Monday, October 5, 2015


The information provided in earlier parts are indications that countries are greatly interested in introducing “similar biologics” within their territory. Defined regulatory pathways for introducing “similar biologics” in different countries are paving the way towards the goal of introducing “similar biologics” within their territories in the shortest possible time. Asian countries as well as South American countries are rich in technical skills in handling diverse aspects of fermentation based technologies with proficiencies in downstream processing techniques. Most of these countries have taken steps to introducing “similar biologics” within their territory by announcing regulatory procedures. Entrepreneurs from all over the world can now take bold steps to set up integrated facilities for the production of some of these “similar biologics” within these territories with eyes on capturing a part of the global market. If efforts are made sincerely in these directions and if access to investments to the tune of USD 25-40 million is made available and further if concerted efforts are made over a period of 3-5 years to introduce “similar biologics” by a group of professionals, it would be an excellent business proposition in these territories.

India has already made a beginning in this direction. There are presently 11 companies that are manufacturing “similar biologics”; there are other units which are importing and selling and thereby acquiring experience in sale which is indeed a tough experience to master. Of the major manufacturing companies in India, are Intas Pharmaceuticals Ahmedabad which has developed its own core competence for handling different aspects of manufacture of “similar biologics”. Intas had also signed an agreement with Canadian drug major Apotex Inc. in May 2008, to co-develop and market the low-cost version of a biotech cancer medicine filgrastim (G-CSF) in North America and Europe. Dr. Reddy’s Labs, Hyderabad has developed competence in production of a wide range of “similar biologics” including Darbepoetin Alpha, Herceptin/Trastuzumab, IFN PEG, Rituximab etc. Biocon India, Bangalore is engaged in the production of Insulin, Bevacizumab, Granulocyte Stimulating Factor (GSF), Pegylated Granulocyte Stimulating Factor (Peg-GSF), Herceptin/Trastuzumab etc. They have teamed up with Mylan Inc., USA as also with a Cuban company. Reliance Life Sciences, Navi Mumbai is engaged in the production of Erythropoietin (EPO), Granulocyte Stimulating Factor (GSF), IFN Alpha, IFN PEG, Infliximab, Palivizumab/Synagis, Rituximab, Streptokinase, Tissue plasminogen activator (t-PA) etc. Bharat Biotech, Hyderabad is engaged in the production of Epidermal Growth Factor (EGF), Human Growth Hormone (hGH), Palivizumab/Synagis etc. Cipla, Mumbai is engaged in the marketing of a selected range of “similar biologics” including Etanercept based on collaboration with foreign companies such as Shanghai CP Guojian Pharmaceuticals Co. Ltd., China. Wockhardt, Aurangabad produces a large number of “similar biologics” based on technologies originally imported from Germany; the products include insulin, cytokines, erythropoietin etc.

Production of “similar biologics” includes the stages of development/procurement of host cells, establish a host cell bank, develop facilities for growing the host cells where the target “similar biologics” proteins are secreted/included as “inclusion bodies” within the host cells; isolation of the target proteins; purification; analysis; formulation development and finally storage and handling followed by marketing.

For faster development in any region, genetically modified host cells could be procured through collaboration and thereafter these could be multiplied to produce the target “similar biologics”, which would then be transformed into formulations. A developmental laboratory set up within the facility with a group of competent and highly modified personnel can convert the procured technologies into usable ones, within the shortest possible time. Examples are the many Indian companies that have gone into production during the last one decade or so.

Presently, pegylation technologies are fast catching up. Pegylation of already used biologics is showing an upward global trend as pegylation process enhances the circulation time of biologics within the body and thus is available for manifesting biological activity for longer time. Pegylation technologies are available for purchase. Technologies for pegylated products of specific biologics are also available for purchase. Presently, the world trend is to introduce a biologically active molecule in the form of its “pegylated” version. Pegylation is a chemical reaction for introducing a highly hydrophilic moiety within the backbone of the “similar biologics” to make the “similar biologics” more effective as by pegylation, the clearance of “similar biologics” from the body is substantially delayed. At the same time, pegylated “similar biologics” do not lose their specific therapeutic activities.

Pegylated erythropoietin, Interferon alpha 2b and G-CSF have already been approved by US FDA and therefore introduction of such products would not pose any problem for introduction as “similar biologics” from and within many other countries.

There are presently more than 150 “similar biologics” which include human proteins such as insulin, erythropoietin, cytokines and a host of other products besides the more recently introduced monoclonal antibodies which are utilized for treating different life threatening conditions. “Similar Biologics” are better therapeutic agents than the generic drugs (which are small molecules) in most situations where the ailments are chronic and life threatening.  

“Similar Biologics” as such or their pegylated forms are the future for the treatment of chronic diseases. These are presently the most important alterative for increasing the life span of individuals suffering from chronic life threatening diseases. Use of these medicines would also improve the quality of life of the patients. Such products are expected to reign the world for at least another 2-3 decades till better alternatives come out from nucleic acid stretches as medicines or stem cell therapy or some other most modern therapy that are yet far away for deployment as therapies for treating diseases of human kind. 

Wednesday, September 23, 2015


 Manufacture of “similar biologics” by entrepreneurs other than the original inventors give rise to ‘products’, which will always be different from the original ‘inventor’s products’ because of one reason or the other. Even if the “similar biologics” are manufactured using the same human “gene/s” as those used by the   ‘inventor companies’, cloning of the gene/s into a “DNA vector” followed by its/their transfer into “host cells”, where production will take place can be different. Host cells can generally either be “bacterial cells” or “yeast cells” or “mammalian cells”. Usually to have access to the same host cells is always not feasible and practical. However, near equivalent “host cells” can be obtained where the cloning of the “target human gene” can be carried out using a “suitable DNA vector” for  effecting transfer into “host cells”.

‘Host cells’ are the cells where the “similar biologics” are transcribed and translated (produced). Currently world over, three kinds of “host cells” are used as mentioned above. Among the “bacterial cells”, a wide range of Escherichia coli (E. coli) are used for expressing “similar biologics”. Among the “yeast cells”, use is made of a wide range of Saccharomyces cerevisiae, Pichia pastoris and Hansenula polymorpha. Among the “mammalian cells”, used as host cells are the  Chinese Hamster Ovary (CHO), Bos primigenius (Bovine), Mus musculus (Mouse), Human Embryonic Kidney(HEK) cells and Baby Hamster Kidney (BHK) cells; among these again the most widely used and characterized cell lines are the CHO cell lines.

By using specific types of “host cells” close to the inventor’s host cells, while the expressed “similar biologics” would be ‘similar’ to the inventor’s products, the other metabolites remaining adherent to the “similar biologics” would be different and therefore the downstream processing technologies would have to take care of purifying/isolating the active “similar biologics” in a manner that would make the “similar biologics” closely similar to the inventor’s product. Often this is not exactly feasible to be duplicated as the downstream processing methods of different companies are different.

Further, once the bulk “similar biologics” are manufactured, these are to be formulated into finished medicines; during the manufacture of formulated products also, differences can crop up. Because of these inherent limitations, “similar biologics” are never considered to be the ‘exact copies’ of the inventor’s products, although the “similarities” would certainly be very high and often more than 99.5% coherent in physic-chemical , biological and clinical manifestations. The small differences in many situations cannot even be quantified by the instruments that are available presently to people. Generally therefore, ‘Regulators’ all over the world define physic-chemical and biological properties of the inventor’s products and ask the manufacturers of “similar biologics” to comply with such defined properties. In addition, the Regulators also insist on developing clinical data on human subjects to ensure that the “similar biologics” are mimicking all the properties of the inventor’s products in terms of efficacy and safety.

 It is also the desire of the Regulators to get information generated through clinical trials for “similar biologics” to demonstrate comparable safety and efficacy to the “inventor’s/reference products” in terms of PK/PD comparability data from the Phase I trial onwards. If the Phase I clinical trial data show congruence in PK/PD comparability data moving to the Phase III trials becomes easier. Merely based on Phase III trials without supporting PK/PD data through Phase I is usually not acceptable. On a risk based approach, the three-arm Phase I trials are increasingly being used to demonstrate comparability between the “similar biologics” and the inventor’s products/reference products.

PK refers to ‘pharmacokinetic’ and PD refers to ‘pharmacodynamic’ modeling , which are techniques that require studies of time course of effects of intensity of dose -response of  ‘similar biologics’ formulations in patients/target study populations . The study is integrated in to a set of mathematical expressions that enable description of the effect of the dose of ‘similar biologics’ formulations over a period of time. Presently, there exist several models of studying the PK/PD values and the manufacturers of ‘similar biologics’ are required to generate data in accordance with the requirements of the ‘Regulators’ in each country.

 Even with such stringent regulatory requirements, several manufacturers have come out to develop “similar biologics” after the expiry of the patents as the market  for ‘similar biologics’ is very large, the prices are quite high (remunerative), thus guaranteeing faster paybacks even though the prices are lower than the prices of the inventor’s products. Presently, some 425 “similar biologics” are in the development pipeline world over and more than 350 companies are globally involved in the development of “similar biologics”. The global interest in developing “similar biologics” is increasing very fast as is evidenced by some eight fold increase in the number of clinical trials of “similar biologics” between 2007 and 2014 (rising from 5 trials in 2007 to over 40 trials in 2014).
(Source:  , Challenges in Global Biosimilar development: A regulatory perspective-CONTRACTPHARMA.COM, Jun 02, 2015 Issue).

 Almost all countries are coming out with guidelines for introducing “similar biologics” within their territory as these would ease availability of such life saving products in the local market. The European Union came out with its guidelines on “similar biologics” in 2005. Following suit came out Australia in 2007; Malaysia, Turkey and Taiwan in 2008; Japan, Korea, Singapore and WHO in 2009; Brazil, Canada, Saudi Arabia and South Africa in 2010; Argentina, Cuba, Iran, Mexico and Peru in 2011; Columbia, Egypt, Jordan, Thailand, India and USA (Draft) in 2012; European Union with their revised guidelines in 2014; and China in 2015. At present, there are globally more than 150 reference products for “similar biologics” to emulate and that about 40 of these have sales of more than USD 1 billion per year. If any one of more of “similar biologics” companies can capture even 5-10% of the market, these would mean considerable profits besides establishment of the image of global presence.  This is therefore the right time and precious opportunity  for the entrepreneurs of venturing in to right  projects on ‘similar biologics’ in developing and developed world.



In India, presently 26 “similar biologics” are approved for marketing which are as under:

Certain type of leukemia as anti-cancer chemotherapy
Taj Pharmaceuticals, Manufactured and Sold
Chandra Bhagat Pharma India
Imported and Sold
Platelet aggregation inhibitor mainly used during and after coronary artery procedures like angioplasty
Eli Lily India
Imported and Sold
Treating lung cancer
Biocon India
Manufactured in India
Darbepoetin Alpha
Stimulates erythropoiesis and increases red blood cell levels, to treat anemia
Dr Reddy’s Labs India
Manufactured in India
Erythropoietin (EPO)
Stimulates erythropoiesis and increases red blood cell levels, to treat anemia
Wockhardt, Biocon India, Shantha Biotechnik, Cadila Pharma, Cadila Healthcare, Claris Life Sciences, Intas, Panacea, Reliance Life Sciences, Serum Institute etc.
Manufactured in India
Epidermal Growth Factor (EGF)
Targeted therapies against certain cancers and treatment of diabetic foot ulcers
Bharat Biotech
Manufactured in India

Treat autoimmune diseases such as rheumatoid arthritis
Cipla, Intas Pharma etc.
Imported and Sold
Follicle Stimulating Hormone (FSH)
Used for the maturation of germ cells
LG Life Sciences, Intas Pharma, Serum Institute etc.
Imported as well manufactured in India
Granulocyte Stimulating Factor (GSF)
Stimulates the bone marrow to produce granulocytes and stem cells and increases WBC count
Biocon India, Cadila Healthcare, Claris Life Sciences, Emcure, Intas, Ranbaxy, Reliance Life Sciences, Shantha, Wockhardt etc.
Imported as well manufactured in India
Pegylated Granulocyte Stimulating Factor (Peg-GSF)
Stimulates the bone marrow to produce granulocytes and stem cells and increases WBC count. Long acting product
Biocon India, Emcure, LG Life Sciences etc.
Manufactured as well as imported in India and sold
Granulocyte Macrophage Colony Stimulating Factor (GM CSF)
Stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes.
Intas Pharma
Manufactured in India

Human chorionic gonadotropin (hCG)
Interacts with specific receptors of ovary and promotes the maintenance of the corpus luteum during the beginning of pregnancy
Lupin, LG Life Sciences, Serum Institute etc.
Imported and sold in India

Human Growth Hormone (hGH)
Used to treat children's growth disorders
Bharat Biotech, LG Life Sciences, Scigen Biopharma
Imported and sold in India
Used to treat certain breast cancers
Biocon, Dr. Reddy’s Labs, Intas etc.
Manufactured as well as imported and sold in India
IFN Alpha
Used to treat and control multiple sclerosis
Cadila Healthcare, Intas, LG Life Sciences, Reliance Life Sciences etc.
Manufactured as well as imported and sold in India
IFN Beta
Used to treat relapsing-remitting multiple sclerosis
Intas, Sun Pharma etc.
Manufactured in India
Used to treat and control multiple sclerosis
Dr. Reddy’s Labs, Reliance Life Sciences, Virchow etc.
Manufactured as well as imported and sold in India
Interleukin 2
Used for the treatment of cancers (malignant melanoma, renal cell cancer)
Intas Pharma, Genotech, Shantha etc.
Manufactured as well as imported and sold in India
Used for the treatment of Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis.
Reliance Life Sciences
Manufactured in India
Luteinizing hormone (LH)
Used to stimulate the ovaries to produce eggs before cycles of IVF treatment
Serum Institute
Imported and sold in India
Omalizumab/ Xolair
For treating patients 12 years and older with moderate to severe allergic asthma
Eli Lily, AstraZeneca
Imported and sold in India
Parathyroid Hormone (PTH)
Regulates serum calcium
Imported and sold in India
Used in the prevention of respiratory syncytial virus (RSV) infections
Reliance Life Sciences, Wockhardt, Bharat Biotech, Shreya Life Sciences etc.
Imported and sold in India
Used to treat cancers of the white blood system such as leukemias and lymphomas, including non-Hodgkin's lymphoma
Dr. Reddy’s Labs, Reliance Life Sciences etc.
Manufactured as well as imported and sold in India
Thrombolysis medication in some cases of myocardial infarction (heart attack) and pulmonary embolism
Cadila Pharma, Shantha Biotech, Reliance Life Sciences etc.
Manufactured in India
Tissue plasminogen activator (t-PA)
Thrombolysis medication in some cases of myocardial infarction (heart attack) and pulmonary embolism
Reliance Life Sciences
Manufactured in India
Compiled by Dr. P.K. Ghosh

Thursday, September 17, 2015



Recombinant DNA products in the pharmaceutical industry in the global context refer to biologics that are medicines manufactured and marketed by the inventors. All such products are initially patented and the product-proprietary rights are vested upon the inventors. With the passage of time, as and when such medicines are patent-expired, other new companies start producing them. Worldwide, the accepted practice for adoption of such patent-expired products for human use in medicines from manufacturers other than the original inventors are based upon providing properties of the product manufactured by the new supplier/s as equivalent to the product of the inventor through processes of identification of the product physico-chemically, biologically and through accepted clinical studies on human subjects. Such products introduced by new companies are named in different countries as “biosimilar products”, “follow-on biologics” and “similar biologics”. In India, these products are known as “similar biologics”.

The global market for “similar biologics” is anticipated to grow to USD 10 billion in 2015. (Source: This growth is largely driven by “similar biologics” going off patent by 2020 worth value of USD 67 billion. (Source: The number of companies likely to enter into “similar biologics” market would however be large even though the numbers would be limited, as the lead time is high and would require high developmental costs. Such “similar biologics” are “different” from “patent-expired small molecules”, where developmental requirements are much simpler. “Patent-expired” small molecules are parts of “generic drugs” manufacturing outfits.

The “similar biologics” industry is fast growing the world over and has a strong economic value proposition as the profitability prospects are very high. “Similar biologics” are medicines that are more effective than “generic” drugs and treatment with “similar biologics” hold the hope of not only providing increased longevity but also of extending better quality of life, especially in situations of chronic diseases including diabetes, cardio-vascular diseases, arthritis and a wide range of cancers. Setting up of “similar biologics” industry would ensure the availability of such drugs from multiple sources resulting in market competition and therefore, the prices would also be cheaper and more affordable than when supplied by the “inventors”.

Worldwide, because of large and growing market of “similar biologics”, the regulatory frameworks of all major countries are newly emerging to provide fast structured approvals so as to enable the consumers to get the benefits of use of such medicines within a territory. There is however considerable resistance from certain countries particularly from the US regulators to formally approve the production of “similar biologics” from new “similar biologics” manufacturers. Such steps and conditions would not hold for long as the healthcare costs in any country need to be rationalized and made affordable to suit the needs of poor and middle class people too, especially in situations where medical costs are not borne by the state or where patients are not fully covered with medical insurances.

The competitive pressure as well as the market for “similar biologics” varies from country to country. World over, there are “regulated markets” as well as “semi-regulated markets” for “similar biologics”. The following figure depicts the present world scenario on “similar biologics” usage:

Adopted and modified by Dr. P.K. Ghosh from IBEF Report at