjective (whether reported by the patient or the clinician), imprecise and not fully quantitative. Key opportunities in ocular drug delivery
The isolated environment of eye gives great opportunity to treat the ocular diseases with potentially no systemic side effects. Different target strategies are thus employed by the formulation scientists and researchers globally in order to design and develop an effective and patient acceptable drug delivery system that transport the drug to the target area bypassing different ocular barriers. Conventional ocular formulations like solutions, emulsions, suspensions, and ointments still retain their place in
the ophthalmic market at large due to their improved solubility, pre-corneal residence time and ocular bioavailability of drugs. Much efforts are also being made to deliver the therapeutics to the posterior segment of the eye with these conventional carriers. However, various associated side effects such as ocular irritation, vision interference, inflammation, redness and stability issues demand further research to improve the in vivo performance of these formulations and to minimise their side effects. Cyclodextrins, permeation enhancers (surface active agents, chelating agents, bile salts) and viscosity enhancers (hydroxy ethyl cellulose, sodium carboxy methyl cellulose, hydroxypropyl methyl cellulose, polyalcohol) improve the corneal uptake, permeation, drug contact time and ocular bioavailability. Marketed ocular emulsions in the United States includes Restasise™, Refresh Endura® and AzaSite®. Also, high viscosity of Tobra Dex® suspension was improved to give (TobraDex ST®) with better formulation characteristics and in vivo pharmacokinetics along with bactericidal activity. Despite considerable efforts being made to optimise conventional formulations, to overcome their drawbacks, research horizons are expanding in the field of nanotechnology. Novel strategies (appropriate particle size) are designed to deliver therapeutics to the target ocular tissue in both anterior and posterior segment, with low irritation, adequate bioavailability, and ocular tissue compatibility in a controlled/sustained manner. Several nanocarriers, such as nanoparticles, liposomes, nanomicelles and dendrimers have been developed for drug delivery to eye. The dendrimer have a unique structure that increases water-solubility of drugs and enhance corneal residence time of topically administered therapeutic agents. Biocompatible vesicular systems like liposomes are widely used to deliver both hydrophilic and hydrophobic drugs to the eye but are not completely devoid of the drawbacks. Thus, liposomes have been
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opportunity to target the therapeutics to these transporters in-turn increase their levels and therefore decrease the dose required. A more recent approach has been taken into account by Neurotech to develop an Encapsulated Cell Technology (ECT) implant that consist of genetically engineered cell lines to continuously deliver therapeutic proteins directly into the vitreous for up to two years. Conclusion
Regardless of various challenges in ocular drug delivery, newer products are continuously entering the ophthalmology market owing to its market size. The focus should be directed towards the design and development of a noninvasive, easy to use, sustained drug release system for eye disorders in both the segments with minimum side-effects. This would be possible only if the understanding and knowledge about
AUTHOR BIO
modified by the use of polyol or coating with chitosan, in order to overcome the problems of stability (aggregation), leakage of drugs, low encapsulation efficiency and improve the residence time in the cornea. Nanomicelles (Polymeric, Surfactants and Polyionic complex micelles) are also utilised in ocular drug delivery due to the advantages like easy permeation through the ocular epithelium, minimal drug degradation, enhanced bioavailability and no irritation. Biodegradable implants like Ozurdex® and Surodex® and contact lens are also used largely to deliver drugs to the eye. Additionally, for the treatment of posterior segment diseases, non-invasive methods like microneedle, ultrasound, and iontophoresis-based ocular drug delivery systems are employed to deliver drugs to intraocular regions. Corneal permeability of atenolol, carteolol, timolol and betaxolol, has been significantly enhanced with ultrasound. Transcorneal iontophoresis of ciprofloxacin hydrochloride and gentamicin have also gained much attention. Advanced ocular iontophoresis device has been developed by EyeGate. Currently, biocompatible devices like Punctum plugs/occludes or lacrimal plugs are developed that are inserted in the tear ducts to block tear drainage. These are non-invasive and provide controlled drug release to the anterior segment of the eye. Non-biodegradable Punctum Pug Delivery System (PPDS) are made from silicone, polycaprolactum and hydroxyethyl methacrylate. Some of the examples includes SmartPlug®, Ocular TheraputixTM (Bedford, MA, USA) and Dextenxa®. Furthermore, for the delivery to posterior segment, technologies like DurasertTM, NovadurTM and I-vationTM have been investigated upon. To overcome the problems of insufficient solubility and transport of the therapeutics, prodrug technology is utilised, for example, acyclovir dipeptide prodrugs have been synthesised in order to target the oligopeptide transporter hPEPT1 on the cornea. Similarly, expression of transporters on various ocular tissues like cornea, conjunctiva and RPE gives us an
the complexities associated with normal and pathological conditions, anatomical and physiological barriers, apt animal modelling and drug pharmacokinetics is increased. A combination of technologies may provide successful outcomes. The persistent challenge faced by the ophthalmic care is the ageing of the eye. Increased prevalence of ocular diseases, especially posterior segment diseases in the ageing populations gives us an opportunity and motivation for further innovation. Global ophthalmic therapeutic market is growing at two-and-a-half times the rate of the overall pharmaceutical industry and is expected to grow exponentially in the near future with many commercial benefits (high revenues) of ophthalmic drugs if the research is directed in the right direction. References are available at www.pharmafocusasia.com
Reshal Suri is currently pursuing PhD, Pharmaceutics from Jamia Hamdard, New Delhi under the guidance of Prof. Kanchan Kohli, Head, Department of Pharmaceutics, Jamia Hamdard. She is a proud recipient of Senior Research Fellowship from Indian Council of Medical Research (ICMR), New Delhi. She has completed her graduation from DIPSAR, New Delhi in 2015 and Post-graduation in Pharmaceutics from Jamia Hamdard in 2017. She has qualified GPAT exam conducted by AICTE with All India Rank 91 in 2015. She has presented various papers in different National and International conferences/seminars. Sarwar Beg is currently Assistant Professor at Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi. He has 8 years of teaching and research experience in the field of pharmaceutics and biopharmaceutics, especially in the development of novel and nanostructured drug delivery systems employing Quality by Design paradigms. Prior to joining Jamia Hamdard, Dr Beg was working as Research Scientist at Jubilant Generics Limited, Noida. He has authored over 150 publications, 45 book chapters, 12 books and 03 Indian patent applications, along with Google Scholar H-Index of 27 and over 2800 citations to his credit. Kanchan Kohli is currently the Head, Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi. She has over three decades of teaching and research experience in the field of pharmaceutics, especially in the development of varied dosage forms and cosmetic products. Kohli has authored over 190 publications, 08 book chapters, 12 Indian patent applications and 01 granted US patent, along with Google Scholar H-Index of 37 and over 5831 citations to her credit. She has attended several national and international conferences and bestowed with several prestigious awards from UGC, AICTE, PCI, IPA and APTI.
MEDICAL MANUFACTURING ASIA 2020
Strategic platform for medical technology solutions Mark your calendar for the 5th Manufacturing Processes for Medical Technology Exhibition and Conference from 9 to 11 September 2020
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T
he Asian medical market is booming. According to management consulting firm, McKinsey & Company, the company predicts that Asia will account for a third of global sales by 2025. In the ASEAN countries, with its population of over 600 million people and a GDP of 2.76 trillion U.S. dollars, there is a rapid growth of the middle class
and expansion in healthcare coverage. Both of which are factors driving the use of medical devices across Southeast Asia. Such products are likely to see growth of between 8 to 10 percent in most markets, led by the consumables, diagnostic imaging and lab devices segments. As a specialist exhibition on manufacturing processes for medical technology, the 5th edition of MEDICAL MANUFACTURING ASI Amakes a return to Singapore as the region's leading specialist trade fair for Asia's MedTech and medical manufacturing processes sectors. Jointly organised by SPETA and Messe Düsseldorf Asia, MEDICAL MANUFACTURING ASIA 2020 will feature an extensive product range covering the upstream and downstream processes in MedTech sectors, including new materials, components, intermediate products, packaging and services, to micro and nanotechnology, testing systems and services, as well as materials, substance and components for medical technology.
Singapore: The heart of MedTech in Asia As Singapore continues to grow as a competitive economic hub for the region in terms of, ease of doing business, best labour force, strong IP protection and robust logistics infrastructure, it has also presented itself as a competitive MedTech manufacturing hub. The 3-day exhibition therefore strongly reflects Singapore’s focus on moving upstream to not just production but also value engineering. For companies keen on engaging global MedTech companies and see Singapore as an ideal base to develop products for the Asian region, MEDICAL MANUFACTURING ASIA 2020 provides a highly relevant springboard. This sentiment is also seen in Singapore’s continued growth in manufacturing, where MedTech output has grown annually by 11 per cent versus 6.3 per cent in general manufacturing for the past 5 years. Backing this is Singapore’s strong supplier base – with 6 of the world’s Top 10 EMS companies undertaking activities from the entire value chain, in medical imaging equipment, analytical lab instruments, medical consumables, patient care devices and diagnostics equipment in the Lion City and the government’s commitment to R&D capabilities, having set aside US$ 19 billion for Research, Innovation and Enterprise (RIE) activities. Singapore is also home to a growing community of start-ups thanks to the availability of public funding and a favourable infrastructure for early stage innovation.
Against this industry landscape, MEDICAL MANUFACTURING ASIA 2020 continues to attract a highly international exhibitor base coming mainly from Asia and Europe and a trade visitor base that is predominantly represented by the medical devices and instruments, medical and healthcare, and electrical and electronic sectors from around the region.
Industry-focused, knowledge-based business conferences and forums
Headlining MEDICAL MANUFACTURING ASIA 2020 areindustry-relevant conferences and forums including: High-Tech for Medical Devices 9 Sep 2020 | 1pm to 5pm Forum Stage, Hall F, Basement 2 Organised by IVAM Microtechnology Network, the forum will bring together leading companies in the specialised fields of the micro- and nanotechnology sectors, providing insights on the latest innovations and share best practices through presentations. Main topics covered are: Modules and components for medical technology, Lab-on-a-chip technology, Inspection equipment and testing services, Assembly, automation and production technology, Process technology, Biocompatible materials, Sensors and more. Medtech in Focus Seminar 10 Sep 2020 | 1pm to 5pm Forum Stage, Hall F, Basement 2 Jointly organised by SPETA and Messe Düsseldorf Asia, this seminar will bring together industry experts, government, academics and trade professionals to discuss the latest trends and challenges in redefining modern manufacturing in the Medtech industry. MEDICAL MANUFACTURING ASIA 2020 is also synergistically co-located with the region’s leading medical and healthcare exhibition, MEDICAL FAIR ASIA – thus providing an end-to-end solutions and business sourcing platform across the entire value chain for the medical, healthcare, medical manufacturing and medtech sectors. Both MEDICAL FAIR ASIA and MEDICAL MANUFACTURING ASIA 2020 are part of the MEDICAlliance’s network of trade fairs – sharing the global expertise of MEDICA, REHACARE and COMPAMED – by the Messe Düsseldorf Group in Germany. For booth space booking and more information on MEDICAL MANUFACTURING ASIA 2020, please visit www.medmanufacturing-asia.com. Advertorial www.pharmafocusasia.com
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MULTI-FACETED GATEWAYS FOR DRUG REPURPOSING Need for an integrative approach
Traditional drug discovery process is perturbed with high attrition rates, necessitating a paradigm shift towards drug repurposing, a contemporary research gaining paramount importance in reconnoitering new indications for existing drugs. This article focusses on application of multi-dimensional cutting edge technologies in accomplishing a successful drug repurposing endeavour. Saraswathy GR, Associate Professor, Department of Pharmacy Practice, Faculty of Pharmacy, Head of Pharmacological Modelling and Simulation Centre, Ramaiah University of Applied Sciences V Lakshmi Prasanna Marise, Assistant Professor, Department of Pharmacy Practice, Faculty of Pharmacy, Member of Pharmacological Modelling and Simulation Centre Ramaiah University of Applied Sciences Hema Sree, Doctoral Research Student, Pharmacological Modelling and Simulation Centre, Ramaiah University of Applied Sciences Mamatha K, Assistant Professor, Department of Pharmacy Practice, Faculty of Pharmacy, Head of Pharmacological Modelling and Simulation Centre, Ramaiah University of Applied Sciences Rachana R Pai, Faculty of Pharmacy Ramaiah University of Applied Sciences Swarna Mariam Jos, Faculty of Pharmacy Ramaiah University of Applied Sciences
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C
onventional drug discovery path is arduous, timeconsuming, and demands massive fiscal investments. Despite all the efforts put forth during gross drug development processes, newer drug molecules entering clinical trials either lack therapeutic efficacy or demonstrate erratic safety profiles that result in dwindling approval rates for new drug applications and revocation from the market, if already in use. Furthermore, emergence of new diseases along with growing population, dearth of promising therapeutic regimens for neglected tropical diseases and orphan disorders, pandemic, and epidemic infectious outbreaks combined with accelerated drug-resistance, tachyphylaxis, adverse effects, and idiosyncratic reactions are immensely pressurising pharmaceutical companies to design, discover and bring about authentic, safe, and effective drugs to the market in a prudential manner. To cater these never ending therapeutic requirements, a paradigm shift towards drug repurposing (DR), which is deep-rooted in polypharmacology background, is of paramount importance (Figure 1). DR, a present day trend to identify new indications for pre-approved or banned drugs, furnishes an equivalent or superior outcome over the conventional de novo methods. This conspicuous strategy has achieved notable impetus over the last decade. The evolution of DR over years from its humble serendipitous start to the space-age incorporation of artificial intelligence is an enticing feat. Recent updates on multifaceted approaches for DR and the work flow from a conceptual note to approval from regulatory agencies are depicted in Figure 2.
RESEARCH & DEVELOPMENT
From genes to repurposed drugs, the story of genomics
Genomics is a fascinating omics science that entwines structural and functional genomics with genetic elements. Excavating the gene expressions using genomic insights offer colossal support for discovering novel therapeutic disease targets for DR. Stephen Wan Leung et al., mined Cancer Cell Line Encyclopedia and The Cancer Genome Atlas data and predicted over-expression of HMGA2 (High Mobility Group AT-Hook 2) in Colorectal Cancer(CC). Subsequent microarray profiling of gene signatures exposed the druggable vulnerability of S100 calcium-binding protein A4 (S100A4) corresponding to the aforesaid gene. Later Connectivity Map (CMap) analysis revealed inhibition of S100A4 can reverse the expression of HMGA2. This analysis identified Niclosamide, an anti-helminthic drug, as a potential
suppressor of S100A4 for CC by intervening WNT signaling pathways, which was later validated through in-vitro and in-vivo analysis. Protein structures to reveal novel treatment options through proteomics
Proteomics portrays the total protein content of a cell, tissue, or organism and investigates protein-protein and protein-nucleic acid interactions that play a key role in regulating protein functions. They provide crucial data on role of a single protein in multiple pathways that might trigger multiple signalling mechanisms which might be involved in disease pathogenesis and side effects of drugs. These complex details reinforce the rationale for implementing proteomic approaches in DR. Pei-Feng Liu et al., retrieved 1312 approved drugs from the US Food & Drug Administration (FDA) via
DISEASE - 3 DRUG-1+2
Physiological Process
Metabolic Process
virtual screening against ATG4B, an autophagic protein. These drugs were clustered and subjected to molecular dynamics (MD) and binding energy calculations. This resulted in 22 drugs, of which, Tolfenamic acid, Mefenamic acid, Ticonazole, and Entacapone were found to inhibit ATG4. Ticonazole was reported to possess the highest inhibition. Further, in-vitro evaluation of Ticonazole also exhibited diminished autophagic activity, cell viability and synergised the cytotoxic effects of starvation in cancer cells. Ticonazole-treated mice in-vivo reduced the xenograft tumour volumes. Novel drug targets, a gift of gene expression conveyed through Transcriptomics
Transcriptomics describes RNA transcription by genome and illuminates the responses of individual genome against functional and environmental perturbations. This is essential for elucidating
DISEASE - 2 Regulatory Process
Cellular Signal Process
DRUG-2
DRUG-1
DISEASE - 1
Figure 1: The above image depicts the concept of polypharmacology which is the basis of drug repurposing. Polypharmacology introduces the theory of drug activity on a single protein which may be involved in multiple pathways such as cellular signalling, regulatory process, physiological process and metabolic processes. As presented in the image, Drug 1 is an FDA approved drug indicated for a disease resulting from the disrupted functioning of a protein in cellular signalling mechanism. Drug 2 is another FDA approved drug for a disease occurring as a repercussion of imbalances in regulatory process of the same protein. Therefore, a disease caused due to distortion of physiological process fostered by this protein may be corrected by Drug 1 and/or Drug 2. www.pharmafocusasia.com
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DATA ACQUISITION AND INTEGRATION Signature Based
Target Based
Drug Based
• Genomics • Transcriptomics • Epigenetics
• Proteomics • Metabolomics • Side Effects
• Structural Similarity • Literature Mining • Electronic Hralth Records
Drug-Drug
Drug-Target
Drug-Gene
Drug-Disease
Disease-Gene
Construction of Drug-Gene-Target-Disease Network
Artificial Intelligence & Machine Learning
Computational Biology
• Neural Networks • Partial Least Square • K Nearest Neighbourhood • Support Vector Machine • Multiple Linear regression
• Pharmacophore Modelling • Molecular Docking • Molecular Dynamics • Homology Modelling
In-vitro validation
In-vivo validation Figure 2: From the virtual world to the real world: The expedition of drug repurposing
the complex mechanisms underlying disease pathogenesis, thereby, assisting in identification of potential disease targets. This approach has paved way for DR research. Nasir Mirza et al., retrieved transcriptomic signatures of chronic temporal lobe epilepsy from a mouse model and used it as query in ‘The Library of Integrated Network-Based Cellular Signatures’ to identify drugs capable of reversing these signatures. The search resulted in 123 compounds, of which, 36 were shortlisted 22
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Clinical Trials FDA Approval
for Drug set Enrichment Analysis. This identified five drugs that share similar pathways. Sitagliptin, a well-tolerated anti-diabetic drug was one amongst the five. Ultimately, in-vivo validation of Sitagliptin exhibited antiepileptic activity at 500 mg/kg dose. Uncovering the realm of novel therapeutic possibilities by the assistance of epigenomics
Epigenomics evaluates the induction of abnormal alterations in the phenotypic
characteristics by external factors (age, lifestyle and environment or disease state) via DNA methylation, non-coding RNA associated gene silencing, and/or his tone modification, without genetic sequence mutations. This is emerging as an unconventional path for DR. Paulami Chatterjee et al., obtained 54 Alzheimer’s Disease (AD) related epigenetic genes from Human Protein Reference Database, BioGRID and MENTHA. A curated list of genes was assessed for Epigenetic Protein-Protein
RESEARCH & DEVELOPMENT
Interactions (PPI) and significant proteins extracted from PPI were used to retrieve drugs from Drugbank to construct DrugTarget Network. This resulted in 1,920 drug-target interactions between 886 drugs and 419 proteins. Ultimately, Aspirin, Tamoxifen, Caffeine, Sorafenib, Glyburide, Spironolactone, Methotrexate, Diclofenac, Lamivudine, Ibuprofen and Etoposide were identified as repurposable drugs. Metabolomics: Using cellular metabolites to unveil therapeutic advances
Metabolomics involves commissioning of sophisticated instrumentation techniques to determine alterations in the concentration of metabolites or metabolic profiles for individual patients. This data on aberrant pathways offers clues to explore novel targets to redirect existing drugs towards DR. BesteTuranli et al., retrieved 8558 genes overlapped between transcriptomic
and proteomic data, 3328 proteomespecific and 2892 transcriptome-specific genes from NCBI GDC and Human Protein Atlas for Genome-scale Metabolic Model creation. Network analysis was carried out with Integrative Network Inference for Tissues algorithm by exploiting iCancer model to identify metabolic reactions specific to Prostate Cancer (PC). This resulted in 2655 genes, 6718 reactions, 86 up regulated and 76 down regulated PC metabolites. Amongst the total, 23 genes were involved in steroid biosynthesis pathways. Subsequently, network mapping via Differential Rank Conservation analysis revealed dominance of lipid and riboflavin metabolism, pentose phosphate pathway, and thyroid cancer in tumour samples. Later, CMap2 was employed to investigate 81 repurposable drugs. Ultimately, Sulfamethoxypyridazine, Azlocillin, Hydroflumethiazide, and Ifenprodil were found to possess significant potential to ameliorate PC.
Structural Similarity: Know the structure and unveil the trait
This approach assumes structurally similar drugs to possess similar pharmacological actions. The hypothesis thus generated focuses on forecasting plausible opportunities to carryout DR research. Various computational approaches like 3D fingerprints, pharmacophore similarity, scaffold similarity etc., have been developed to explore potentially repurposable candidates. Nikhil Pathak et al., screened the compound library comprising 187,740 from ZINC database against four dengue NS3 proteases. Top 3000 compounds were ranked by considering binding energies and pose scores. Based on interaction profiles, pharmacophore anchors were modelled and core pharmacophore anchors were identified by aligning all pharmacophore anchors for each NS3 protease. This protocol was validated by performing molecular docking with known respective inhibitors against each
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Therapeutic Possibility was computed to derive drug-phenotype relationships. The resultant hypothesis elucidated DR potential of (i) Fenofibrate, Losartan, Valsartan and Spironolactone for prostate cancer; (ii) Cimetidine, Dacarbazine, Ezetimibe, Flurbiprofen and Lovastatin for Myelogenous Leukemia; (iii) Chloroquine, Estradiol, Metformin and Propofol for Melanoma; (iv) Sulindac, Tadalafil, Metoprolol and Niclosamide for Bladder cancer; and (v) Chloroquine, Naltrexone and Ritonavir for Cerebro-vascular disease.
Electronic Health Records: A massive collection of patients’ data directed towards innovative DR
Real world data on a patient’s encounter with any health care delivery system is documented in electronic health records (EHR). It accumulates patient’s demographics, past medical and medication history, family history, diagnosis, laboratory data along with therapeutic regimens. This common data when extracted using relevant retrieving strategies like natural language processing (NLP) technique shall appraise the unstructured data stored in EHR. Further, this technique if streamlined towards identifying new drug indications serendipitously, serves as an unparalleled approach towardsDR. Hyojung Paik et al., extracted EHR of 530 K patients and 8693 K drug prescriptions from a tertiary hospital. A novel algorithm “Clinical and Genomics signature-based prediction for Drug Repositioning” was constructed by calculating drug-drug similarity and disease-disease similarity matrices, using Wilcoxon sum test, before and NS3 protease. Finally, interaction energies were analysed for each anchor and top 100 docking poses were integrated to screen 1384 FDA approved drugs. This yielded Boceprevir, Telaprevir and Asunaprevir which were further evaluated in-vitro using Huh7 and DENV2-NGC virus treated Huh-7 cells for evaluating cytotoxicity and dengue plaque formation. This proved theanti-dengue effect of Asunaprevir. Literature-based DR: Mining through history to avail resources for the future
Retrieval of information on disease specific targets buried in enormous valuable literature sources is a herculean task which can be simplified through application of computational techniques to abridge drug discovery timelines. Literature mining (LM) is one such
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after drug administration. Single similarity matrix was designed by incorporating drug-drug matrix and disease-disease matrix based on their Gene Ontology and PPI. This approach revealed similarity between structures of Terbutaline and Ursodeoxycholic acid (UDCA); Kawasaki syndrome and Amyotrophic Lateral Sclerosis (ALS). EHR also revealed that UDCA and Terbutaline sulfate can be used to treat Kawasaki syndrome and ALS respectively. approach that uncovers key elements obscured in textual data resources to frame a substantial research hypothesis. LM is useful in (i) extracting data of research interest from huge literature, (ii)format unstructured data to a well organised one, and (iii) decode the data in an analysable pattern. Currently, numerous hypotheses were generated using LM to promote advanced research in drug discovery and DR. Giup Jang et al., screened 1,454,763 abstracts from the PubMed database to extract drug-gene co-occurrence and phenotype-gene co-occurrence. Sentences were then parsed to identify entities i.e. genes, phenotypes and drugs. A dependency graph was formulated to extract relationships between entities. Subsequently, Gene Regulation Score (GRS) was calculated to identify significant gene-drug and gene-phenotype relations. Using GRS,
The revolutionary application of side effects data to uplift DR hypothesis
Side effect databases provide vast data of undesirable and untoward extensions of drugs’ activity. These unwelcome phenotypes of the drug rely on polypharmacology concept which highlights the likelihood of multi target actions of drugs that are interlaced in numerous disease networks. The utility of this novel conception resulted in the advent of a distinctive DR approach. Hao Ye et al., mapped 6495 side effects of 2183 FDA approved drugs from SIDER, MedDRA, Meyler’s Side Effects of Drugs and Side Effects of Drugs Annals. Consequently, unique side effect fingerprint for individual drugs was created and similarities among side effects and drug was calculated using Jaccard Index (cutoff = 0.275) in order to construct a drug network. This revealed 17,400 drug-drug pairs, spanning 1647 drugs based on side effect similarity. Of the total, 1234 drugs were selected as they contained a minimum of 2 neighbors which were mapped to 81 Anatomical and Therapeutical Classification (ATC) with 584 unique indications. Dynastat (Parecoxib) initially approved for pain management was found to be enriched in rheumatoid arthritis. Tramadol (analgesic) and Tolcapone (a FDA approved drug for adjuctive therapy of parkinson’s disease) were found to possess anti-depressant activity.
RESEARCH & DEVELOPMENT
Collaborating approaches for DR: Does strength come from unity?
AUTHOR BIO
Aforementioned computational approaches adopted in DR research offer quick forecast, yet, they are not devoid of certain boundaries. In case of targetbased approaches, investigation of target binding site is of prime importance in exploring new indications. However, none of the existing algorithms are precise in predicting the binding sites of new or unrelated proteins, thereby restricting their applicability in identification of novel compounds through DR. Explicating the mechanisms underlying gene expressional changes, post drug treatment, faces challenges in terms of noise that can result in biased network predictions. The same pitfalls are experienced in PPI network construction and mining side effect data. Drug based approaches, by default, encounters some drawbacks due to deficit of pertinent details related to proprietary norms and erroneous chemical structures selection. In case of molecular docking studies, ligand matching with binding grove of the target protein is unreliable. Though this technique offers flexibility to the ligand, the receptor is left rigid. This necessitates the exploitation of MD studies which can
contribute flexibility to ligand and the receptors, to simulate natural condition, which demands expensive high-performance computing facilities. In order to overcome the inadequacies pertaining to individual approaches, a multifaceted integrative approach is highly recommended to accomplish a vibrant DR outcome. Ming Zhang et al., developed an innovative DR approach by integrating genomic, proteomic, epigenetic and metabolomic data from Genome Wide Association Studies catalogue, Uniprot, Literature and Human Metabolome Database respectively. 220 genes associated with 244 variants, 98 proteins, 86 metabolites and 14 epigenetic associations were mapped. PPI analysis revealed association of 524 proteins in AD pathogenesis. These proteins were later mapped to FDA approved drugs from Therapeutic Target Database and Drugbank to identify potential repurposable drugs. Amidst the 524 proteins, 19 were indicated as targets for 92 FDA approved drugs. A ranking algorithm was developed based on their level of change of protein expression and availability of literature evidence. This algorithm identified Gemtuzumab, Ozogamicin, Pyridostigmine, Endrophonium, Verapamil, Reteplase, Streptokinase,
Tranexamic Acid, Pergolide, Ropinirole, Apomorphine, Rotigotine etc., as potential anti-AD drugs. Humanising Machines: A beacon of hope for DR market
Artificial Intelligence utilises techniques such as machine learning and deep learning to simulate human characteristics to address complex problems encountered in the computational world. Incorporation of AI in DR has proven to be revolutionary. Machine learning techniques have eased the process of subgroup classification of diagnosis, determination of drug efficacy, ADME prediction, disease target discovery, and decision making, which are the backbone in the various omics approaches. Further, deep learning techniques incorporate artificial neural networks to mine databases using algorithms that aid in unveiling novel therapeutic possibilities. This unique amalgamation of AI with DR, though convenient, is but a start of the transition towards a modern era that involves the integration of the various databases and approaches in DR to minimise clinical trial failures, and provide a safe, economical and effective means to retrieve novel polypharmacological agents.
Saraswathy GR has 17 years of teaching experience and is actively involved in research activities focusing on Alzheimer’s Disease, Drug Repurposing; clinical research in psychiatry, cardiology and endocrinology.
Mamatha K has 10 years of teaching and research experience. Her research interests include early detection of extravasation, oral mucositis, peripheral neuropathy in oncology patients and drug repurposing.
V Lakshmi PrasannaMarise is an academician and an aspiring researcher with 5 years of teaching experience. Study on epigenetic modifications that serve as the root cause of various diseases, pharmacovigilance, cheminformatics and the art of drug repurposing technologies are her areas of interest.
Rachana R Pai is currently a final year Pharm D intern who has been trained in molecular docking and pharmacophore modelling using Schrodinger from the Pharmacological Modelling and Simulation Centre, Ramaiah University of Applied Sciences, Bangalore, India.
Hema Sree is currently pursuing her Doctoral project related to Drug Repurposing inAlzheimer ’s disease. She has been working as a research scholar from past two years and has developed expertise in computational analysis.
Swarna Mariam Jos is a Pharm D Intern whose research interests are Ecopharmacovigilance and Drug Repurposing. Having been trained in Computational Drug Discovery Techniques, she wishes to build a competent career in the field of research.
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NANO-BASED DRUG DELIVERY Road towards cancer therapy management Cancer is a leading cause of death globally. Despite therapeutic advancement, the rate of cancer mortality has increased in past few years. The major drawback of anti-cancer drugs is non-specific delivery, which causes adverse side-effects and toxicity. Nano-based drug delivery systems could help us minimise adverse sideeffects and in better cancer therapy management. Dhruv Kumar, Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University 26
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n the past few decades, nanotechnology has emerged as one of the most important approaches for cancer diagnosis and therapeutics. More recently, nanoparticle (NP) based specific drug delivery approaches have gained attention of researchers and clinicians to take one step towards specific tissue/organ specific drug delivery against cancer. NPs display an adaptable role in disease/cancer diagnosis and treatment and showed several
RESEARCH & DEVELOPMENT
pH (7 - 7.2) Sensitive Polymer
Cell Penetrating Peptide
Anticancer Drug
pH (6.5 -7) Sensitive Polymer
pH (5.5 - 6.5) Sensitive Polymer
Figure-1: pH sensitive nano drug delivery system for solid tumour
advantages over the other conventional techniques. NPs and NP-based drugs are very selective and efficient towards specific cancer cells, tissues and organs. The selective targeting of specific cancer cells, tissues and organs by nanoparticles, nano-carriers, nano-drugs/nano-medicines also excellently minimises the risk of side effects in cancer patients. There are several types of nanomaterials/nanocarriers, including polymers, dendrimers, liposome-based, carbon-based, iron-based, and gold-based, which extensively studied in cancer biology to understand their therapeutic potentials. The size range of the well-defined nano-materials varies between one and 100nm, which impacts the limits of nano-medicine starting from microfluidics, biosensors, drug delivery to tissue engineering. Nanotechnology employs therapeutic agents at the nanoscale level to develop nanoparticles, nano-
carriers, nano-drugs/nano-medicines. Nanoparticles are designed in such a way at the atomic or molecular level, so that,they can acquire small nano-spheres, nano-tubes and nano-disk, which can easily move freely in the human body as compared to the bigger materials. Altogether, nano-particles exhibit unique physical, chemical, structural, mechanical, electrical, magnetic and biological properties, which tune nanoparticles, nanocarriers, nano-drugs/nano-medicinesto be utilised as delivery agents by encapsulating drugs or attaching therapeutic drugs and to deliver them to the specific cells, tissues and organs with more precisely with a controlled release. Despite these recent advancement in diagnostics and therapeutic approaches, cancer is still the leading cause of death globally. The early detection and effective treatment of cancer is still a big challenge of researchers and clinicians.
The major challenge for the researchers in the development of therapeutic approaches for cancer is to deliver anticancer agent specifically to the site of disease. The conventional way of cancer treatment and drug delivery results in a serious side-effects. With the advancement of nanotechnology-based tools and drug delivery systems, it has become relatively easier and simpler for researchers and clinicians to diagnose cancer early and alsoto treat cancer patients effectively with reduced side effect. Cancer metabolism is a hallmark of a solid tumour and it has been extensively studied in the past few decades. Most of the solid tumours are highly glycolytic and it produces lactic acid in the tumour microenvironment, which bring extracellular environment acidic. Whereas in a solid tumour, pH varies between 5.5 to 7.2. It has been observed that pH normally varies between 5.5 to 6.8 in
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the core of the solid tumour because of the hypoxic condition and in the outer core it varies between 6.8 to 7.2. The variation in pH in solid tumour leads to the heterogeneity, which increases tumour aggressiveness and drug resistance. The recent advancement in the area of nanobased drug delivery system can be used to deliver drug in pH sensitive manner in solid tumour (Figure-1). Specific targeting of drugs using nanoparticles has been broadly studied on a tissue and organ level. The use of nanomedicines in cancer diagnosis and therapy is still under the developmental phase. The evolution of nanoparticle-based drug delivery is catching all the attention due to its uniqueness in biomedical applications and specific tumour targeting. Using nanoparticles depends on their ability to accumulate in desired cells or tissues. Nano-medicine includes the use of preciselywangled materials for the development of novel therapies which can increase efficacy inside tumours and reduce toxicity of specific targeting of drugs to the normal tissues and organs as compared to the conventional anticancer drugs. Nano drug formulations have several advantages such as improved solubility, increased selectivity for tissues, enhanced efficacy, less toxicity. They can also cross the blood-brain barrier. The conjugation of nanoparticles with existing drugs increases the pharmacokinetic and pharmacodynamic properties and effective treatment outcomes. Therefore, it is important to understand the target region while designing nano-drugs and make specific delivery to the site of disease. Delivery of nano drugs can be categorised under active and passive targeting. Active targeting involves conjugation of tissue specificity, ligands such as proteins, antibodies, or small biomolecules are attached to the surface of the drug-NP conjugate, which increases the intracellular drug accumulation and cellular uptake of the target tissue. Passive targeting is achieved through localisation of NPs into specific organs via mechanisms such as the Reticuloendothelial System (RES),
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or Efficient Permeability and Retention (EPR) system. Several studies have demonstrated the potentiality of nano-drug delivery (doxorubicin) to breast cancer and prostate cancer cells using silver decorated gold nanorods, the use of iron oxidebased nanoparticles that released the drug under the influence of magnetic fields. Curcumin, which is commonly found in turmeric, has been known for long to have anticancer properties but known to have poor bioavailability. Encapsulating curcumin polymorphic nanoparticles resulting in ‘nano curcumin’ has improved its solubility and bioavailability. Nano curcumin can effectively mimic the action of free curcumin in cancer cells and induce apoptosis through blocking of nuclear factor kappa B activation (NF-κB), and suppression of pro-inflammatory cytokines like IL-6, Il-8 and TNF-α. Nanoparticles are also designed in a manner to target specific organs in the system for the direct delivery of drugs to the targeted organ where the tumour is located. Drug targeting in organs such as lungs, livers, kidneys, brains has been widely studied. Drug targeting in the liver is achieved by both active and passive targeting. The kidney is another organ that uses targeting strategy by size-controlled drug carriers and prodrug approaches for drug delivery. The brain possess considerable challenges in taking up drugs along with in treating brain diseases. The blood-brain barrier (BBB) tightly regulates the entry
of substances to brain, which makes the drug delivery process difficult. Several strategies have been used for drug delivery into the brain, such as direct injection of drug into brain. Nanoparticle drug delivery through active targeting involves the modification of drug or drug carriers to facilitate drug delivery through bloodbrain barrier. During the last few decades, several novel drug delivery systems have entered the market and have been developed using various nanomaterials. To achieve controlled and targeted delivery of drugs, nanotechnology modifies many of its properties such as the size and other physical characteristics. The conventional and most commonly used cancer treatments include chemotherapy, surgery, radiation, targeted or a combination of any of these treatments. However, there are challenges associated with toxicity, non-specificity, side-effects etc. The optimisation of the pharmacological action of the drug, and the minimisation of its toxicity are some major challenges of current anti-cancer therapy. In general, the distribution of the anti-cancer drugs at the cancer sites needs to be high, while at other noncancerous tissues low to prevent any negative reactions. Nanotechnology has the potential to solve these limitations through delivering anti-cancer drugs to the site of disease. Designing nanoparticles, nano-carriers loaded with multifunctional drugs, and functionalising their surfaces with recognition proteins can target specific cancer cells. Certainly, this approach would be able to deliver anticancer drugs specifically to the cancer cells, tissues, and organs and significantly reduce any adverse effects of drugs on healthy cells.
After completion of B.Sc from BHU and M.Sc from the University of Allahabad, India, Dhruv completed his PhD from the University of Bologna (UNIBO), Italy. He has received postdoctoral training from the University of Kansas Medical Center, USA. Currently, he works on translational cancer research, including prostate, pancreatic, brain, breast and oral cancer.
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Advanced Computational Drug Discovery Tools Through user friendly web servers
The discovery of new drugs is a very slow and costly process, but advanced computational drug discovery techniques can drastically speed it up. However, such tools are very complicated for nonexpert users. We provide an overview about how user friendly web servers can dramatically help them. Antonio J Banegas-Luna, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Universidad Católica San Antonio de Murcia (UCAM) Maria Paredes-Ramos, PhD student, Metals in Environment and Medicine (METMED), Physical Chemistry Department, Universidade de Courña(UDC) Marién M Moreno, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Universidad Católica San Antonio de Murcia (UCAM) Josefina M Vegara-Meseguer, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Higher Polytechnic School, Universidad Católica San Antonio de Murcia (UCAM) Horacio Pérez-Sánchez, Principal Investigator, Bioinformatics and High Performance Computing Research Group (BIO-HPC), Universidad Católica San Antonio de Murcia (UCAM)
D
rug discovery is one of the most time- and cost-consuming processes in the industry. From active pharmaceutical ingredients (API) discovery to final approval it involves a total duration of 10 – 15 years (Figure 1) and US$1 – US$2 billion investment. After the protein target identification, the search for a specific drug-like molecule that matches the binding site is an arduous process which requires the screening of hundreds of molecules to test their bioactivity. Employing an experimental trial-and-error procedure, this task would take years to be accomplished. Thus, during the past few decades, different theoretical approaches based on quantum and molecular mechanics have been developed to simulate and test real systems before entering the laboratory.
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The explosion of biotechnology resources has enabled the disease process to be better understood and evaluated for drug targets. So, nowadays, drug design cannot be imagined without computational aided methodologies such as CADD. Therefore, CADD has gained importance in the pharmaceutical industry, at research centres, and universities. CADD involves techniques such as molecular docking or virtual screening, which are employed to inspect the binding poses of a ligand (or a database of ligands) on a particular receptor. Despite being much more efficient than the aforementioned experimental ones by far, these procedures require large calculations and extensive chemical data repositories to simulate their highly complicated systems. Hence, its
related computational cost, in terms of memory and processing capacity, is huge. Accordingly, to transcend computing barriers of the traditional personal computers (PCs), high-performance computing systems have been developed. High Performance Computing (HPC) is the application typically used for solving advanced computational problems that are too large for standard computers and performing research activities through computer modeling, simulation and analysis. Computer-aided drug discovery methodologies have become essential components of the drug discovery and Virtual Screening (VS) methodologies have emerged as efficient alternatives for the discovery of new drug candidates. Protein-ligand interactions are common targets for medicine. Refining
RESEARCH & DEVELOPMENT
Evolution of Drug Discovery Software
Figure 1 Drug discovery process.
computational models would help in developing new medicines more efficiently. The problem of finding potential dual target ligands is addressed from different points-of-view: similarity analyses, QSAR-derived (Quantitative Structure Activity Relationship) ligandbased virtual screening studies, and molecular docking approaches. Virtual screening (VS) refers to a group of in silico techniques oriented towards finding novel hit and lead compounds. The technique has become prominent in the last few decades as a means to study diseases such as malaria, diabetes and Parkinson’s disease. Although its computational cost is considerable, VS is one of the most used methods when it comes to assessing large chemical spaces and shorten the time devoted to in vivo experimentation. VS techniques are manifold and can be divided into two
broad categories: structure-based,(SBVS) when the 3D structure of the target is known, and ligand-based (LBVS) when it is not. Alternately, LBVS depends on the notion of small molecules that connect the target and it comprises several methods, such as pharmacophore modelling, similarity searching and QSAR. The idea behind pharmacophore modeling is the alignment of two or more molecules to identify the pharmacophore features they share. Molecular similarity is then characterised by compounds with pharmacophoric features that resemble the identified pattern. Similarity searching is the preferred method due to its simplicity, which also makes it cost-efficient. It rests on the comparison of built fingerprints for molecules that can be easily compared while maintaining the information necessary to determine similar biological activity.
Before the explosion of web technologies and the Internet, software packages used to be installed on local machines and users required physical or remote access to them. That was the way that Autodock, DUD and many other packages were used far in the past. This classic approach presents several disadvantages and limitations. First, users must be granted to access the machine where the software is. This approach may work well with few users, but it does not scale when the number of users increases. Moreover, it represents an important security issue because users should only be granted to run the software they require. Second, running a command-line programme implies an in-depth knowledge of the parameters in order to receive the expected result back. Unfortunately, drug discovery is a multidisciplinary science and not every user is familiar with all the concepts involved or has advanced computing skills as to deal with complicated options. Finally, installing a programme in a new machine might not be an easy task due to software dependencies. The destination environment must be compatible with the source one and provide all required dependencies. Once more, not every user is able to cope with certain steps of the installation process. To overcome these drawbacks, web technologies came to the rescue. They provide a common, accessible and simple environment that hides the complexities of the underlying software and centralise the access to resources. By means of web servers, millions of users can execute drug discovery tasks at no installation cost. The advantages of web technologies in the context of drug discovery are several. As stated, they provide unlimited access to the published resources at any time and from any place (Figure 2). Security risks can be easily handled in one single entry point. Furthermore, only one installation is necessary, and it is transparent to users. In addition, since users are unaware of the hardware
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behind the web interface, it is simple to rely on an HPC infrastructure to carry out complex calculations and speed up time consuming tasks. Finally, the way the users interact with the software can be simplified through a nice web interface by limiting the number of input parameters and formatting the output to be more understandable. In the context of drug discovery several applications have moved to web environments, making it one of the main reasons behind the most important achievements experienced by CADD. Nowadays, web servers are just the tip of the iceberg of the complex HPC infrastructure based on distributed computing environments such as grid computing, cloud computing and general-purpose computing on graphics processing units (GPGPUs). Biomedicine was one of the first areas that moved to distributed infrastructures, which rely on the idea that any simulation can be carried out by a service. In this type of paradigm supercomputers, clusters or workstations are services, but also databases and authentication mechanisms represent services. These new paradigms have the ability to execute multiple calculations simultaneously to accelerate the most time-consuming tasks resulting in a greater number of simulations and, consequently, in more
chances to shorten the delivery time of new drugs. Examples of web servers and databases
As discussed above, the use of web servers to deliver drug discovery services has gained a lot of importance in the recent decades. The main techniques, such as virtual screening, homology modelling or target prediction, have been migrated progressively to the web. Moreover, the data that those services consume have been published on databases that are accessible from the Internet. The typical example of drug discovery process on the web are VS methods (e.g. similarity searching, molecular docking, pharmacophore modelling, QSAR). Due to their ability to deal with the overwhelming amount of data available in the chemical databases and the speed of calculation they exhibit, LBVS methods are suitable to be implemented on the web and many servers can be presented as a model. A typical example is SwissSimilarity1 which provides a simple interface to screen a disparate of datasets by a collection of 2D and 3D software packages. Another example is
BRUSELAS server2 that carries out either similarity searching or pharmacophore screening tasks by combining different programs. It applies consensus scoring functions to return unbiased predictions and the results can be exported as a PyMOL session. Other similar servers such as USR-VS3 or ZincPharmer4 are more restrictive and only allow performing one type of VS on a single certain dataset but are also suitable in some cases. In general, all LBVS servers share some common features including the set of parameters (e.g. databases, software), simple and intuitive interfaces and the way the results are interpreted. Many other techniques can also be executed via web servers. SBVS methods are represented by HADDOCK5, DOCK Blaster6, SwissDock7 or Blind Docking Server8 which implement different versions of molecular docking. 3-D QSAR, E-Dragon and MOLFEAT are web servers to perform QSAR related processes, including QSAR modelling 2 http://bio-hpc.ucam.edu/Bruselas 3 http://usr.marseille.inserm.fr 4 http://zincpharmer.csb.pitt.edu 5 https://haddock.science.uu.nl 6 https://blaster.docking.org
1 http://www.swisssimilarity.ch
7 http://www.swissdock.ch 8 https://bio-hpc.ucam.edu/achilles
Figure 2: Web infrastructures applied to CADD.
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between them. In any case, current chemical databases can be easily explored via web browsers that allow running fast queries without having direct access to the physical store. Conclusion
The development of web technologies has dramatically changed the drug discovery process and has paved the way to the most remarkable achievements in this area. Old fashioned commandline programs are now accessible by millions of users worldwide through simple web interfaces that hide all the complexities of the underlying software and encourage the use of HPC platforms to accelerate calculations. Simplicity in the use of software is a critical point in drug discovery because it is a multidisciplinary process and computing is only a part of it.
AUTHOR BIO
and molecular descriptors calculation. Molecular dynamics (MD) is another remarkable approach in the context of CADD that has experienced the transition from command-line programs to the web. MDWeb, the Gromacs server, Vienna-PTM and MoSGrid are some representative examples of MD services on the web. The evolution of HPC paradigms has opened a way to accomplish exhaustive investigations on contexts that were inconceivable a few decades ago. For example, the Cancer Genome Atlas helps to split genome data into small pieces for parallel processing. The Collaborative Genomic Data Model (CGDM) improves the performance of the queries on genomic databases. Rosetta@home is a distributed computing project that has been applied to research on Malaria and Alzheimer’s disease. The aforementioned examples are only a sample of the full catalogue of CADD related services available on the web. Nowadays, almost every step in the drug discovery pipeline is automated and several web services provide that functionality through a nice interface. A complete collection of those services is maintained by the Swiss Institute of Bioinformatics and available at the Click2Drug portal9). Though services are a key point in the drug discovery process, they are only half of the equation. The other half is made of data. Those data are stored in huge databases that frequently provide a simple web interface to browse them and, sometimes, even a web API to retrieve information through web services. The diversity of chemical databases that can be explored on the web is enormous, from the commercial ones such as Specs, Mcule, and May bridge to the freely accessible ones, such as PubChem, ChEMBL, ZINC, and GDB-17. They all contain many different attributes (e.g. identifiers, chemical descriptors, biological pathways) and records. Although they do not share a common structure, their web interfaces facilitate the navigation
Nowadays, researchers can access a disparate set of web tools that implement different approaches for each task in the drug discovery process, ranging from single and well-defined steps (e.g. molecular descriptors calculation, prediction of ADMET properties) to more complex simulations (e.g. molecular dynamics, homology modelling) and calculations (e.g. molecular docking, QSAR). Furthermore, web development has changed data availability. Chemical databases are often freely accessible and non-expert users can explore them and build complex queries in their web browsers. The application of these tools has allowed significant progress in the field of drug discovery, resulting in a shorter time to deliver new drugs, which has a great impact on society, especially in global emergency situations, such as Zika and Wuhan virus crisis.
Antonio J Banegas-Luna is an IT Consultant with more than 15 years of experience in software development, PhD and member of the Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC, http://bio-hpc.eu). His research area is mainly focused on the usage of high performance computing (HPC) to discover new potential drugs. Maria Paredes-Ramos is a PhD student and member of the METMED group from Universidade da Coruña. Her research area is related to material science and bioactive compounds discovering for functional food development.
Marién M Moreno PhD in Physical Chemistry and currently Assoc. Prof. at Degree in Pharmacy (UCAM). Research area in electrochemistry and drug discovery using web servers. Josefina María Vegara-Meseguer PhD in Biophysics and member of the Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC, http://bio-hpc.eu). Research area in ion channel biophysical and functional features. The study of ion channels often involves biophysics, electrophysiology and pharmacology. Horacio Pérez-Sánchez is PI of the Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC, http:// bio-hpc.eu). He has discovered more than 30 novel bioactive compounds and produced more than 150 publications, several international patents and lead drug discovery projects.
9 http://www.click2drug.org
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CLINICAL TRIALS IN A PETRI DISH Closer to reality
Clinical trials are pilot studies conducted on human volunteers and patients in a phased manner to evaluate the investigational new drugs developed before introducing into the market. Innumerable registered and well planned clinical trials fail every year regardless of promising animal and preclinical modelling. By the power of the grey star, human sourced stem cells, organoids modelling in the in vitro conditions simulating human systems has the potential to revolutionise the way clinical trials and the phases could be directed in future. Subhadra Dravida, CEO, Transcell Oncologics
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C
linical trials include experiments and the related observations done in clinical settings as part of prospective biomedical research studies on human participants. The studies on human participants are usually designed and performed to answer specific questions about biomedical or behavioural interventions, new treatments, and known interventions/medicines. These studies generate data on safety and efficacy surrounding the medical intervention. The concept of clinical
CLINICAL TRIALS
any treatment given to the real patients. In other words, without clinical trials phased and designed as being practised, there is a big risk that patients are given treatments which may not work or which may be harming instead of serving the purpose of treatment. There are 4 known phases of clinical trials being practised for ages: Phase 0 is conducted on a small sample size using a small dose of medication under investigation to make sure that it is not harmful to human healthy volunteers before testing higher doses. In this phase, if the test medications effect is different than expected, the study is bound to go back to preclinical research to revisit the functions, re-evaluations. Phase 1 is conducted on a slightly bigger sample size but again on healthy individuals with key objectives like establishing the highest dose of the medicine tolerated with no serious side effects. Additionally, the best route of administration visa vis the efficacy as well becomes secondary objective of the trial in Phase 1. Phase 2 is known to involve the patients as subjects but with inclusion and exclusion criteria met as per the design of the trial. Phase 2 is known to involve bigger sample size than Phase 1 while the data collected during this phase supports the strategy and design for Phase 3.
trials has undergone several mutations while modern trials design and principles have precipitated on the importance of randomisation, replication, and factorial experiments. Clinical trials are conducted on humans while designed to specifically address set questions and broadly to improve health, quality of life. Experiments and evaluations have been part and parcel of medical field, without which there would be no evidence to know the safety and effectiveness of
With all the ethical issues surrounding Phase 1 clinical trials where the inves-tigational new drug candidates would be clinically applied for the first time with no data available from clinics, into healthy volunteers, alternative strategies like clinical trial in a petri dish utilising healthy donors-sourced stem cells prepared as platforms for in vitro read outs that can match the clinical settings.
Phase 3 requires patients’ participation in larger cohorts while the purpose of conducting is to evaluate the new medication’s efficacy in comparison to the one already being practised for the same condition. Phase 3 is traditionally double blinded and built on a process called randomisation to help eliminate any bias interpreting results. Phase 4 is undertaken after the regulatory approval on the use of medication is obtained involving thousands of participants. Phase 4 delivers the new medication’s long term safety and efficacy with study duration lasting for several years. Phase 1 – the most controversial clinical trial stage
For long and forever, Phase I studies have been debated and the debate dates back to the history of human experimentation to discover medicines. In Phase 1, the drug is being tested in humans for the first time with no data available on the species and no benefit to the participant. Participants are asked to be willing volunteers to subject themselves as guinea pigs in research, which is questioned and argued by bioethicists on ethical principles as therapeutic misconception. For a healthy volunteer enrolling in a toxicity trial, there is only risk but no medical benefit. Correspondingly, Bioavailability and Bioequivalence (BA/BE) studies are conducted to establish the generic drug’s equivalence to the new drugs and are usually carried out in healthy human volunteers. They are non-therapeutic in nature without any direct benefit to the participants. “Bioethics and the principles include that we ought not to deceive others, we ought not to harm others or allow harm to come to others, and we ought not to use others as means to an end.” By Christopher K. Daugherty, M.D., of the University of Chicago Monetary reparation and the supplications to altruism for the benefit of humankind involved as part of the informed consents obtained by the
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volunteers who are participants are only opportunities for ethical misapplication. Phase 1 first-in-human studies in Oncology differ from other Phase 1 studies in that they are conducted on cancer patients rather than healthy volunteers. Here, objectives as well alter from the definition of a maximum tolerated dose to the estimation of a recommended Phase 2 dose. Other challenges related to the efficacy and safety profile of novel targeted anti-cancer drugs are conspicuous in Phase 1 for anti-cancer new drugs trial. Likewise, Phase 1 first-in-human studies for progressive Neurodegenerative diseases conducted on human volunteers do not yield data that can justify the design, dose and method of treatment.
on efficacy, toxicity, pharmacokinetics and safety of application. After pre-drug discovery research establishing either target or function discovered, wide doses of the drug candidate are tested using in vitro and in vivo (animal) experiments while insilicoprofiling of the drug–target interactions is an integral tool in the framework. Much like clinical trials, there are certain types of preclinical trials such as exploratory toxicology leading to regulatory studies, and other trials that are specific to the particular question. The only goal of preclinical trials is to move into the clinical stage while the preclinical exploratory and regulatory studies are designed around this goal.
Drug repurposing in clinics – A totally new wine in an old bottle
There are broadly five different preclinical model systems in use: insilico, in vitro, ex vivo, in vivo and xenografts based. In all the systems, there are fundamental cell based platforms that have found their spot re-creating the tissue or organ of importance to the extent of humanising animal models. When it comes to cell based platforms, primary cells and transformed cell lines are the only variations put in use. The sources of these cells have been broadly human or animal tissues relevant till date in drug discovery pitch. There are stem cells giving rise to
Drug repurposing (repositioning or re-profiling or re-tasking) is a new approach for identifying new uses for approved or investigational drug candidates that are outside the scope of the original function attributed. Preclinical trials dictating clinical trials
To determine whether a drug is ready for clinical trials, it involves wide-ranging preclinical studies that produce data
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Preclinical model systems
tissue specific cells and tissue derived terminally differentiated cell types known to the researchers. Stem cells – Classification
Stem cells are unspecialised cells of the human body that have the capacity to become any cell of the body with an ability to self-renew. Stem cells are present both in embryos and adult tissues/organs. Totipotent stem cells divide and differentiate into cells of the whole organism. Totipotency is the power to form both embryo and extra-embryonic structures. Zygote is a totipotent cell. Pluripotent stem cells form cells of all germ layers but not extra-embryonic structures, such as the placenta. Embryonic stem cells, Induced pluripotent stem cells are pluripotent cell type examples. Multipotent stem cells can specialise into discrete lineage specific cell types. Haematopoietic and Mesenchymal stem cells are classical examples of this stem cell type. Oligopotent & Unipotent are the types with narrower differentiation capabilities. The role of stem cells in preclinical modelling – the role less spoken in comparison to clinical applications
Owing to their unmatched properties, stem cells have been found to be acting like base platforms available for multiple genetic diseases, including neurological disorders like Parkinson’s, blood diseases, cardiac syndromes, diabetes and hepatic disorders. The tissue models created can be scaled up to systems that mimic entire organs. Stem cells can be harvested from either patient’s body or healthy donor while transcriptomics and proteomics of the stem cells vary between patient and healthy donor. Patient sourced stem cells are usually utilised in re-creating disease microenvironment in the petri dish while preclinical stage in vitro assays specific to the disease of interest are performed. Healthy donor harvested stem cells have been trialed and in vitro systems developed are best suited in high throughput screening of chemical libraries, toolbox, exploratory toxicity related testing proto-
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cols, drug repurposing. These in vitro model systems used in toxicity testing are known to have diverse advantages on top of human relevance together with the decrease in the number of animals used for experimenting, the reduced price of maintenance, shortening of the time needed, and increase in throughput for evaluating larger number and their metabolism related data points. If healthy donor is the source chosen, biopsy as the starting material to harvest stem cells cannot be the ethically accepted mode especially when the preclinical research involves volumes and reproducibility. The only option left to the serious researcher or the industry is to consider human biological discards that have proven credibility as ethically immuned, available in large quantity to access sterile, residing stem cells that are shown to be multi-pluripotent in nature, as the raw material. Human umbilical cord blood, cord tissue, deciduous teeth and adipose tissue are the most popular biolog-
ical discards qualifying as raw materials to produce stem cell based platforms in petri dish mimicking human physiology. The only way to source this raw material is from the biobanks cryopreserving biosamples as there is no second chance that human life gives to collect these biosamples other than the destined event. Some of the well accepted in vitro cell based assays in preclinical research that include regulatory need are: Cell viability, Apoptosis, Necrosis, Membrane integrity, Mitochondrial toxicity, DNA damage, Cytokine signatures, Toxicity pathways, Toxicogenomics, Proteomics, Embryotoxicity, Tumorogenicity, Lethal dose, Neurotoxicity, Hepatotoxicity, Cardiotoxicity. Advantages and features of stem cell-based platforms for preclinical trials
The alternatives to stem cell-based platforms in preclinical research stage that have been (low hanging), tried and tested
but not with any specific advantages are: cell lines and animals Human sourced stem cell based platforms have distinct advantages owing to their origin that is closer to clinical reality, their ability to proliferate in culture conditions simulated in petri dishes, their ability to self-renew to result in volumes that can be managed while retaining Stemness, their ability to differentiate under controlled conditions to other lineage specific cell types like: neurons, adipocytes, osteocytes, chondrocytes, heart cells, liver cells, their ability to humanise 3D models. Clinical trials in a Petri dish
Clinical trials in a petri dish or in vitro clinical trials use specimens collected from humans to test how a particular disease will react to a specific therapy or combination of therapies. This strategy can be also used for the development of drugs for specific populations, for precision medicine purposes to predict
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responses in individual patients or for establishing safety of investigational drug candidates. US FDA has the history of engaging and participating in a publicprivate partnership involving the Health and Environmental Sciences Institute, the Safety Pharmacology Society, and the Cardiac Safety Research Consortium, multiple global regulators, pharmaceutical companies, and academic laboratories, to develop a comprehensive in vitro proarrhythmia assay with a goal to use a combined in vitro and insilico
(computational) testing strategy to predict the risk of drug-induced arrhythmias. This was planned to be part of regulatory clinical trial performed for all new drugs in place of a current clinical trial in drug development - An example for clinical trials in a dish in real time. Phase 1 of Clinical trials – A compelling case for surrogation in Petri dish
With all the ethical issues surrounding Phase 1 clinical trials where the inves-
tigational new drug candidates would be clinically applied for the first time with no data available from clinics, into healthy volunteers, alternative strategies like clinical trial in a petri dish utilising healthy donors-sourced stem cells prepared as platforms for in vitro read outs that can match the clinical settings. The success of the strategy in real time application purely depends on the standardised assays with integrated tools measuring end points evaluating safety related clinical end points.
CaseStudy Transtoxbio A unique portfolio that can be integrated into preclinical and clinical trials For pluripotent imagination of user’s mind
T
ranstoxbio has all primary, stem cell-based in vitro real time platforms that can predict: biocompatibility, target, functional efficacy, and safety profiles of simple to complex molecules that are being investigated or developed as drug candidates. This real-time platform technology has the potential to
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support next-generation phenotype based drug discovery (PDD), which is believed to be forward pharmacology. The portfolio’s bandwidth and power to read high throughput screens, phenotype, genotype, proteomics that play crucial role in target identification, pathways recommends integration in preclinical exploratory drug discovery
and trials in the labs. Also, some of the platforms of the portfolio can humanise animals in developing human disease models to test the investigational new drug candidates’ efficacy; listing the platform’s wherewithal to participate in preclinical in vivo trials. Owing to it’s human sourced stem cell compositions, primary with
proliferating capacities (to passage and mimic prolonged drug candidate’s exposure time), the platform has the power to read human safety related toxicology specific, measurable endpoints when exposed to lead compounds. It is the predictive property that answers critical concerns like Embryotoxicity, Genotoxicity, Metabolomics, Transcriptomics, Toxicity related predictive markers (Toxicogenomics), Stem cell cytotoxicity (IC50 on human primary stem cells), Stem cell permeability, Cell distribution of druggable candidates to the extent of mimicking regulatory studies compelling the platform’s adoption in not just preclinics but also in early stages of futuristic clinical trial modalities like that of Phase 1. The portfolio’s eligibility as surrogate podium to be considered for Phase 1 clinical trial emerges from the following features surrounding
the suitability: Source, Abundance of source, Availability and access of the sources chosen, Established protocols in harvesting primary, progenitor cell types either from healthy donor or patient, Producing phenotypically responsive large scale cell based platforms as products that have the power to predict and read the assay end points simultaneously in real time, Bandwidth to access large sample size, Relevance to human species, Not genetically manipulated Any cell-based platform is of great use for a researcher, user to reproduce
V2_ half page_Pharma Focus Asia - X-Pure - February 2020_vectorized.indd 1
the results and obtain meaningful, consistent, statistically significant data output, if it is available in large, batch wise required quantities, which is possible only if the source is available in abundance. Transtoxbio portfolio falls under the category where the source is not donors’ biopsies that has limitations with harvest, yield, and reproducibility; has all new league of human biological discards sourced (ethically immuned) primary progenitor cell-based platforms for speciality next generation invitro to in vivo applications in pre and clinical research. AUTHOR BIO
S Dravida is the Founder CEO of Transcell Biologics, Hyderabad, India. She is a technocrat with track record of commercialising research driven findings to business opportunities through Transcell.
1/29/2020 12:08:39 PM
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PATIENT ENROLMENT
Doing it the phygital way Patients form the centerpieces in determining the validity, efficacy and success of clinical trials. With identification, screening and enrolment of the patients tricky enough, the retention of enrolled patients proves to be an insurmountable hurdle as trends state that nearly 85 per cent of the clinical trials are unable to retain patients till the end of the trial. Various techniques have been discussed and employed for attaining a healthier statistic including incorporation of patient inputs in designing the trial. Innovation today has helped boost this further in the forms of utilisation of technology in effective patient engagement. R B Smarta, Chairman & MD, Interlink Marketing Consultancy Pvt. Ltd.
I
ntroducing a new drug or treatment regimen is a laborious task which is filtered at various levels before it reaches the general populace. One of the final filters is Clinical trials which
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establishes the efficacy and safety of the regimen; improves patient outcomes and maximises the success of the new entity in the later stages. Although testing of a regimen prior to the efficacy and safety establishment poses a risk to the participants voluntarily enrolled in the trial, the clinical trials today are under strict regulations and take sufficient meas-
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Improving patient enrolment and retention
ures to minimise the risk. Additionally, the patients enrolled are benefitted by being administered a treatment not only before it is publicly available but also with personalised attention, care and frequent monitoring. Despite the numerous benefits, enrolment of patients in clinical trials often proves a bottleneck for the researchers. Enrolment of patients for the process of clinical trials is a long and multistep
Identified
screening process critical for achieving the objectives for a clinical trial. The first hurdle is identifying the right patients that fit your requirements. Once identified, the patients are screened for suitability, educated and informed about the trial and finally randomised. At each step of the process, the pipeline of the patients leaks and tapers to give a final randomised patient list which are enrolled. Figure 1 Enrolling patients successfully is only half the battle won. Since participation in a trial is a voluntary activity, it becomes strenuous to ensure the retention of participants till the complete schedule of the generally lengthy clinical trials. As research shows, only 7 per cent participants of the initially identified participants successfully complete the trial. The validity of these trials depends largely on the discipline of the patients enrolled and their adherence for the regimen.
Screened
Consented
The foremost requirement for improving patient enrolment and retention is to understand the roadblocks and hurdles in the process. Considering patients an integral part of the process, it is important to understand the concerns and expectations of the patients with respect to all the stakeholders while designing a clinical trial. Figure 2 maps the clinical trial process and the problem areas encountered in each phase which generally leads to low enrolment and poor retention. Figure 2 Once the barriers are identified and understood, the improvement strategy in each stage can be chalked out and implemented. To maximise the retention of participants through the length of the trial, the regimen must ensure transparency covering the length of the trial and beyond. Various studies have been carried out to determine these factors and optimise the trials. Despite the palliative steps undertaken to reduce the ‘leakage’ of the participants through the trial, it remains an uphill task. With the advent of technology which is so closely associated and accessible to the participants, an enormous potential emerges for their effective engagement. It is important to tap this potential for not only improving the enrolment and retention but also enhancing patient outcomes.
Randomised
Figure 1: Patient enrolment steps
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Phygital transformation of Clinical trials
As the industry is getting disrupted by introduction of digitisation and artificial intelligence at every step of the drug development process, clinical trials have not been untouched. Digitisation has wriggled its way to the minutia of the process and opened an entirely new horizon of possibilities. Coupled with the current physical ways of handling the task, it paves way for a novel ‘Phygital’ strategy which provides end-to-end interventions and decongests the common bottlenecks encountered. Fig. 3 Let us have a look at the common bottlenecks encountered during clinical trials and how Phygital transformation helps them. i. Creating awareness: The skepticism of patients to enroll in a clinical trial stems from the lack of trust on the reliability of the trial. It is significantly improved with the presence of an expert whom they perceive to be dependable such as a
doctor or other healthcare professionals. Engaging influential figures for creating awareness about clinical trials can help to motivate the patients. Influencers from the digital sphere are increasingly getting engaged with clinical trials and promote such trials to rope in participants. ii. Identification of patients in qualitative and quantitative spectrum: A clinical trial is designed to achieve a set of objectives which can be attained through data obtained from a specific group of individuals. The parameters for screening these individuals often involve a complex web of requirements including but not limited to disease conditions, ethnicity, genetic profile, gender and age to develop a robust trial. Traditionally, each prospective participant was identified and screened to determine their suitability. With digitisation and AI, apps have been developed that take the profiles of the participants through a network of algorithms and find the right match suitable for you! Not just qualitatively,
Creating awareness
Identification of patients
ENROLMENT
Number of patients
Figure 2: Steps and Problem areas in phases of clinical trials
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the intervention greatly reduces the time frame required thus increasing the number of patients identified in the given time period. iii. Ensuring transparency of the trial: Misunderstood expectations and incomplete understanding of the particulars of the trial prove to be a hindrance in the smooth running of a trial. Recent technological advancements allow creation of interactive web experiences that provide a walk-through of the process and empower the participants. Such a platform is helpful not just at the beginning of the trial but also assists, guides and counsels them at every step. iv. Communication: Through the course of the trial, patients often find themselves demotivated due to lack of any significant improvement in their condition or even the lack of appreciation for their effort. Creating milestones and providing a regular feedback recognising and applauding their effort can go a long way in motivating the patient.
Ensuring transparency and consent
PROCESS
Effective and continuous communication
Side effects
RETENTION
Lack of motivation
Non-compliance
CLINICAL TRIALS
PHYSICAL Presence of influencers creates awareness, ensures trust and builds motivation
Digital interventions promote ease of access, personalised care and efficient operations
Phygital DIGITAL
Figure 3 Phygital transformation of clinical trials
Way towards qualitative and costeffective clinical trials
Nearly 85 per cent of the clinical trials are unable to retain the enrolled patients till the entire cycle of clinical trial. They lose about 15-40 per cent of the participants on an average due to various reasons. This leads to discrepancies in the data and sometimes even an inconclusive trial result. The reasons for drop-outs are varied and are generally difficult to control through a broad scale of measures. Retention calls for a more personalised care and constant mentorship for each participant. Having a personal mentor which patients can perceive to be dependable, capable and trustworthy greatly motivates them to adhere to the requirements. Such personalisation for a large population AUTHOR BIO
Automation of a personalised feedback mechanism presents an opportunity for regular positive communication highlighting the significance of the contribution the participant is making towards better healthcare. v. Minimising risk of side effects: The biggest hitch in patients enrolling for clinical trials is the possibility of encountering side effects. Often, identification and reporting of side effects are delayed. These can be curbed by continuous monitoring which is at our disposal by the benefit of the internet and interactive ‘chat-bots’. This additional dimension makes the process of trials conducive for the patients since assistance is just a click away. vi. Maintaining compliance: A major reason that proves a hurdle for successful data collection is that compliance for the regimen is not maintained at the patients’ end due to various reasons such as incomplete knowledge or simply forgetting the schedule for visits and dosage. An easily accessible digital planner and reminder which provides consistent updates of the schedule can markedly improve the compliance and thus the validity of the trial. It ensures the collection of right information from the right patient at the right time!
becomes manageable through digital platforms and AI along with the physical presence of a trustworthy influencer such as a doctor. On the whole, incorporation of Neuro-linguistic programming and machine learning can provide a holistic solution wherein the key lies in execution and flexibility of the platform. Optimised clinical trials can prove highly cost-effective in the areas of recruitment and retention of the patients as demonstrated by a pioneering app in this field — a 92 per cent reduction in resource requirement for conducting the study. With higher enrolment, clinical trials would lead to introduction of better and advanced care for the world and help us combat diseases better in a reduced time frame.
R B Smarta is the Chairman and Managing Director of Interlink Marketing Consultancy Pvt Ltd. Through Interlink he has added value to corporate brands, therapeutic brands, fast moving healthcare brands, in-organic and organic growth of corporates and sales & marketing ROI of corporates. He is also a member of CII Drugs and Pharma National Committee for the Year 2007-08. He is currently working on Business Models, Business Strategy, Emerging Markets and Global Business Opportunities for Pharma, Healthcare Industries.
www.pharmafocusasia.com
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SPRAY DRYING ISOLATOR
FPS solutions for Pharmaceutical and Fine Chemical industries Frederic Le Pape, General Manager, FPS FPS is an Italian company specialised in the production of containment systems and micronisation equipment for Pharmaceutical, Biotech and Fine Chemical companies. In the past 18 years FPS has grown to become the world leader for High Containment Isolators for fine powders with over 1,200 systems installed. FPS has a global technical team that supports these systems in the 40 countries where they are installed. One of the reasons for this success is the high level of expertise of our staff. This expertise has been gained over 18 years of innovating in our field. The entire design and production process of the systems takes place in our state-of-the-art plant of Fiorenzuola d'Arda in Italy. This allows for optimum knowledge sharing & team work. As a result, each team player becomes an expert in his/her field and it really shows in the level of innovation and quality delivered. Another reason for FPS success is our ability to listen to the specific needs of the customer, to focus
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on its process and to design a custom solution to address all those needs. It has been one of the strengths of FPS over the years. Once the needs are well understood, the next step is to conduct the initial study of the project: a specialised team proposes a solution and works closely with the customer to ensure compliance with the technical specifications required. As far as containment systems are concerned, spray-drying is a commonly adopted technology in pharmaceutical to obtain a powder from a liquid solution. Given that pharmaceutical companies are handling High Potent API more than ever before, high containment solutions are necessary to safely operate the equipment. In the past year, some of the isolators that FPS has designed and manufactured have been specifically to contain spray drying equipment. By using an isolator, pharmaceutical manufacturers want to ensure full operator protection without the need for bulky
and process engineering departments to design the isolator. Mock-up of those systems were built to simulate the activities and validate the technical solutions. Operators were also part of the process. In the end these isolators had the following features: - adjustable height for isolator optimum access to the processing equipment, with - proper rating to work in hazardous conditions (according to the area classification) - cooling of working chamber to keep the temperature constant (to counter heat created by the spray dryer) - isolator creatively designed and delivered in small sections to pass narrow doors and assembled on site as one unit Personal Protection Equipment full-suits that can be cumbersome, costly and may provoke falls. One of the key requirements that pharmaceutical companies have for isolator manufacturers is not to alter the current process. The goal is to avoid lengthy and costly process re-validation. Another requirement is to ensure excellent ergonomics to avoid operating errors, product loss and work injuries. The FPS design team is very familiar with those aspects and can also accommodate others. For example, one of FPS customers flagged that their multi-cultural team had a very wide variation in height. Their workers were very concerned that the isolator would be too low or too high for their own height and they worried about potential long-term health issues. Another customer had to fit the isolator into a very tight space and the equipment had to be brought in the installation room through narrow doors.
AUTHOR BIO
To address those issues FPS engineers worked in close collaboration with the end-user technical, safety
"The users were very excited to do away with the cumbersome personal protective equipment. The ergonomics are much improved to perform the process and they like the flexibility of going in and out of the lab without gowning and disgowning" says Frederic Le Pape, the FPS America General Manager. One customer uses a micronisation step in a separate chamber of the spray drying isolator and sees many benefits. For example, there is no need to use a split butterfly valve for product collection which are costly and time consuming to assemble, disassemble and clean. Finally, the isolator protects the product from moisture during feeding and collecting phases for the spray dryer (and for the jet mill when used after the spray drying). As always, the objective of FPS is to be of service to the Pharmaceutical and Fine Chemical industries. The mock-up is one of the tools that help us fulfill 100 per cent of the needs of our customers.
Frederic Le Pape has 20 years of technical sales experience in the Pharmaceutical industry in North America. He was first involved with solid dosage applications before joining FPS and focusing on containment of potent powders and sterile liquids. The containment can be provided by custom rigid-wall isolators but also by RABS (Restricted Access Barrier Systems), Downflow booths and LAFs. He is also well versed in powder micronisation from R&D, to pilot, to commercial applications. Advertorial www.pharmafocusasia.com
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EMERGING TECHNOLOGIES FOR PARTICLE ENGINEERING Particle engineering is normally associated with particle size reduction techniques, such as media milling and homogenisation, and particle formation techniques, such as spray-drying, supercritical fluid technologies, and precipitation. The emergence of nanotechnology and spray-freezing into cryogenic liquids, supercritical fluid technology, and 3D printing technology are revolutionising the development and manufacture pharmaceutical dosage form. Dilip M Parikh, President, DPharma Group Inc.
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he constant requirement for the targeted delivery of therapeutically active agents has been the key driver in particle engineering and processing within the pharmaceutical industry. Particles are making advances in the area of human healthcare where they are being used to diagnose illnesses, cure cancer, deliver drugs and retard aging. Particle Science is becoming recognised as an enabling technology that helps us create new
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energy sources, clean our air and water and build stronger and lighter materials1. Traditional methods of producing particles suitable for pharmaceutical applications employ dry or wet granulation process, fluid bed processing to agglomerate, or coat to produce modified-release products, or spray drying as well as hot-melt extrusion process to enhance water solubility of poorly soluble drugs. Particle generation and handling have been an integral part of pharmaceutical processing because of the wide use of solid dosage forms. Recent additions to the pharmaceutical particle engineering technologies include sprayfreezing into cryogenic liquids, template emulsion, and self-assembly. There are few commonly used particle generation methods such as mechanical milling, precipitation, and spray drying among them. In the case of the manufacture of Active Pharmaceutical Ingredient (API), the API molecule is engineered to a crystal form, which is then processed into particles and finally 'formulated' into the dosage form. Excipient manufacturers have produced a range of products that can modify the formulation, processing, and delivery of APIs through elaborate excipient material and particle engineering. Solubility issues are typically the most common hurdles to achieving ideal bioavailability. These can be divided into molecules that are poorly soluble and 1 http://perc.ufl.edu/pst.asp
those that are just too slow to dissolve. Approximately 80 per cent of the drug candidates in the R&D pipeline exhibit poor solubility in water. Spray drying for producing particles suitable for pulmonary application is a well-established technology. Pulmonary drug delivery for both systemic and local treatments has many advantages over other delivery routes because the lungs have a large surface area, thin absorption barrier, and low enzymatic activity. An enormous diversity of therapeutic agents is currently administered to the patients via aerosol inhalation, and the number of potential drug candidates for pulmonary application increases daily. Protein powders find increasing application in the dry powder inhalation and sustained drug delivery. Powders for pulmonary
application require powder to be dispersible which in turn depends on the efficiency of the device and the physical characteristics of powders such as size, shape, crystalline form, and structure that directly affects the stability and releasing pattern of drugs. In some cases, the spray drying technique provides particles that some time may be denser and may not deposit deep in the alveolar region. The technique of spray freeze drying creates particles which are porous balls thus changing the particle density and the probability of effective deposition of drug in the lungs. Another approach that is being widely used is the use of Liposomes for drug delivery. Liposomes are promising vehicles for pulmonary drug delivery owing to their capacity to target drug to cells, such as macrophages, and to alter the pharmacokinetics of drugs. They also provide sustained release, prevent local irritation, increase drug potency, reduce toxicity, and uniformly deposit active drugs locally. Lu and Hickey used a model protein that was used to evaluate both the feasibility of delivering dry powder liposome formulations for protein and, more importantly, whether the process of lyophilisation could be used to prepare dry powders suitable for pulmonary delivery. Recent developments in nanoscience, combining physics, chemistry, material science, theory, and biosciences, have brought us to another level of understanding of ‘‘Nanotechnology 2 Nanotechnology is the science and technology at the nanoscale, which is about 1 to 100 nanometers. The prefix ‘nano’ means ten to the minus ninth power, or one-billionth and is about a thousand times smaller than a micron. Nanoparticulate systems are being explored for the purpose of solving the challenges of drug delivery. Nanotechnology researchers are working on several different therapeutics where a nanoparticle can encapsulate or other2 https://shodhganga.inflibnet.ac.in/bitstream/10603/78861/6/06_chapter%25201.pdf
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wise help to deliver medication directly to cancer cells and minimise the risk of damage to healthy tissue. Research in the use of nanotechnology for regenerative medicine spans several application areas, including bone and neural tissue engineering3. There are wide varieties of techniques that can create nanostructures with various degrees of quality, speed, and cost. These approaches fall under two categories, bottom-up and top-down. Both these processes similar to dry and wet granulations generate materials with different properties. Targeted delivery of proteins and DNA requires a carrier system in sub-micron size or nano size. Nanosuspension has been used to deliver drugs by injection while the nanoparticles of protein have been prepared for the pulmonary application. Researchers are looking for ways to grow complex tissues with the goal of one-day growing human organs for transplant. Researchers are also studying ways to use graphene nanoribbons to help repair spinal cord injuries; preliminary research shows that neurons grow well on the conductive graphene surface 4. Nanoparticles do have great potential for anticancer drug delivery and tumour targeting. Another very promising area for nanoparticles is the possibility to deliver drugs that normally cannot cross the blood-brain barrier to the brain after intravenous injection. One of the major challenges in drug delivery is to get the drug at the place it is needed in the body thereby avoiding potential side effects to non-diseased organs5. This is especially challenging in cancer treatment where the tumour may be localised as distinct metastases in various organs. A narrow particle size distribution and a uniformly small particle size are often critical quality attributes of pharmaceutical solids, particularly for injectable suspensions and drugs intended for aerosol administration. 3 https://www.nano.gov/you/nanotechnology-benefits 4 https://www.nano.gov/you/nanotechnology-benefits 5 https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC2527668/
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Since the mid-1980s, a new method of particle generation has appeared involving crystallisation with supercritical fluids like carbon dioxide (CO2). The process is especially suitable for forming engineered particles for inhaled medicines, both in suspension metered-dose inhalers and dry powder inhalers. The main advantages over other technologies are that highly crystalline and stable particles are formed, and processing from drug solution to dry particle is a single-step process. Another emerging technology for particle size reduction uses supercritical fluid technology to produce finely divided powders. One such method, supercritical anti-solvent precipitation (SAS), accomplishes particle size reduction by using the supercritical fluid as a non-solvent to precipitate a drug from an organic solvent. The supercritical fluid, typically (CO2), is at least partially miscible with the organic solvent. The CO2 will cause high supersaturation ratios within the drug solution, forming many nuclei, leading to crystal growth. The mild conditions used in the process are favourable for most pharmaceutical compounds and the majority of the organic solvent may be extracted by using a continuous flow of CO2 following precipitation A different technique, the Particles from Gas-saturated Solutions/suspensions technique (PGSS}, makes use of the fact that compressed gases sometimes show better solubility in liquid or dispersed drugs than these drugs in the compressed gases. Melts of drugs are, generally, saturated with the supercritical fluid and this mixture is expanded through a nozzle. In the last 15 years, researchers have utilised 3D printing technologies to address the current limitations in the manufacturing of drug products and challenges in the treatment of patients. 3D printing, also aptly named as additive manufacturing, is revealing its potential in the pharmaceutical industry as it turns personalised medicine into reality. In fact, additive manufacturing has the unique ability to deliver quickly, flexibly and economically set amounts of patient-
specific drugs with properties, such as formulations, dosages or geometries. The shift from bulk manufacturing of drugs, towards the design and production of personalised medication and dose tailoring, requires the optimisation of different 3D printing technologies and the processing of suitable. The medical use of 3DP includes the creation of custom prosthetics, body tissue, organ fabrication, anatomical models, dental implants, pharmaceutical research regarding drug dosage forms, drug delivery and discovery. Pharmaceutical applications for 3D printing are expanding rapidly and are expected to revolutionise healthcare. 3D printing technologies are already being used in pharmaceutical research and fabrication6. The advantages of 3D printing include precise control of droplet size and dose, high reproducibility, and the ability to produce dosage forms with complex drug-release profiles. The recent launch of antiepileptic drug SpritamŽ by Aprecia in 2015, using 3-D printing has created enormous interest in this rapidly growing segment to cater to patients requiring special personalised medications for long term care or life cycle management. Although 3D printing technology showed promising results in drug delivery applications, the technology is still under the developing stage. The challenges include optimisation of the process, improving the performance of the device for versatile use, selections of appropriate excipients, post-treatment method, etc., need to be addressed to improve the 3D printed products’ performance and to expend the application range in novel drug delivery systems7. Another novel approach is the particle engineering of biomolecules using Protein-Coated Microcrystals (PCMCs). The formulation and stabilisation technology of proteins, nucleic acids, and vaccines by the co-precipitation of a 6 http://drrajivdesaimd.com/2017/06/26/3d-printing/ 7 http://docplayer.net/52661013-Application-of-3dprinting-technology-in-the-development-of-novel-drugdelivery-systems.html
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water-soluble carrier, such as amino acid or carbohydrate, with a dehydrated biological macromolecule, makes them highly suitable for delivering biomolecules by a number of routes, including pulmonary and parenteral administration. Another unique particle engineering technology incorporating a combination of droplet evaporation and anti-solvent crystallisation by a sonication process known as solution atomisation and crystallisation by sonication, which has been developed to produce nanoparticles within a well-defined particle size range while manipulating the nucleation and crystal growth process within the supersaturated droplets. Summary
As can be seen by the brief introductions to these emerging technologies in this article, the scientific pursuit of modification of particles is gaining momentum as the commercial exploitation propels the scientific community more intent on
delivering the particles, especially for the pharmaceutical industry. Particle engineering, a young discipline, combines elements of many others, including chemistry, pharmaceutics, interface, and colloid science, mass and heat transfer, aerosol and powder science, and solidstate physics. Considering that the current level of development of pharmaceutical particle technologies is relatively limited,
and the understanding of the relationships between such materials and processes in the development and manufacturing of pharmaceutical products is at an early stage, there remains an onerous path for the successful development and implementation of particle-based technologies in the pharmaceutical industry. References are available at www.pharmafocusasia.com
Dilip M Parikh is president of the pharmaceutical technology development and consulting group DPharma Group Inc. USA. He has more than 45 years of experience in product development, manufacturing, plant operations, and process engineering at various major pharmaceutical companies in Canada and the U.S. He is the editor of “Handbook of Pharmaceutical Granulation Technology” 3rd ed. And the author of the recently published book “How to Optimise fluid bed Process Technology”. He has been an invited speaker at scientific conferences worldwide on solid-dosage technologies development and manufacturing.
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Hong Kong International Airport: A leading transport hub for pharmaceutical cargo The world’s busiest cargo airport continues to enhance its ability to capture fast growing markets
R
ising affluence and living standards, most notably in Asia and Mainland China, is driving global demand for high-value products, particularly temperature-controlled pharmaceuticals. The trend calls for quality cold chain solution to provide assurance in transportation and storage condition for these products. The rise in demand for time and temperature sensitive shipments and growth of international trade has given a significant boost to the global cold chain logistics market. Research projected that the market will register a CAGR of 17.9% from 2019 to 2026 while Asia-Pacific will continue to account for the highest share1. Pharmaceutical is a fast-growing segment in cargo industry. According to Seabury Consulting, 1. Cold chain logistics market by end use industry, global opportunity analysis and industry forecast 2019-2026, Allied Market Research (Jul 2019)https://www.alliedmarketresearch. com/cold-chain-logistics-market
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pharma shipments are expected to grow at 16% annually from 2016 to 2023 at Hong Kong International Airport (HKIA). HKIA, as a transshipment hub for pharmaceuticals, is committed to offering peace of mind for the forwarders and shippers. To protect product integrity on one hand and maximize shelf life on the other, pharmaceuticals require stringent control processes throughout the logistics chain and are best served by air cargo. In respond to the needs, HKIA has pioneered new service offerings to provide shippers a unique quality assurance.
Quality assurance for pharma shippers In January 2019, HKIA announced collaboration with Brussels Airport, Europe’s key air cargo hub for pharmaceutical shipments, to launch an airportto-airport Pharma Corridor (Pharma Corridor) under
Pharma.Aero, a cross-industry international collaboration platform. Both airports have attained the International Air Transport Association’s (IATA) Center of Excellence for Independent Validators in Pharmaceutical Logistics (CEIV Pharma) by community approach; certifying all air cargo service providers at both ends adhering to the highest standards in handling pharmaceutical shipments. Connected by Cathay Pacific, also an IATA CEIV Pharma certified carrier that offers direct service between two places, a seamless temperature-controlled chain of handling from origin airport to destination airport is materialized. Coupledwith sophisticated cold storage and cool dollies for apron transportation, HKIA and Brussels are committed to pioneering a trustworthy model and proving that is what the shippers ultimately want. The Pharma Corridor is the first of its kind to invite leading pharmaceutical companies, Pfizer and Merck Sharp & Dohme, to take part in. Besides standard Service Level Agreements (SLAs), Key Performance Indexes (KPIs) were set up to stress test the corridor in terms of product temperature, documentation, security, lead times of handling processes, and quality and product integrity. A trial including close to 50 live shipments with various temperature profile and packaging have been completed and fully analyzed. A dashboard recording the end-to-end shipment activities has offered unprecedented visibility on the actual performance. Report shows the consolidated effort of two CEIV Pharma certified airport communities have achieved zero case of temperature excursion and over 95%
fulfillment for all KPIs. After monitoring a predominant majority of shipments that have been transported by cool dollies on ramp at both airports, result corroborates its effectiveness in protecting shipments from prolonged exposure to ambient temperature. The study reaffirms the handling along the Pharma Corridor consistently adheres to high CEIV Pharma standards. From now on, shippers whenever shipping via Pharma Corridor, they can be provided with full confidence and peace of mind that their shipments are well taken care of. Apart from acknowledging the quality assurance is indeed in place, the quality handling of Pharma Corridor also creates the opportunities for shippers and handling agents to further optimize their packaging and operating procedures that cater to the peculiarity of different products. Moving forward, HKIA and Brussels Airport are now working to expand the corridor network to other qualified airports, with an aim to form a network of Pharma Corridors, offering shippers the quality choices to ensure their products to reach more corners of the globe intact and efficiently. In parallel, HKIA continues to invest in cold chain facilities and apron shelters, that add another layer to protect pharmaceutical shipments from direct weather elements, would be available in mid-2020. By attaining CEIV Pharma accreditations and pioneering the world’s first Pharma Corridor, HKIA continues its dedication to serve pharma shippers with comprehensive facilities.
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INTRAPERITONEAL SUSTAINED - RELEASE CHEMOTHERAPY FOR REFRACTORY OVARIAN CANCER O
verall death cases from Ovarian Cancer (OC) accounts to be the highest among different gynaecological malignancies affecting cervix, uterus and ovaries. The extremely poor survival rates of 15-30 per cent at late stages of OC is mainly due to the advanced-stage detection of the disease, viz, Stage III or IV, wherein, the aggressive tumour spreads within and beyond the peritoneum. The highly asymptomatic nature of the disease coupled with inadequate screening methods also contribute to the disease lethality. Epithelial Ovarian Cancer (EOC), wherein the tumour originates from the surface layer of ovaries, constitute about 75 per cent of the total disease incidences and the long term survival of EOC patients remains poor according to recent reports. Unlike other
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A localised metronomic approach sustaining low chemotherapy drug concentrations in the peritoneal cavity can be very effective for late stage ovarian cancer therapy. Biodegradable polymeric woven nanotextiles can serve as suturable intraperitoneal depots by providing extended drug elution for>2 months, wherein the metronomic doses render both anti-angiogenic and anti-tumour effects. Smrithi Padmakumar, Post-Doctoral Researcher, Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University Deepthy Menon, Professor, Centre for Nanosciences and Molecular Medicine Amrita Institute of Medical Sciences Mansoor Amiji, Professor, Pharmaceutical Sciences, and Professor, Chemical Engineering, Northeastern University
tumours, EOC metastasizes via transcoelomic route by which the malignant cells exfoliate along the peritoneal cavity by virtue of peritoneal fluid flow. Hence,
peritoneum is the primary and predominant site of EOC metastasis (Stage III) which subsequently spreads to omentum and later to distal organs such as liver and
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lung (Stage IV). Peritoneal metastasis is mainly favoured by the absence of an anatomical barrier within peritoneum and the continuous flow of fluid rich in tumour cells. Obstruction of lymphatic vessels by tumour cells impairs the drainage mechanism, particularly in late stages, thereby leading to the accumulation of massive amounts of peritoneal fluid, a condition termed as cites. Ascitic fluid circulation increases the rate of metastatic tumour progression at distant sites beyond abdomen. Furthermore, EOC is considered to be a richly vascularised tumour which is dependent on Vascular Endothelial Growth Factor (VEGF) mediated angiogenesis, which concurrently enhances the peritoneal vascular permeability increasing the ascites accumulation. Intraperitoneal (IP) chemotherapy and metronomic dosing in OC
The current mainstay of ovarian cancer therapy is debulking surgery to remove peritoneal tumour nodules, followed by intravenous (IV) chemotherapy of a combination of platinum and taxane drugs at their Maximum Tolerated Doses (MTD). However, the cumulative, doselimiting, and irreversible toxicity issues caused by IV drug doses cannot be negated, although the overall therapy provides substantial survival benefits. Most importantly, almost 80-90 per cent of EOC patients manifest a disease relapse even after the conventional therapy schedule involving surgery and standard six cycles of IV chemotherapy. Acquisition of resistance owing to frequent drug administration is another phenomenon typically observed upon tumour relapse. In such a context, a localised intervention facilitating chemotherapy drug delivery exclusively to peritoneal tumour nodules would enhance drug retention within peritoneal cavity and associated organs. Such an approach termed intraperitoneal(IP) chemotherapy mitigates the systemic toxic effects imparted by IV chemotherapy. The existence of peritoneal plasma barrier and physico-chemical properties of drugs with a high peritoneum/plasma
AUC ratio helps in exploiting the pharmacokinetic advantages of IP therapy. Along with the direct peritoneal drug uptake by tumours via microcirculation, systemic drug absorption also takes place in tumour tissues and the submesothelial space of peritoneum. Additionally, IP route also enhances the targeting of avascular residual tumour nodules left after debulking, thereby maximising the overall tumour targeting (Figure 1). Although several clinical trials have established significant survival benefits conferred by IP therapy in debulked OC patients, it is still underutilised and has not yet become a standard of care in the clinics. This is due to the practical difficulties imposed by indwelling intraperitoneal catheters, which are used to administer frequent and intermittent IP doses. These include leakage and port access issues, resultant bowel obstruction and IP bolus dose-imparted toxicity. Alternatively, a different approach to circumvent these concerns caused by the intermittent and frequent drug administration at MTD, is the continuous elution of drug without sequential breaks, at lower doses. Such a dosing regimen, also called as ‘metronomic therapy’ aims at shifting
the target of action of the chemo drugs from tumour cells to its vasculature, correlating with the enhanced sensitivity of endothelial precursor cells to low doses of several drugs. Metronomic dosing can also help to overcome drug resistance, cause immunomodulation and improve anti-tumour effects. Over the years, extensive pre-clinical data is available, pertaining to the advantages of IP therapy via both intermittent and metronomic dosing regimens, for refractory OC therapy. Nanoparticles, microparticles, injectable hydrogels, etc. have been developed as IP depots and investigated in detail by various groups. While nanoparticulates appeared to clear quickly from the peritoneal cavity, microparticulates caused the formation of undesirable peritoneal adhesions in animal models. Injectable depots on the contrary, retained the peritoneal drug levels, however, non-homogenous drug distribution and viscosity issues curtailed their potential application as IP depots. Microdevices formulated by Cima et al, released cisplatin for a long duration of about 42 days in peritoneal cavity of mice model. Nevertheless, these devices were found to migrate to the extra-peritoneal
AVASCULAR TUMOR NODULE
VASCULARIZED TUMOR
Ascites fluid
Mesothelial layer Basement membrane Connective tissue
Maligant cell
Tumor mateix
IP affinity targeted drug
Mesothlial cell
Blood vessel
Systemic affinity targeted drug
Tumor fibroblast
Connective tissue matrix
Figure 1: IP therapy maximises the amount of drug reaching tumour by both direct penetration and systemic circulation. Reprinted with permission from.
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regions, thereby triggering a probable non-uniform drug distribution in peritoneum. Although there has been considerable progress in the development of IP drug delivery systems for refractory OC, no specific formulations have been approved by FDA till date. Biodegradable Implants for Sustained-Release IP Delivery Design criteria for long-acting sustained release IP delivery in OC
Specific design criteria needs to be considered for developing an ideal IP drug delivery platform for refractory OC therapy (Figure 2). The most important amongst these is the peritoneal drug retention that prevents rapid clearance of the drug, ensuring prolonged anti-tumour activity. This can be achieved by adopting various drug encapsulation strategies so as to improve drug residence time in the peritoneum, which improves its penetration into microscopic tumour nodules, especially post debulking surgery in EOC
patients. Toxicity issues can be obviated by having precise control over the drug dosing regimen, as in metronomic scheduling of continuous low drug doses. Additionally, the depots should be fabricated from biocompatible and preferably biodegradable polymers, mainly to avoid the undesirable toxic effects which can otherwise be imparted by the matrix or its residues. Considering all these attributes, implantable depots would be ideal candidates for IP therapy owing to their ability to elute drug for prolonged durations. Moreover, considering the large peritoneal cavity space accommodating all of the abdominal organs, it is important to prevent migration of the implant to other regions. An implantable depot which can be fixed to the peritoneal wall by simple suturing can be an ideal solution. In the clinical context, this is a feasible option owing to the ease of implanting the depot after surgical debulking of tumour, ruling out the need for another surgical invasive procedure.
DESIGN CRITERIA FOR SUSTAINED DRUG ELUTING INTRAPERITONEAL DEPOT Biocompatibility of matrix
• Fabrication of depots from biodegradable polymers • Wide flexibility in selection of polymers with different degradation time frames • No toxic by-products of degradation
Prolonged IP drug retention
• Enhancement of drug residence time • Prevention of rapid clearance of drug • Augmented drug retention in peritoneal fluid and tissues for long-term anti-tumor activity
Metronomic dosing regimen
• No need for frequent drug administration • Better anti-tumor efficacy by anti-angiogenic approach • Less systemic toxicity issues
Suturability of depot
• Prevention of implant migration to extra-peritoneal region • Improved homogenous drug distribution localised within peritoneal cavity • No need for pumps or indwelling catheters
Figure 2: Schematic illustration showing the specific design criteria for sustained drug releasing intraperitoneal depots for OC therapy.
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Such a depot could facilitate a long-term drug release into peritoneal cavity and consequently prevent the chances of a probable disease relapse. Development of drug-eluting biodegradable woven fabrics
The technique of electrospinning has been established as a feasible method for the fabrication of fibrous matrices using biodegradable polymers entrapping different therapeutics and bioactive constituents. It offers wide flexibility in the selection of polymers with varied degradation time-frames and thus enables the modulation of drug release profiles. Moreover, it also aids in the fabrication of scalable quantity of continuous fibres with nano/micro morphology and different architectures, and facilitate high drug loading via appropriate choice of polymer: drug: solvent combinations. Adopting the technique of modified electrospinning using a rotating collector (our patented technology), our group has developed uniform and continuous nanofibrous yarns from the biodegradable polymer polydioxanone (PDS), entrapping the chemodrug, paclitaxel (PTX) with an efficiency of ~90 per cent. These yarns with an average diameter of ~240 µm and good mechanical strength were subsequently woven into nanotextile fabrics by applying textile technology-principles of plain weaving. Woven fabrics of different packing densities were developed by modulating weaving parameters such as number of warp/weft yarns and the distance between heddles in weaving-loom, thereby forming tightly-packed and loosely-packed implants. PTX-loaded yarns were found to render a drug release profile for over 90 days in vitro in PBS, which almost correlated with its complete degradation in vitro within 120 days. Mechanistic modelling considering the nanofibrous architecture of these yarns proved that the overall biphasic release profile was rendered by a combination of both PTX-diffusion and PDS-degradation. Drug release studies from woven fabrics showed that tightly-packed fabrics eluted
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PTX at a much slower rate in comparison to loosely-packed ones that released drug at a rate similar to yarns. Highly-packed matrices in general, take longer time to undergo complete hydrolytic degradation, which consequently slows down the drug release rate. Similar findings were observed for drug release experiments conducted in patient-derived peritoneal fluid samples, wherein the overall amount of drug released was higher owing to accelerated degradation of nano-fibers. Loosely-packed woven fabric implant was chosen for in vivo experiments considering its ability to offer higher loading dose and optimal drug release kinetics. In vivo experiments performed in healthy BALB/c mice by suturing the implant to peritoneal wall showed that the implants remained intact at the sutured site without any adverse effects for a duration of >56 days. The in vivo drug release profile from the woven implant was biphasic, constituted of a burst phase within 5 days, followed by a continuous metronomic phase for nearly 60 days. This burst phase mimics the clinically administered bolus IP dose of chemotherapy drug and the metronomic regimen correlates with the maintenance therapy that would prevent disease relapse. This long-term drug release profile was also found to retain good therapeutic PTX-levels in both peritoneal fluid and all peritoneal tissues for >28 and 56 days respectively. These results were in total contrast to mice injected intraperitoneally with PTX in solution (single bolus dose as clinical control @20mg/kg dose relative to the single implantation of fabric), wherein the drug levels were found in tissues only on the first day of drug release, owing to its abrupt clearance. Efficacy and Safety of Drug-Eluting Biodegradable Fabrics in OC IP implantation of biodegradable fabrics in ID8-VEGF OC model
In order to study the anti-tumour effects of woven fabric implant, efficacy studies were performed in ID8-VEGF syngeneic
Suturing to healthy BALB/c mouse peritoneal wall
PTX-loaded woven fabric implants
ID8-VEGF ovarian tumor bearing C57BL/6 mice with swollen abdomen (untreated mice)
ASCITES BUILD-UP (Day 35)
No tumor & no ascites upon PTX- woven fabric implantation
PTX-woven fabric implants as IP depots
In vivo PTX release from implant in ID8-VEGF ovarian tumor mice model
Figure 3: PTX-woven fabric implants as intraperitoneal depots for OC therapy: a gist of the important results.
ovarian cancer mice model developed by injecting 4 million ID8-VEGF cells intraperitoneally into C57BL/6 mice. This model was chosen owing to its physiologic resemblance of human EOC metastasis. Previous studies had confirmed the onset of tumour growth in these mice at day 8 post tumour injection, through increased VEGF levels (~36-fold higher than that of naïve mice) and presence of Tumour Associated Macrophages (TAM) in peritoneal lavage by ELISA and FACS respectively. Considering these results, PTX treatment via woven fabric implantation and IP injection were also performed on day 8 post tumour inoculation. The in vivo PTX release profile was similar to that observed in naïve mice wherein over 55 per cent and 70 per cent of total entrapped PTX were released within 7 and 28 days respectively (Figure 3). In vivo efficacy studies
The in vivo efficacy response to PTX therapy (given at a clinical dose of 20mg/ kg) was studied in ID8-VEGF tumour
model over a course of 35 days post tumour injection. It was observed that control animals (untreated mice and those implanted with woven fabrics without PTX) showed a gradual development of ID8 tumour manifesting swollen abdomen with tumour nodules in peritoneal tissues and diaphragm, accompanied by a progressive accumulation of ascitic fluid (~5-7ml) by day 35. Although PTX-solution injected animals did not show tumour nodules, and only blood traces in the initial stages, metastatic lesions were present by day 24 along with ascites formation(~2ml) by day 35 (Figure 3). The reported short half-life of PTX in solution form might have hampered its peritoneal retention concurrently leading to tumour recurrence post its clearance. On the contrary, PTX-loaded woven fabric implanted animals manifested clean peritoneum consistently throughout the study, with no tumour nodules, blood traces or ascites accumulation at all time-points, resembling naïve animals. VEGF being the important
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In vivo safety studies
In vivo safety attributes of woven fabric implant at day 35 were studied by analysing the serum and lavage levels of liver enzymes, Alanine aminotransferase(ALT) and Aspartate Aminotransferase(AST) as well as complete Blood Cell Count (CBC). PTX treatment was observed to bring down the elevated ALT and AST levels of control groups both in serum and lavage. A slightly higher enzyme level was noted for PTX-solution injected animals relative to woven fabric implanted ones, possibly due to the hematologic toxicity imparted by PTX bolus doses. Reduction in WBC and RBC counts noted for control animals were negated by PTX treatment, particularly for PTX-fabric implanted mice, wherein the levels were almost similar to those of naïve ones. Furthermore, neutropenia exhibited by control groups and PTX-injected animals was also absent in the case of woven fabric, wherein the levels correlated with naïve animals. These results affirmed the non-toxic effects of metronomic-PTX dosing from woven fabric implants. The bolus dosing as well as the presence of Cremophor® in PTX-solution can be considered as the reasons for toxicity imparted by PTX-solution. On the
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other hand, PTX-woven implants being fabricated from biocompatible and biodegradable PDS yarns did not induce any inflammatory response or other adverse events, signifying its safety profile. Conclusions
The pharmacokinetic advantages of intraperitoneal therapy when coupled with the anti-angiogenic effects of metronomic dosing can be effectively exploited for the treatment of refractory ovarian cancer. Sustained and metronomic release of chemo drugs exclusively into the peritoneal cavity can aid in the retention of prolonged drug levels with peritoneum, thereby hampering the chances of a probable disease relapse. Nanotextile fabric implants woven from biodegradable polydioxanone yarns can serve as suturable intraperitoneal drug depots for OC therapy. These implants when sutured to the peritoneal wall of ovarian tumour bearing animals were found to render substantial anti-tumour effects with enhanced safety for a long period owing to the continuous elution of metronomic PTX upon single implantation.
AUTHOR BIO
regulator of angiogenesis, triggering ascitic build-up and hence tumour progression, peritoneal lavage samples retrieved from mice of all groups and different time points were assessed by ELISA. While the control groups displayed a time dependent VEGF-level increase by day 35, PTX-woven fabric implanted animals showed a gradual decrease in VEGF levels, such that its day 35 levels were ~600-fold lesser than that of control groups (also similar to naive mice).This emphasized the effect of metronomicPTX dosing on the long-term suppression of VEGF-mediated angiogenesis and thereby tumour spread. These results of metastatic spread and angiogenesis were also confirmed by histology and immunohistochemistry using anti-CD-31 antibody respectively.
This low dose approach also aided in the mitigation of the adverse toxic effects of bolus PTX-doses. The overall strategy is also a clinically translatable technology which can be practically adopted by clinicians in a patient-compliant manner. Acknowledgements
Authors acknowledge financial support obtained from Pilot Project Grants, Program for Young Investigators in Cancer Biology of the Department of Biotechnology, Government of India and United States National Cancer Institute of the National Institute of Health through grants R21-CA179652 and R56- CA198492, and the Northeastern University-Dana Farber Cancer Center Joint Program on Cancer Drug Development. SP acknowledges DST-INSPIRE, Government of India for her Senior Research Fellowship and Amrita Vishwa Vidyapeetham for PhD Scholar’s Fellowship and other infrastructural support. References are available at www.pharmafocusasia.com
Smrithi Padmakumar is a Post-Doctoral Researcher in the Department of Pharmaceutical Sciences at Northeastern University, Boston, MA. She completed her MTech in Nanoscience and Technology and Technology (with a gold medal) and received a PhD in Nanomedical Sciences from Amrita Vishwa Vidyapeetham in2019. For her doctoral research, she received the prestigious INSPIRE-PhD Fellowship of the Government of India. Deepthy Menon is a Professor at the Centre for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham in Kochi. She completed her Masters degree in Physics from Cochin University of Science & Technology and a PhD in Physics from the Indian Institute of Science in Bangalore. Her lab focuses on the design of multifunctional nanomaterials for various biomedical applications including cancer therapy and regenerative engineering. Mansoor M Amiji is currently the University Distinguished Professor, Professor of Pharmaceutical Sciences, and Professor of Chemical Engineering at Northeastern University in Boston, MA. He received a BS degree in pharmacy from Northeastern University in 1988 and a PhD in pharmaceutical sciences from Purdue University in 1992. Amiji’s research focuses on the development of biocompatible materials from natural and synthetic polymers, target-specific drug and gene delivery systems, and nanotechnology applications for medical diagnosis, imaging, and therapy.
INFORMATION TECHNOLOGY
The CyberPhysical Security of Pharmaceutical Manufacturing Processes The cyber-physical security of any manufacturing system, specifically food and drug manufacturing, is essential. The technology in the pharmaceutical industry advanced significantly in last decade to improve upon every aspects of drug manufacturing. However, much less attention has been paid to identify and proactively mitigate the risk of cyberphysical attacks. Viruses that threaten these systems are very real and in recent years have proven very harmful and costly. Those that target drugs consumed by billions of people worldwide will inevitably have deadly consequences. Even with dedicated IT departments focused on determining cyber-physical attacks, it is imperative that a base layer of protection should be integrated into pharmaceutical manufacturing plants for the well-being of manufacturing system as well as consumers. This paper gives the overview of methods and tools useful for cyber-physical security of pharmaceutical manufacturing processes. Ravendra Singh, Engineering Research Center for Structured Organic Particulate Systems (ERC-SOPS), Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey
T
he cyber-physical security is no longer an area that should be overlooked. Unfortunately, cyber-physical attacks of all kinds may
cost companies a great amount of money and countless lives. In a recent PharmaIQ report, an increasing trend of ‘cyberphysical security risk’ has been found.
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Therefore, a systematic framework is needed to mitigate the risk of cyberphysical attacks. Pharmaceutical plants need to employ security measures in order to lay the foundation of a comprehensive cyberphysical security plan. These measures will be the integration of cyber-physical security tools into the pilot-plant network in order to prevent and deter infiltration. It should be noted early on that the Work Station (WS) computer should not be used for any purposes outside the scope of the manufacturing plant to minimise risks of possible cyber-physical attacks. This includes trivial activities such as checking emails and surfing the web because after all, the most common type of cyber-physical attacks are malicious software downloads caused by clicking seemingly harmless links and attachments.
Process and pilot-plant
The direct compaction pilot plant at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers comprises of three different levels which utilise gravity as the main force responsible for transporting powders from and to each step of the process. The top floor holds the feeders that discharge API and excipients. The middle floor holds the mill, blender and lubricant feeder. The ground floor contains the final operation unit, the tablet press. The more details of the pilotplant can be found in Singh et al. (2014). In the pharmaceutical Manufacturing Plant, the local host belongs to the desktop computer that is referred to as the work station. The work station’s network is shared by the PLC, unit operation, and the Windows Server that runs control software.
Systemic framework for cyberphysical security of pharmaceutical manufacturing process
A systematic framework for cyber-physical security of pharmaceutical manufacturing process is shown in Figure 1. The pharmaceutical industry needs protection with expansion into cyber-physical defense as it can be integrated into the plant. The need of some of the tools such as network traffic analyser, file integrity monitoring tool, and data block monitoring tool are highlighted in the figure. A novel Cyber-physical Security (CPS) tool (developed in-house) is also shown in the figure. The pharmaceutical manufacturing plant is typically connected to various software/hardware via numerous pathways. The PLC is the industrial computer that allows control of the pharmaceutical manufacturing process. All unit operation except the
Profibus, Serial port
Ethernet
Snap7
Ethernet
CPS Tool (New Developed) R Software Wireshark
Data Monitoring/Control
Database and models OPC communication Figure 1: Cyber-physical Security of Pharmaceutical Manufacturing Plant
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INFORMATION TECHNOLOGY
Wireshark
Tablet Press
Simatic S7 400 PLC
Feeders
Mill
Feeders
Wireshark HMI
Network Interface PCS7
- Detailed data packet information - Statistics - Possible courses of action
Figure 2: Wireshark as a Network Traffic Analyser
tablet press of the plant is connected to the PLC via Profibus or a serial port. The tablet press is connected to the PLC by an OPC protocol, using OPC Scout. The work station has installed a Distributed Control System (DCS), a software that allows high level programming control as well as visualisation of the entire process. The work station also provides a center for which all IT and process data can be monitored and controlled as well as host the plant specific CPS Tool integrated into the plant. (Figure 1) A brief description of some of the cyber security methods and tools needed for cyber-physical security of pharmaceutical manufacturing are given below.
use the baseline of the network interface for a specific CPU in order to detect any abnormal activity (Figure 2). The baseline of the network interface is used as a reference in deciding routine traffic. The work station of a pharmaceutical plant should only allow packets of information that are familiar to be exchanged through the network. Wireshark’s role as a network analyser is demonstrated below. (Figure 2)
Network protocols are simply different sets of rules of communicating between computers. Setting these rules allows computers to transfer information in practical ways. But different activities on the computer require different protocols. Therefore, identifying protocols is essential to manufacturing operations to ensure only the activities that are allowed are successfully executed. The hypertext transfer protocol (HTTP) for example, in theory, should not be captured in Wireshark because the work station should not be used for browsing the web as mentioned in the introduction. But simply identifying different protocols is not enough to protect the plant. Additional pieces of information that Wireshark conveniently provide such as the source and destination IP addresses need to be examined as well. In the simplest scenario, an air-tight pharmaceutical manufacturing plant network would only allow exchange of information between the components under the same few IP addresses. Companies may work up to classify other networks that are allowed to communicate with the outside components. Information exchange through the work station’s Network Interface Card (NIC) would only see traffic to and from these addresses for manufacturing purposes. Once IT engineers build a permitted network system, they now have a foundation of regular traffic that
Network traffic analyser
The ease of access to pharmaceutical plants have increased with the advances of automation technology used in industry. Remote operation of the plant via DCS may make manufacture monitoring much more convenient but also opens the risk of vulnerabilities in the network. Network traffic analysers such as Wireshark may
Figure 3: Application of the network traffic analyser tool
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is allowed to pass through the interface. For example, Wireshark’s ability to filter specific IPs can help expose unwanted network infiltration. Filtering is the most basic of Wireshark’s function but also one of the most effective. The number of packets captured in a single analysis is substantial and the filter therefore eliminates ‘noise’ that is useless for seeking undesired packet exchanges. File integrity monitoring tool
The sheer amount of data stored in any given computer is nearly incomprehensible to the ordinary person. Data integrity, defined as the accuracy and consistency of stored data, is critical for pharmaceutical companies to keep accurate and credible as outlined by FDA guidelines. Tripwire is a file integrity monitoring tool to capture a baseline of system files and network device configurations. In short, Tripwire uses an authentic reference of the system’s state to continuously seek out any and all changes made in the system. While doing so, it ensures the inevitable changes made to the system are authorised and expected. Data block monitoring tool
SNAP7 is an open source library enabling communication designed for Siemens S7 PLC. It is primarily used in this regard to download data blocks directly from the PLC so that it gives users the ability to monitor and analyse data on multiple layers. The ability to supervise process data on different layers makes potential masking of values less effective for hackers. Reading data blocks gives way for the design of the CPS Tool to directly read information from the PLC without referring to equipment and software HMI where it has been known to be vulnerable to detrimental manipulation. Cyber-physical Security (CPS) tool
A new software tool has been developed catered to the needs of a pharmaceutical manufacturing plant. The tool takes advantage of the fact that operators and engineers have the upper hand in manufacturing knowledge. Ultimately, the CPS Tool serves as the defence mechanism most relevant to the continuous pharmaceutical manufacturing pilot plant to date.
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Figure 4: Demonstrative case study: Unauthorised Changes in File System
Results and discussion
The above mentioned tools have been integrated with pharmaceutical manufacturing plant to protect it from cyberphysical security risk and their performance have been evaluated. One of the applications of the network traffic analyser tool is shown in Figure 3. As shown in the figure, by typing “ip.adr == X.X.X.X” into the filter tool bar, the application will enable the access and security of that network. (Figure 3) One of the applications of the file integrity tool is shown in Figure 4. As shown in the figure, the authorised and unauthorised access of the work station can be identified using this tool.
For demonstration purposes, a baseline was set shortly after download for the application’s reference. It should be noted that, for the demonstration purposes the base line was set purposefully in such a way so that some unauthorised access can be created. Scan frequency was set to daily for seven days. It showed 48 unauthorised changes most days, implying the baseline should be updated or action be taken to stop them. Similarly, the applications of other cyber-physical security tools have been demonstrated for the security of pharmaceutical manufacturing process. (Figure 4) These methods are some of the most basic strategies employed by many compa-
INFORMATION TECHNOLOGY
Conclusions
Existing cyber-physical security measures such as those mentioned previously, and proactive IT teams have proved inadequate against malicious attackers. Pharmaceutical manufacturing plants need to accept that even with advanced cyber security, the human element in the setup of network infrastructures allows gaps, allowing criminals access to the plants. A proposed cyber-physical security tool boosts the defence against an attack by implementing an additional protection layer. The Cyber-physical Security Tool
(CPS Tool) may work in the favour of manufacturing plants by customisation of its defence scheme. Utilising inner knowledge of the complex process that is continuous manufacturing provides the upper hand to its users. Inspection of Critical Process Parameter (CPP) data in multiple layers for particular unit operations separately and collectively grants the most complete and authentic view into the manufacturing plant. A novel CPS Tool (developed in house) recognises the advantage of incorporating plant actuators and sensors to curb attempts at
AUTHOR BIO
nies worldwide. No matter the amount of resources exhausted into prevention of cyber-physical attacks, those such as Stuxnet and WannaCry continue to show that attackers are often one step ahead in finding network vulnerabilities. For long term safety and success, the pharmaceutical industry must go the extra mile and strive to be proactive.
maliciously manipulating the system. This is an absolute necessity which should have been implemented in all pharmaceutical manufacturing plants long ago. Acknowledgements
This work is supported by the National Science Foundation Engineering Research Center on Structured Organic Particulate Systems (C-SOPS), and Siemens Corporation Inc. References are available at www.pharmafocusasia.com
Ravendra Singh is Assistant Research Professor at C-SOPS, Rutgers University, NJ, USA. He is the recipient of prestigious EFCE Excellence Award from European Federation of Chemical Engineering. His research focus is pharmaceutical systems engineering. He is PI/Co-PI of several projects funded by FDA and pharmaceutical companies. He has published more than 64 papers, written 12 book chapters, presented at over 100 conferences and edited one pharmaceutical systems engineering book published by Elsevier.
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MEDAPP: Paving the way for Patient Support Programs The modern society is growing rapidly and while healthcare seems to be becoming more accessible and affordable, at the grass root it still doesn’t seem to become patient-friendly. We have more apps than ever before to serve even the most remote regions of the country, yet as the capital of chronic diseases, we are simply not being to cope up with the burden of chronic diseases and manage them well. What began as a one-stop home healthcare solution to address these concerns, Medapp has now evolved into a service provider to pharmaceuticals and fortune companies to enable better healthcare delivery. In spite of immense technological advancements, it’s largely the urban population that benefits the most of these upgrades. The rural areas still battle with healthcare basics and even primary healthcare is a challenge there. In a country where the mere awareness of a possibility of a condition remains low, it is obvious that a large population is undiagnosed and therefore, untreated. Taking healthcare down these by-lanes of the country is the challenge.
Who is Medapp It is said that the speed of the slowest member of the team determines a team’s speed. Medapp, founded by Niranjan Swamy, a trained nurse himself further to be a principal of a nursing college and seasoned educator for nurses and paramedics, was formed with the intent to delivering better healthcare than what’s prevalent - Dr Shiraz Nisar who is a co founder and Chief medical officer comes with a baggage of experience, he is an alumni of Cleveland Clinic and now serves as a Chairman of Medicine for University chain of hospitals back in Cleveland Ohio. Nabeel Ahmed on the marketing front comes with over 9 years of experience in the field of sales and marketing. Dr Vinod Singh is at the helm of operations and brings over a decade of healthcare and hospital industry experience. Sinu George, Director of Medapp, and a master’s in Nursing education and administration has ably guided over 5000 nurses and carries this passion for teaching and guiding the nursing staff of Medapp with a deft hand. Co-founder and Direc62
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tor, Krishna Raghavan, with his extensive industry network, is indispensable to business development. Together, this passionate and immensely talented team is what truly sets Medapp apart.
The Journey so far Medapp began as an app to Uberise home healthcare in Mysore, Karnataka delivering services like sample pickups, ECG at home, vaccination, fever management, wound management, and chronic disease management. Seeing the need of the healthcare in a town like Mysore, the team quickly realised what must be the plight of individuals in smaller towns and villages across the country. Quickly, the company evolved and branched out into a service provider for pharma giants and fortune companies to reach out to a greater patient base. They quickly headquartered in Bangalore and Delhi was a must-do right after and they soon put up offices across locations. The company’s presence in a span of 18 months grew from one state to 12 states. In fact, by the end of 2019, Medapp has successful presence in 80% of Tier II and III cities in India. Looking at figures from a strategic and financial stand point the company chose to be bootstrapped and continues to grow under the leadership of the dream team.
Products and Services Nursing excellence and operational astuteness are the two pillars of Medapp’s success, the team takes pride is stating that there have been 0 no shows in their entire journey. The two major services that drive business and growth for Medapp are Patient support programmes and Point of Care Diagnostics. Figure 01: Artboard PSP a. Patient Support Programs Primary and secondary care has been made convenient by our programs. Our programs include counselling, home infusion, geriatric care, drug and medicine administration, care and disease management, physiotherapy and dietician services.
attack, bone mineral density, pulmonary embolism, lung function tests, etc. Figure 02: Artboard POCT c. One-stop solutions for all healthcare services As an enabler of wellness, we provide one stop solution for all healthcare needs of a corporate entity or manufacturing companies. Be it onsite injections or infusions, emergency medical services or primary healthcare services like wound care, Medapp is an all-in-one healthcare solution.
Figure 01: Artboard PSP
d. Corporate Wellness Customised wellness solutions for corporates are our forte. Ranging from providing tailor-made solutions via empanelling nutritionists, personal trainers, physicians, to specialty consultants, we ensure that everyone gets what they need as healthcare requirements differ for each individual. We can create packages that differ based on therapy areas, or geographical location, or seniority, and so on.
There has been an increase in the shift of mind set of pharmaceutical companies from being product oriented to patient oriented on dealing with certain type of therapy areas. In fact, spending on such initiatives has risen nearly three folds in the recent years. To provide patient service is when Medapp comes into play.
e. Screening and awareness camps Starting with diabetes screening programs, Medapp has now diversified into respiratory as well as allergy screening camps. These camps enable pharmaceuticals to reach out to thousands of patients in one session and not just empower them with knowledge to improve their health, but also with a clear path of treatment and counselling sessions at the end.
b. Point of care services In a world where nobody has time, point of care diagnostics make a huge difference in ensuring timely diagnosis, and planning treatment regimen. They also reduce leakage of patients from hospitals and private clinics of doctors. Medapp uses the latest machines for accurate and rapid diagnosis of some of the commonest conditions like diabetes and its complications; coronary heart disease and heart
f. Occupational Healthcare Centre for industries Injuries are very natural while you have physical work. As per the factories act of 1948 any industry that deals with hard labour and that has more than 500 employees must have an OHC in place. We take the micro management of this from industries and take over as our expertise lies there. Medapp for it’s tremendous contribution in the field of healthcare has been awarded many awards like The Global Achiever’s award for the Best Solution Based Healthcare Startup. Living in the capital of diseases yet not a leader for disease management, that is where Medapp wants to fill up. An end-to-end healthcare solution company is how the dream team envisions Medapp of the future. With every step, slowly but surely, Figure 02: Artboard POCT this goal appears closer. Advertorial www.pharmafocusasia.com
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PRODUCTS & SERVICES Company........................................................................Page No.
Company........................................................................Page No.
STRATEGY
CLINICAL TRIALS
Cantel Medical............................................................................ IFC
Emirates SkyCargo...................................................................OBC
Bachem.........................................................................................37 Hoong-A Corporation...................................................................05 Quantys Clinical Pvt. Ltd...............................................................49 Rousselot......................................................................................39
Medical Manufacturing Asia................................................... 17-18
MANUFACTURING
Qatar Airways................................................................................11
Cantel Medical............................................................................ IFC
Swiss World Cargo.......................................................................15
Dishman Carbogen Amcis Limited...............................................07
Dishman Carbogen Amcis Limited...............................................07
F. P. S. Food and Pharma Systems Srl............................. 23, 44-45 RESEARCH & DEVELOPMENT
Hoong-A Corporation...................................................................05
Bachem.........................................................................................37
Kompress (India) Pvt. Ltd.............................................................09
Dishman Carbogen Amcis Limited...............................................07
Lonza...........................................................................................IBC
F. P. S. Food and Pharma Systems Srl............................. 23, 44-45 Kompress (India) Pvt. Ltd.............................................................09 Lonza...........................................................................................IBC Quantys Clinical Pvt. Ltd...............................................................49
Rousselot......................................................................................39 Valsteam ADCA Engineering........................................................03 INFORMATION TECHNOLOGY Kompress (India) Pvt. Ltd.............................................................09 medapp.................................................................................. 61- 63
SUPPLIERS GUIDE Company........................................................................Page No.
Company........................................................................Page No.
Bachem...................................................................................... 37 www.bachem.com
Lonza........................................................................................ IBC http://pharma.lonza.com/
Cantel Medical......................................................................... IFC www.cantelmedical.com
medapp.................................................................................61-63 www.medapp.in
Dishman Carbogen Amcis Limited............................................ 07 www.dishmangroup.com
Medical Manufacturing Asia.................................................17-19 www.medmanufacturing-asia.com
Emirates SkyCargo................................................................ OBC www.skycargo.com/emiratespharma
Qatar Airways............................................................................. 11 www.qrcargo.com/qrpharma
F. P. S. Food and Pharma Systems Srl...........................23, 44-45 www.foodpharmasystems.com
Quantys Clinical Pvt. Ltd............................................................ 49 www.quantysclinical.com
Hong Kong International Airport...........................................50-51 www.hongkongairport.com
Rousselot................................................................................... 39 www.rousselot.com
Hoong-A Corporation................................................................ 05 www.ha1511.com
Swiss World Cargo.................................................................... 15 www.swissworldcargo.com
Kompress (India) Pvt. Ltd.......................................................... 09 www.kompressindia.com
Valsteam ADCA Engineering..................................................... 03 www.valsteam.com
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