Pharma Bio World December 2018

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Traditional Indian Medicine Sourcing From The Heart Of The Earth

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INTERVIEW 08

“Green Chemistry is a competitive advantage for Indian pharma...”

Dr. Bapu Gawde, Founder & Director, Cleanchem Laboratories LLP

16

FEATURES Bringing Quality Forward Pays Off

18

Stirring Things Up In The Lab

16

INSIGHTS 26

Global Biosimilars Market (2018 – 2023)

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Biosimilars: Success Thus Far And Roadblocks Ahead

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Traditional Indian Medicine: Sourcing From The Heart Of The Earth

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Can Indian Traditional Medicinal Systems Show The Way Forward?

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interview

“Green chemistry is a competitive advantage for Indian pharma…”

The pharma industry produces life-saving drugs but some of its byproducts are harmful chemicals. But, green chemistry can help the industry change this perception as per Dr. Bapu Gawde – Founder & Director, Cleanchem Laboratories LLP in this brief interview with PBW.

What are the services offered by Cleanchem to the pharma industry in general?

Cleanchem Laboratories is an independent R&D based company working in the CRAMS space dealing with custom synthesis and supply of impurities as per EP, USP, BP and IP. We are also involved in pharmaceutical & agrochemical intermediates, fragrances & flavouring agents, speciality chemicals & NCEs, drug discovery and metabolites. We initially started out in the field of isolation, c h a ra c t e ri z a t i o n a n d id e n t if ica t io n o f unknown impurities especially process related impurities. Now, we also provide technical consultancy services and undertake projects of pharma R&D departments as well as manufacturing units related to pharma, biotech, specialty chemicals and allied industries.

Could you please elaborate a bit on process related impurities with reference to the pharma industry?

The impurities are the unwanted substances/ chemicals that are present in the APIs or develop during formulation. They are 8 ◄ December 2018

mainly detected during stability studies.

The presence of these impurities even in trace amount may influence the efficacy and safety of the medicine. The International Conference on Harmonization (ICH) has formulated certain guidelines regarding the control of impurities which are strictly inspected and recorded by various regulatory authorities like USFDA, European regulatory agencies, FDA (India), etc. The elimination or minimization of these substances in drugs as per the prescribed regulatory limits is of vital importance in the pharmaceutical industry.

How do you isolate and characterize unknown impurities?

Impurities are isolated by various physical, chemical and instrumental techniques based on its physicochemical properties.

Prior to its isolation, impurities are enriched in bulk mass or mother liquor by various chemical and physical methods for easy and quick isolation. Liquid impurities can be isolated via atmospheric, fractional or high vacuum distillation. Solid impurities can be separated and purified by recrystallization, column chromatography, preparative HPLC

or flash chromatography. These isolates and purified samples are then subjected to different analytical techniques like mass spectroscopy, FTIR, TGA, 1H-NMR, 13C-NMR, GC, HPLC, etc. Collection and interpretation of all these data help us in profiling the chemical structure, properties and purity of the sample. All this data is eventually used to generate the COA and SER reports.

You had also mentioned about metabolites earlier. What is its significance in dosage regimen design?

Metabolites are chemicals that are formed during various metabolic pathways of biological systems. In this process complex organic compounds are converted into simple molecules (eg. digestion of food and medicinal compounds in biological systems).

Metabolism gives us better understanding of drug action and help us in doing further studies like chemical activity, toxicological action, half-life, bioavailability of drugs, etc.

Accordingly, we can arrive at the optimum dosage level and cycle for a p a r tic u la r medicine. Studies of metabolic pathways Pharma Bio World

interview of drugs are very important while doing new drug discovery. This part of research includes theoretical design of scaffold, checking its activity with the help of advanced molecular modeling software, chemical synthesis of best fit molecules for maximum effect, in vivo and in vitro clinical trials, toxicological reports, impurity profiling, bioavailability studies and drug elimination/excretion analysis.

The pharma industry produces life-saving drugs but some of its byproducts are harmful chemicals. Can Green Chemistry help the industry to change this perception?

Yes, Green chemistry can change this perception as it's a zero waste concept where some of the chemicals used in the process can be recovered and reused.

The pharmaceutical and agrochemical industries are said to generate about 80-90% waste till the completion of the finished product. Hence, it is imperative to apply principles of green chemistry both at the concept and process stage. We need to consider the use of safer and less hazardous products in the manufacturing processes apart from ensuring that minimum waste is generated. We must think about green solvents or solvent free processes. Catalysts are one of the best alternatives that can play a key role in making processes greener. Most of the petrochemical and bulk chemical manufacturing processes that are catalyst based and continuous type are atom economical. In recent times, some of the hydrogenation processes are being carried out using phase transfer catalyst (PTC) which is a typical example of green chemistry and the right step towards sustainable development.

Do you see green chemistry as an impediment or a competitive advantage for the Indian pharma industry?

Green chemistry is an advantage for the Indian pharma industry as chemicals are 12 ◄ December 2018

reused and also there is less hazardous waste discarded in the environment. Novel and alternative options of processes will not only reduce production costs but also effluent treatment overheads which will all add up to substantial economic benefits.

Green chemistry applications reduce time and cost of processing/manufacturing materials as it involves the design of processes that reduce or eliminate the use and generation of hazardous substances in the product manufacturing cycle from start to end. The concepts of green chemistry enable the waste from one industry to be used as an input or raw material for other industries thus solving the problem of waste disposal. It aims to create sustainable development that is beneficial to both our society and the economy without causing environmental damage.

In short, the principles of green chemistry would enable the Indian pharma industry to improve efficiency, reduce waste and produce safer chemicals for users. Above all, it helps the industry to comply with existing legal requirements laid down by regulatory authorities like pollution control board, FDA, etc.

What are the green chemistry solutions provided by Cleanchem to the pharma industry?

At Cleanchem, our motto is to develop ecofriendly and economical processes. We provide eco-friendly process solutions to the pharma, agrochemical, petrochemical and allied industries. Our solutions lead to reduction of hazardous and toxic effluents, which is not only beneficial in terms of process safety but also a plus for the environment. We focus both on batch process as well as continuous processes and try to make it green via the design and application of novel catalysts. Our team is also working on biocatalysts, advanced downstream processing, development of novel herbal drugs and phytopharmaceuticals.

Teva, Johnson Matthey, Croda, etc) Indian corporates (Godrej, Reliance, RPG, Torrent, Lupin, Alembic, Glenmark, Macleods, etc) as well as academic and research institutes (IITs, UDCT/ICT, etc).

Does Cleanchem have any research collaborations with academia?

Cleanchem is engaged with many reputed a c a d e m i c i n s t i t u t i o n s l i k e I C T, I I Ts , University Mumbai, SNDT University and various other colleges. We have signed MOUs with them under joint research initiative as part of industry–academia collaboration. As part of this collaboration, our experts deliver lectures and guide students/faculty about the recent industry trends and technological breakthroughs.

We also offer students the opportunity to directly work on our research projects in our R&D laboratory whereby they get exposure to industry practices. Research students can avail our instrumental analysis facilities for testing of their samples You are registered as a LLP. Is there any specific benefit of being registered as a LLP? We had registered as a LLP as per the advice of our financial advisor. There is no special benefit of being an LLP; instead it is a millstone mainly because bank officials do not consider it at par with private limited enterprises and thus we are not able to avail the benefits of various schemes and loan facilities. Hence, my personal advice to all entrepreneurs who have proper expansion plans is to register as a private limited company rather than a LLP. It is always better to take a second/third opinion regarding such matters and not rely only on one source.

Could you list out a few of your notable clients?

You are a pharma startup in the true sense since you started your firm while doing your Ph.D. How has the entrepreneurial journey been so far?

We are working with more than 100 clients including MNC companies (Sanofi, Novartis,

Being a doctorate student at ICT (formerly UDCT), I had the good fortune to meet many Pharma Bio World

Pharma Bio World

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interview

VOL 16 | ISSUE 05 | DECEMBER 2017 | MUMBAI | TOTAL PAGES 60 | PRICE ` 150

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1) Be clear about your objectives and stay focused on them.

2) Get a strong team since you as an entrepreneur cannot do everything.

3) Be confident, self-motivated and inspired.

4) Always try out new technologies and new applications.

5) The market is very fickle and hence you have to be always in tune with it. In other words, follow the trends of the market and fulfill unmet needs.

6) Do long term projections and financial planning based on your past and current business volume.

7) You may come across some type of people who will divert you from your aim for various reasons. So, the best strategy in such cases is to avoid engaging with them and stick to your objectives.

8) If you can provide competitive prices, good quality and prompt customer service then your business is bound to succeed sooner or later.

TOTAL PAGES 60

Most of the enterprises in India are family owned ventures. Many technically qualified professionals are hesitant to venture out on their own due to lack of knowledge and guidance regarding the joys and pitfalls of being an entrepreneur. Hence, there is a need to spread awareness about the benefits of becoming an entrepreneur and also support them financially and t e c h n i c a l l y. M y a d v i c e t o b u d d i n g entrepreneurs is as following:

MUMBAI

14 ◄ December 2018

VOL 16 | ISSUE 04 | NOVEMBER 2017 | MUMBAI | TOTAL PAGES 60 | PRICE ` 150

NOVEMBER 2017

An entrepreneur has to initiate and manage a lot of things single-handedly. But, to be honest, there is no meaningful support or guidance from the government or the banking sector, which are the two crucial pillars of support for any entrepreneur.

These two pillars have totally failed the small Indian entrepreneur who typically does not have that strong financial background.

Most of the schemes for entrepreneurs a n d s t a r t u p s d o n o t p e rc o l a t e t o th e needy ones. Most of the entrepreneurs are facing huge financial stress due to lack of financial support and burden of various taxes to be paid within the stipulated time.

For some entrepreneurs, getting business is not a problem but delivering products/ services within the given time frame is the main struggle. Such startups are closing down or being declared sick mainly due to debt overhang, unclear industry/trade policies or lack of understanding of the government policies and schemes.

Therefore, the government should start a cell with multiple branches all over the nation, which can act as a consultant / bridge between the entrepreneur and the government. India can experience a startup revolution only if the government becomes more supportive and creates a solid and conducive ecosystem for budding entrepreneurs. Furthermore, bank funding is the biggest hurdle which needs to be sorted out urgently via pragmatic policy decisions.

Contribute to PBW VOL 16 ISSUE 04

Did you get any support from the government or the banks for your entrepreneurial venture?

Would you like to proffer some useful tips/advice to budding pharma / biotech entrepreneurs?

PHARMA BIO WORLD

of our illustrious alumni who are managing their own enterprises both big and small.

These luminaries used to visit the institute frequently and share their success stories especially during the alumni meets. ICT has created thousands of first, second and third generation entrepreneurs who are contributing to the nation’s economy in a big way. I was really motivated and inspired by these industry stalwarts. Our ultimate goal is to generate employment and contribute to the Indian economy by developing import alternatives as well as promote exports in our sector.

HYDERABAD - 2017

GUJARAT - 2018

13-15, December 2017 Venue: Hyderabad, India

23-25, January 2018 20-23, February 2019 Venue: Ahmedabad, Gujarat, India Venue: Mumbai, India

MUMBAI - 2019

GUJARAT - 2018

MUMBAI - 2019

23-25, January 2018 20-23, February 2019 Venue: Ahmedabad, Gujarat, India Venue: Mumbai, India

Dear Readers, Launched by Chemtech Foundation in 1992, Pharma Bio World (PBW) features contents from Pharmaceutical and Biotechnology industries. PBW provides in-depth information on business practices, latest trends, technologies, research & innovation and processes across the entire industry pipeline.

Each monthly edition of PBW covers a separate area of pharma and biotech industry and includes articles from a range of peers, consultants and commentators, interview with industry experts, Market research analyzing industry trends, News Features, News Updates, Product Trends, Events Diary and Bookshelf.

Target readers for PBW are Drug manufacturers, Intermediates, Pharma machinery/equipment manufacturers and suppliers, Pharma packaging firms, Research institutes, Academic institutes, Biotechnology firms, Consultants and Government bodies.

You are most welcome to share editorial content with us such as technical articles, case studies and product write-ups. The length of the article should not exceed 1500 words with maximum three illustrations, images, graphs, charts etc. All the images should be high-resolution (300 DPI) and attached separately in JPEG or JPG format.

Have a look at our editorial calendar on our website www.pharmabioworld.com.

To know more about Chemtech Foundation, Jasubhai Media and other publications and events, please visit our website – www. chemtechonline.com Thank you, Regards, Thomas Antony Editor Jasubhai Media Pvt Ltd Tel: +91-22-40373636 E-mail: thomas_antony@jasubhai.com

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Bringing Quality Forward Pays Off

W

ith biologics filling the pipelines of life sciences companies more than ever, the biopharmaceutical industry needs to rethink its view of quality. Once primarily considered a focus in downstream drug development and manufacturing, quality now demands just as much attention in upstream discovery research.

The need to focus on quality during early biologics research stems in part from the complexity of biologics, but it also results from the increased regulatory scrutiny required when working with living organisms as source materials from early research through production of biologics.

Complexity of biologics Biologics are often produced in cell lines, which are complex entities.

Heterogeneous and even homogeneous

16 ◄ December 2018

populations are susceptible to somatic mutations and environmental stimulation, leading to changes in methylation states and, subsequently, expression. Cell line developers in discovery now need to have the necessary traceability, documentation and security in place to support handoff to process development. For example, a cell line developer in discovery may need to prove to the FDA that the biologic came from a single (mono) clonal cell line. The added complexity of development and manufacturing processes can often be mitigated by instituting quality processes in the early stages of biologics discovery. And it’s a two-way street. The development of standard operating procedures for functional assays (e.g., example studies and cellbased assays) can often be optimized in early research, saving both time and money in later stages of development.

Increased regulatory scrutiny The industry faces increased regulatory requirements for documenting the use of predictive analytics on vast data sets, combining knowledge from early-stage research, historical data from the public domain, preclinical experimentation, clinical trials data and even post-market analysis data. Many of the regulations imposed during biologics development and manufacturing require reports on processes that can be tested early in the product development lifecycle (e.g., reports covering biophysical characterization, post-translational modifications, aggregation propensity and other developability properties).

Additionally, regulatory agencies require comparability studies from preclinical to clinical product development samples.

Pharma Bio World

Quality by design in biopharma R&D The concept of quality by design, postulating that quality cannot be inspected into products, but rather is created by processes along the end-toend development continuum, has become increasingly important for organizations committed to designing and developing successful therapeutics. Done well, quality by design works like a lever, enhancing good scientific practices and encouraging scientists to take the long view and not cut quality corners on the long road to releasing an approved therapeutic.

Quality by design is not a single event, but a series of events that constitute a planned journey aimed at accelerating high-quality products to market with lower cost and risk. Quality becomes something that the organization defines for itself and strives to achieve during every phase of product creation-from research through Pharma Bio World

development to manufacturing (much like the near-constant retooling and reinvention of manufacturing processes in the automotive, semiconductor and electronics industries where the quality by design paradigm has been fully embraced).

The journey begins with the transition from paper to digital, which includes both the transfer of paper-based processes to ‘glass’ and the identification and adoption of information and process standards to harmonize data exchange.

The completion of this step propels the organization down the path towards clean, traceable and tractable data, driving out human variability and improving data integrity. Automated laboratory systems speed execution by eliminating the need for scientists to manually document everything they execute. Vast, rich data sets can be mined and modeled to

improve data-driven, predictive control.

Most importantly, scientists gain improved scientific methodologies with better qualified workflows extending from the simplest research tasks to the most advanced planning of clinical trials.

Quality by design is a journey that takes time and careful planning across the research, development and manufacturing continuum, but the trip is worth it. The biopharma organization arrives at a much better understanding of the many interrelated product and process variables impacting quality and continuous product improvement. In an industry grappling with both scientific complexity and spiraling regulatory compliance costs, it’s never too soon to focus on quality.

Source: DSB December 2018 ► 17

Stirring Things Up In The Lab

G

etting real value out of IoT (Internet of Things) can be viewed as a ‘perfect storm’ in the sense that it presents a rare combination of circumstances with the potential to result in an event of unusual magnitude. IoT can be defined as physical objects that are connected to a network to collect data, like a fitness tracker recording personal activity data.

Internet of things in the lab In the context of the laboratory, the direct interfacing of objects removes the need for manual data entry or transcription, which safeguards the integrity of the collected data, as well as aiding compliance with standards and regulations like 21 CFR Part 11. Efficiency is boosted through the removal of non-value-adding activity, while more data (and more complete data) of higher quality is collected, being attributable (who created a record and when), legible, contemporaneous, original and accurate.

In addition to providing a greater volume of complete data, the IoT gives an overview of processes and activity. Once analytics are applied, insight can be gained into trends or the effect of implemented changes, enabling organizations to act in a pre-emptive manner. When an organization has disconnected standalone equipment, however, it becomes difficult to obtain such an overview, especially when devices may be spread in various locations around the world. Questions can then arise as to whether each device is correctly calibrated, its maintenance status, where this information is documented, and how the data can be linked to that of the samples being tested in order to provide evidence that the instrument was in perfect working order during the time of measurement.

or used in a more efficient way rather than an organization needing to incur the cost of purchasing additional equipment.

However, there are two key difficulties in leveraging this data; the first being that the documentation often remains in the form of paper records or Excel spreadsheets; and the second is the equipment being disconnected, making the access to data difficult.

Internet of Laboratory Things (IoLT) – What does it include?

In the lab, connecting both equipment and systems to the network is the most obvious point to address, as a lack of integration leads to manual steps in the process – and therefore a higher likelihood of error and increased compliance risk – as well as to large efforts to configure and maintain all the different applications.

Data capture is an important component within the drive for connectivity. Scientists should be able to enter data and observations directly into a mobile device, and to include instrument data directly through the automated transfer from the connected instrument. Other methods

of capturing data within the laboratory include barcode scanners, which are primarily used for automatic identification of samples and chemicals, and radio frequency identifications (RFID) that use electromagnetic fields to automatically identify and track objects and small electronic devices. Likewise, the work of the scientists can be supported by wearable displays that offer a quick overview of a sample or alert the user when a sample needs to be measured.

Furthermore, technology such as biometric ID bracelets can boost efficiencies by simply helping the people in the lab to be automatically recognized. The entering of usernames and passwords is not only a non-value-added and time-consuming activity; it’s a task that can occur up to one hundred times per day.

Another option to leverage for IoT would be a heads-up display (like Google Glass) whereby an analyst can get additional information about the environment (augmented reality) by simply looking at the storage cabinet, freezer or sample, or by having a procedure displayed that

From a cost perspective, having detailed information regarding the location of equipment and how it is being used may reveal that instruments could be relocated, 18 ◄ December 2018

Pharma Bio World

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needs to be followed. Finally, motion sensor technology can be applied to start processes or record an experiment so that at a later time it can be shared with other members of the team. By utilizing these technologies in a connected IoT way, organizations can streamline workflows and limit the amount of time being diverted away from the science.

Standardization must be considered from the perspectives of the data format as well as processes and methods. Without standardization, analysts must deal with a plethora of data formats that cannot be easily shared or leveraged, making collaboration, collation, accessibility and re-use of past knowledge difficult.

When data is locked away in various systems and applications that are unable to communicate with each other, access to that data becomes a barrier for further analysis, and the opportunity to take past 20 ◄ December 2018

experiences and apply that information in knowledge-driven decision making is lost.

IoLT for a new lab experience The IoLT enables the automatic transfer of data, helps organizations to immediately get an overview of the status of the equipment, samples and materials, people and activities, enables analytics, and allows real time data sharing and collaboration with peers.

However, in order to reach the ‘perfect storm’ there are elements other than the ‘things’ that need to come into play. As discussed, standardization is a significant factor – as are data storage, the technology that needs to converge to provide the optimum environment for the IoLT, and the analytics being applied to the data. Combined, these components offer a next generation laboratory experience.

T e c h n o l o g y convergence The laboratory informatics landscape within an organization can be complex, as often there isn’t just one single Laboratory Information Management System (LIMS) but several, and all for different purposes.

Numerous Electronic Lab Notebooks (ELNs) may be used for different areas of application, and there could be a Laboratory Execution System (LES), Scientific Data Management System (SDMS), Chromatographic Data System (CDS), Enterprise Resource Planning (ERP) system, and a variety of different inventories. It becomes obvious that this typical scenario is not supporting the ability to leverage the data of the IoLT in a consistent and efficient manner.

Harmonization and technology convergence that eliminates the duplication and overlap of functionalities are required, and a platform approach will support this. Users and scientists can then work consistently with one single user interface to capture, access, and review the data. With applications being connected to a platform, it becomes easier to share that data and collaborate on projects. A convergence of technology can therefore bring capabilities traditionally spread over multiple systems into one single system, avoiding the duplication of capabilities and data, and ensuring a single version of the truth.

Big data Another aspect is the amount of data being created. Conversations surrounding a large quantity of data invariably lead to ‘Big Data’, which means that organizations need to look into not only the volume of data created but also the variety and veracity of Pharma Bio World

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And equally important for an organization is to define what should be achieved with the analytics and which questions should be answered. This will then define the type of analytics being applied, and the method or technology for doing so. Those can be descriptive analytics (what has happened), diagnostic (why has it happened), predictive (what will happen) or prescriptive (what can we do to avoid or cause it to happen). To get the right answers to these questions specifically in the lab environment the system used needs to be science-aware in order to understand the data and their context. that data. The latter is assured by the IoLT because of the direct integration of the instruments and other items.

The large volume of data means that storage becomes a concern, especially when we consider whether the information is held with a high degree of organization, like a spreadsheet, or unstructured in that it has not been optimized in a pre-defined manner or applied to a predefined data model.

To address the issue of data variety, organizations have teamed up with precompetitive alliances and consortia to find standard data formats, data models and ontologies. The Pistoia Alliance, for example, is a group of life science industry experts that want to address issues around aggregating, accessing and sharing data which are central to innovation. As a body, they have projects like Ontologies Mapping to standardize tools and metrologies, and to better integrate, understand and analyze the data more effectively. Another example is The Allotrope Foundation, an international association of pharmaceutical and biotech companies dedicated to building a laboratory framework in order to improve efficiency in data acquisition, archiving and management through a standardized approach.

24 ◄ December 2018

Data storage In terms of storage, many organizations still have data that exists in silos that are relatively integrated but not entirely cohesive, as they are sometimes only accessible through proprietary vendor software and often utilize incompatible data formats. A modern alternative is an enterprise data lake, which stores structured and unstructured data together in an object-oriented flat architecture, making it much easier to scale and manage. By using data-lake technology and storing large amounts of information in the cloud, that data can be mined and re-used across different domains in an organization, independent of the system from which it was originally produced.

Adding technology to access and re-use the data will then enable users to leverage the knowledge created throughout the organization.

Data analytics One final aspect to add to the IoLT is Big Data Analytics. The first consideration here is context – is the data scientific in nature, from collaboration or from production? The data needs to be contextualized through metadata.

IoLT-The vision Visions of environments leveraging the IoLT are not far away and elements of it can already be experienced today. We can expect laboratory experiences where analysts are automatically identified and can execute actions through gestures; where video can aid instantaneous collaboration and immediate information sharing; and where visual displays on eyewear offer information in a combination of identification, and augmented reality.

Forward-thinking organizations who want to transform the way they are working in the lab with the IoLT need to establish a comprehensive strategy supported by advanced informatics tools. Partnering with providers who share this vision and whose solutions are aligned with it will help find the best way to leverage the IoLT. Pragmatically applying new technology can turn this vision into reality, and lead to deep impacts throughout the organization.

Source: Biovia

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insights

Global Biosimilars Market (2018 – 2023) Several blockbuster biopharmaceuticals going off-patent in the next 5-10 years

B

iosimilars refer to a similar, but not identical copy of the original product, with parallel properties to a product that has already been licensed. Biosimilars can be made only when the patent for the original product expires. The global biosimilar market has been segmented based on the product class into monoclonal antibodies (adalimumab, infliximab, rituximab, trastuzumab, bevacizumab, and others), recombinant hormones (insulin, human growth hormone, and follicle stimulating hormone), recombinant growth factors (granulocyte colony stimulating factor, erythropoietin, and others), immunomodulators (interleukins, cytokines, immunomodulatory imide drugs, and others), anti-inflammatory agents (TNF inhibitors and others).

Further, based on geography, the market can be categorized into North America, Europe, Asia-Pacific, Middle East & Africa, and South America. The North American segment includes Canada, the United States, and Mexico. The European segment includes the United Kingdom, Germany, France, Italy, Spain, and rest of Europe. The AsiaPacific segment includes Australia, New Zealand, China, India, Japan, South Korea, and rest of Asia-Pacific. The Middle East & African segment includes Gulf Cooperation Council (GCC), South Africa, and rest of Middle East & Africa. The South American segment includes Brazil, Argentina, and rest of South America.

Product / Molecule

Patent Expiry

Herceptin

2014

Avastin

2019

Remicade

2014

Rituxan/Mabthera

2013

Humira

2018

Enbrel

2015

Lantus

2015

Orencia

2017

Owing to the biological patent expiration, innovator companies (Amgen, Pfizer, Merck, Boehringer Ingelheim, etc.) and generics manufacturers (Cipla, Dr. Reddy’s, Mylan, Sandoz, Teva, etc.) are devoting resources to biosimilars and many contract research organizations (CROs) (Biocon, Parexel, Quintiles, etc.) are offering services, which Product / Molecule

Patent Expiry

Rituxan

2016

Humira

2016

Sample Erbitux

Remicade

2018 2018

Global Biosimilars Market

Major Biological Patent Expiries: Europe

Avastin 2019 expected to make up an increasing share Herceptin 2019 of the biologics market. A study reported that about 32 drugs lost patent protection at Lantus 2015 the time of the passage of Hatch-Waxman Levemir 2017 Market Drivers Amendments. Pfizer lost patent protection The patent for blockbuster drugs (that Enbrel 2028* for Zoloft (antidepressant) and Celebrex have been the top-selling drugs for many Mordor Intelligence Orencia 2019 years) has either expired or is expected to (NSAID), Merck for Zocor (cholesterol drug), +1 617-765-2493 | No. 30 Padma Nilaya, RT Nagar, Bengaluru, India 560 032 | info@mordorintelligence.com expire in the coming years. The expiration Teva for Copaxone (immunomodulator), Major Biological Patent Expiries: United States of patents opens up opportunities for AstraZeneca for Nexium (GERD), Bristol- (*The patent on Enbrel was set to expire in 2012; biosimilars to enter the market and increase Myers Squibb for Pravachol (cholesterol however, a second patent has been issued in the United States, which grants exclusivity for 16 years.) industry competition. Hence, biosimilars are drug), etc.

26 ◄ December 2018

(2018 – 2023)

Pharma Bio World

The Development and Manufacturing of Biosimilars 01. Characterization of the Reference Biologic

insights

Biosimilar development begins with a characterization of the reference biologic by analyzing and identifying its quality attributes, such as the molecule’s physicochemical properties, immunochemical properties, biological

are specifically tailored toward biosimilars.

activities and quantity and types of impurities. The data collected is used to define the Critical Quality Attributes Science of Biosimilars Some of the aforementioned drugs have (CQA) of a biosimilar.

Biosimilars are biologic medicines which are far more complex to develop compared to generic chemical drugs.

The Development and Manufacturing of Biosimilars

therapeutic applications in diseases, such as cancer, diabetes, cardiovascular diseases, and others. As disease incidences are increasing globally (more rapidly in low and middle-income countries), the demand for similar drugs (biosimilar drugs) is expected to increase. This demand is expected to drive the market for biosimilar drugs. Biosimilars are drawing the market’s attention as a result of patent cliff, which is expected to place nearly 36% of the biologic drug market at risk.

Market Restraints l Line Development An interchangeable product is one that would be expected to produce the same clinical results in any given patient and the biological a cell line, the DNA sequence encoding the target product is incorporated into an expression vector, product may be substituted for the reference n transfected into a host cell for stable expression of the biosimilar drug. Typically, more than 15,000 product, without the intervention of the s are screened for generation of a lead cell line that will ultimately become the production source for the prescriber. Interchangeability is considered ug. a major benefit for biosimilar development, 01. Characterization of the Reference Biologic as section 351(I) of the Public Health Service Biosimilar development begins with a characterization of the reference biologic by Act allows for interchangeable biosimilars to analyzing and identifying its quality attributes, such as the molecule’s physicochemical be substituted for their reference product at properties, immunochemical properties, biological activities and quantity and types the pharmacy level. Among few differences of impurities. The data collected is used to define the Critical Quality Attributes in the regulatory approach of EMA and FDA, (CQA) of a biosimilar the most important difference is regarding the designation of interchangeability.

EMA’s approach does not include any designation of interchangeability, while FDA plans to create a level of approval for an interchangeable biosimilar. FDA requires licensed biosimilars and interchangeable biological products to meet the agency’s rigorous standards of safety and efficacy.

02. Cell Line Development To generate a cell line, the DNA sequence encoding the target product is incorporated into an expression vector, which is then transfected into a host cell for stable of the biosimilar drug. Typically, more than 15,000 single clones are nufacturingexpression Process Development screened for generation of a lead cell line that will ultimately become the production source for the biosimilar drug.

line is subjected to manufacturing process development at lab scale, in order to meet biosimilarity

The post marketing data collected from products first licensed and marketed as biosimilars are not sufficient to demonstrate interchangeability. This data may be helpful to determine the data that is necessary to support interchangeability; however, the data itself is not enough. This means that even the already-approved biosimilar products may be able to obtain interchangeable status, if sponsors provide switching study data. The data and information needed to support a demonstration of interchangeability can be influenced by factors, like product complexity

s. The cell culture conditions are refined to improve yield and reduce impurities. Hundreds of cell culture are conducted to develop a process that maintains optimal growth conditions. Hundreds of purification Pharma Bio World

are performed for each product to effectively remove impurities and to help achieve consistency and

December 2018 ► 27

03. Manufacturing Process Development

insights

The lead cell line is subjected to manufacturing process development at lab scale, in order to meet biosimilarity requirements. The cell culture conditions are refined to improve yield and reduce impurities. Hundreds of cell culture experiments are conducted to develop a process that maintains optimal growth conditions. Hundreds of purification

and product-specific immunogenicity risk. Such complexity in substitutability and interchangeability is challenging the biosimilar market’s growth.

experiments are03. performed for each product to effectively remove impurities and to help achieve consistency and Manufacturing Process Development quality.

The lead cell line is subjected to manufacturing process development at lab scale, in order to meet biosimilarity requirements. The cell culture conditions are refined to improve yield and reduce impurities. Hundreds of cell culture experiments are conducted to develop a process that maintains optimal growth conditions. Hundreds of purification experiments are performed for each product to effectively remove impurities and to help achieve consistency and quality.

Monoclonal Antibodies Adalimumab Adalimumab (originator drug: Humira) is an anti-TNF drug. TNF (tumor necrosis factor) is produced in excess in certain conditions, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. This factor causes inflammation, pain, and damage to the bones and joints.

Adlimumab blocks the action of TNF, reduces inflammation, and provides relief from the disease condition. Humira is approved by 04. Scale-Up US FDA for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic Pilot scale studies entail extensive quality assessments, including real-time monitoring and product quality control.

04. Scale-Up Cultures often behave differently at large scale than at lab scale, and a careful monitoring of the essentialarthritis, quality Psoriatic arthritis, ankylosing attributes is required. At the mass-production scale, control strategies are put in place to maintain the quality of the spondylitis, Crohn’s disease, ulcerative biosimilar product.

Pilot scale studies entail extensive quality assessments, including real-time monitoring and product quality control. colitis, and chronic plaque psoriasis.

Cultures 04. often behave differently at large scale than at lab scale, and a careful monitoring of the essential quality Scale-Up attributesPilot is required.

At the mass-production strategies including are put in real-time place to maintain the quality scale studies entail extensive scale, qualitycontrol assessments, monitoring and of the

Amjevita, Amgen’s version of Humira is the first adalimumab biosimilar to be careful monitoring of the essential quality attributes is required. At the mass production scale, approved by US FDA in September 2016. control strategies are put in place to maintain the quality of the biosimilar product.

Two European versions, named Amgevita and Solymbic, were recommended in the European Union (EU) in January 2017.

Amgevita and Solymbic are the first adalimumab biosimilars recommended for approval in the EU. In the EU, Amgevita is prescribed for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, 05. Final Product axial spondyloarthritis, psoriatic arthritis, The formulation of the final product can also affect quality. Final drug products are manufactured under current psoriasis, pediatric plaque psoriasis, good manufacturing practice (cGMP) regulations, following a manufacturing process that has been validated to hidradenitis suppurativa, Crohn’s disease, meet the requirements of various regulatory agencies. The final form can be a vial, pre-filled syringe or auto-injector. pediatric Crohn’s disease, ulcerative colitis, and uveitis. Solymbic is intended to treat similar inflammatory disease conditions.

05. Final Product Other than Amgen, companies, such as The formulation of the final product can Boehringer Ingelheim, Merck, Samsung also affect quality. Final drug products Bioepis and Sandoz are also expected to are manufactured under current 05. Final Product good manufacturing practice (cGMP) enter the market shortly. The adalimumab regulations, following a manufacturing biosimilar is also marketed in India, by The formulation the has finalbeen product can also affect quality. Final drug products are manufactured under current processofthat validated to meet Zydus and Torrent Pharmaceuticals. good manufacturing practiceof(cGMP) the requirements variousregulations, regulatory following a manufacturing process that has been validated to meet the requirements of various regulatory agencies. The final form can be a vial, pre-filled syringe or auto-injector. agencies. The final form can be a vial, Market Potential pre-filled syringe or auto-injector.

Currently, the United States is a very (Source: PBW) small market for biosimilars. However, the biosimilarproduct product.quality control. Cultures often behave differently at large scale than at lab scale, and a

28 ◄ December 2018

Pharma Bio World

insights US market is anticipated to grow, as it is expected to be the largest contributor of biosimilars, and account for a major share in the global revenue, during the forecast period. This can be attributed to patent expiration of existing biologics. The United States has an approximate patent expiration limit of 15 years, for innovator drugs.

The country has great opportunities for biosimilars, as biologics carry higher price.

By 2020, the US market is estimated to become susceptible to biosimilar competition.

The key products in the US market are Remicade, Enbrel, Rituximab, Adalimumab, Infliximab, Etanercept, Darbepoetin Alpha, etc. Presently, there are four biosimilars (Zarxio-biosimilar to Neupogen, Inflectra for Remicade, Erelzi for Enbrel, and Amjevita for Humira) that have been approved. However, only two of the four approved biosimilars are currently in the market. Sandoz was the first to obtain approval for a biosimilar (Zarxio) in the United States, as per the new FDA biosimilar regulatory pathway. M923, biosimilar HUMIRA (adalimumab), is under phase-III trial, and is expected to be sold soon by Momenta.

Many biosimilars are in the pipeline by Teva Inc., including TVB018 CT-P10 (Rituxan), and CTP6 (Herceptin). The company has received approval for tbo-filgrastim (XM02 filgrastim). Herceptin is expected to be marketed by Mylan, with FDA biosimilar approval. Pfizer has introduced Remicade biosimilar, with a 15% discount in the country. The key players in the US biosimilar product market are - Sandoz, Amgen, Teva Pharmaceutical Industries, Hospira, STADA Arzneimittel, and Mylan. As per a recent report, 41 biosimilars are under development, out of which, 23 biosimilars are ready to be released into market, and an even larger number (estimated to be 260) of biosimilars are in the pipeline, which are anticipated to be marketed soon.

Leading Player Novartis/Sandoz Novartis is leading global supplier of generic Pharma Bio World

pharmaceuticals. Through a merger of CibaGeigy and Sandoz, Novartis was formed in 1996; it is headquartered in Basel, Switzerland.

The company business is segmented into innovative patented medicines, generics and eye care devices across the globe.

Sandoz holds number one position in sales of ophthalmic, transplantation medicines, biosimilars and of generic anti-infectives worldwide. In 2016, Sandoz acquired, from Pfizer, the rights for the production and commercialization of biosimilar infliximab. In production of certain significant therapeutics such as generics, cardiovascular, injectables, gastrointestinal, dermatology, respiratory, central nervous system, pain and metabolism, Sandoz holds a leading position, globally.

Products Sandoz Erelzi Biosimilar of etanercept for the treatment of multiple inflammatory diseases, Erelzi was approved in the United States and it is indicated for rheumatoid arthritis (RA), active polyarticular juvenile idiopathic arthritis (JIA), psoriatic arthritis ankylosing spondylitis (AS), and plaque psoriasis.

Zarzio First biosimilar to be approved in the United States. Zarzio is the biosimilar of Granulocyte Colony Stimulating Factor (G-CSF).

Sandoz Rixathon A biosimilar of rituximab, indicated for the treatment of blood cancer and several immunological diseases.

Financial Overview (in USD million) (+/-) %

Revenue

2017

2016

Total Revenue

9,895

10,144

(-)3

980

1002

(-)2

1350

1445

(-)7

7263.8

7707.8

(-)6

Biopharmaceuticals

Change

Operating Income or Loss Net Income

Source: Mordor Intelligence Analysis

in the biosimilar market. Sandoz, a Novartis division is expected to launch five biosimilars [LA-EP2006 (pegfilgrastim), HX575 (epoetinalfa), GP2013 (rituximab), GP2017 (adalimumab), GP1111 (infliximab)] of immunology biologic and oncology across the globe by 2020. Sandoz has a strong focus on biosimilars. The key products launched in the United States, include amphetamine salts extended release (Shire’s Adderall XR®), linezolid solution for infusion/injection (Pfizer’s Zyvox®), mometasonefuroate (Merck & Co. Inc.’s Nasonex® nasal spray), and oxiconazole nitrate (Fougera’sOxistat®). Sandoz has a strong distribution channel and is the first company to get approval under the new regulatory pathway in the United States, in 2015, for biosimilar products.

Omnitrope Omnitrope is a biosimilar of growth hormones. It is prescribed for children who lack growth hormones.

Binocrit Binocrit is used for the treatment of symptomatic anemia.

Analyst View Sandoz holds the highest market share

(Source: Selected excerpts from the Mordor Intelligence report – ‘Global Biosimilars Market [2018-2023]’.)

December 2018 ► 29

insights

Biosimilars: Success Thus Far and Roadblocks Ahead #

Product

Companies Based on currently approved biologic drugs and pipeline analysis for anticipated approvals during Approvals the period, in the most optimistic scenario, the global biosimilar market is estimated to be north of $ 240 billion and Indian biosimilars market to be north of $ 40 billion by 2030 20

T

he Indian pharma industry has come a long way in elevating itself from a large volume low cost manufacturer of small molecule generics to being an active participant in the higher value biosimilars segment. With India being one of the earliest markets to open for similar biologics, there has been a long track record of approvals in the country.

Currently there are over 70 biosimilars approved in India. While the first biosimilar draft guidance was released in 2012, first approved biosimilar in India dates back to 2000, and approvals prior to the biosimilar guidance were through an abbreviated new drug pathway dealt on a case-to-case basis.

The most popular biosimilars in India by number of current approvals are first generation Granulocyte Colony # Product Approvals Companies 20

Reliance Lifesciences, Intas Pharma

7

Biocon

12

Cadila Healthcare, Wockhardt, Dr Reddy’s Laboratories

7

Hetero, Emcure, Shantha Biotechnics

12

Claris Lifesciences, Torrent, Zenotech Labs, USV, Virchow Biotech, Lupin

8

Cadila Pharma, Bioviz Technologies, Biocad, Epirus BioPharma, Ranbaxy, Gland Pharma, Serum Institute, Cipla

30 ◄ December 2018

Reliance Lifesciences, Intas Pharma

Stimulating Factors (GCSF) and for their biosimilars, resulting in larger Erythropoietin Molecules number of marketers for many of the above 7 (EPO) products.

Biocon wise, Epoetin alpha for anemia, filgrastim products. Pertinent examples include Cadila Healthcare, Wockhardt, Dr registrations, Reddy’s with 10 product for low blood neutrophil and rituximab for Filgrastim 12 oncology and autoimmuneLaboratories indications are but 33 marketers and Pegfilgrastim with some of the most crowded biosimilars in 5 product registrations and 15 marketers.

Hetero,brands Emcure, Shantha Biotechnics India, with 7 11, 10 and 6 biosimilar 2016 Revised Guidelines - Key approved respectively. Claris Lifesciences, Torrent, Zenotech attributes and implications for industry 12 Labs, USV, Virchow Biotech, Lupin While there is large diversity in approved Although biosimilar guidance in India has 2012, there has biosimilar products, there are justPharma, a been in existence Cadila Bioviz since Technologies, handful of companies holding noteworthy been excessive global criticism on the lax 8 Biocad, Epirus BioPharma, Ranbaxy, number of product registrations, with a regulatory requirements of the guidelines. many Institute, of the currently long tail of companies with lesser number Gland Pharma,WithSerum Ciplaapproved biosimilars having gone through this old of product approvals. pathway, Indian-made biosimilars are However, the competition gets more viewed in an inferior lens in global markets. intense at the commercial end, with India released its revised biosimilar several manufacturers also exploring a guidelines in 2016, which overcomes contract manufacturing business model several pitfalls in the earlier guidelines

New-Innovator Biologicals and Similar Biologicals Approved in India by Drug Class Insulin, 5, 7% Anti-CD20, 6, 8%

Anti-VEGF, 5, 7%

Others, 17, 22%

Interferon, 6, 8% Anti-TNF, 7, 9%

GCSF, 16, 21% EPO, 14, 18%

Source: IPSOS data, June 2017

Pharma Bio World

insights Non-Innovator Biologics & Similar Biologics Approved in India by drug class & molecule Recombinant human granulocyte macrophage colony…

1

pegfilgras�m

GCSF

5

filgras�m

10

epoe�n alfa

EPO

11

darbepoe�n alfa

3

infliximab

1

etanercept

An�-TNF

2

adalimumab

4

rituximab

An�-CD20

6

Pegylated recombinant human interferon alfa 2b

1

interferon beta-1a

1

Interferon

interferon alfa-2b Insulin

3

insulin glargine

2

ranibizumab

An�-VEGF

1

bevacizumab

An�-HER2

trastuzumab

Parathyroid hormone

teripara�de

Enzyme

4

human insulin

4 4 3

streptokinase

2

reteplase (�ssue plasminogen ac�vator)

1

follitropin beta (follicle s�mula�ng hormone)

1

follitropin alfa

1

chorionic gonadotrophin hormone r-hCG

1

Vaccine

hepa��s B vaccine

1

An� - glycoprotein IIb/IIla

abciximab

1

Hyperuricemia

rasburicase

1

PDGF

rh-PDGF-BB + β-TCP

Fer�lity

1

0

2

4

6

8

10

12

Source: Company websites and other publically available documents

with respect to patient safety. The main changes in the revised guidelines include • Allowing use of reference drug approved in India or any other ICH country • Minimum study sizes of 100 patients for clinical studies and single arm studies are no longer permitted • Post-marketing studies are mandated for additional safety validation with a minimum study size of 400 patients The new guidelines have been widely appreciated in the global biopharma community as being suitable to the developing country context but having sufficient safeguards and threshold of validation required to ensure patient safety. With the new guidelines, Indian companies are now better-placed competitively to leverage India as a hub for development and manufacturing of biosimilars.

Pharma Bio World

Roadblocks Ahead for Sustainable Success Although there is an active engagement landscape in biosimilars as demonstrated by the sheer number of approved products in the country, there are several roadblocks hindering the market from reaching its true potential.

A) Relatively small market size and poor volume penetration despite price control Biologic drugs in general have remained sub-optimal in penetration in developing markets such as India, mainly due to affordability qualms. Lack of national insurance schemes also renders the market to be largely out of pocket in nature, which exacerbates the problem multifold. Although the advent of biosimilars was expected to overcome

affordability barriers, the same has not been translated to reality, as exemplified in the below case study on Trastuzumab.

Being the largest biosimilar market in India, market size for the drug is relatively lower than one would expect, at INR 286 crores in 2017 (including originator sales). With the first Trastuzumab biosimilar launched in 2013, the pace of growth and market development is glaringly unimpressive for such a crucial drug compared to other benchmarks in Indian pharma market, such as gliptins/insulin in chronic care setting or private market vaccines such as varicella. As outlined below, this poor market development is not for want of price rationalization but is rather attributable to extremely low volume penetration.

Volume Penetration of Trastuzumab in India - A Case Study Trastuzumab is prescribed for HER 2 positive breast cancer as neoadjuvant / primary systemic therapy as well as Adjuvant therapy. Neoadjuvant chemotherapy refers to medicines that are administered before surgery most probably to reduce the size of the tumor prior to surgery, while adjuvant therapy refers to administration of trastuzumab after surgery, mainly to prevent recurrence of the disease. Apart from these breast cancer indications, trastuzumab is also prescribed for HER 2 positive metastatic gastric cancer.

As seen in the above table, the current market penetration of trastuzumab in India is abysmally sub-optimal at less than 10%. It is evident that, at the current cost of care for overall therapy estimated at close to INR 7 lakhs per patient per year, access to care is a looming challenge.

Moreover, market data shows that although prices have eroded significantly in the past 3 years, it has only contributed to marginal volume expansion. This further proves that the market has reached an equilibrium state with respect to affordable population at the current price economics.

Hence, substantially expanding market access hereon and enhancing ROI for December 2018 ► 31

insights Breast Cancer

Gastric Cancer

5 year prevalence in India -2012

3,97,000

45,000

Incidence of Disease in India

1,45,000

63,000

15%

22%

HER 2 Positive Cases - Target market for Trastuzumab

Target Population for Trastuzumab treatment Adjuvant Therapy: 37,800 (based on incidence and prevalence) Neoadjuvant Therapy: 21,750 Annual Volume Requirement of Trastuzumab Adjuvant Therapy: 262.5 kg (based on dosing regimen) (kg) Neoadjuvant Therapy: 75.5 kg

Total

9,900

69,450

36.8 kg

374.8 kg

Annual Volume Sales of Trastuzumab (kg)

29.2 kg

Volume Penetration of Trastuzumab

7.8%

Volume Penetration of Biosimilar Trastuzumab

4.7%

Source: IPSOS data many essential drugs enable better affordable access, there including trastuzumab is negligible scope for expanding value already price capped realization for manufacturers without by the National additional initiatives covering overall cost ₹ 296 80,000 Pharmaceutical Pricing of care. Thus, biosimilar manufacturers 71,701 Authority (NPPA). On lack the incentive to further rationalize ₹ 291 58,577 ₹ 292 57,921 top of this, there are price to expand market penetration in 60,000 about 10 competitors this landscape. Thus, concerted multi₹ 288 for trastuzumab in stakeholder efforts involving clinical ₹ 50,293 ₹ 48,111 ₹ 286 40,000 India (Source: IPSOS education, expansion of adoption and ₹ 39,918 ₹ 284 data, public resources) most importantly, coverage for overall cost competing on price, of care in oncology is needed to rescript 20,000 ₹ 282 ₹ 280 which further brings the the current landscape. prices down. However, considering that most B) Slow Pace of Portfolio Development ₹ 276 biosimilars including and Sunk Costs as Deterrents to 2015 2016 2017 trastuzumab are IV Investment infusions, dispensing Indian biosimilar companies also lag Volume (# Vials) Price per Vial (INR) of drugs is heavily behind their global peers in terms of Revenues controlled by hospital pace of portfolio development. Time to channels.

While market is of crucial essence in biosimilars manufacturers is contingent on expanding companies provide discounts on list as rapid price erosion implies that only access to population where overall therapy price to win business of hospitals, pricing the first few companies to market reap is currently unaffordable. benefit is not necessarily transferred maximum benefit. In this backdrop, most Analyzing current pricing economics, we to the patient, and potentially has no Indian companies continue to chase note that prices for most biosimilars in impact on expanding access. Even if first generation assets, while the global Cancer Gastric Cancer Total India, are at their lowest globally, with Breast prices were to be slashed any further to peer group is embarking on second and

Revenues (INR Crore)

Trastuzumab - Past 3 year Market Economics

December 2018 32 5 ◄year prevalence in India -2012

Incidence of Disease in India HER 2 Positive Cases - Target

3,97,000 1,45,000

45,000 63,000

Pharma Bio World

insights third generation biosimilar opportunities.

This lag in contemporariness of portfolio stems from problems at multiple levels.

Firstly, even larger companies lack the risk appetite to invest substantially in yet-to-open high value markets due to the high degree of binary risk. The quantum of investment required for a biosimilar development is twenty to hundred times the investment required for a small molecule generic. While this is a significant leap for even large companies, smaller companies lack the financial wherewithal to pursue assets at a pace aligned with global peers. At this pace, by the time Indian made assets reach markets, markets erode significantly, making ROI questionable. Thus, there is an urgent need for Indian companies to upgrade portfolio robustness to match global standards.

Market access and scale-up in RoW markets has also been slower than anticipated. Several assets approved under the earlier regulatory framework don’t necessarily have robust data packages as needed for registration in several RoW countries. This has further delayed market entry in export markets and has limited RoI for early entrants.

Given this context, several companies are straddled with sunk investments in first and second generation biosimilars (including monoclonal antibodies) in assets that have limited merit to advance into clinical validation and approved products that have not reaped financial returns as expected.

In most cases, this serves as a deterrent to expansion of corporate investment commitment. Supporting creation of more attractive market dynamics and tangible comfort on RoI will be critical to address this investment bottleneck and catalyze greater level of corporate engagement.

C) Need for improving manufacturing competency Manufacturing competency and technical expertise is the cornerstone for success and long-term sustainability in the biosimilars market. Another key challenge Pharma Bio World

in the road to biosimilar success in the country is lack of access to state of the art manufacturing technology for biomanufacturing competence. Although biosimilar development in India dates back close to two decades, several companies still grapple with issues related to high performance clones that ensure lean and efficient manufacturing capability. Yield maximization is the key in boosting value generation and sustained competitiveness in both domestic and export markets. As prices erode, yield becomes paramount for viable business continuity. This needs attention early on as it is complex to make upstream technology changes for marketed products. Hence, upstream technology development needs greater focus (especially cell line and clone development) across the industry. While technology access from global sources can address the problem in the near term horizon, in-country capacity building is needed for a long term solution.

ROW Markets - Need for Expanding Markets and Value Realization Potential Semi-regulatory markets with regulatory rigor similar to that of India have so far been the next logical step for the biosimilar portfolio for most Indian companies.

ROW markets have been attractive for companies with lower risk appetite or capital allocation to the segment as they demand relatively lower regulatory rigor.

However, the real risk profile is far from acknowledged, with multiple levels of market entry as well as access concerns in semi-regulated markets. Although these markets present lower investment profiles and thus appears to be near term low hanging markets, they also present lower rewards, making ROI questionable.

Lack of Regulatory Harmony, a Market Entry Risk Regulatory pathways are highly country specific and non-harmonized with country level approvals needed for most markets. This in turn makes the entire

commercialization effort heavily time consuming, thereby delaying market entry and value realization. The time and efforts laid in gaining market access in multiple small opportunity countries result in high sunk costs and also rob companies of precious time, investment and resources.

Low Market Maturity, a Significant Risk for Market Access and Realization of Return While regulatory approvals present a market entry risk, lower market maturity presents an added layer of market access risk. High price of biologics have always limited penetration in emerging markets; and biosimilars hold the promise of smashing affordability barriers and expanding access. However, in reality, penetration of biosimilars have been sub optimal in many ROW markets. This is similar to the concerns discussed above on uninspiring levels of market expansion in India. Most ROW markets have high level of out-of-pocket payments with lower level of payor influence. The multistakeholder approach needed for market creation has been largely amiss. The low level of market maturity implies relatively smaller markets in each geography.

Bridging Studies for Indian-made Assets Apart from the above market entry and access related challenges, difficulties also persist in the level of market readiness of Indian-made assets for approval in these semi-regulated markets. Considering very few Indian biosimilars are approved under the new biosimilar guidance released in 2016, most of the molecules approved under the old regulatory framework are likely to need significant bridging studies for semi-regulated markets. Even under the new guidance, significant differences could exist for marketability in other markets. For instance, at least one repeat dose in-vivo toxicity study is sufficient in either rodent or non-rodent models for approval in India, with adequate justification on choice of species under the new guidelines, while repeat-dose toxicity studies in two species (one rodent and one non-rodent) are required by some December 2018 ► 33

insights countries. Additionally, some countries such as Mexico also require clinical bridging studies to be done in the local population. Such requirements warrant additional investments and combined with uncertainty stemming from low market maturity, decrease the overall value realization potential for Indian companies.

Regulated Markets - The need to catalyze greater market thrust While there are close to 70 biosimilars approved in India, and more than 20 companies are active participants in product development for domestic market, only a few companies have as of now committed critical level of investment for foray into regulated markets. Several factors such as disparity in regulatory rigor, quantum of investment and uncertainty about the levels of market maturity have served as deterrents for Indian biosimilar players to actively pursue regulated markets. Europe has been a pioneer in the biosimilar regulatory landscape; and with greater expanse of single payor markets triggering the shift, markets in Europe have evolved to a greater degree.

The US market for biosimilars is relatively more nascent given long-standing FDA reticence that has only recently started to recede. As the regulated markets embrace biosimilars and move towards higher market maturity, it is optimal time for the industry to expand thrust on regulated markets, that will constitute majority of the near term global markets by value.

European Landscape More established markets, yet mixed levels of penetration Biosimilar usage is growing rapidly in Europe but the market penetrations of different biosimilars varies considerably across European countries due to the varied incentives, purchasing policies, distribution channels and awareness of concerned authorities such as physicians and pharmacists.

The European Medicines Agency (EMA) established a set of harmonised rules and guidelines that manufacturers must 34 ◄ December 2018

follow in order to get their biosimilar evaluated and approved centrally. This was a major first step that Europe adopted in increasing patient access to biologic medicines at affordable prices.

Although there is a central governing body that makes decisions regarding the approval and indications of new biosimilars, the decisions of interchangeability are left to individual countries. In addition to this, countries also specify their own policies regarding pricing, purchasing and utilization of biosimilars and their originator medicines. Since incentive policies applied to biosimilars are heterogeneous across countries, it leads to unique market access regimens. These vastly different environments in European countries have resulted in highly varied levels of penetration for the same biosimilar in different countries. The level of penetration, along with other factors, determines the level of competition and price erosion.

As seen in the chart, the range of biosimilar uptake can vary vastly from country to country in Europe, with some countries such as Denmark, Finland, Poland and Bulgaria witnessing much higher penetration across products than many of the other developed countries such as Germany, France and UK. Wide ranges of market penetration can also be observed between different therapy areas in a single country, such as UK which has only a 6% share for Epoetin alfa and a high 98% for GCSF. Another trend observed is that Insulins and Follitropin Alfa biosimilar have a low market penetration in most countries in Europe, with the highest being 35% and 26%, respectively.

Analysis of the varying uptake levels points to many intercrossing factors playing a significant role in driving biosimilar adoption at the country level.

Purchasing Mechanism Purchasing policies play a significant

role in driving biosimilar adoption at the country level. Firstly, it is important to note that the retail sector and hospital sector in most European countries vary as the hospital sector is more stringently regulated and controlled through the use of tenders and contracts. Single winner tenders, such as national tenders reflect very high uptake levels soon after the launch of the biosimilar. This is exemplified in the case of rituximab biosimilars which reached 80% volume share in less than 6 months in Norway. (Advancing Biosimilar Sustainability in Europe, IQVIA Institute For Data Science, September 2018). Other countries such as Germany have contract based purchasing in which negotiations occur directly between manufacturer and insurer. Such contracts and other multiple tender models (hospital tenders, regional tenders) lead to multiple biosimilars entering the market at the same time.

As such, single authority/single payor tendering has led to benchmark levels of adoption in an accelerated manner with lower levels of adoption in multiple tendering markets.

Competitive Pressure Given the lower expanse of out of pocket markets in Europe, competitive pressure could result in greater price erosion in a tendering or contracted buying context and faster price rationalization resulting in wider adoption. In markets where there are multiple payors, more number of competitors could imply greater share of voice for stakeholder engagement and hence could help push the boundaries of adoption.

Regulations & Policies Incentives Direct incentives are offered by payers to different stakeholders to influence product choice and there are also indirect incentives relating to funding, and reimbursement.

Pricing Rules Pricing rules are in place to ensure that there are sufficient price drops in

Pharma Bio World

insights Data published by Quintiles IMS for European Commission services , for biosimilar penetration across countries and therapy classes.

Country

EPO

GCSF

HGH

Anti-TNF

Follitropin Alfa

Insulins

Denmark

70%

93%

97%

90%

16%

3%

Poland

100%

96%

99%

24%

7%

23%

Finland

100%

98%

57%

61%

24%

1%

Norway

87%

86%

29%

82%

35%

1%

Bulgaria

100%

100%

34%

48%

32%

2%

Romania

70%

100%

56%

11%

Sweden

94%

94%

33%

29%

Greece

98%

100%

0%

Hungary

100%

100%

13%

Czech Republic

99%

100%

Slovakia

100%

Germany

3% 18%

4%

14%

5%

26%

15%

5%

17%

25%

6%

10%

100%

0%

6%

3%

26%

81%

78%

32%

17%

19%

4%

Austria

76%

88%

37%

23%

3%

0%

Portugal

87%

88%

13%

18%

14%

1%

Spain

60%

83%

30%

19%

21%

5%

Italy

65%

92%

29%

20%

2%

7%

France

45%

86%

34%

14%

13%

0%

UK

6%

98%

22%

33%

18%

1%

Netherlands

30%

45%

31%

32%

0%

1%

Slovenia

46%

56%

8%

14%

0%

3%

Ireland

91%

23%

0%

5%

0%

0%

Switzerland

22%

52%

19%

2%

Belgium

2%

3%

28%

5%

0% 17%

0

(source: www.medicinesforeurope.com)

Aggregate Market Penetration of Different Biosimilars in Europe 400% 300% 200% 100% 0%

EPO Pharma Bio World

GCSF

HGH

Anti-TNF

Fertility (Follitropin Alfa)

Insulins December 2018 ► 35

insights Purchasing Mechanism

Purchasing Mechanism •Tendering system •Contracts

•Tendering system •Contracts Competitive

Pricing Rules

Pressure

•Price erosion Pricing Rules •External •Price erosion Reference Factors •External Pricing Incentives

•Market Penetration •Competitor concentration

Reference Driving Pricing Biosimilar

Factors Driving Uptake Biosimilar Regulations & Incentives Policies Uptake

•Provider financial incentives •Patient Incentives •Prescription Quotas

has been slow to warm up. US FDA’s historically slower pace of embracing biosimilars is a known point of debate in the pharma world, with just one approved biosimilar (Sandoz’s filgrastim) until early 2016. The US market for biosimilars has truly opened only in 2016 and the year 2017 was a landmark year with back to back biosimilar approvals, ushering in an era where the biosimilar opportunity is Competitive more tangible. As of October 2018, there Pressure are a total of 13 approved biosimilars in the •Market US which is a highly commendable Penetration feat, considering the short time span in which this has been achieved.

•Competitor

•Provider •Switching financial •Substitution incentives •Treatment Guidelines •Patient Incentives •Prescription biosimilars across all products, maintainQuotas (Germany, France, UK).

concentration

Challenges Limiting Market Potential in US Biosimilars While the past 2 years have been extremely fruitful in terms of regulatory Regulations & in US, tangible commercial openness success of biosimilars in the market has Policies been limited by several factors:

•Switching •Substitution A) High investments amid high competitive threat to market share in •Treatment regulated markets Guidelines External

a healthy competition and also level reference pricing is present in around the playing ground between originator half of the European countries which product and biosimilars. Level of price provides guidelines on price slashing for erosion has a direct correlation with new biosimilars and is another factor that adoption, as seen in the chart below. In could potentially drive uptake. countries where there is a higher level of price erosionFinland (Denmark, Norway, Finland Denmark US Markets - Nascent backdrop, Norway Poland FrancemarketGermany and Poland), there is also higher level of with newfound regulatory clarity biosimilar uptake compared to countries While the US is the largest near term with lower level of biosimilar penetration market for57%biosimilars, 58% 62% the USFDA 53%

34%

32%

28%

Norway 27%

18%

Finland 14%

32%

28%

53%

39%

France 30%

57%

58%

Avg Biosimilar Market Penetration 27%

18%

Avg Price Erosion 36 ◄ December 2018

32% Denmark

7%

Avg Price Erosion 34%

Poland

The cost of development of a single biosimilar for regulated markets ranges north of $100 million, ranging anywhere between $ 150 million – $ 200 million.

With such high investments, and price erosions in Europe having breached 60% thresholds, even for billion dollar markets, UK financial viability and ROI is bleak beyond the first 5 competitors. Considering such high criticality in time to market, the

14%

Germany

UK

62% 32%

39%

30%

7%

Avg Biosimilar Market Penetration Pharma Bio World

insights Medicine Name

Active Substance

Marketing Authorization Holder

Zarxio

filgrastim

Sandoz

Authorization date 06-03-2015

Inflectra

infliximab

Celltrion

05-04-2016

Erelzi

etanercept

Sandoz

30-08-2016

Amjevita

adalimumab

Amgen

23-09-2016

Renflexis

infliximab

Samsung Bioepis

21-04-2017

Cyltezo

adalimumab

Boehringer Ingelheim

25-08-2017

Mvasi

bevacizumab

Amgen

14-09-2017

Ogivri

trastuzumab

Biocon/Mylan

01-12-2017

Ixifi

infliximab

Pfizer

13-12-2017

Retacrit

epoetin alfa

Pfizer

15-05-2018

Fulphila

pegfilgrastim

Biocon/Mylan

04-06-2018

Nivestym

filgrastim

Pfizer

01-07-2018

Hyrimoz

adalimumab

Sandoz

31-10-2018

business case and profitability weakens for later entrants, thus limiting value realization and commercial success. For instance, Sandoz’s recent decision to abandon rituximab biosimilar after FDA required generation of additional data is a classic example of how any stretch on time to launch threatens value realization in the high investment regulated markets.

B) Concerns surrounding interchangeability and automatic substitution Automatic substitution of originator drug with biosimilars and switching between originator drugs and biosimilars are critical considerations that can impact uptake of biosimilars. While automatic substitution does not yet prevail in EU for any approved biosimilar, EMA, per its revision of the 2005 guidelines, leaves the decision on interchangeability to the EU Member States.

On the other hand, in US, the regulatory uncertainty on biosimilar substitution has long been a big market access concern for manufacturers because, although an interchangeable biosimilar product can be substituted for the reference product without provider intervention, no approved biosimilars were deemed interchangeable so far by the USFDA. A welcome development in this direction was the Biosimilars interchangeability guidance issued in 2017.

Pharma Bio World

Biosimilars Interchangeability Guidance The Biosimilars Interchangeability Draft Guidance was issued in early 2017 specifying data and information required from switching studies by sponsors to establish interchangeability.

The switching study is expected to be designed in a way that there is a study with a lead-in period of treatment with the reference product, followed by a randomized two-arm period — with one arm incorporating switching between the proposed interchangeable product and the reference product (switching arm) and the other remaining as a non-switching arm receiving only the reference product (non-switching arm). This guidance is still in draft status and there is some level of manufacturer concerns with respect to some terminologies such as ‘fingerprintlike’ which are quite subjective. However, the guidance has lifted some level of ambiguity surrounding biosimilar substitutability and if executed will foster better consumer confidence in biosimilars.

Slow-evolving co-operation from the payor and prescriber communities Patient influence in brand choice is very limited and there is no incentive to shift from originator drug to biosimilars as

long as insurance covers the drug. Thus, payors and providers / prescribers play a larger role in influencing switching.

Considering no approved biosimilars in the US are deemed interchangeable so far, prescriber comfort is heavily lacking for switching patients to biosimilars and this is a serious factor affecting biosimilar uptake. There are no signs of immediate change as interchangeability guidance is new, still a draft and the prescribed switching studies are time-consuming. On the other end, while there is significant cost benefit from biosimilars warranting substantial payor thrust on biosimilars, with interchangeability being a clinical decision, payers remain apprehensive about providers pushing back. With oncology being a high risk disease category, payers are also apprehensive about mandating switching without stamp of the regulator. Additionally, some large payers have heavy discount contracts on innovator drugs linked to not favoring biosimilars. This causes an additional layer of complexity in biosimilar adoption.

With such challenges hampering true potential of biosimilars in the US, future market access is heavily dependent on how interchangeability evolves and level of discount provided by biosimilar manufacturers to large payors to incentivize switching.

Innovator counter strategies to circumvent biosimilar competition Given large single product revenue contribution of blockbuster biologics to originator companies, it is only natural that they do everything in their power to sustain their market positioning and prolong commercial exclusivity. Such roadblocks include aggressive direct to consumer marketing and legal settlements. Innovator companies have well-structured television ads promoting biologics (Ex: Enbrel, Humira, Remicade), and some go to the extent of advising superiority of innovator brand over biosimilars. At the other end, innovators exert financial muscle in waging hard-hitting legal battles against biosimilar companies, pushing for legal settlements delaying biosimilar market entry.

December 2018 ► 37

insights for Trastuzumab and Pegfilgrastim under registration). The relatively more open European market itself can be divided into 2 distinct segments based on current level of market receptiveness for biosimilars.

On one end, there are markets like Denmark and Finland with landmark levels of biosimilar adoption but higher than anticipated levels of price erosion. At the other end are markets such as Germany and France, where true market potential is yet to be tapped and there is scope for multifold expansion of market adoption.

Overall, the region presents an active partnership landscape, high regulatory support for biosimilars and expanding levels of market maturity. While Indian companies have successfully launched

Interchangeability Requirements When product is administered more than once per patient

When product is only administered once per patient

Switching study needed Products with low structural complexity, fingerprint like similarity, and low adverse reactions Only switching study needed

Drug

Drug

Innovator

Innovator

Biosimilar Amgevita

Humira Humira

Hyrimoz Abbvie Abbvie

Enbrel Enbrel

Herceptin

Biosimilar

Biosimilar Manufacturer Amgevita Amgen Sandoz

Approval

Biosimilar Manufacturer

Hyrimoz Imraldi

Hulio

Mylan MSB11022 EU – Sep2018

Erelzi

Amgen

Erelzi

Sandoz

US - Sep2016 EU - Mar2017

To launch in US in EU – July2018 July/ EU - Mar2017 Sandoz September/ US – Nov2018 November 2023 and EU – July2018 in Europe upon EU – May2018 US – Nov2018 Samsung Bioepis approval EU – May2018 Mylan EU – Sep2018

SamsungHulio Bioepis Fresenius Kabi

Approval

Nature of Settlement

US - Sep2016

Imraldi

MSB11022 Amgen Amgen

Products with high structural complexity, high biosimilarity but not fingerprint like similarity, high adverse reactions Switching study+ postmarketing data needed

No switching study needed. Can seek interchangeability with proper justifications

Fresenius Kabi

Pipeline asset

Pipeline asset

Sandoz

US - Aug2016

Ongoing patent suit

US - Aug2016 EU - June2017

EU - June2017

Roche

Ogivri

Ogivri

Mylan-Biocon

US - Dec2017

Global settlement atUS - Dec2017 Mylan-Biocon

confidential terms for withdrawal of patent challenges List of a few legal settlements executed between Innovator companies and Biosimilar companies.

Herceptin

Roche

While such challenges have impacted commercial success of biosimilars in the US market so far, it is clear that the regulator has already taken cognizance of the prevailing issues, as the new Biosimilars Action Plan (BAP) issued by FDA acknowledges many of these issues.

FDA Biosimilars Action Plan A new Biosimilars Action Plan (BAP) was announced by the US FDA in July 2018, which is yet another milestone to ease market access of biosimilars in 38 ◄ December 2018

Nature of Settlement

To launch in US in July/ September/ November 2023 and in Europe upon approval

Ongoing patent suit Global settlement at confidential terms for withdrawal of patent challenges

the US. Below, is a summary of the key elements outlined in the BAP and the |6 expected market impact for Page biosimilar manufacturers.

first generation biosimilars, there is substantial need to expand the level of thrust of Indian industry to realize the full potential of the biosimilar segment.

Indian Industry Participation in Regulated Markets Europe There is relatively more encouraging level of engagement in European markets, with some Indian made biosimilars having already secured EMA approval and a few others under registration (Biocon/ Mylan - positive opinion issued by CHMP

USA While the wave of Indian made biosimilars have already seen the light of day in US, with FDA approval of Biocon-Mylan’s biosimilars, there is great need to expand level of industry engagement in targeting this opportunity.

Today, the regulatory environment is more conducive, and there is high thrust from the regulator Pharma Bio World

insights Expected Impact for Biosimilar Competitors

Key Element of BAP Initiatives to be Undertaken

1.Improving biosimilar development & approval process

2.Maximizing scientific & regulatory clarity for biosimilar development community

3.Communications to improve perception among payers, clinicians patients 4.Supporting competition by reducing gaming of FDA requirements by innovators

• Developing application templates specifically for 351 K BLA • Transitioning to Office of Therapeutic Biologics & Biosimilars (OTBB) • Develop tools for efficient biosimilar development - in silico modeling tools for PK & PD correlation vs expected clinical responses using existing clinical data • Additional guidance - for applicants who seek approval for lesser number of conditions than reference product because of patent protection; • Enhancing purple book with exclusivity info & additional info, with an interactive user interface • Strengthening partnerships with EU, Japan, Canada regulatory authorities & data sharing agreements with possibility of using non US licensed comparator products in biosimilar applications and for real world evidence against safety, efficacy • To develop audience-appropriate innovative and effective educational material including videos that can clarify key scientific concepts of biosimilars

• More regulatory clarity & competitive intelligence available for biosimilar manufacturers • Improved regulatory reciprocity for biosimilar assets approved & in pipeline for other more mature regulated markets

• Will enhance confidence on biosimilars among payers, providers & patients expected

• Co-ordinate with FTC to address anti-competi- • Prevent anti-trust activities from the innovators tive behavior • Work with legislators to close any regulatory loopholes that prevent biosimilar entry even after • Better commercial viability & value realization potential exclusivity • Address instances where drug makers refuse to sell samples

to streamline approvals. With about 12 biosimilars approved so far, there are enough precedents for Indian companies to equip themselves with knowledge of regulatory requirements. Each new approval has also paved the way for greater regulatory clarity, with the long-awaited draft guidance on biosimilars interchangeability and the new Biosimilars Action Plan being two milestone regulatory developments that can make commercial markets more accessible.

There is greater regulatory guidance now on designing clinical programs for extrapolation and interchangeability.

With more efficient program design, there is also great potential for level of

Pharma Bio World

• More streamlined development & approval process for biosimilars • In-silico models can reduce development cost of biosimilars in the long term

Medicine Name

Active Substance

Marketing Authorization Holder (Indian)

Authorization date

Accofil

filgrastim

Intas Pharmaceuticals

18-09-2014

Semglee

insulin glargine

Biocon/ Mylan

23-03-2018

Pelgraz

pegfilgrastim

Intas Pharmaceuticals

21-09-2018

investment per asset to get optimized in the mid-term horizon.

Recommendations and Way Forward for Indian Biosimilars Industry Tectonic shift of global healthcare from small molecules to biologics is hard to ignore anymore

and considering the imminent problems biologic drugs bring forth in terms of drug pricing and affordability, role of biosimilars has never been more important. While there has been no significant engagement in novel biologics from Indian pharma majors, biosimilars are a hard to ignore growth opportunity for Indian companies going beyond small molecule December 2018 ► 39

insights Medicine Name

Active Substance

Marketing Authorization Holder (Indian)

Authorization date

Fulphila

pegfilgrastim

Biocon/ Mylan

04-06-2018

Ogivri

trastuzumab

Biocon/ Mylan

01-12-2017

Company Intas Biologicals

Pipeline Info

very low level of market penetration and there is negligible commercial incentive for companies to expand markets further.

Thus, there is an urgent need for government intervention and a multistakeholder approach for expanding volume penetration and propelling the

Target Markets

Stage of Development2

5 biosimilars in the pipeline for India, and 5 for regulated markets of EU and USA Adalimumab

Biocon

Dr. Reddys

Global Phase 3 completed

Trastuzumab

Approved in USA, Under review in EU, Canada & Australia, Filed/Marketed in Emerging markets

Pegfilgrastim

USA, EU, Canada, Australia, EM

Filing

Bevacizumab

Marketed in India

Global Phase 3

Filgrastim

-

Etanercept

-

Pegfilgrastim

EU, USA

Rituximab

EU, USA

Bevacizumab

EU, USA

Early Development Approval enabling studies initiated

2 new molecules entering clinical development in coming months

Zydus Cadila

8 biosimilars in the pipelines for regulated markets and India

Reliance Life Sciences

14 biosimilars in global pipeline

Lupin Pharma

5 biosimilars in global pipeline

Wockhardt

4 biosimilars in global pipeline

generics ridden with intense competition and price pressures. There is growing interest in the Indian landscape and is evidenced by increasing number of new companies jumping on the biosimilars bandwagon. The segment is critical if Indian industry is to obtain the targeted $100 billion bio-economy.

With record number of domestic approvals, active engagement in semi-regulated markets and growing footprint in regulated markets, the Indian biosimilar industry is poised at the cusp of growth. There is an active pipeline in the country today, with many companies marching towards regulated markets.

It is imperative to nurture the vibrant industry landscape and support the industry in value realization. It is important to equip participants with the right arsenal to combat commercial challenges around market entry and access in domestic as well as international markets.

40 ◄ December 2018

Expanding Markets in Domestic Landscape - Need For A MultiStakeholder Approach As highlighted in earlier sections of the publication, the volume penetration of biosimilars within the country is appallingly low, with less than 10% for the largest biosimilar market of trastuzumab. Despite price control of key biosimilar drugs, overall penetration of drugs remains sub-optimal.

Wielding price control as an arsenal has always been a double-edged sword and high caution needs to be exercised to ensure right balance between affordable access and reward for innovation. In the case of biosimilars, it has mostly resulted in shrinking of markets without a corresponding impact on expansion of access to care due to overall cost of care still being unaffordable for more than 80% of the target population.

The market has reached a point of limbo where value realization has saturated at a

domestic success.

biosimilars

market

towards

(Pushpa Vijayaraghavan - Director and Practice Lead - Healthcare, Aparna Balasubramanian - Senior Consultant and Shreya Chadalavada – Analyst) [Extracts from the report – ‘Indian Biosimilars Industry: Roadmap to actualize Global Leadership’, prepared by Sathguru Management Consultants.]

Pharma Bio World

research

Traditional Indian Medicine: Sourcing From The Heart Of The Earth In spite of incredible advances in modern science, technology and allopathic medicine at large we are unable to provide quality healthcare to all. Traditional medicine particularly herbal medicine considered as a major healthcare provider around the globe particularly in rural and remote areas. A large section of people depends on such medicine for their primary healthcare mainly in underdeveloped or developing countries. Indian traditional medicinal system like Ayurveda, Siddha and Unani has a very rich history of their effectiveness; modern research has also acknowledged the importance of such medicine.

Indian traditional medicine or medicinal plants are also considered as a vital source of new drugs. Mainstreaming of traditional medicine is important for the people. Several steps have been taken in India to promote such medicine and integrate them into clinical practice. The incorporation of evidence based Indian traditional medicine in clinical practice will help to provide quality healthcare to all.

T

he evolution of society has been parallel to the history of medicines.

Humans have been continually striving to create increasingly powerful medicines to combat pathogens and disorders in order to ensure survival and longevity. The arms in this perennial struggle have always been provided by nature.

Since prehistoric times, humans have used natural products, such as plants, animals, microorganisms, and marine organisms, in medicines to alleviate and treat diseases.

According to fossil records, the human use of plants as medicines may be traced back at least 60,000 years. The use of natural products as medicines must, of course, have presented a tremendous challenge to early humans. It is highly probable that when seeking food, early humans often consumed poisonous plants, which led to vomiting, diarrhea, coma, or other toxic reactions — perhaps even death. However, in this way, early humans were able to develop knowledge about edible materials and natural medicines. Subsequently, humans invented fire, learned how to make alcohol, Pharma Bio World

developed religions, and made technological breakthroughs, and they learned how to develop new drugs. Traditional medicines make use of natural products and are of great importance. Such forms of medicine as Ayurveda, Unani, Siddha, Traditional Chinese Medicine (TCM), folk medicine of Africa, etc employ natural products and have been practiced all over the world for hundreds or even thousands of years, and they have blossomed into orderly-regulated systems of medicine. In their various forms, they may have certain defects, but they are still a valuable repository of human knowledge.

Throughout our evolution, the importance of natural products for medicine and health has been enormous. Since our earliest ancestors chewed on certain herbs to relieve pain, or wrapped leaves around wounds to improve healing, natural products have often been the sole means to treat diseases and injuries. In fact, it has only been during the past decades that natural products have

taken a secondary role in drug discovery and drug development, after the advent of molecular biology and combinatorial chemistry made possible the rational design of chemical compounds to target specific molecules. The past few years, however, have seen a renewed interest in the use of natural compounds and, more importantly, their role as a basis for drug development.

The modern tools of chemistry and biology—in particular, the various ‘-omics’ technologies—now allow scientists to detail the exact nature of the biological effects of natural compounds on the human body, as well as to uncover possible synergies, which holds much promise for the development of new therapies against many devastating diseases, including dementia and cancer.

From the history of drug development, it is evident that many drugs have been derived as a result of inspiration from traditional medicine. The application of, and research into, natural products are far from satisfactory. A number of problems need to be addressed in the future. For example, synergistic effects may exist among the December 2018 ► 41

research compounds that occur in natural products; however, the modes and mechanisms of action are seldom very clear. It is, therefore, necessary to make full use of such synergetic effects toward improving the effectiveness of drugs. However, it is also requisite that any adverse effects of natural products be properly reduced to meet safety standards.

Traditional Indian medicine is based on thousands of years of medical practice and experience, and is rich in experiential data which guarantee its effectiveness and efficacy. It has developed techniques with respect to such areas as correct dosage, methods of preparing, processing materials, and the appropriate time to collect the various medicinal parts of plants. It is notable that there is increasing convergence between traditional medicine and modern medicine.

With the development of modern technology, it has become possible to determine the pharmacology and mechanisms of action of many herbs, and traditional medicine is rapidly become comprehensible in terms of modern medicine. With advances in the theoretical background, therapeutic principles, associated technologies, and understanding of the life sciences, a clearer understanding of the active compounds of traditional has become possible. At the beginning of the nineteenth century, the era of modern drugs began. In 1805, the first pharmacologically-active compound morphine was isolated by a young German pharmacist, Friedrich Sertürner, from the opium plant. Subsequently, countless active compounds have been separated from natural products. Among them, some follow their traditional uses and the others do not.

Later, the development of synthetic techniques led to a significant reduction in the importance of natural products, and there were concerns that the use of some natural products for medicinal purposes might be completely banned. However, natural products are important for the development of new drugs, and these products have been 42 ◄ December 2018

in constant use. Some type of medicines, such as anticancer, antihypertensive, and antimigraine medication, have benefited greatly from natural products. The development of new drugs relying purely on modern technology appears to be reaching something of a limit. In developing new drugs, the pharmaceutical industry has tended to adopt high-throughput synthesis and combinatorial chemistry-based drug development since the 1980s. However, the considerable efforts made in this direction have not resulted in the expected drug productivity. Some large pharmaceutical companies are facing great challenges to develop new products. Over the past dozen years, increasing attention has accordingly been paid to natural products in the search for novel drugs in combination with new technology, such as high-throughput selection. Natural products, which have evolved over millions of years, have a unique chemical diversity, which results in diversity in their biological activities and drug-like properties. Those products have become one of the most important resources for developing new lead compounds and scaffolds. It is bound to be in continual use towards meeting the urgent need to develop effective drugs, and will play a leading role in the discovery of drugs for treating human diseases, especially critical diseases.

Natural products have a wide range of diversity of multi-dimensional chemical structures and its utility as biological function modifiers has also won considerable attention. Subsequently, they have been successfully employed in the discovery of new drugs and have exerted a far-reaching impact on chemicobiology. From the past century, the high structural diversity of natural products have been realized from the perspective of physical chemistry.

Their efficacy is related to the complexity of their well-organized three-dimensional chemical and steric properties, which offer many advantages in terms of efficiency and selectivity of molecular targets. As a successful example of drug development

from natural products, artemisinin and its analogs are presently in wide use for the anti-malaria treatment. This shows how research using natural products has made a significant contribution in drug development.

Among anticancer drugs approved in the time frame of about 1940–2002, approximately 54% were derived natural products or drugs inspired from knowledge related to such.

For instance, the Vinca alkaloids from Catharanthus roseus, and the terpene paclitaxel from Taxus baccata, are among successful anticancer drugs originally derived from plants. During the period between 1981 and 2002, the application of natural products in the development of new drugs — especially in the search for novel chemical structures — showed conspicuous success. In that 22-year time frame, drugs derived from natural products have been significant. That is especially true in the case of antihypertensives, where about 64% of newly-synthesized drugs have their origins in natural product structures. Considering their incomparable chemical diversity and novel mechanisms of action, natural products have continued to play a pivotal role in many drug development and research programs. With time, those natural products have undergone interesting and meaningful developments in their ability to interact with numerous, varied biological targets, and some have become the most important drugs in health care system. For example, plants, microorganisms, and animals manufacture small molecules, which have played a major role in drug discovery. Among 69 smallmolecule new drugs approved from 2005 to 2007 worldwide, 13 were natural products or originated from natural products, which underlines the importance of such products in drug research and development. Over the past 50 years, there has been a great diversity of new drugs developed using high-throughput screening methods and combinatorial chemistry. However, natural products and their derived compounds have continued to be highly-important Pharma Bio World

research components in pharmacopoeias. Of the reckoned 2,50,000 – 5,00,000 existing plant species, only a tiny proportion has been scientifically researched for bioactivities.

Therefore, there is great potential for future discoveries from plants and other natural products which, thus, offer huge potential in deriving useful information about novel chemical structures and their new types of action related to new drug development.

Traditional medicine is the oldest form of health care in the world and is used in the prevention, and treatment of physical and mental illnesses. Different societies historically developed various useful healing methods to combat a variety of health and life-threatening diseases.

Traditional medicine is also variously known as complementary and alternative, or ethnic medicine, and it still plays a key role in many countries today. The medicaments used in traditional medicines are mostly derived from natural products and ‘clinical trials’ have been conducted since ancient times.

In the case of traditional Indian medicine, considerable experience and advances have been accumulated and developed over the past thousands of years with respect to methods of preparation, selection of herbs, identification of medicinal materials, and the best time for obtaining various different plants. Appropriate processing and dose regulation are urgently needed in these traditional medicinal systems to improve drug efficacy and reduce drug toxicity.

Considerable amounts of data have been acquired through clinical experiments, and in this way traditional medicine has assisted in the development of modern drugs. Through its use of natural products, traditional medicine offers merits over other forms of medicine in such areas as the following: discovery of lead compounds and drug candidates; examining drug-like activity; and exploring physicochemical, biochemical, pharmacokinetic, and toxicological characteristics. If any form of traditional medicine is applied successfully, it may surprisingly assist in the development Pharma Bio World

of new drugs, thereby resulting in many benefits, such as significant cost reductions.

Ayurveda along with other Indian traditional medicinal systems is now gradually getting integrated into the Indian public health system. In recent years, Ayurveda has rapidly gained considerable approval as a complementary or alternative medicine in Western countries. Indian herbal medicine, which is the most important component of traditional Indian medicine is currently used in the health care of an estimated 1.5 billion people worldwide. It should be noted that in traditional Indian medicine, several herbs and ingredients are combined according to strict rules to form prescriptions.

Traditional Indian medicine comprises the following:

mainly

Ayurveda Ayurveda is a comprehensive scientific medicinal system indigenous to India. The term Ayurveda means ‘knowledge of life’ which comprises two Sanskrit words, Ayu (life) and Veda (knowledge or science).

The four vedas, considered as the oldest Indian literature (5000-1000 BC) contain information about natural remedies.

Ayurveda was established as a fully grown medicinal system in ancient India. The Charakha Samhita (focusing on internal medicine) and Susruta Samhita (focusing on surgery) were written systematically and considered as a classical text of Ayurveda. Vital details of Charaka Samhita and Susruta Samhita were compiled together and updated additionally in Ashtanga Sangraha and Ashtanga Hridaya.

Some other ancient classics which include minor work of Ayurveda includes Madhava Nidana (focussing on diagnosis of disease), Bhava Prakasa (focusing on additional information related to plant and diet), Sarngadhara Samhita (focusing on formulation and dosage forms). Ayurveda was classically divided into eight major clinical subdivisions: Kayacikitsa (internal medicine), Salya Tantra (surgery), Salakya (diseases of supra-clavicular origin), Kaumarabhrtya (paediatrics, obstetrics and

gynaecology), Bhutavidya (psychiatry), Agada Tantra (toxicology), Rasayana Tantra (rejuvenation and geriatrics), Vajikarana (aphrodisiology and eugenics).

Siddha Siddha system of medicine is considered to be a brilliant achievement and symbol of Tamil culture which originated in the southern parts of India. Siddha medicine evolved during Dravidian times and grew parallel to the Indus valley civilization. Chinese alchemy, Taoism and Taoist Patrology are considered as main sources of inspiration for Siddha alchemy. It is believed that the system was developed by eighteen siddhars (a class of Tamil sages). Though the Siddha system of medicine resembles Ayurveda in many aspects, it has own philosophy and concepts.

Unani Unani system of medicine is the fusion of contemporary traditional medicinal system in Egypt, Syria, Iran, Iraq, China, India and several other oriental countries. It originated in Greece and later developed in the Arab region. Arab and Persian settlers in the 11 th century introduced Unani medicine in India.

The system got recognition and became enriched during the Mughal rule.

Amchi Amchi or Sowa Rigpa is another ancient well documented traditional medicinal system, which was popular in Tibet, Mongolia, Nepal, Bhutan, Himalayan parts of India, some parts of China and former Soviet Union. Though opinions vary on the origin place of Amchi medicine, some believe that it originated in India while others consider Tibet or China to be its source. Amchi has close similarity with Ayurveda, though the influence of Chinese traditional medicine and Tibetan home remedies are also observed in this system.

Folk medicine Other than the codified traditional medicinal system, the uncodified folk medicine also plays a vital role in the maintenance of health December 2018 ► 43

research and cure of diseases for a large number of people, especially the rural, indigenous and ethnic communities. This type of knowledge is not documented properly and propagates verbally through generations and regions.

Nearly 8000 plants species are utilized in folk medicine and approximately 25,000 effective plant-based formulations are used by the rural and ethnic communities in India.

It has been noted by WHO that a large quantity of people in the world still depend on traditional medicine for healthcare.

The current status of traditional medicine differs in different countries. In 2012, the total value of the TCM industry was equivalent to around one-third of the total for China’s pharmaceutical industry.

It has been determined that 80% of the population in Africa makes use of traditional medicine — either alone or in conjunction with conventional medicine. By contrast, traditional Aboriginal medicine in Australia is in danger of vanishing owing to the prevalence of conventional medicine.

In many countries, modern medicine is prevailing and traditional medicine is declining. Many practitioners of Western medical science think such traditional medicinal systems as being short on reliability even though they are adopted by the majority of people in the world. It is possible to produce remarkable synergy and yield great benefits in developing reformed medicines and new drugs by connecting powerful modern scientific techniques and methods with the reasonable ethnobotanical and ethnomedical experiences of traditional medicine.

Traditional medicine is too valuable to be ignored in the research and development of modern drugs. Though it has an enigmatic character, there are also wide contexts for its use in terms of non-Western medical technology or activities. In traditional medicine, a single herb or formula may contain many phytochemical constituents, such as alkaloids, terpenoids, flavonoids, etc. Generally speaking, these chemicals function alone or in conjunction with 44 ◄ December 2018

one another to produce the desired pharmacological effect. It is notable that a lot of plant-originated drugs in clinical medicine today were derived from traditional medicine. In addition, it has been demonstrated that the many valuable drugs derived from plants were discovered through their application in traditional medicine. About 20 years back, a thorough investigation of the pharmacopoeias of developed and developing nations and the associated world scientific literature was conducted as part of the WHO’s traditional medicine programme. The aim of that study was to determine whether traditional medicine really had inspired modern drug discoveries and whether there was any correlation between the current use of various compounds and their application in traditional medicine. The study focused on various compounds used in drugs derived from plants in different countries, and it established that traditional medicine had indeed played a significant role in developing effective new drugs. That study focused on 122 compounds, 80% of which were found to be related to the remedial materials used in traditional/ folk medicine, and it was determined that these compounds originated from 94 plant species.

of traditional medicines contains a large number of chemical constituents, including active, invalid, and possible synergistic components. Therefore, great effort should be made at first to remove the dross and understand the essence of these natural drugs. Furthermore, in many cases, the role of a single compound from a particular natural product receives exclusive attention at the cost of other equally significant compounds within the drug. As a matter of fact, one advantage of traditional medicine’s therapeutics is the ‘synergism’ wherein the multiple components in a traditional medicine mixture often play a synergistic role which is greater than that of the individual active compound/component. It has increasingly become clear that the ‘single disease - single target - single drug’ model cannot treat complex diseases effectively, especially cardiovascular diseases and diabetes. Thus, the treatment protocols have lately seen a shift to the ‘multi-drugs and multi-targets’ mode for combination therapies. Therefore, in the future, multidisciplinary collaborative research, closely embedded with network pharmacology and big data, will enable researchers to unravel the synergism and other mechanisms of traditional medicines, leading to newer and better drugs along with positive treatment outcomes.

With the riches of modern technology, such as in synthesis, fermentation, pharmacology, pharmacodynamics combined with a wealth of knowledge about natural products via traditional medicine, it is possible to establish a large compound library for drug screening. This will enhance the possibilities for individual treatment and prevention of disease. Mankind needs to learn more from natural products and traditional medicines. In order to further promote the development of modern medical research on natural products, all the stakeholders have to face up to the various difficulties and challenges. Valuable information on natural products and traditional medicine has been mixed up in a large number of useful but scattered documents and useless rumors. Furthermore, one plant or formula

(Source: PBW)

Pharma Bio World

research

Can Indian traditional medicinal systems show the way forward?

Indian traditional codified medicinal systems and folk medicine are a vast lexicon of herbal formulations and medicinal plants. In last few decades, the popularity of herbal medicine/ products has increased worldwide, not only as part of conventional treatment strategies but also for health care management, and thus the opportunity to promote Indian traditional medicine is increasing globally. Recently people from several developed and developing countries have been attracted toward traditional Indian herbal medicines. A large number of modern medicines are derived from the plants used in Ayurveda and other traditional medicinal systems.

Ayurveda and other traditional herbal medicines are capable of addressing some modern unmet medical needs, and can provide the basis for developing potential medicines. Lack of drug standardization, information, quality control, and strict monitoring are the primary lacunae in the promotion of traditional Indian herbal products. In recent years several regulatory and promotional approaches have been undertaken to overcome such problems. Quality control, rigorous research to establish the effectiveness and safety, and credible clinical trials of the herbal products are required. Thus, the careful and scientific integration of Indian traditional herbal medicine into evidence-based clinical management of diseases is essential to provide better health care facilities to people.

I

ndia, a rich chest of biodiversity, has a large diversity of plant species. India consists of 2.4% of the total geographical area of the world, but accounts for 8% of global biodiversity, with around 49,000 plant species of which 5,150 species are endemic. 1–3 The Himalayan range, Western Ghats, North-Eastern Indian hills (Khasi and Mizo hills), and Vindhya and Satpura ranges of the northern peninsula of India are the gold mine of higher plant species.

Herbal medicine has special importance in the society, culture, and traditional medicine of India. 1 Plant-based medicines are at the root of the modern health care system, and are acknowledged for their economic importance also. 4 Traditional medicinal knowledge and plants play a central role in biological research and drug development.

Herbal products or constituents are not only used directly as curative agents, but also as lead molecule in the discovery of new drugs. Current research and understanding suggest that the use of crude herbs or herbal products can confer real benefits on health when used long-term. 2,5 Increasing population and the incidence of side effects Pharma Bio World

of synthetic medicines also accelerate the popularity of alternative medicines. The World Health Organization acknowledged that the goal of ‘Health For All’ cannot be accomplished without herbal medicines.

In a wider context, demand for medicinal plants, herbal medicines, health products, pharmaceuticals, food supplements, cosmetics, etc is growing in all parts of the world, which indicates the popularity and belief of people in herbal medicines. This in turn has created great scope for India to utilize its traditional knowledge of herbal medicine and repository of medicinal plants in the service of the world population and for the economic growth of India. 2,6,7

such systems to prepare curative agents, but use of plants have been the basis of treatment in these systems. It is estimated that Ayurveda uses 1,200 species of plants, while Siddha and Unani include 900 and 700 species of plants, respectively, in their medicinal preparations. 11 Ayurveda and other ISMs are judicious combinations of modern science and contemporary clinical medicine, which have the potential to cure a number of diseases in better ways and leverage new leads for modern medicine. 12 Currently, more that 1.5 million traditional medical practitioners in India are using medicinal plants for preventive, promotional, and curative purposes. 13

Indian systems of medicine Concepts and practices of different traditional medicinal systems in India are about several thousand years old. A large proportion of the Indian population still believes in and receives traditional medical care, which is based on the principles of three ancient codified Indian systems of medicine (ISMs): Ayurveda, Siddha, and Unani. 8–10 Though different chemicals, minerals, and animal products are used in

Ayurveda, perhaps the most ancient (6000 BC) of the different organized traditional medicinal systems, is native to the Indian subcontinent and has been practiced since the beginning of the Indian civilization. It can be described as the ‘science of life’, accounting for an integrated observation of the mental, physical, spiritual, and social facets of human beings. 14,15 Preventive and curative measures are the key components of the Ayurvedic system.

December 2018 ► 45

research Major treatment approaches include the use of ‘aushadhi’ (drugs); ‘anna’ (diet); and ‘vihara’, which includes exercises and a healthy mode of life. 14–16 The Charak Samhita, Sushrut Samhita, and Samhitas of Vagbhat, together referred to as the Brihattrayee, are considered the three key classics in Ayurveda. Charak Samhita and Sushrut Samhita(100–500 BC) describe over 700 plants, along with their detailed classification, pharmacological, and therapeutic characteristics. 12,17 In the pre-Vedic period (approx. 3000 BC2000 BC), the Siddha system of medicine originated in the southern part of India, 18 ‘siddhas’ (ancient practitioners of Siddha medicine) are believed to have developed this system which are written in Tamil and mainly practiced in Tamil Nadu. 14,18 The Siddha medicinal system recognizes three humoural concepts: ‘vata’ (wind), ‘pitta’ (bile), and ‘kapha’ (phlegm). Examination of the pulse, urine, and different anatomical features like the tongue, voice, complexion, eyes, touch (to find dry, warm, cold, sweating condition), and stools are commonly used as diagnostic criteria in Siddha medicine. 16,18,19 The basics of the Unani system of medicine were laid by Hippocrates and later by Galen. In the eleventh century, the Unani system was introduced in India by Arabs and Persians. The fundamental theory of the Unani system is ‘humoral theory’, which presupposes the presence of four humors – blood, phlegm, yellow bile, and black bile – in the body, and for Unani practitioners diagnosis mainly depends on pulse reading, and examination of the urine and stools. 20,21 The main therapeutic approaches in this system include dietotherapy, or ‘Ilaj-bighiza’ (use of specific diet); regimental therapy, or ‘Ilaj-bil-tadbeer’ (exercise, change of climate, massage, venesection, leaching, cupping); pharmacotherapy, or ‘Ilaj-bi-dawa’ (use of medicines from herbal, mineral, and animal sources); and surgery, or ‘Ilaj-Bil-Yad’. 20–22 Folk medicine (also known as ‘tribal’ or ‘indigenous’ medicine) also plays an important role in Indian society, mostly in rural/indigenous/ethnic communities.

This type of knowledge is usually passed verbally from ancestors of the particular group of people without any written script.

46 ◄ December 2018

It has been estimated that more than 8,000 species of plants are used by the tribal and ethnic communities in India as part of their healthcare systems. 7,23 Approximately 25,000 effective plant-based formulations are used in folk medicine and are commonly used by rural and ethnic communities in India. 13

medicinal systems believe in a holistic approach, and are considered as ancient forms of system-biology-based medicine.

Diagnosis and treatment strategies provide more individualized methods. ISMs have a very complex and logical approach to diagnosis, which are based on rational observation, and use a number of potent herbal preparations. They thus have become an important target of medical research.

Importance of herbal medicine Herbal medicines are truly in a league of their own, and have stood the test of time until now. But unfortunately the utilization of herbal medicine for the management of diseases is less despite of its potential. A large number of ethnic and rural people use and stoically play a crucial role in protecting the ancient medicinal knowledge related to plants from fading away into oblivion.

Herbal medicine is due for a revival.

However, incorporating herbal medicine into the true mainstream of modern health care and ensuring modern safety and efficacy standards is not an easy task.

A key area for the popularity of herbal products is nutritional supplements. Herbal supplements afford nutrients that are lacking or not consumed in an adequate quantity through the diet. Herbal supplements may contain vitamins, minerals, macronutrients, and antioxidants, etc, which are essential for good health. Thus, the demand of several Indian formulations – like chyawanprash, musli pak, and ashwagandhadi lehyam – is increasing. 27 Figure.1 shows the strategy for advancement and integration of traditional herbal medicine into modern medicine.

In India, about 65% of the population mainly uses traditional medicine for their health care needs. Inequities in the accessibility, availability, and affordability of modern healthcare make herbal drugs more popular in rural and remote areas .24,25 Demand for traditional medicine in developed countries is also increasing. About 40%–50% people in Germany, 42% in the USA, 48% in Australia, and 49% in France are using traditional medicine. In the twenty-first century, herbal drugs and products from plant sources are increasingly being acknowledged in developed countries and also among the people who can afford costlier allopathic medicines, with the hope of a more ecofriendly, bio-friendly, and relatively safer treatment strategy. 4,24,25 Among the 49,000 plants of the Indian subcontinent, about 20% are global species. It was estimated that more than 3,500 higher and lower plant species have medicinal value, although only 500 species of medicinal plants are used by the Ayurvedic industry. 1,2 Several reports have suggested that almost 80% of drug molecules are of natural origin or inspired by natural origin. It has been estimated that almost 50% of drugs approved since the 1990s are based on natural products. 26 Undoubtedly, a lot of plants contain substances of medicinal value which have yet to be discovered. Indian traditional

Present scenario and future Review of different national pharmacopeia reveals that at least 120 distinct chemical products/moieties from herbal sources have been utilized as lifesaving drugs.

It is predicted that among the estimated 250,000-400,000 plant species of world only 6% have been screened systematically for their biological activity and 15% have been investigated phytochemically. 28 It is predictable that natural compounds and their derivatives comprise nearly 60% of all drugs in clinical use and medicinal plants contribute not less than 25%. Between 1981 to 2002, around 119 drugs were approved and of those around 60% of anticancer and 75% anti-infective drugs could be related to natural substances. 29 Thirteen natural products were approved as drugs between 2005 and 2007. Currently, more than 100 natural products (drugs) are in clinical trials and about 100 molecules or compounds are in the preclinical phase of drug discovery. 30 Several bioactive molecules from plants, especially from those used in Ayurveda, have been discovered, such as reserpine for high blood pressure, psoralens for vitiligo, alkaloids from Holarrhena antidysenterica (L.) against amebiasis, Mucuna pruriens for Parkinson’s disease, piperidines as bioavailability enhancers, vasicine and vasicinone as bronchodilators, Pharma Bio World

Dovepress

integration and advancement of indian herbal medicine Cultivation, cell culture, and use of other scientific approaches to save endangered species

Record of unpublished folk information

Gathering of scientific evidence

Indian traditional herbal medicine

Identify potential plant species

Traditional herbal formulation

Marketed herbal formulation

Pharmacological screening of plant extract or fraction

Biological activity

Standardization and quality control as per international guideline

research

in ISMs have the potential to become the drugs of the future. Indian herbal medicine could meet some modern unmet medical needs, provide basic health care needs, and can offer the basis for developing potential medicines. Increase in the demand and utilization of herbal products provides fertile ground for the revival of Indian herbal medicine. 34

Role of Indian organizations Phytochemicals from ISMs, particularly from Isolation and characterization Ayurveda, are beginning to attract interest of active molecule Preclinical study across the world and huge efforts have toxicological profile been initiated to include traditional herbal Preclinical trial medicine in modern medicine. India has enormous facilities for research; the Central Semisynthetic/synthetic molecule Clinical study Clinical trial Drug Research Institute (CDRI), Council of Scientific and Industrial Research (CSIR), Promoting the drug Structural modification Central Institute of Medicinal and Aromatic New drug molecule (internationally) Plants, National Botanical Research Figure 1 Strategy for advancement and integration of traditional herbal medicine intoofmodern medicine.

Figure 1 Strategy for advancement and integration traditional herbal medicine into modern medicine. Institute, Regional Research Laboratories, and National Chemical Laboratory are hydroxycitric acid for obesity, bacosides especially Ayurveda, around the world is playing vital roles in this regard. Several accessibility, availability, affordability of modern health A key forbeing the popularity herbal products is nutrigovernment and nongovernmental to treat and mental retention, picrosides as mainly duearea to its a holisticofapproach 32 organizations hepatoprotective agents, phyllanthins to treatment.

Ayurveda, a well-written care make herbal drugs more popular in rural and remote tional supplements. Herbal supplements afford nutrients from different countries have actively started researching on plants and infections, andinwithanolides and medical text, describes scientific traditional medicine developed counareas.24,25 Demandforforviral that are lacked or not consumed in anview adequate quantity 28 formulations steroidal lactones as immunomodulators. on diseases and treatment that makes it tries is also increasing. About 40%–50% people in Germany, through the diet. Herbal supplements may contain vitamins,described in Ayurveda.

Current scientific knowledge along with unique. Currently, Ayurveda is included 42% in the USA, 48% in Australia, and 49% in France are minerals, macronutrients, and antioxidants, etc, which better clinical observation would help to in the Indian national health care system. Indian traditional medicinal plants in using traditional explore medicine.Indian In the traditional twenty-firstmedicine century, herbal are essential for good demand of several preclinical and clinical trial in an Several countries, like health. the UK,Thus, the the United drugs and products from plant sources are increasingly being Indian formulations – like chyawanprash, musli pak, and acceptance of Ayurveda is increasing advanced way and utilize old molecules for Arab Emirates, Sweden, Indonesia, and Global 27 demand therapeutic applications. instance, USA have acknowledged the Ayurvedic acknowledged innew developed countries and alsoFor among the the Figureand 1 shows thefor medicinal plants from India ashwagandhadi lehyam – is increasing.

35 is in upsurge. is currently acknowledged system andandmore than of 30traditional strategycare for advancement integration herbal In recent years, a number people who can forskolin afford costlier allopathic medicines, as witha health potent adenylate cyclase activator and countries are modern on the medicine. verge of doing the of drugs from ISMs have undergone clinical the hope of a more eco-friendly, bio-friendly, and relatively medicine into 33 antimicrobial berberine alkaloids are used to same.

It has been estimated that almost trials to verify their efficacy. Products safer treatment strategy.4,24,25 Among the 49,000 plants of cure dyslipidemia. 26,31 A typical, systematic two-thirds of people in the USA use one or from Ayurveda have been successfully the Indian subcontinent, 20% to arefind global It more Present scenario andstrategies, future of evaluated in clinical trials for the treatment research about on plants newspecies. bioactive alternative treatment Reviewmost of different pharmacopeia that at asthma, rheumatoid arthritis, was estimated that more thanis 3,500 higher and plant which of bronchial molecules expensive and lower inefficient. are drugsnational from herbal sources. revels least demand 120 distinct chemical products/moieties from herbal species have medicinal value, species of The heart disease, and cancer, among The high cost although of and theonly time500 taken for this for dietary supplements and ischemic 1,2 of the other illnesses. 28,38–41 Indian medicinal arethethe main hurdles.

One medicines is high in the US drugs. and It sources have been utilized as lifesaving is predicted medicinal plants process are used by Ayurvedic industry.

Several traditional herbs (eg, of ashwagandha, guggulu, haridra, most important approaches in themolecules discovery thus more than 1,500 herbals are sold for plant that among the estimated 250,000-400,000 species reports have suggested that almost 80% of drug 31 kutki, shatavari, of a new drug would be recourse to the such proposes.

A survey in 2007 revealed are of natural origin or inspired by natural origin. It has been world only 6% have been screened systematically for their atmaupta, amruta, brahmi, information accessible in traditional Indian that more than 200,000 American adults guduchi, amla, and ginger) and complex been investigated phyestimated that almost 50% of drugs approved since 1994 biological activity and 15% have medicinal systems, which are based on the have used Ayurvedic medicine. 34 Ayurveda herbal formulations (rasagenthi lehyam, 26 28 tochemically.

Undoubtedly, lot medicinal of plants is It is predictable natural compounds are based on natural products. brahma and rasayana, semecarpus lehyam, proven therapeutic utility of athe gaining momentum as a that successful contain substances of medicinal their derivatives comprise nearly 60% of all drugs in clinitriphala, and other rasayanas) were plants of India. 12 value which have yet to be alternative to the conventional medicinal evaluated through preclinical studies and through its systematic strategy not of less discovered. Indian traditional medicinal systems believe in system cal use and medicinal plants contribute than 25%.

33,42,43 reported to Indian herbal medicine makes numerous curing and preventing diseases using natural a holistic approach, and are considered as ancient forms of Between 1981 to 2002, around 119 drugs were approved and possess positive effect.

35 The US National Center for Complementary medicalmedicine. claims Diagnosis for the and treatment of resources.

Increased and and misuse system-biology-based treatment of those around 60% of use anticancer 75% anti-infective Alternative Medicine has funded many acute and chronic diseases and of current allopathic medicines provides and strategies provide more individualized methods. ISMs have drugs could be related to natural substances.29 Thirteen symptoms, the prevention of disease, enthusiasm for integrating alternative several research works based on Ayurvedic a very complex and approach to diagnosis, are medicine natural products approved as drugs between 2005 and 36 medicine – for example, on the use of andlogical the improvement of qualitywhich of life. and were conventional medicine. based on rationalHerbal observation, and use potent Ayurvedic 2007. Currently, than confers 100 natural products (drugs) are in cardiovascular diseases, a curcuminoids medicines alsoa number contain ofdifferent herbal more medicine benefits herbal preparations, thus have becomethat an important in 75% clinical trials and about 100 molecules compounds chemical constituents could act target singly to of the sub-continental population of orcompound from M. pruriens (L.) used against or synergistically. The advancement and 1,000 and millions of others around the 30side effects of anti-Parkinson’s drugs, of medical research. are in million the preclinical phase of drug discovery.

Several success of Indian traditional medicine, the world. 37 Herbal therapies or plants used the use of three plants (ginger, turmeric, Botanics: Targets and Therapy 2015:5

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research and Boswellia) to cure arthritis and asthma, and to validate the effect of Centella asiatica (L.) against Alzheimer’s disease. 34 Potent vaccine adjuvant activities of Withania somnifera (L.) and Asparagus racemosus wild have been evaluated in experimental systems, which suggest their importance in immunobiological preparations.

Controlled clinical trials are essential to establish the effects of drug and to compare the potency of traditional medicines with allopathic medicines. Clinical trials on Indian traditional medicines are encouraging but warrant many more. For instance, ‘piperine’, a bio-enhancer from pipali, has been successfully evaluated in clinical studies; a multicenter study found that Vijayasar (aqueous decoction of Pterocarpus marsupium Roxb) was effective as a hypoglycemic and antidiabetic drug; a US patent has been approved for the development of a herbal anti-psoriatic medicine containing Argemone mexicana (L.); the CDRI developed a product containing fraction of gugulipid from Commiphora wightii for the treatment of hyperlipidemia and atherosclerosis. Boswellia serrata Roxb gum resin has been commercialized by Regional Research Laboratories (Jammu) as a nonsteroidal anti-inflammatory drug, which also demonstrates hypolipidemic effect.2 8,44–47 A double-blinded clinical trial has been carried out with “arogyawardhini” (an Ayurvedic product containing amla, bahera, harar, guggulu, kutki, neem, chitrak mool) in viral hepatitis, while effects of M. pruriens, Phyllanthus amarus, and Tinospora cordifolia have been investigated in the treatment of Parkinson’s disease, hepatitis, and obstructive jaundice, respectively.48 The CSIR and CDRI have developed a bacoside-enriched standardized extract of plant brahmi (Bacopa monnieri L.) used to enhance memory and learning; the product is already marketed in Asian and European countries under different brand names.

Brahmi is described in the Charak Samhita and Sushruta Samhita, and has been used as a brain tonic for 3,000 years. 49 Traditional medicinal formulations containing plants A clinical trial of a well-known classical 48 ◄ December 2018

Ayurvedic formulation, ‘triphala’, which is prepared by combining the fruits (without seeds) of Terminalia chebula Retz, Terminalia bellerica Roxb, and Emblica officinalis Gaertn, showed potent effects against constipation and other gastric problems.50 A standardized formulation prepared with purified extract of ashwagandha (W. somnifera), guggulu (B. serrata), and haldi (Curcuma longa) was effective in improving a joint-swelling condition and has a good safely profile when given to people suffering from rheumatoid arthritis. 39 Another classical example of herbal formulation is `prostalyn’, which contain two traditional Indian medicinal plants (Murraya koeniggi and Tribulus terrestris) and used to treat benign prostate hyperplasia. A short-term clinical trial demonstrated that ‘tarika’, an Ayurvedic pimple remover herbal powder (containing T. chebula fruit, T. bellerica fruit, Santalum album heartwood powder, Curcuma aromatic rhizome, Embelia ribes fruit, Berberis aristata dried stem, Acorus calamus rhizome, Embelia officinalis fruit, Taxus baccata leaf, Myristica officinalis fruit endosperm, and Cyperus rotundus rhizome) has good effect in patients suffering from moderate to severe degrees of acne vulgaris. 52 ‘Guduchyadi ghrita medhya rasayana’, an Ayurvedic formulation containing several Indian medicinal plants like guduchi, apamarga, vidanga, shankhapushpi, vacha, haritaki, kushtha, and shatavari has showed promising effects in clinical trials by improving the mental health, memory, stress, and depression conditions, which might be helpful in slowing down the aging process.53 ‘Amalki rasayana’, an Ayurvedic herbal product, has showed promising effects in patients suffering from age-related macular degeneration. 54 A number of traditional plant-based formulations have been developed by the CSIR. Some of these are α, β arteether (E-mal – which was included in India’s National Malaria Control Programme) and elubaquine (Aablaquin) as antimalarial drugs; Asmon to cure asthma; Sallaki of B. serrata to treat rheumatoid arthritis and osteoarthritis; Livzon poly-herbal formulation, which has been evaluated as a hepatoprotective agent; and immines, a multi-herbal drug to cure immune-modulatory activity. 55 A number of Siddha herbal formulations like Gly Cyn Neu ointment against diabetic neuropathic

symptoms, combination of amukkara choornam and linga chenduram, and two other poly-herbal (for internal and external use) formulations against rheumatoid arthritis have also undergone successful clinical trials. 56–58 Since the Vedic period, ISMs have been enriched with a number of herbal drugs to cure jaundice and viral hepatitis. It has been estimated that more than 6,000 commercial herbal medicines are used worldwide for the management of liver disorders, and among them nearly 40% patents are for poly-herbal formulations (including silymarin from Silybum marianum L. Gaertn seed, Picrorhiza kurroa Royle ex Benth extract, and extracts of plants of different Phyllanthus sp. and glycyrrhizin preparation) consisting of different combinations of 93 Indian herbs, which are widely available in the Indian market. 48 Several patented and proprietary herbal medicines, like Arishtas, Churnas, Rasayanas, Ghrits, and Ras, have been marketed in the form of modern medicines such as tablets, capsules, powders, syrups, ointments, or even as gels. According to a survey, more than 70% of all drugs sold as Ayurvedic medicine in the Indian market are branded editions – patented and proprietary medicines.12 The Traditional Knowledge Digital Library (TKDL) is a unique approach by the Government of India to compile and preserve traditional medicinal knowledge and is in the public domain. Currently, a number of botanicals are undergoing clinical trial using reverse pharmacology processes to find new drugs to cure/prevent hepatotoxicity, viral hepatitis, cancer, diabetes, and arthritis based on the traditional knowledge of India. 12 Herbal medicines and medicinal plants described in ISMs, including folk medicine, have emerged as a great source of new drugs.

Potent phytochemicals from Indian medicinal plants Turmeric (C. longa) is a classical Indian medicinal herb recognized for its great clinical utility by ISMs. It is used in the treatment of pain, wounds, and sprains, as well as skin, pulmonary, gastrointestinal tract (GIT), and liver disorders. ‘Curcumin’, the bioactive component of turmeric, has emerged as a potential therapeutic molecule against Alzheimer’s disease, different malignant Pharma Bio World

research diseases, diabetes, allergies, and arthritis, among other disorders. 59,60 Rauwolfia serpentina L. (sarpagandha), an ancient medicinal plant of India, is used to treat hypertension, mental disturbance, insomnia, gastrointestinal disorders, epilepsy, anxiety, and schizophrenia. The plant is also used to cure several hypertension-related problems like headache, dizziness, amenorrhea, oligomenorrhea, and dysmenorrhea in Siddha medicine.61,62 In the beginning of 1930, R. serpentina was investigated for its tranquilizing and sedative effects. In 1949, Indian cardiologist Rustom Jal Vakil reported a hypotensive effect of its root extracts, which attracted the interest of researchers.

The alkaloids ajmaline (an antiarrhythmic agent) and reserpine were isolated from sarpagandha root in 1931 and 1952, respectively.63 The discovery of reserpine was a breakthrough for the treatment of hypertension and psychotic disorders, though this drug is seldom used now.48 B. monnieri is a potent medicinal herb of Ayurveda used to cure epilepsy, asthma, ulcers, tumors, and inflammation, among other things. Subsequent investigations led to the discovery of bacosides. 51,64 A labdane diterpene, ‘forskolin’ was isolated from the root of Indian medicinal herb Coleus forskohlii (makandi). Forskolin has a potent and direct adenylate cyclase activating property and could be a potent molecule to treat congestive cardiomyopathy, glaucoma, and asthma.

Clinical studies of forskolin to manage obesity and weight are ongoing. A number of semi-synthetic derivatives of forskolin have been developed and have been approved for several clinical studies. 65,66 ‘Flavopiridol’ and ‘P-276-00’ are the novel semi-synthetic derivatives of an alkaloid (rohitukine) isolated from Amoora rohituka (Roxb) Wight and Arn. and Dysoxylum binectariferum (Hook.f.), and are in advanced stages of clinical trials as anticancer drugs. 67,68 The anti-inflammatory, anticancer, anti-fertility, anti-implantation, and immunomodulatory activities of rohitukine have also been investigated. ‘Dysobinin’, a compound from D. binectariferum fruits, has exhibited potent central nervous system depressant and mild anti-inflammatory effects. 69 Both the plants (A. rohituka and D. binectariferum) have been used by physicians of ISMs for a number of disorders related to the liver and Pharma Bio World

spleen enlargement and inflammation. 69,70 ‘Diosgenin’ is a major bioactive steroidal sapogenin isolated from several traditional medicinal plants including Trigonella foenumgraecum L. and Dioscorea spp. These plants are commonly used in Ayurvedic and Siddha formulations. Dioscorea bulbifera L. (varahi) is used to treat dysuria, urinary calculus, urine disorders, calculus, and trauma, while T. foenum-graecum (methi) is used against pain, facial palsy, abdominal problems, hernia, and neurological disorders. 71,72 Catharanthus roseus L. (nityakalyani) has a long history in ISMs as a diuretic, antidysenteric, hemorrhagic, and antidiabetic drug.

Two alkaloids, vinblastine and vincristine, have been isolated from Catharanthus roseus leaves and recognized as anticancer agents for variety of cancers such as lymphocytic lymphoma, Hodgkin’s disease, testicular carcinoma, and choriocarcinoma.

Vincristine is used in acute leukemia, lymphosarcoma, and Wilms’ tumor. 73 Guggulsterone was discovered from the gum resin (guggulu) of Commiphora mukul.

Guggulu is an important constituent of Ayurvedic medicine used to cure several disorders like obesity, bone fractures, arthritis, inflammation, and cardiovascular disease. 74 The CDRI has successfully completed clinical trials of gugulipid as a lipid-lowering agent, and marketed it in the form of tablets and granules .50 ‘Darakchasava’, an ancient Indian herbal preparation containing grape (Vitis vinifera L.) extracts, is used as a cardio tonic and for the treatment of other disorders. Analysis of darakchasava indicated the presence of resveratrol and pterostilbene. Resveratrol was isolated in 1940 from Veratrum grandiflorum, and is also found in grapes, berries, and peanuts. Resveratrol has been found to possess cardioprotective and anticancer effects. 74 W. somnifera L., a medicinal plant described in Ayurveda, is known to possess antiinflammatory, cardioactive, and central nervous system boosting properties.

Withanolides, which is extracted from W. somnifera and used in Ayurvedic medicine to cure arthritis and menstrual disorders, has been found to be an inhibitor of angiogenesis, inflammation, tumor development, and oxidative stress, as well as a promoter of

cardioprotection. 74 The gum resin of salai guggul (B. serrata) is used in Ayurveda to cure rheumatic diseases and respiratory and liver disorders. Several researchers have discovered the active biomolecule of this resin to be boswellic acid. Boswellic acid and its derivatives have emerged as future anticancer agents. 74,75 The chemical investigation of a few Ayurvedic antiarthritic drugs has led to the discovery of synthetic anti-inflammatory drug molecules like phenylbutazone, indomethacin, and corticosteroids. 28 Indian medicinal plants have been found to be a source of many different modern bioactive agents; for example, quinine from Cinchona spp., pilocarpine from Pilocarpus jaborandi, atropine from Atropa belladonna L., cocaine from Erythroxylum coca Lam., morphine and codeine from Papaver somniferum L., cardiac glycosides from Digitalis spp., artemisinin from Artemisia annua L., paclitaxel from Taxus baccata L. and Taxus brevifolia L., berberine from Berberis spp., pristimerin from Celastrus paniculatus Willd., quassinoids from Ailanthus spp., plumbagin from Plumbago indica L., allicin from Allium sativum L., emetine from Cephaelis ipecacuanha (Brot.)

L.Andersson, glycyrrhizin from Glycyrrhiza glabra L., nimbidin from Azadirachta indica A. Juss., catechin from Acacia catechu Willd., sophoradin from Sophora subprostrata, thevenerin and neriifolin from Thevetia spp., podophyllin from Podophyllum emodi, homoharringtonine from Cephalotaxus, camptothecin from Camptotheca acuminata. 73 Challenges The National Medicinal Plants Board, India, estimated about 77% of the medicinal plants used in the country for several traditional medicinal formulations are from forests and wastelands. The International Union for Conservation of Nature Species Survival Commission estimated that there are 19 extinct, 43 extinct/endangered, 149 endangered, 108 vulnerable, and 256 rare plant species in India. 4 Thus, reducing overexploitation, stopping deforestation, cultivating medicinal plant, and using cell cultures and other scientific methods are required to protect the medicinal plants.

Further, the incidence of biopiracy is a major December 2018 ► 49

research impediment to the advancement of Indian herbal medicine. A survey by a TKDL task force based on 4,896 references revealed that 90 medicinal plants were listed in the US Patent and Trademark Office database, and about 80% of references were related to seven medicinal plants (kumari, mustaka, tamraparna, garjara, atasi, jambira, and kharbuja) of Indian origin. The task force also revealed that 360 of 762 patents were based on medicinal plants that could be classified as ‘traditional’. 76 This indicates the potential of Indian traditional knowledge and herbal drugs to address a large number of ailments in the future.

The primary lacunae with Ayurvedic and other traditional herbal products are the lack of drug standardization, information, quality control, and strict monitoring. 73 About 13 Asian herbal products have been found to contain a number of contaminants.

A study has found that among 260 Asian patented medicines, about 25% contained heavy metals beyond the limit, while undeclared drugs to increase therapeutic efficacy were found in 7% of those medicines. A large number of Ayurvedic formulations are available in spurious, adulterated, or misbranded forms, and several preparations do not follow the traditional proper rules or texts on how to prepare such formulations. 28,77 A report on Ayurvedic medicine has found that about 20% of such medicines purchased through the internet contained high levels of lead, mercury, and arsenic. Recently, the US Food and Drug Administration found that several herbal supplements contained currently available drugs like lovastatin (e.g, Mevacor), sildenafil (e.g, Viagra), estrogen, alprazolam (e.g, Xanax), indomethacin (e.g, Indocin), and warfarin (e.g, Coumadin) as adulterants.34,78 Herbal manufacturers from India usually follow World Health Organization guidelines for quality control, but the adulteration of formulations remains a major concern for both the domestic and export markets of Indian herbal products. 28,77 The majority of Ayurvedic formulations contain crude extracts in mixtures of different ingredients. Some studies have showed that the active principles of such products fail to produce the desired effects 50 ◄ December 2018

when isolated individually. This may due to the synergistic activity of several components present in a formulation. In the absence of pharmacopoeial data on such herbal formulations, it is difficult to isolate or standardize the active components.

Currently, the Ayurvedic Pharmacopeia has been compiled on modern lines and is updated often as per requirement. 73 Quality control and drug–herb interaction are other drawbacks. Several herbal products can interact with food, allopathic drugs, or pharmaceuticals, but unfortunately, for the majority of products, such information is lacking. In general, after 1 year of collection, herbs lose their medicinal value; powders prepared from such herbs remain effective for nearly 6 months, while pastes or ointments are effective for 1 year.77 Several herbs may be responsible for serious adverse effects – for example, creosote bush causes hepatotoxicity, ephedra may be responsible for cardiovascular complications and hepatotoxicity, and kava may also induce hepatotoxicity. Several manufacturers do not follow the appropriate methods of preparation and do not use the proper parts of the plant, which may be responsible for toxicity – as in the case of kava-induced toxicity.79 This situation needs to be addressed properly for the growth of Indian herbal medicine.

In the last 30 years ISMs, especially Ayurveda, have become remarkably popular in European countries; it has been estimated that over 5 million European people have used such traditional medicine in the last few decades. Due to the popularity of traditional medicine, thousands of under-/non-qualified traditional medicinal practitioners/institutions have emerged in Europe, which has led to a serious situation. 37 In the last decade, the European Union demanded bibliographic evidence and preclinical safety data before the marketing of traditional medicinal products.

Thus, proper standardization, research and data on the products’ quantitative and qualitative particulars of constituents, methods of manufacturing, therapeutic uses, contraindications, toxicity profiles, posology, forms, and routes of administration are essential for the promotion of Indian traditional medicine in Europe. 80 In Europe, due to some legal problems, the future of

Ayurvedic medicine is in the dark, and this requires urgent attention.81 A recent survey has concluded that Ayurveda has the potential to satisfy the needs of therapists and patients, despite differences of opinion in Europe.82 Herbal medicine and Indian economy Markets for medicinal plants and herbal medicine are lucrative and important for economic growth of India. Several pharmacopoeias have included a number of important herbs and herbal products.

For instance, the Ayurvedic Pharmacopoeia of India included monographs for 258 Ayurvedic drugs, the Indian Pharmacopoeia 2010 incorporated 89 monographs for herbs and herbal products, while the Indian Herbal Pharmacopoeia 2002, published by the Indian Drug Manufacturers Association, included 52 monographs on widely used medicinal plants of India. 4,28 Domestic trade of the ayurveda, yoga, naturopathy, unani, siddha, and homeopathy (AYUSH) industry is about INR 80 – 90 billion. Exports of medicinal plants and their products from India are about INR 10 billion. In 2010, the production of herbal drugs in India was about INR 4,000 crores, with 1,650 herbal formulations.4 The global trade of herbal products has crossed US$100 billion and is expected to reach to US$7 trillion by 2050. 83 In spite of the vast potential, the Indian share of this trade is at present quite low.

About 500 plant species are used in Chinese medicine, whereas more than 7,000 species are used in ISMs. China’s global share of medicinal plant exports is about 28%, while India’s share is only 8.13%. India ranked second in medicinal plant exports after China in 2009. 4 A report from the Associated Chambers of Commerce and Industry of India estimated that the value of the herbal industry was about INR 7,500 crores in 2010 and that its value would reach INR 30,000 crores by 2030. 85 India’s share in export of AYUSH products has shown an average increase of 10% per year over the past 5 yrs. Globally, the demand for Indian herbs and herbal medicines is increasing. Growth of about 11% annually in the export of herbs and herbal medicines to the European Union has been noted for the past 5 years. 83 It has been estimated that about 880 medicinal plants are involved in Indian trade. Of these, 42 species are imported and 48 species are Pharma Bio World

research exported.85 European countries hold the greatest share of the total herbal market (45%), followed by ASEAN (19%), Japan (16%), and North America (11%).86 Some of the important medicinal plants/products of India are E. officinalis Gaertn, isabgol (psyllium husk), the leaves and pods of senna, the leaves and powder of henna, myrobalans, jojoba seed, gymnema powder, and garcenia. 4,86 Traditional Indian medicinal knowledge and the diversity of plants in India are well recognized and therefore urgent attention is required to use this knowledge nationally and internationally.

Future aspects and India’s position Currently, the paradigm of medicine has shifted from not only curing clinical diseases but also maintaining good health. Today, medicines are available not only for treating illnesses but also for enhancing quality of life and health more broadly. 87 Thus, the integration of traditional herbal medicine into the modern health care system is the need of the time. The inclusion of traditional herbal medicine in modern health care offers a large benefit to society: it tenders reciprocal advantages to each system, improves the knowledge of general health care, increases the number and quality of practitioners, endorses the dissemination of primary health care knowledge, and is also helpful in providing basic health care to people in all parts of society. 78 However, several fundamental problems – like basic differences between different medicinal systems, differences in the concept of spiritualism, fear of the harmful effects of traditional preparations, and decline in the quality due to lack of regulation and standardization – are associated with this. 88 The increasing use of herbal traditional therapies like Ayurveda has to be supported with more systematic and sound scientific evidence vis-à-vis the therapies and the effectiveness of the medicines. 28 The promotion and globalization of Indian traditional herbal medicine requires a more realistic and strong approach to overcome the difficulties. China has effectively modernized its approaches by introducing government-sponsored proactive agricultural policies and good manufacturing practices for traditional medicine. Similar integrated strategies are essential for the growth of Ayurveda, Pharma Bio World

Siddha, and Unani medicines globally. The Government of India has started several drug testing laboratories and upgraded several existing laboratories for ISMs. India has also introduced new regulations since the year 2000 and several approaches like the introduction of good manufacturing practices have been initiated for traditional systems of medicine. These measures have created high hope for fruitful results. A good example is that, after such measures were put in place, a US patent was granted to a poly-herbal formulation (Artrex) for the treatment of arthritis. 28 Current approaches to promote Ayurvedic medicine are in process. The Indian Government formed the Department of AYUSH, which has accountability and authority related to the production, development, quality assurance, and standardization of ISMs. In 2010, the Department of AYUSH modified several rules to facilitate the licensing and export of Ayurvedic herbal medicines under the categories of Ayurvedic cosmeceuticals, Ayurvedic nutraceuticals, and Ayurvedic extracts. Several other Indian organizations, like the Banaras Hindu University, Gujarat Ayurveda University, National Institute of Ayurveda, Institute of Ayurveda and Integrative Medicine, are working on the global promotion of Ayurveda. 35 India has acknowledged the importance of Ayurveda for providing better primary health care to all people and thus Ayurveda was integrated into the Indian national health care system a few years back.33 It has been a useful measure to provide basic health care facilities to all and has proven the effectiveness of Ayurveda for public healthcare to a certain extent.

A recent status report released by the Ministry of AYUSH on Indian medicine and folk healing highlighted the health-seeking activities of consumers and the existing policy of the government on the integration and globalization of Ayurveda, Unani and Siddha medicine.

In the 21st century, medical tourism emerged as a key approach to attract people toward herbal medicine and to promote international business. With globalization,

patients have the opportunity to seek better treatment strategies across the globe. In several countries, including Japan, USA, UK, and European nations, the number of elderly people has increased rapidly since life expectancy has increased progressively, which has resulted in increased demand for natural health care strategies. 90,91 India has the ability to deliver such strategies. It was estimated that about 1.27 million medical tourists from several countries around the globe, such as UK, USA, Canada, China, Bangladesh, and Sri Lanka, visit India with the hope of better, safer traditional herbal medicinal treatment. It has been estimated that foreign-exchange earnings for this are nearly US$ 4 billion and the market will grow to around US$ 10 billion by 2020. 91 These figures clearly indicate the benefit and acceptance of Ayurveda and other Indian medical systems around the world. The potential of ISMs would increase manifold if it is integrated into the modern health care system. Medical tourism also presents the opportunity to boost the country’s economic conditions and will encourage more and more Indians as well toward its ancient and effective traditional herbal medicinal systems. 91 The Materia Medica of India contains 2,000 drugs of natural origin along with their therapeutic utilities, which are derived from traditional systems of medicine.

Among these, 400 are from mineral and animal sources, and the rest are from plant sources. 92 The TKDL contains information regarding 500 Ayurveda, 500 Unani, and 200 Siddha formulations and also includes information about 291 plants that are used as ingredients in different traditional formulations. 76 There are plenty of opportunities to develop new products or formulations based on the therapeutic potential of Ayurvedic medicinal plants and getting them accepted as dietary supplements, nutraceuticals, prescription drugs and over-the-counter medicines. 24 In India, a lot of public and private hospitals as well as private dispensaries are providing treatment based on Ayurveda and other ISMs. These approaches are showing inspiring results and have attracted the attention of people globally especially with reference to public healthcare. For centuries, herbal medicine has been acknowledged as having safer drugs and December 2018 ► 51

research more compatibility with physiological flora.

Indian traditional medicine provides the scientific basis and process of utilizing medicinal plants to cure several ailments.

In combination with modern science, technologies and approaches, Indian herbal products/medicinal plants can provide basic and advanced medical care around the world.

Conclusion Indian traditional herbal medicine is prevalent around the globe and a large number of people have integrated them along with moden medicine for their different health needs. In spite of their popularity, the rational design, proper standardization, and careful monitoring of Indian traditional herbal formulations and botanicals, along with robust scientific evidence, are essential for their promotion.

Indian traditional herbal medicine can cause a global shift in healthcare if it is promoted based on the parameters of modern evidence-based medicine.

Thus, the identification of resources and finding of molecular mechanisms are essential, as it could be a resource for new medicine. Current research has shown the potentiality of Indian medicinal plants in drug discovery, though a lot of plants have not been studied and need to be investigated. The careful and scientific integration of herbal medicines from ISMs into the modern system is essential in safeguarding the interests of the Indian people and to provide better health care facilities for all.

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(Saikat Sen & Raja Chakraborty, Institute of Pharmacy, Assam Down Town University, India.)

Pharma Bio World

research

Basic Principles in Siddha Pharmaceutical Science - An Overview Pharmaceutics in Siddha system of medicine is an important component with scientific background.

As per the mode of application and medicinal forms, the pharmaceutical products in Siddha system have been classified into 32 internal and 32 external formulations. Basically the formulations are designed as per the concept of five elements and six tastes employing the principles of synergism, antagonism and transformation into atomic or ionic form for the production of effective molecules.

This review paper highlights the GMP and guidelines mentioned in the Siddha literature along with the scientific background of the same. One part of this paper is devoted to the discussion on the influence of different factors in the expression of pharmacological activity of drugs. The paper also discusses the noteworthy endeavours in the standardization and commercialisation of Siddha formulations and contemplates on the quality control aspects of traditional medicines. The aim of this review paper is to illustrate the scientific advancements in the ancient drug processing methods of the Siddha system of medicine.

T

he Siddha system of medicine is a complex system of science as it has treatises on medicine, alchemy and an extensive set of pharmacopoeia. It has its own fundamental principles of therapy and pharmaceuticals with specialization in iatrochemistry well before the development of modern science.

As per Siddha, the human body is the replica of the universe; food and drugs irrespective of their origin are made of five basic elements namely, Earth, Water, Fire, Air and Ether. 1 The proportion of the elements present in the drugs vary and their preponderance or otherwise is responsible for their actions and therapeutic results.

According to basic Siddha concept the Pancha bhootham (five elements), Arusuvai (Six tastes) and Uyirthathu (three humours) are interlinked. That is, predominance of fire and water element expresses salty taste; fire and air element expresses pungent taste.

Both are having hot potency and intake of them results in vitiation of Azhal humour.

Similarly, the earth element with water element produces sweet tasting substance which can vitiate Iyya humour. 2 Hence, Siddha formulations are designed based on the understanding of these reactions.

The knowledge of plants and minerals from all the branches of science is used in the Pharma Bio World

preparation of medicine in Siddha. In Siddha system the knowledge of chemistry had been honed into a science complementary to medicine. Moreover the knowledge in this system is not static and is inherently dynamic in nature and evolves in response to challenges posed by the environment.

The practitioners of Siddha applies several procedures divided into processes such as calcination, sublimation, distillation, fusion, separation, conjunction/combination, fermentation, purification, incineration of metals, liquefaction and extraction for the preparation of formulations.

Drugs In Siddha System The source of pharmaceutical preparations in Siddha system comprises Thadhu (metals, minerals & arsenical compounds), Thavara (herbs), and Jeeva (materials and products of animal origin) elements. Apart from the vast herbal sources, Gunapadam (Materia Medica) describes the detailed classification of Thadhu drugs as well.

For example, the verse: ‘Kaelappa kaaramodu yirunoorodu yirupa thaache’ Bohar Karasarathurai, denotes the types of Thadhu drugs; they are: 11 types of metals, 25 types of karasaram (i.e. different types of salts), 64 types of Pashana drugs that do not dissolve in water but emit vapours when put in fire, 120 Uparasa (mineral) drugs. 3

The system has a classification of metals and alloys, which melts on heating and solidifies on cooling. These include gold, silver, copper, tin, lead and iron. These are incinerated by special processes and are used in medicine after purification or ore dressing. There is a group of drugs that exhibit sublimation on heating, which includes mercury and its different forms like red sulfide of mercury, mercuric chloride and red oxide of mercury etc. Sulphur, which is insoluble in water, finds a crucial place in Siddha Materia Medica along with mercury for usage in therapeutics and in maintenance of good health. In addition there are drugs obtained from animal sources like milk and milk products, conch, bones, teeth, bile, etc.

Even though the usage of Thadhu ingredients are more advanced in Siddha system, it was mentioned that the application of metallic preparations is preferred only after the use of herbal preparations as mentioned in the following verse: ‘Vaerpaaru thazhaipaaru minjinakkal mella mella parpam chendhooram paaru’4 The Siddhars (experts) applied the Pancha bhoothic principles for raw materials and classified them as Panchabhootha ulogam, Pancha bhootha uppu, Panchabhootha Pashanam, Panchabhootha uparasam, and formulated the preparations according to the dominating Pootham, Suvai and Veeriyam. 3 December 2018 ► 55

research 3. Process involving distilled (Dhravagam) 4. Process involving Ceyneer 5. Process involving Muppu.

acids

Uloga maaranam is the process for detoxification of metals and to increase the efficacy and potency of metallic compounds.

Certain drugs are combined systematically and changed into liquid form known as Ceyneer. This Ceyneer helps to convert the drugs of combustible nature into noncombustible nature. The salt Pooneeru, the melted salt prepared from Fuller’s earth is converted into calcine powder form and used in Muppu processing. 4

Basically the drugs are explained in five characteristics namely Suvai (taste), Gunam (quality), Veeriyam (potency), Vibaham (class) and Ceykai (action). The details regarding antagonistic - agonistic (chathru mithru) compounds of drugs, dose, duration, season for ingestion, its compliance with geographical location and food restriction are well explicated in the Siddha Materia Medica.

As per the sorting in Siddha texts, 32 types of internal medicines based on the form, methods of preparation, shelf life, etc and 32 types of external medicines based on the modes of application have been elucidated and practiced since ages.3 Certain medicines, method of preparation and therapeutic procedures are unique to the Siddha system of medicine. Lakhs of formulations are available in Siddha literature though only a few are documented whilst a vast number are still in palm leaves recorded in the classical script.

Designing of Formulations In Siddha The formulations and treatment methods in Siddha system are not uniform for all cases or patients. It has to be customized and modified in accordance with the climate, habitat, body constitution and individual body conditions. Hence the quality control of the final product is an exigent task of this system.

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Siddha formulations are in natural form and contain in unison the active ingredients, inactive fibres, debris, etc. The functional principles of Siddha do not attempt to haul out the active ingredients and are disinclined to the concept of employing drugs as chemicals.

This adds to the therapeutic value to these drugs by way of either neutralizing the toxic material, if any or facilitating the excretion of unwanted chemicals by entrapping them within fibres, debris, etc. 5 The inorganic substances occurring in nature have to be brought into atomic form for their effective usage as medicine. The Siddhars developed the knowledge of transforming inorganic substances into atomic and ionic form through specific processes, whereby they can be easily absorbed in the desired pathways resulting in a highly efficacious product. The ideology behind the customised formulations as practiced in Siddha is to circumvent side effects / after effects. 5 Siddhars have followed various methods for medicinal preparations. Important among them are 4: 1. Process involving drugs based on combined ratio of five elements - Aeaga mooligai prayogam 2. Process involving antagonism and synergism – Maarana prayogam

Preparation of specialized drugs like Kattu, Urukku, Kalangu and Chunnam which have long shelf life and the medicinal forms like Chatthu, Gurukuligai of infinite life span, are accomplished by such ingenious processing methods.

Factors Affecting the Pharmacological Actions of Drug The pharmaceutical procedures for any drug involve various steps starting from identification and collection of authentic raw material, application of standardised processing techniques for purification and formulation, packaging and storage of prepared drug, usage of adjuvant on application. In each step, the factors influencing and/or detaining the expression of pharmacological activity of drugs has to be considered.

The season of collection of raw drugs and geographical area of collection have great impact in the expression of pharmacological activity. According to ancient Siddha classics, the geographical areas (Kurinji - mountains, Mullai – forests, Marutham - cultivation area, Neithal – seashore and Palai - deserts)6 have features that are specific to that area.7 As per Siddha, the plants usually collected in Marutham and Kurinji areas are highly nutritive and possess medicinal value; but the herbs from other areas imbalances three humours and paves the way for certain pathological conditions.4 Genetic variants lead to the variability in the chemical composition of the population.

Geography, altitude, soil composition, microbial load, climate, temperature, Pharma Bio World

research Karandi (spoon) is used for scrapping the medicines from Kalvam and also for stirring or mixing of ingredients while processing.

Steel or silver spoon is utthamam (good).

Spoon made of wood or horn is matthimam (moderate). As iron has a tendency to rust, the usage of iron spoon may reduce the effectiveness of the drug. 3 The ladle to be used in the preparation of oils and ghees should be made of coconut shell (akappai); churning sticks made of wood for churning; wooden spatula for the preparation of elagam. Iron ladles should not be used for preparing perfumed oils, medicated ghee, lime juice and decoctions made of milk, butter milk, etc. It should also not be used in preparations that involve mercury, arsenic and toxic herbs because of the demineralisation of iron on exposure to such chemicals. 4 season, etc can cause fluctuation in the phytochemical ratio. A variation in the alkaloid composition in the leaves of Adhatoda vasica seasonally has been recorded. It is lowest in February - March and highest in August - October. Similarly, variation of alkaloid contents based on the age of the plant is reported in Holarrhena antidysenterica. 8

Hence, while making changes in the classical formulations, the impact factors should be noted. The modification in classical formulations (form, ingredients, adjuvant, etc) should not be made without any valid reason or supporting information.

The pharmaceutical processing of drug depends upon nature of the raw material fresh or dry, solubility and heat stability of ingredients, route of administration, shelf life of drug, etc. Alteration in the drug processing method has a strong adverse impact on the formulation. Thus, misprocessing may lead to adverse effects of Siddha drugs.

For example, while processing Rasam, if the impurities namely Thodam / Chattai are not properly removed, it may lead to disorders like skin ailments, haemorrhoids, neurological disorders, respiratory ailments and seldom death also. 3

GMP In Siddha Literature The techniques and instruments used for the preparation of Siddha drugs are clearly explained in the literature. Raw materials used in the manufacture of drugs should be authentic, of prescribed quality and free from contamination. The impurities (Thodam) in each of the drug and methods for the purification of drugs, etc are clearly elucidated in the classical Siddha texts. As per the classical texts, it is essential that the principles regarding the collection of raw material (eg: collection of the roots of plants directed towards north [Vadakku ver]10, collection of plant parts in the morning, etc), purification procedures, preparatory time, etc should be followed strictly to ensure the safety and efficacy of the drug.

The adjuvant or vehicle used along with the drugs may not be inert and per se may produce significant pharmacological activity.

For example, usage of honey while treating anaemia supports the therapeutic efficacy of drug. This is due to the presence of minerals like iron and vitamins like ascorbic acid in it.9 Most of the adjuvants enhance the activity of drugs, some of them neutralizes the toxic reactions while others balance the humours, etc.

Tools of Siddha drug processing Kalvam (stone mortar) is being used for grinding drugs in Siddha pharmacy. As per the classics, black coloured stone mortar is preferred for the grinding process. This type of mortar will not release particles and thus the medicines may be obtained without impurities. 11 On the other hand, use of yellow or white coloured mortar results in neutralisation of the activity of the drug and ends with inactive substance. 3

Pharma Bio World

The mud pot used for the preparation of decoction and distillation processes is made by using astringent and sour materials.

For sublimation, vapourising, mezhugu processing, etc, the mouth of the processing vessel should be narrow; for roasting process, the mud vessel used should be of shallow surface with brim and the vessel for decoction preparation should have a deep bottom. The vessels made of Navaloga (nine metals) are not suitable for preparation of decoctions, medicinal ghee and distillation process. Also, the vessel used for the preparation of a particular medicated oil should not be used in the processing of other oils, because it not only spoils the medicine, but also the health of the patient and the reputation of the physician. In case of a new pot, care should be taken that the ghee does not percolate too deep 4.

Temperature for drug processing is also accomplished by various methods like Pudam – which can be classified according to the number / type of dung cakes used; Kaadai pudam – 1 cow dung cake, Kavuthaari pudam – 3 cow dung cakes, Kukkuda pudam - 10 cow dung cakes, Varaaka pudam – 50 cow dung cakes, Manalmaraivu pudam – 90 cow dung cakes, Keja pudam – 1000 cow dung cakes and Bhoomi pudam – sheep or goat dung. In the processing of medicinal preparations the source of fire, type of fire and method of exposure to heat is basically designed according to the nature of the drug material and the application of the drug.

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research A few of the unique processes used in the preparation of some Siddha medicines are namely, Thanyapudam - keeping the drug immersed in grains, Umipudam keeping the drug immersed in husk/ chaff, Pattaipudam – keeping the drug within tree bark, Sooriyapudam – keeping the drug under sunlight, Chandrapudam – keeping the drug under moonlight, Panipudam – exposing the drugs to dew. 3 In Pudam processing method, the usage of naturally occurring dung material is vital.

Dried cow dung cakes from the forest are good for preparing medicine while the dung of buffalos is second preference. The use of dung mixed with straw and dust will reduce the potency of the drug. Based upon the necessity of temperature, Calcium stones or sand or soil or ash can also be used in the processing of heavy metals and arsenic compounds like Yellow Orpiment, etc. 3 While using firewood for Thailam processing, the type of fire (Dheepakkini, Kamalakkini, Kathaliyakkini, Kaadakkini) is decided as per the stage of processing, whereas the type of firewood is decided according to the ingredients of the formulation. For example, the firewood of Neem, Coconut palm and Palmyra palm is apt for Mercury preparations while Indian Arabic tree and Indian Kino tree is suitable for preparations containing Iron. 3 On the other hand, the type of firewood to be used is also decided as per the application of the drug. Tanner’s Cassia and Country Mallow is preferred for the processing of medicated oil for fever while firewood of Indian Jujube and Black Siris tree is ideal for the processing of medicated oil for auricular, nasal and ophthalmic applications. Firewood of South Indian Mahua and Tamarind is applicable for the processing of external therapeutic oils. If the notified firewood is unavailable, then the alternative is determined on the basis of the character or contents of the oil being processed. 12 Firewood of dead trees is of no use, whereas firewood cut before three months is good and freshly cut wood is to be avoided as it tends to spoil the drug. Pittha would aggravate if the firewood of very old tree is used for medicinal preparations. If the 58 ◄ December 2018

bark of such a tree is used as fuel, then the drug being processed may cause itching on application. 4 Guidelines of Siddha drug processing 1. The preparations like Utkali, Maathirai, etc should be in the non-sticky stage, i.e. the materials should not adhere to the fingers after the product is fully processed. 3 2. The stages of the processing oil are expressed on the surface as froth and at the end of the processing stage, the sediment should not be sticky and should burn vigorously without any crackling noise when exposed to fire. 12 The oil processing has to be finished in three stages namely, soft stage (Mirudu pakam), waxy stage (Mezhugu pakam) and gritty stage (Karakarappu pakam).

The medicated oil of Mirudu pakam is for the internal application in Vali humour imbalance, medicated oil of Mezhugu pakam is for external application and Azhal diseases while the medicated oil of Karakarappu pakam is for application on the scalp and Iyya diseases. 12 3. As the effectiveness of drug depends upon the tiny or microscopic nature of the particles, a sieve of highly fine mesh is mandatory in the processing of chooranam. The chooranam prepared by the use of mechanical devices like pulverizer should be allowed to cool down by way of spreading and then mixed well for storage and packing. 12 4. As there is a chance of plenty of microbes inhabiting the Choornam, it should be subjected to the process of purification (Choorana thooimai). This involves baking of Chooranam and then processing it into fine powder. 3 5. While processing preparations like manappagu, large spatula or ladle is to be used to stir continuously, otherwise the mixture will deposit in the bottom and get charred. This may lead to burnt smell and bitter taste to the product.

6. Whilst processing nei, at certain stage of boiling froth will appear on the surface of the ghee. At that moment, the sediment should be analyzed by hands. If it is well processed, the sediment would be nonsticky. The ghee should be then filtered off and preserved. 12 7. In the processing of elagam (lehiyam), honey should be added only after

removing the processed drug from the oven and then mixed well into the elagam for suitable consistency. 12 8. As the colour, characteristics and fineness of parpam is based on the quality of grinding process, it should be done in the proper way. While processing, if there is any moisture content in the tablet (villai) material, the colour of the parpam may differ and hence proper drying is mandatory. 12 9. In Pudam method of processing, the cake materials should be placed in earthen bowl properly so that the temperature is spread evenly over the materials. The size of the bowl depends on the quantity of material; bowls with too much depth and breadth should be avoided. 12 10.Place of reasonable air circulation should be selected for pudam processing. A crater of defined breadth and depth is to be dug out in the earth and the circumference is to be modulated by bricks to prevent the seepage of soil in the mixture. Half of the defined cowdung cakes are to be filled up in the crater and the earthen bowl containing the material is to be placed on that, while the remaining cowdung cakes are to be spread on the said bowl and fired. 12 11.Even though the cowdung cakes are the usual burning materials in pudam processing, some herbal barks or dung of goats have been specified for the processing of certain drugs. Dung may also contain certain sand or waste materials and hence the number or quantity should be modified as per the necessity of temperature in the process 12.Certain substances like Ganthagam (Sulphur), Thalakam (Yellow Orpiment) are vulnerable to high temperature, and hence ash or sand is to be used for calcination / pudam process. Suitable quantity of ash is to be spread in the bowl and the material in villai (tablet) form is to be placed within the bowl and covered further with ash. 12 13. The disassembling of the processing setup should be carried out only after all the materials have cooled down.

14.Medicines once prepared should not be reheated. This principle applies for elagam, decoctions, boiled juices, etc. 4 3. Quality Assessment of Drug Quality of drugs like parpam, chendhooram, Pharma Bio World

research etc shall be assessed by the analysis of physical characteristics. Properly finished parpam and chendhooram is tasteless, fine, smooth and devoid of shine or glitter. The finished parpam or chendhooram is said to be as per standards, if a small amount of the mixture when placed on water does not sink.

The perfect parpam or chendhooram will not degenerate to the base elements when exposed to fire.12 The preparations like chooranam should be devoid of moisture content and its particles should be minute. 11 Standardization of Siddha Drugs Standardization of Siddha formulations is one of the mandatory requirements in order to develop quality drugs on a large scale and market it. The effectiveness of the formulations is completely dependent on the raw materials used and also on the quality control of the processes employed. The raw materials such as herbs cultivated in different environmental conditions and geographical areas possess different types of chemical constituents. Hence, harmonization of chemical constituents is complex in nature and therefore fingerprinting profiles of phytoconstitutents is the easiest and cost effective procedure to analyse raw drugs.

Also, the assay of a particular chemical constituent can be done through the identification of chemical markers and their quantification. The analytical reference standard can then be prepared based on this data. Macroscopic, microscopic and physico-chemical tests are now part of the routine analyses in any quality control laboratories pertaining to herbal drugs.

Lately, sophisticated analytical tandem techniques such LC-MS and GC-MS are being used for molecular fingerprinting.

NMR metabolic profiling is also a good tool for the quantification of chemical markers without isolation. The volatile and low boiling chemical constituents can be identified and quantified through GC-MS and non-volatile constituents can be profiled through LC-MS. The DNA fingerprinting methodologies can be effectively used for raw materials of different origin. The test for heavy metals is another critical test with reference to traditional medicine and the same can be done through elemental analysis techniques.

The preparative HPLC techniques can be used to isolate major constituents Pharma Bio World

and through lyophilisation processes, the purest single molecule can be obtained and complete characterization of the molecule would help to identify the structure. This would enhance the ability to study drugdrug interactions and to find out the mode of action of the drugs.

While attempting to commercialize a product belonging to Siddha system, the issues regarding portability of the drug and shelf life of the drug arises, as most of the herbal medicines are in unsophisticated form, having short shelf life and the addition of preservatives for the purpose of marketing results in the reduced efficacy of the drug. In the case of preparations like parpam, chendooram, karuppu, etc, there is no critical issues regarding the shelf life and portability, but the issue is regarding the adjuvant of the drug and dosage, as most of these kinds of drugs are in nano-particulate form and the dosage are in micro or milligram levels. Any minor variation may generate unwanted reactions and also the efficacy of the drug is based on the precise dose and the specific adjuvant 5.

Modification in the route of administration or change of form for portability or adjustments for palatability shows strong adverse impact on the activity of the drug. Hence, further studies are needed to adapt the Siddha formulations as per the needs of the market.

Conclusion Pharmaceutics in Siddha system is essentially a personalised or customized scientific system wherein the collection of raw materials and processing has to be done as per strict guidelines, principally based on experiential wisdom. Transformation of this ancient system into a generalised and commercial system has led to poor quality assurance. Therefore, more research and development efforts are required to optimise the formulation aspects in order to ensure constant availability of standardised products with consistent composition and efficacy.

References [1] Dr. Jayaprakash Narayanan, et al; Siddha Medicine – Fundamentals; Volume –II; Thamil Valarchi Kalagam;

Madras University; Page 1.

[2] S. Noinaadal Shanmugavelan; Noimuthalnaadal Thirattu Part-1; Department of Indian Medicine and Homeopathy; Pages 20-23.

[3] R. Thiagarajan, Gunapadam - Thathu- Jeeva Vaguppu; Department of Indian Medicine and Homeopathy; Pages 1-23, 44.

[4] Dr. C. S. Utthamaroyan; A Compendium of Siddha Doctrine; Department of Indian Medicine and Homeopathy; Pages 10, 46, 437-439.

[5] G. S. Lekha, Patenting of Siddha formulations- Scope and Issues; STM Journal of Ayush; Volume 1, Issue 2, August 2012; Pages 50-62 [6] Dr. K. Durai rajan; Noyilla Neri; Department of Indian Medicine and Homeopathy; Page 2.

[7] G. S. Lekha, P. Sathiyarajeswaran; Management of NCD by Siddha system; Ayushdhara - An International Journal of Research in AYUSH and Allied Systems; July-August 2015, Vol 2, Issue 4; Pages 1-8.

[8]. Palpu Pushpangadan; Raw material: Sustainable availability and concern regarding medicinal plants on negative list; International Conclave on Traditional Medicine 16th & 17th Nov 2006; New Delhi.

[9]. Chemical composition of honey – The Wealth of India; Raw materials – Volume 2: B – A Dictionary of hidden raw materials & Industrial products; CSIR, New Delhi; Page 91.

[10]. Pillai pini Maruthuvam – Part -2; Department of Indian Medicine and Homeopathy; Page 445.

[11].Thanigavelan.V, et al, Antibacterial and haemostatic activities of a Siddha formulation – Pavala Parpam; Pharmacologyonline 1; Pages 613-624 (2011) [12]. The Siddha formulary of India; Part 2 (Tamil Version); Department of AYUSH, New Delhi; Pages 17, 43, 63, 94, 95, 14, 229, 230.

[Dr. Shyamala Rajkumar, Research Officer (Siddha), Central Council for Research in Siddha, Chennai & G.S. Lekha, Medical Consultant, Siddha Central Research Institute (SCRI), Chennai.]

(Dr. Shyamala Rajkumar, Central Council for Research in Siddha & G.S. Lekha, Sidha Central Research Institute, Chennai.)

December 2018 ► 59

marketing initiatives

ATEX/IECEx Certified Level Indicators From Toshniwal

V

isual level indicators combine up to three functions in one instrument: Level indicator, Level switch and Level transmitter. The WEKA range of visual level indicators is characterized by their compact design and the wide range of applications.

Operating pressures can range from a vacuum up to 500 bar as well as calculation

pressures for the float standpipe up to the nominal pressure PN 630. Liquid densities >0.27 g/cm 3 as well as a temperature range from 77 K to 673 K (-196°C to 400°C) allow use in cryogenic liquid gas applications as well as in water hydraulics and steam boilers. Hermetically sealed floats for condensing media are available up to a max operating pressure of 320 bar.

There is also flexibility through the choice of the product in the usual metallic casings as well as other casings.

Standard casing: 316/316L 1.4435/1.4404 Group A4 stainless austenitic steel.

Other casings: 304/304L 1 . 4 3 0 1 / 1 . 4 3 0 6 , 1.4541/1.4571 stainless austenitic steel The WEKA visual level indicator is ideal for the commissioning of systems as the display works automatically without energy as a result of the physical law of liquids in communicating vessels.

Independent of a controller and thus also independent in the event of a power supply failure - visual level indication on site is ensured.

The wide, red and silver coloured flag indicator system is easily and clearly readable, even from a distance.

The fully transparent flag indicator system made of polycarbonate also ensures readability from the side.

The liquids, which are not always unproblematic and sometimes hazardous as

60 ◄ December 2018

well, are safely enclosed in the dense and pressure-tight float standpipe and separated from the indicator.

WEKA visual level indicators can be utilised for almost all operating conditions since the standard WEKA range has suitable products for most applications.

Additionally, customized solutions are also available for special operating conditions.

Many of the customised designs can also be used in hazardous areas and is ATEX/ IECEx certified. This means that the equipment has been fully tested to ensure that it complies with health & safety standards and will not generate a spark.

Any ATEX/IECEx certified equipment also needs to be robust and durable so that when either subjected to extreme temperatures or under any great impact, there is no real threat to safety of the user.

Therefore, Toshniwal’s instruments find wide applications in oil rigs & petrochemical complexes, chemical & pharmaceutical plants, mechanical & plant engineering, water & waste management, shipbuilding, energy, space and research.

For details contact: Toshniwal Hyvac Pvt Ltd Tel: +91-44-26445626 / 26448983 Email: sales@toshniwal.net Website: www.toshniwal.net Pharma Bio World

marketing initiatives

A New Way To Reduce Downtime In Biopharmaceutical Manufacturing The advantages of single-use pumping systems have been taken to an even higher level with the creation of a pump-chamber replacing system that lowers changeout times to mere seconds

W

hen attempting to describe the processes that are inherent to biopharmaceutical manufacturing, words like ‘complex’, ‘precise’ and ‘pure’ come to mind most often. That being said, the importance of those terms would appear to make words like ‘fast’ and ‘quick’ incompatible with the production of biopharmaceuticals.

However, that is not necessarily the case.

The most successful biopharmaceutical manufacturers are those that can reliably produce important drugs that are safe for human use while also getting them to market in a timely manner that maximizes the earning potential of patent windows.

This is where pumps become a critical part of the equation. Today’s most common biopharmaceutical-manufacturing systems require the handling, transferring, processing

and purification of large-molecule drugs produced in living organism like animal-cell cultures, bacterial cells or yeast. This must be done in a liquid phase with the handling of these materials performed by pump technologies that can reliably provide volumetric consistency and accuracy, pressures and flow rates, and low-pulsation, which are required in the process, and low-shear, low-heat input and material compatibility that protects the biological drug from being harmed.

In general, the manufacturing process is separated in two main stages: The first is upstream processing, in which genetically modified cells suspended in liquid culture media are grown in bioreactors to produce the desired product. The second stage is the separation and purification of the target molecule from the cells and byproducts, which is called downstream processing. Traditionally, permanent stainless-

steel pumping and processing systems have been used for these operations, but the time and cost needed to operate, clean, maintain and quality control the system before the next production run could commence became prohibitive. That led to a true innovation for the industry, the creation of single-use pumps that feature a disposable pump head and chamber that can be easily removed and replaced between production runs, eliminating the time and cost needed to revalidate the equipment in a stainless-steel system.

While single-use pumps have been an undoubted boon to biopharmaceutical manufacturers - with positive displacement quaternary (four-piston) diaphragm pumps becoming a go-to technology choice for many manufacturers - there were still improvements that could be made in optimizing their changeover times and simplifying the installation process. A breakthrough in this area came in 2017 with the development of a pump-chamber replacing system that reduces the time needed to replace a disposable single-use pump chamber to mere seconds.

Know Your Unit Operations First, we should take a step back and give some context to just how significant, ‘complex’, ‘precise’ and ‘pure’ are to the biopharmaceutical-manufacturing process. The foundation of biopharmaceutical manufacturing rests on various types of unit operations. While each unit operation features its own set of operational criteria, they are alike in that they can only produce a viable, contaminant-free drug suitable for human administration if the manufacturer strictly adheres to an unbending set of operational parameters and structures.

Here’s an overview of four of the more common unit operations in biopharmaceutical manufacturing:

Figure 1: Quattroflow EZ-Set QF150 – QF1200 Pharma Bio World

• Tangential Flow Filtration (TFF) - Also known as cross-flow filtration, in this process the biopharmaceutical’s feed stream flows December 2018 ► 61

marketing initiatives become fouled. When this happens, the flow rate will not decrease in a linear fashion, which will adversely affect the performance of the filter, product yield and overall quality.

To combat this phenomenon, pumps that combine a high turndown ratio with minimal pulsation in the pumped fluid are used.

The common thread between these various types of unit operations is their need for and use of a pumping technology that can satisfy their specific operational parameters. Again, these unit operations are processes in which the quaternary diaphragm pump excels, while competitive technologies, such as peristaltic (hose), lobe, centrifugal and piston pumps, may struggle to meet a series of strict producthandling and transfer requirements.

Figure 2: QF Single-Use Pump tangentially across the filter membrane at positive pressure. As it passes across the membrane, the portion of the feed stream’s molecules that are smaller than the membrane’s pore size pass through the membrane. TFF is different from what is known as normal-flow filtration (NFF) or ‘dead-end’ filtration, in which the feed flows entirely through the filter membrane with the size of the pores determining which portion of the feed is allowed to pass through and which will remain trapped in the filter membrane. TFF also differs from NFF because the tangential motion of the fluid across the membrane causes any trapped molecules to be ‘rubbed’ off, which eliminates the formation of a gel layer that would lead to blocking of the membrane.

This mode of operation means that a TFF process can operate with relatively high product-load without any fouling (blocking) of the filter. Typically, a membrane pore size is selected that retracts the target molecule in the so-called retentate. The portion of small molecules, including water, that will pass the membrane is called permeate. The result is a high concentration of the target molecules in the retentate.

• Chromatography Columns - While TFF is used to concentrate the product based on the molecule size, chromatography is a process that is used to purify target molecules from the other process stream 62 ◄ December 2018

based on adsorption to a resin. This resin is compressed and immobilized in a so-called chromatography column. When the product is pumped through this column, the target molecule can bind (adsorp) under specific conditions at the chromatography resin, while contaminants either do not adsorb or can be washed off. By changing the conditions again (e.g. pH level or conductivity) the target molecules will be released (eluted) from the resin and collected separately from the other process stream to achieve a purified product. Chromatography columns contain expensive media that need careful handling. Protein A resin, for example, can cost many thousands of dollars an ounce, making proper feeding of the resin extremely important. In this application, pumps are used to pack the resin into the chromatography column and then pump the biopharmaceutical material through the column. Both are critical operations that require a high, constant flow rate and pressure.

• Virus Filtration -These systems are used to ensure the safety of the drugs that are produced. They do this through the removal of potential virus particles via constant pumping pressures with variable flow rates.

Most typical virus-filtration systems run at a constant pressure due to the nature of the tight pores in the filtering medium, but the flow rates will decrease as the filter’s pores

The Single-Use Solution Some additional mention must also be given to the advantages that utilizing single-use quaternary diaphragm pumps in biopharmaceutical manufacturing can deliver.

The main advantage for these pumps – whether used in traditional stainless steel or single-use setups - are their unique form of operation: The four quaternary diaphragms are driven one after another by a connector plate, which moves back and forth out of its central position in a stroke that is generated by an eccentric shaft, with the length of the stroke determined by the angle of the eccentricity.

The four pumping chambers, which actually operate in the same way the human heart does, keep the product flow constantly moving forward in a volumetrically consistent lowshear and low-pulse manner.

The pump’s chambers also contain no rotating parts that can be subject to friction, meaning that there is minimum heat buildup that can compromise the product. This mode of operation means that the pumps can run dry, are self-priming, and produce minimal shear because of low slip. In addition, they offer lowpulsation, leak-free operation while having great dry/wet suction-lift capabilities.

This turndown capability and range for quaternary diaphragm pumps is also unique in the biopharmaceutical industry. As the products go from development to clinical trials and then to commercialization, proper scaleup is essential. In other words, the same pump in a lab may need to handle flow rates as low as 1/2-ounce per minute while also being able Pharma Bio World

marketing initiatives • • •

Push the new pump chamber onto the ring drive Reinstall the pressure plate Slightly rotate the pressure plate to lock according to the markings

The markings on the side of the pressure plate, which show a minimum through maximum range, let the user know what the clamping force is since it is important to have the proper level of compression on the pump drive. In fact, the pressure plate is so simple and easy to dial in, that no physical strength is required, meaning that everyone from a kindergartner to a weightlifter can install the pressure plate.

Figure 3: QF Single-Use_application to deliver commercial production flow rates of 50 gallons per minute or more.

realm of reducing the time needed for pumphead replacement.

The quaternary diaphragm pump is also easily adaptable to single-use production configurations. A single-use pump enables biopharmaceutical manufacturers to essentially eliminate the prohibitive cost of cleaning and validating their pumps and systems. The result is a quicker and more cost-effective production process and one that still delivers preferred levels of product purity and sterility with no chance for cross-batch or cross-product contamination.

The breakthrough came last year with the development and release of the pump-chamber replacing system, namely the EZ-Set model that was created by Quattroflow™ Fluid Systems GmbH, Kamp-Lintfort, Germany, a product brand of PSG®, Oakbrook Terrace, IL, USA, a Dover company. The system essentially eliminates downtime in the production-changeover process, which leads to further optimization of the productdevelopment timeline. It allows manufacturers to replace a single-use pump chamber in 30 seconds or less without the need of torque wrenches or other special tools and equipment – all the while allowing the user to be able to wear rubber gloves during the replacement process.

Pump-chamber replacing systems can also be retrofitted on existing motor drives, which also makes upgrades quick and easy to perform.

The fulcrum of the single-use pump is its product-wetted plastic pump chamber that can be replaced as a complete unit.

The Next Step Forward So, now we arrive at the next step in the evolution of the single-use quaternary diaphragm pump that is used in unit operations within biopharmaceutical manufacturing. While single-use pump technology conquered the question of how to reduce cleaning and revalidation time and costs after production runs, there was still more ground that could be ploughed in the Pharma Bio World

Replacing the pump chamber requires just five simple steps: • •

Remove the pump’s pressure plate Take the pump chamber out of the ring drive

Conclusion Many skills are needed to produce biopharmaceuticals, but in the end the final product must be one that is unquestionably safe to use while simultaneously allowing the manufacturer to reap the financial benefits of an optimized patent window. The arrival of single-use pumps on the scene has virtually eliminated the cost and downtime that were previously required to clean and validate pumping systems. A further leap ahead has been taken, however, with the creation of the pump-chamber replacing system, an innovation that will continue to optimize time, cost, reliability and safety capabilities in the ultra-important biopharmaceutical-manufacturing industry.

Dr. Andreas Frerix Product Manager, Quattroflow Fluid Systems GmbH and PSG Ravi Prasad Director - Sales PSG India (Based in Kamp-Lintfort, Germany, Quattroflow offers a full line of positive displacement multiuse and single-use quaternary (four-piston) diaphragm pumps and accessories for use in the biotech, food-and-beverage, personalcare and nutrition industries. Quattroflow is a product brand of PSG, a Dover company, Oakbrook Terrace, IL, USA. PSG is comprised of several leading pump brands, including Abaque®, Almatec®, Blackmer®, Ebsray®, EnviroGear®, Finder, Griswold™, Mouvex®, Neptune™, Quattroflow™, RedScrew™ and Wilden®.)

December 2018 ► 63

news, events, etc Glenmark Pharmaceuticals enters into an exclusive licensing agreement with Yuhan Corporation, South Korea Glenmark Pharmaceuticals Ltd. (Glenmark), a research-led global integrated ph armaceutical company, today announced that its Suisse subsidiary, Glenmark Specialty S.A., has entered into an exclusive licensing agreement with Yuhan Corporation for commercializing its novel nasal spray Ryaltris in South Korea. The agreement with Yuhan is Glenmark’s second regional licensing deal for Ryaltris. In July 2018, Glenmark entered into an exclusive licensing agreement with Seqirus Pty. Ltd. to commercialize Ryaltris in Australia and New Zealand.

Ryaltris [olopatadine hydrochloride (665 mcg) and mometasone furoate (25 mcg)], developed by Glenmark, is a novel, investigational, fixed-dose combination nasal spray of an anti-histamine and a steroid, indicated for treatment of symptoms associated with seasonal allergic rhinitis (SAR) in patients over 12 years of age. Under the terms of the agreement, Glenmark will be responsible for manufacturing and supply of the product, while Yuhan will be responsible for regulatory filing and commercialization of Ryaltris in South Korea.

Glenmark will receive an upfront payment, regulatory and commercial milestone payments as well as royalties from Yuhan. “This partnership with Yuhan is in line with our vision to make Ryaltris the first global brand of Glenmark by launching it in several key markets. We are happy to collaborate with Yuhan as it is a strong and reputed player in South Korea and is aligned with Glenmark’s objective to provide quality novel products to fulfill unmet needs of patients,” said Glenn Saldanha, Chairman and Managing Director of Glenmark Pharmaceuticals.

In May 2018, Glenmark filed a New Drug Application (NDA) for Ryaltris with the US Food and Drug Administration (US FDA), which is currently under review with the regulator. Glenmark plans to commercialize Ryaltris in various markets globally. The company will continue to explore commercial partnerships for Ryaltris in markets where it doesn’t have direct presence.

The aggregate number of operational beds has gone up by 4%, from 20,665 beds in Q2 FY2018 to 21551 beds in Q2 FY2019 but the aggregate occupancy level has dropped during this period, from 65.6% to 63.9%. This is due to capacity expansion, recalibration of the payeemix and the specialty-mix at some of the facilities and; a sharp drop in occupancy of one of the largest players due to their internal challenges, including corporate governance and liquidity issues. Consequently, the occupied bed nights grew by a modest 2%.

As per ICRA, the hospital sector profile has been witnessing deterioration since the beginning of CY2017 due to several factors that have adversely affected its profitability. These include the implementation of the Goods and Services Tax (GST), the cap on prices of stents and knee implants by the National Pharmaceutical Pricing Authority (NPPA) and stiff regulatory action by certain states, including putting restrictions on procedure rates, levying penalties and placing operational limitations on erring hospitals. Owing to these factors, the ARPOB of the sample set has grown by a muted 2% in Q2 FY2019 on a Y-o-Y basis, much below the five-year compounded annual growth rate (CAGR) of ~7.2%.

The intense competition in some of the key markets of operations of the players in the sample set has also resulted in sub-optimal operating and financial parameters.

The regulatory environment continues to be the overarching challenge for the hospital sector. The wide-ranging regulatory restrictions from multiple authorities continue to supress the average revenue per occupied bed day (ARPOB) of the players with the latest quarter also seeing sub-par growth in ARPOB and a drop in the profitability margin.

Nonetheless, the impact of these factors has likely peaked and sans any additional measure, the worst is behind for the sector. Further, the significant capex in the last four years will start showing marked results going forward and start-up costs of new hospitals will be much lower.

Structurally, in the long term, underlying fundamentals continue to favour the sector. This is because of the significant shortage of beds in the country, and the increase in the disease burden and ageing demographic profile. Further, the demand for quality healthcare will be supported by the rising per capita income, increasing penetration of medical insurance and double-digit growth in medical tourism.

Hospital sector continues to be under weather in Q2 FY2019 Crescendo Biologics announces The muted performance of the hospital sector continues in Q2 FY2019. Humabody evaluation in CAR-T by Takeda The companies in ICRA’s sample set (Apollo Hospitals Enterprise Limited, Fortis Healthcare Limited, Narayana Hrudalaya Limited, Healthcare Global Enterprises Limited, Max India Limited and Shalby Limited) reported a 7% drop in earnings before interest, tax, depreciation and amortisation (EBITDA), from Rs. 556-crore in Q2 FY2018 to Rs. 516-crore in Q2 FY2019 and; drop in operating margin from 15.0% to 13.3% during this period. The aggregate revenues grew by a modest 5% from Rs. 3707-crore in Q2 FY2018 to Rs. 3889-crore in Q2 FY2019. This comes on the back of the already subdued performance in FY2018, which saw the first fall in aggregate EBITDA of the sample set in over six years and also saw operating profitability hitting a multi-year low, dropping to 11.4% in FY2018 from the peak profitability of 15.7% during this six-year period.

64 ◄ December 2018

Crescendo Biologics Ltd (Crescendo), the drug developer of novel, targeted T-cell enhancing therapeutics, recently announced that Takeda Pharmaceutical Company Limited (Takeda) is planning to evaluate the application of recently licensed Humabodies from Crescendo for the development of novel CAR-T therapeutics.

This research will investigate the unique properties of the Humabody VHs for tumour targeting of CAR-Ts. Unlike single-chain variable fragments (scFvs), Humabody VHs do not require a light chain for high specificity and affinity, and can be easily configured for multi-specific target binding. Takeda’s decision to license these Humabodies provides an opportunity to evaluate a large number of different VHs directed to Pharma Bio World

news, events, etc the same target, in order to identify a format that delivers both enhanced safety and functionality.

context of the science they do, and as part of a seamless purchasing experience and integration with their eProcurement platforms.

Crescendo’s global, strategic, multi-target collaboration and license agreement with Takeda was first announced in October 2016. Under this agreement, Crescendo’s proprietary transgenic platform and engineering expertise is being used to identify and configure Humabodybased therapeutics against certain targets selected by Takeda. Dr Peter Pack, CEO of Crescendo commented, “We’re pleased to see the research Takeda is undertaking with our Humabody technology. Their desire to explore the Humabody technology in a CAR-T setting presents an exciting opportunity to evaluate whether Humabodies can address the issues that exist with other CAR-T targeting approaches.

“The large R&D organizations that consume life science products and purchase them through eProcurement platforms see Labviva as transformative in facilitating onboarding of a large number of suppliers, both large and small, onto an eProcurement system, while providing enriched product content and efficient search capabilities across an entire purchasing portfolio,” continued Baharloo. Labviva’s comprehensive listing of 500,000+ products from hundreds of manufacturers and suppliers offers application and protocol driven bundling of products into complementary portfolios. Its powerful search capabilities generate visibility for product selection viewed by price, availability, workflow and scientific relevance with links to over 100,000 peer reviewed papers and more than 7,000 experimental protocols.

Crescendo Biologics is a biopharmaceutical company developing potent, truly differentiated Humabody therapeutics in oncology with a focus on innovative targeted T-cell approaches. Leading its proprietary pipeline, Crescendo Biologics has developed CB307, a novel bispecific PSMAtargeted T-cell enhancer for the selective activation of tumour-specific T-cells exclusively within the tumour microenvironment, thereby avoiding systemic toxicity. This highly modular format can be re-configured to create a pipeline of multiple therapeutic candidates each treating a different cancer indication, by targeting any of a range of alternative tumour-specific markers.

The Company’s ability to develop multi-functional Humabody therapeutics is based on its unique, patent protected, transgenic mouse platform generating 100% human VH domain building blocks (Humabody VH). These robust molecules can be configured to optimally engage therapeutic targets delivering novel biology and superior bio-distribution.

This results in larger therapeutic windows compared to conventional IgG approaches.

Crescendo Biologics is pursuing novel Humabody-based product opportunities, through in-house development and strategic partnerships, including multi-functional immuno-oncology modulators and Humabody drug conjugates (HDCs), the next generation of ADCs. Humabody-based formats can also be applied across a range of non-cancer indications.

New Digital Marketplace for Life Science Products catering to Scientists Labviva, an AI-powered digital marketplace for life science reagents, instrumentation and services was launched recently to create scientifically informed purchasing decisions. “We recognize the critical need to connect buyers and suppliers of scientific products in a new way, with scientific data and product validation information so to inform meaningful choice across a broad spectrum of products for better purchasing decisions as well as liberation from time-consuming product research tasks,” said Labviva co-founder and CEO, Siamak Baharloo Ph.D. “Labviva places science at the heart of the purchasing process to optimize the product value for the buyers and helps suppliers develop closer relationships with their customers.”

The Labviva marketplace has deployed powerful AI-technology to curate and connect relevant information for buyers to have the insight needed to choose the right reagents, instrumentation and service in the Pharma Bio World

“It is important to be able to browse and make purchasing decisions based on a product’s relevance to real-world applications, like up-to-date protocols and peer-reviewed literature,” said Mike O’Donnell, PhD and postdoctoral researcher at Brandeis University. “Labviva now makes this process effortless by directly linking these resources, including product comparisons and availability, which will make identifying the best product and supplier options easy.”

“Finding the right product to meet my specific application needs is a burden requiring many hours spent on database searches, visits to vendor websites and review of literature,” continued O’Donnell. “Labviva has greatly simplified this process by providing a single access point to all available information so I can make the right product choices quickly and reliably, freeing my time to be spent on what matters the most – my research.”

Labviva is a digital marketplace for life science products for accelerating the science of life. The platform is built with scientists in mind to connect researchers with suppliers of reagents, chemicals and instrumentation.

It creates a unique relationship between scientific content and products across hundreds of brands and suppliers, resulting in a simple, efficient and seamless purchasing experience.

Imugene Meets Endpoints in Phase 1b Gastric Cancer Immuno-oncology Trial Imugene Limited, a clinical stage immuno-oncology company recently announced meeting study endpoints and positive top-line results from the Phase 1b study of its HER-Vaxx gastric cancer vaccine in patients expressing the HER2 target protein. The 14 patient study tested three dose levels of HER-Vaxx (10, 30 and 50 micrograms) in combination with current standard of care chemotherapy, cisplatin and fluorouracil or capecitabine. All dose levels showed an increased antibody response in patients.

HER-Vaxx is designed to produce an antibody response against a cancer growth signal receptor protein called HER-2 which is found on the cell surface in breast and gastric cancers. The Phase 2 study will test the efficacy, safety and immune response in 68 gastric cancer patients with metastatic gastric cancer over-expressing the HER-2 protein. The three primary endpoints for the Phase 1 study were safety and tolerability and identification of the optimal dose of the HER-Vaxx cancer vaccine for a Phase 2 study based on data collected over the first eight weeks of treatment.

December 2018 ► 65

events diary    

   

Date: 20 – 23 February, 2019 Venue: Bombay Exhibition Centre, Mumbai

Date: 19 – 21 September, 2019 Venue: HITEX, Hyderabad

BioPharma World Expo 2019 is the best platform for both Indian and international manufacturers/service providers/ startups connected with pharma machinery, CR AMS, CROs/CMOs, packaging, logistics, exports, APIs, generics, biotech, regulatory affairs, etc . It offers a unique opportunity to meet, network and establish business partnerships.

The concurrent conference tracks would highlight latest technological developments, market trends, investment opportunities and challenges facing the industry. The technical sessions would cover pharmaceutical technology, biosimilars, green chemistry, compliance, etc.

The laboratory and analytical market is growing at an exponential rate due to the recent investment plans initiated by the government; which is furthermore complemented by the industry bodies to capitalize on the growth projection. More and more pharma and R&D projects have been commenced leading to increased demand for laboratory and analytical instruments. In order to capitalize on this growth opportunity, Messe Muenchen India is organizing the 13 th edition of India Lab Expo, the leading trade fairs for laboratory technology, analysis, biotechnology and diagnostics at Hyderabad.

 Jasubhai Media Taj Building, 210, Dr. D.N. Road, Fort, Mumbai - 400 001 Tel: 91-22- 40373636 Email: amrita_patil@jasubhai.com

 Messe Muenchen India Pvt. Ltd. INIZIO 507 & 508, Cardinal Gracias Road, Opp. P&G building, Chakala, Andheri (E), Mumbai - 400 099, India.

Tel : +91-22-42554710 Email: info@mm-india.in

  

 

Date: 16 – 17 April, 2019 Venue: Bombay Exhibition Centre, Mumbai

Date: 10 – 12 April, 2019 Venue: Helipad Ground, Gandhinagar

Analytica Anacon India is one of the biggest show in laboratory technology and analysis in India. This is a trade fair that showcases the entire range of lab equipment and instruments including chromatographs, spectroscopes, microscopes, etc apart from lab furniture and other peripherals. The new feature of this year’s event in Mumbai is the introduction of pharma machinery pavilion organized by Indian Pharma Machinery Manufacturers Association (IPMMA). This pavilion will feature pharma machinery and equipment manufacturers from processing, packaging, cleanroom, filling, water treatment, environmental control to name a few.

iPHEX is an exhibition that brings together the drugs, pharmaceutical and healthcare industry- all under one roof.

It is one of the largest showcase of Indian pharmaceutical products and technologies to a global audience. The show will offer the industry majors from India and all across the world a great platform to connect and do business. iPHEX provides visitors and exhibitors with an opportunity to meet new and existing customers actively looking for new suppliers, or looking to assess the current progress of existing projects.

Contact: Messe Muenchen India Pvt. Ltd. INIZIO 507 & 508, Cardinal Gracias Road, Opp. P&G building, Chakala, Andheri (E), Mumbai - 400 099, India.

Tel: +91-22-42554710 Email: info@mm-india.in

 Pharmexcil 101, Aditya Trade Centre, Ameerpet, Hyderabad - 500038 Tel: +91-40-23735462 Email: sales@iphex-india.com

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Dispensers

Peroxide-cured Silicone Transparent Tube Toshniwal Hyvac Pvt Ltd offers dispensers to transfer set for flammable liquids (petrol, kerosene and diesel fuel).

Pump with nozzle holder, easy to install on the barrel through the quick coupling. Dispensing unit equipped with telescopic suction tube for direct connection into the tank allows easy and clear use of the dispenser.

It has a cast iron body, anti-noise filter, flanged components pump, bypass setup with pressure relief valve, thermal protection, non-return valve (NRV) built and suction unit with integrated fine filter.

Meter and filters can be installed or replaced without the use of sealant, making connection quick and safe.

For more information, please contact:

Imapex peroxide grade silicone tubing is designed for general, non-critical applications.

Imapex is translucent silicone tubing having good flexibility and resiliency. It is suitable for peristaltic pump applications for non-critical fluid transfer.

Imapex is manufactured by using quality grade peroxide-cured silicone rubber and packaged in dust-free environment of ISO 9001 QMS, ISO 14001 & OHSAS 18001 Certified facility. It is odourless and tasteless. It has good flexibility and flex crackresistance. It conforms to FDA 21. CFR 177.2600. It is steriliseable

by Autoclaving, ETO and Gamma Rays. It is available with FDA compliant colour-coding for ease of identification.

For more information, please contact:

Toshniwal Hyvac Pvt Ltd 267 Kilpauk Garden Road Chennai 600 010 Tel: 044 - 2644 8558 / 8983 Fax : 044 - 2644 1820 E-mail : sales@toshniwal.net

Ami Polymer Pvt Ltd 319 Mahesh Indl Estate Opp: Silver Park, Mira-Bhayander Road Mira Road (E), Thane, Maharashtra 401 104 Tel: 022-28555107, 28555631, 28555914 E-mail: mktg@amipolymer.com

Integrated Measuring Point Manager Monitoring incoming goods and product quality is very important for a lot of processes. These measurements are often done at various stages in the production process. SensoTech’s mobile LiquiSonic Lab system is the perfect solution to get fast, precise and reliable measurements.

Additionally, the LiquiSonic Lab System creates detailed datasets every time the user saves a measuring, which simplifies the subsequent analysis tremendously. The controller menu provides an overview of historical data for every measuring point. Deviations, eg, in quality are well comprehensible at any time. These data can be easily transferred to the process control system via ethernet or USB devices. Every recording generates an entry with date, time and the name of the measuring point in the event logbook.

Prospective, the LiquiSonic Lab system optionally comes with a scanner for an easier handling. After scanning, eg, a QR code, the controller will automatically switch to the correct measuring point and the measurement can be taken right away.

For more information, please contact: SensoTech GmbH Steinfeldstr 1, 39179 Magdeburg–Barleben Germany Tel: +49 39203 514100, Fax: +49 39203 514109 E-mail: info@sensotech.com

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December 2018 ► 67

Processing Machine The VENTILUS V 5 processing machine from Romaco Innojet is suitable for both aqueous polymer solutions and hot melt coating formulations.

The laboratory-scale version of the Romaco Innojet VENTILUS V 5 is used for particle sizes from 10 µm to 2 mm. Only one product container is required for the granulation, drying and coating steps. Due to its special design and enhanced processing efficiency, the VENTILUS V 5 allows up to 85 per cent shorter batch times with hot melt coating applications and up to 25 per cent with polymer coatings. The homogeneous flow conditions inside the cylindrical product container enable extremely gentle intermixing of the batch and hence play a crucial role here. The air flow bed technology ensures accurate control of the product movement and equally precise application of the spray liquids. The process air is controlled by the ORBITER booster, an ingenious container bottom consisting of overlapping circular plates. Together with the ROTOJET, the central bottom spray nozzle, the booster forms an innovative functional unit that meets all the requirements for linear scale-ups.

Self-priming Delivery Pump Units Self-priming delivery pump units consist of external gear pumps which are made from standard materials 0.7050 (housing)/1.8550 (shafts and gears) and FKM (static seals). They are especially suitable for the low-pressure range and can convey almost every low viscosity media as well as uncritical media without fillers, which are compatible to the materials used. The engine power of the 4-pole asynchronous three-phase motor is sufficiently assessed for achieving differential pressures of up to 40 bar. Additionally, delivery pump units are available within a short delivery time, thanks to standardized units. It finds application in filling plants, printing machines, paint industry, filter technology, generator construction, cooling machine, mechanical engineering, hydraulics, oil processing, tank facility construction, compressors, vacuum plants and machine tools.

For more information, please contact:

Romaco Group Am Heegwald 11, 76227 Karlsruhe, Germany Tel: +49 (0)721 4804 0 Fax: +49 (0)721 4804 225 E-mail: susanne.silva@romaco.com

For more information, please contact: Bedaflow Systems Pvt Ltd W-7, Sector-11 Noida, Uttar Pradesh 201 301 E-mail: info@bedaflow.com

STYL’ONE Evolution Single-Stroke Tablet Press Romaco Kilian offers compression tests with the STYL’ONE Evolution single-stroke press, which was specially designed for research and development activities. The laboratory press will be equipped for this purpose with ANALIS, the intelligent PAT software; amongst other things, ANALIS supports the development of new formulations, analyses of process data and also scale-up tests. The compression force that is necessary to produce tablets with the required thickness or breaking strength can be easily determined using this technology. The STYL’ONE additionally simulates the compression force profiles of all standard high speed presses and carries out fully automatic compression and performance studies. It achieves compression forces of up to 80 kN with a maximum output of 1750 tablets per hour.

Depending on the test set-up, it is capable of compressing mono-layer, multilayer or core tablets. The ROCO Pack software can moreover simulate the roller compaction process, resulting in realistic powder compression and remarkably precise test batches. The user friendly R&D press is an invaluable tool for optimising processes or diagnosing errors. The time saving when analysing and evaluating the results is likewise a big advantage.

For more information, please contact: Romaco Group Am Heegwald 11, 76227 Karlsruhe, Germany Tel: +49 (0)721 4804 0 Fax: +49 (0)721 4804 225 E-mail: susanne.silva@romaco.com

68 ◄ December 2018

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bookshelf Ayurvedic Medicine: The Principles of Traditional Practice Authors: Sebastian Pole Price: $71 Pages: 400 Publisher: Jessica Kingsley Publishers The book clearly and comprehensively presents the unique theories and traditions of Ayurveda making them accessible to the health practitioner of today. With a brief history of traditional medicine in India and discussion of principles, treatment strategies and traditional Ayurvedic pharmacy and pharmacology, the book offers an essential overview of the culture in which Ayurveda has developed and the scientific basis behind this holistic approach. It details over 100 plant profiles of Ayurvedic herbs, with images of fresh and dried plants, and 50 traditional formulas, including characteristics, usage, combinations, contraindications, and safety and dosage information for each. This essential resource explains the traditional medical system of Ayurveda, and provides guidance to students and practitioners on how to incorporate herbal medicine into their life and practice.

Therapeutic Use of Medicinal Plants and Their Extracts: Pharmacognosy Authors: A.N.M. Alamgir Price: $153 Pages: 546 Publisher: Springer This volume focuses on the importance of therapeutically active compounds of natural origin.

Natural materials from plants, microbes, animals, marine organisms and minerals are important sources of modern drugs. Beginning with two chapters on the development and definition of the interdisciplinary field of pharmacognosy, the volume offers up-to-date information on natural and biosynthetic sources of drugs, classification of crude drugs, pharmacognosical botany, examples of medical application, WHO´s guidelines and intellectual property rights for herbal products.

Herbal Medicine: Biomolecular and Clinical Aspects Authors: Iris F. F. Benzie (Editor) & Sissi Wachtel-Galor (Editor) Price: $132 Pages: 500 Publisher: CRC Press The global popularity of herbal supplements and the promise they hold in treating various disease states has caused an unprecedented interest in understanding the molecular basis of the biological activity of traditional remedies. ‘Herbal Medicine: Biomolecular and Clinical Aspects’ focuses on presenting current scientific evidence of biomolecular effects of selected herbs and their relation to clinical outcome and promotion of human health. It includes experimental approaches for looking at the bioactive components in herbs. This book also addresses the ethical challenges of using herbal medicine and its integration into modern, evidence-based medicine. The fact that composition of natural products can vary greatly and contamination and misidentification can occur are important issues in the use of herbal medicines. To help bring a new level of quality control to the production of herbal extracts, the use of mass spectrometry and chemometric fingerprinting technology is presented as a means for improved identification and authentication of herbs.

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December 2018 ► 69

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Pharma Bio World

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