Implementation of Advanced Chromatography techniques to Mitigate Purification Concerns in Bispecific Monoclonal Antibody Manufacturing

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1 WHITEPAPER December 2012 inc.com Implementation of Advanced Chromatography techniques to Multi Column Solvent Gradient Purification or MCSGP chromatography process is a better solution to Bispecific Mabs purification as compared to batch chromatography Abstract: Bispecific Monoclonal Antibodies have taken the biotechnology market by storm due to their improved effectiveness and efficacy over traditional Monoclonal Antibodies. Bispecific Mabs Bi-specific monoclonal antibodies or BsMabs are second generation Biologicals and are an upgraded version of normal monoclonal antibodies due to their structure and functionality. These antibodies have two different functional binding sites instead of one due to which they are expected to be more effective in treatment of diseases where multi-functional targets can be addressed, such as in cancer. With some of the major biopharmaceutical companies such as Amgen, Fresenius Biotech etc. already being out on the market with new advanced Bispecific Mabs, the future Biologics market is expected to see a spike in this segment, as more companies realize the potential of this technology. Historically, bi-specific antibody development has been hampered by the manufacturing challenges posed by the occurrence of homodimeric and heterodimeric isoforms that were difficult to separate resulting in low product yields. Bispecific Antibody developers/manufacturers such as Amgen (Micromet), Fresenius Biotech and F-Star Bio are facing low yields in the downstream purification stages, resulting in low product purity and/or high cost of goods. The classic way of purifying BsMabs is by standard batch chromatography processes. However unlike the 1 Copyright Beroe Inc., All Rights Reserved

2 mono-functional monoclonal antibodies where effective production platforms have been developed, for bi-specific monoclonal antibodies such an effective production platform has not yet been available. The whitepaper discusses a solution to the problems in downstream purification of Bispecific Mabs, specifically the usage of new advanced chromatography processes and their effect on the Bispecific antibody purification in future. Industry to be impacted Biologics Food, Beverage & Tobacco Pharmaceuticals Chemicals Medical Devices CRO/CMO Consumer Products Packaging 2 Copyright Beroe Inc., All Rights Reserved

3 Introduction The Monoclonal Antibody Industry, to date being the only general Biologics Medicine platform, has seen a booming growth in the past few years. The industry has been growing at a CAGR of 13.5% and is expected to grow at a similar rate till % of all drugs in the FDA pipeline are presently Mabs, as quoted by Talkbiotech online journals. However, the classical mono-specific Mabs market is expected to become saturated in the near future, as newer companies enter into this industry and Biosimilar Monoclonal Antibodies are developed. Barriers to entry into the Mabs market being low, small scale biologic manufacturers are flooding the market with more cost-effective means of manufacturing Mabs. As the major blockbuster Mabs in the market are expected to go off patent by , all big biopharmas would need to look at newer avenues to maintain their profit margin. One such profitable venture that most biopharmas would be looking at is Bispecific antibodies. As Bispecific Mabs become more common, they are expected to substitute classical monoclonal antibodies and also drive up the demand for biologic drugs in the near future. ( What are Bispecific Antibodies? Bispecific Antibodies are artificial proteins composed of conjugated chains of two different monoclonal antibodies that bind to two different types of antigens or two different epitopes of one antigen target. The manufacturing process of Bispecific antibodies is highly complicated, as the two different monospecific antibody chains produced by mammalian cell culture have to dimerize in an effective manner into a bi-specific antibody. The advantage of Bispecific antibodies over normal monoclonal antibodies is their ability to attach to two separate antigens in the Fab sections, which gives them better effectiveness and efficiency as compared to normal monoclonal antibodies. Bispecific Antibodies are currently being used in cancer immunotherapy, where they are engineered to bind simultaneously to a cytotoxic cell and a target Tumor cell, for a more effective treatment. Bispecific Mabs are the future of the biologics industry. In the near future, Bispecific Mabs are expected to spearhead the biologics market growth. First generation Bispecific antibodies called tri-functional antibodies have already impacted the drug research market. These antibodies consist of two heavy and two light chains, and can bind two separate antigens through their Fab segments, while the Fc segment makes up for the third binding site. Advantages of Bispecific Antibodies over Normal Monoclonal Antibodies Due to the Presence of an extra antigen binding region in Bispecific antibodies, they can recruit both T cells as well as accessory cells as part of the innate immunity, such as macrophages, dendritic cells and natural killer cells, to the tumor site. Due to more effective signaling, Bispecific antibody bound target cells can be attacked by other effector systems in the immune system. 3 Copyright Beroe Inc., All Rights Reserved

4 Effective dosage of Bispecific antibodies is significantly lesser than ordinary monoclonal antibodies. The effective dosage is around 0.01 mg/m 2 /d 1 (milligrams per square meter body surface area per day). Major Biopharmas and their Interest in Bispecific Mabs Major Biopharmas have already started investing on R&D in Bispecific Antibodies. One such development can be seen in the recent takeover of Micromet by Amgen in January 2012, for a value of USD 1.6 Billion. Company Macrogenics F-star Amgen/ Micromet Fresenius Biotech/TRION Pharma Domantis /GSK Bispecific MAB Technology Investments DART (dual-affinity retargeting) platform Modular antibody technology BITE (Bispecific T-cell engager) technology Catumaxomab Dual targeting domain antibodies (dabs) Some other companies active in the field of Bispecific Monoclonal Antibodies Research and Development are Roche, Chugai, Novartis, Sanofi, Merrimack and Genmab. However, manufacturers of Bispecific Monoclonal antibodies are impeded by several roadblocks in the supply chain. Some of the major issues are: 4 Copyright Beroe Inc., All Rights Reserved

5 complexities and Raw Material availability Product Stability and Quality Concerns Downstream Purification Concerns Logistics and Transportation Concerns Funding issues Impact: Medium Technology issues Impact: Medium This whitepaper concentrates on one of the major bottlenecks for Bispecific Mabs manufacturers, specifically the downstream processing of Bispecific Monoclonal antibodies, which is a major cost factor for the manufacturer. Bispecific Mabs manufacturing are impeded by bottlenecks in downstream purification stages. The introduction of advanced chromatography techniques is expected to speed up the manufacturing process and increase the yield and purity of the Bispecific Mabs. 5 Copyright Beroe Inc., All Rights Reserved

6 Problem Statement One of the major hurdles faced by Biologics manufacturers is the stage of downstream processing during the process of manufacturing. During the process of manufacturing, Bispecific antibodies are expressed in mammalian cell cultures along with a high amount of impurities. Impurities include monospecific isoforms of the respective Bispecific antibodies, proteins etc. High purity and high yield of Bispecific antibodies is difficult to obtain with traditional batch chromatography methods. The yield of ultra-pure (above 90% purity) Bispecific antibodies through batch chromatography was as low as 50%, as quoted by experts in the industry. With production cell lines becoming very productive, the major costs incurred by a biopharmaceutical manufacturer are from downstream processing which includes Purification and chromatography of the biologic products. In Biopharmaceutical manufacturing, close to 20% of the costs are incurred by upstream processing, 30% from bio-manufacturing and a significant 40% comes from downstream processing, as quoted by industry experts. Chromatography is the major cost driver in downstream biologics processing. Solution Improving the Downstream Processing stages by the introduction of Advanced Chromatography techniques in Bispecific Mabs Purification Bispecific Monoclonal antibodies were traditionally purified by batch chromatography which used the principles of Ion-Exchange purification. There are a variety of chromatography techniques which are used in downstream biologics processing, namely: Adsorption Chromatography Partition Chromatography Ion-Exchange Chromatography Exclusion chromatography Affinity Chromatography 6 Copyright Beroe Inc., All Rights Reserved

7 (Source: According to a report published on Prnewswire, the global chromatography market is expected to grow at a CAGR of 5.1%, between 2011 and 2017 to reach a value of USD 8.9 Billion, from the present value of USD 6.6 Billion. The robust market growth is expected to be driven by the significant demand from the biologics industry which is the major end-use demand for the chromatography industry. These traditional chromatography techniques have limitations in their yield and raw material requirements. Newer advanced techniques in chromatography are being developed which eliminate these limitations in these traditional techniques. According to a report published in Wmctv online articles, the advanced chromatography market is expected to increase at a CAGR of 5.8% between 2011 and 2017 to reach a value of USD 1.4 Billion. (Source: New Advanced Chromatography techniques such as the Multicolumn Countercurrent Solvent Gradient Purification Chromatography System or MCSGP process helps in obtaining highly pure Bispecific antibodies at high yields. The MCSGP process eliminates the biggest problem in BsMabs purification, namely, to obtain a commercial throughput of Bispecific Mabs at a specific yield and purity. The Multicolumn Countercurrent Solvent Gradient Purification Chromatography System The Multi-column Solvent Gradient Purification system or MCSGP consists of twin chromatographic columns arranged in a specific arrangement such that the mixture flowing through it gets separated and purified into several fractions. The key principle is the recycling of product-containing side fractions inside a contained process achieving significant improvements in yield purity and throughput. The MCSGP efficiently purifies complex mixtures containing early and late eluting impurities which overlap with the target product. In batch chromatography, the overlapping sections in the chromatogram are usually lost, leading to a high product loss. The MCSGP chromatography process utilizes Ion Exchange Chromatography and has been bracketed under advanced chromatography. The MCSGP process has recently been developed and presently a company, Chromacon AG holds the patent for a technology called Contichrom which utilizes MCSGP system to operate. 7 Copyright Beroe Inc., All Rights Reserved

8 The technology has been recently developed in response to the complexities with respect to Mab purification which was hindering most Biopharma manufacturers throughout the years. The process utilizes significantly less amount of raw materials and consumables as compared to traditional batch chromatography processes. Some of the advantages of the process as compared to batch chromatography have been given below. Advantages of utilizing MCSGP process in BsMabs purification as compared to Batch Chromatography: Large Volume Processing of BsMabs Savings on an average 30% of Capital expenditure on BsMabs purification. Impact: Medium-High Savings on an average 50% of Operational Expenses in BsMabs purification Increases purity and yield on average by 50% Increases on average throughput 10-fold Impact: Medium-High Reduces process development time by up to 50% Reduction of footprints of units and utilities in the manufacturing process by 70% Buffer consumption reduction by 75% Impact: Medium-High Low Switching Costs Impact: Medium Limitations of the MCSGP system: High complexities in manufacturing of the system. Requirement of technical personnel for setting up of system at the manufacturing facilities. Greater time to market. Lack of easy availability of the system due to current patent restrictions. The MCSGP system was invented in However, commercial manufacturing of the system commenced only in late The delay was primarily due to the prevailing complexities in 8 Copyright Beroe Inc., All Rights Reserved

9 manufacturing of the system. Several modifications were introduced into the equipment prototype, which simplified the system significantly to make it more user-friendly. How would the traditional Sourcing Model in Downstream Processing Industry be affected? (Source: Expert Interactions) The introduction of MCSGP technique in the downstream processing supply chain of Bispecific Mabs would lead to significant cost savings for any contract biologic manufacturer, service provider for biologics purification or big biopharma company doing in-house manufacturing. 9 Copyright Beroe Inc., All Rights Reserved

10 Impact on Patent Approval Structure of Biologic Drugs: One of the main advantages of introducing the Multicolumn Countercurrent Solvent Gradient Purification Chromatography System (MCSGP) in Biologic drug manufacturing is that a drug manufacturer will not have to modify its patent application process for that drug. For a manufacturer who already has a biologic drug in the market: The manufacturer does not have to reapply an existing patent on a biologic drug, due to the introduction of MCSGP in the process flow chart. This saves a large amount of time and revenue that would have been lost, if a manufacturer had to go through the patent reapplication process for its existing drug. This also implies that a manufacturer can better cater to the demand of the drug to the market due to improvement in the manufacturing process and better and faster supplies. For a manufacturer who is developing a biologic drug: The MCSGP system not only optimizes the downstream process for a current manufacturer, but also impacts the manufacturing of a drug presently in its clinical stages. The MCSGP process, if used in small scales for purification of any drug in clinical stages, can highly impact biologic drug manufacturers, who traditionally invest close to 15% to 20% of their revenue in R&D of their drugs (Source: Evaluatepharma). The drug manufacturer does not have to modify its patent application process due to the introduction of the MCSGP system in its supply chain. Impact on Big Biopharma companies: Big Biopharmas such as Amgen, Biogen IDEC, etc. have already shown interest in Bispecific Monoclonal antibodies as the next big thing in the biologics market. The revenue growth trends of Catumaxomab in the last 2 years have been a major eye-opener for big biopharmas as they realize the potential of Bispecific Mabs in the near future. The impact can be seen in the recent takeover of Micromet by Amgen who is majorly looking into the Bispecific Mab industry. With the introduction of Bispecific Mabs in the market, Big Biopharmas would move towards advanced chromatography technologies such as MCSGP, to bolster their production of these Bispecific Mabs. With the success of MCSGP in purification of Bispecific Mabs in trial stages, Biopharma companies would definitely be moving towards MCSGP in future to support their downstream processing strategies. Impact on the Chromatography Market As major pharmaceutical companies are starting to direct their R&D towards Bispecific Mabs, the demand for Multicolumn Countercurrent gradient chromatography is going to increase in the future. Companies offering contract purification and chromatography services are expected to adopt the MCSGP system more readily as compared to Batch Chromatography, in the future. The Multicolumn 10 Copyright Beroe Inc., All Rights Reserved

11 Countercurrent Solvent Gradient Purification Chromatography market presently holds close to 15% of the overall chromatography market, as quoted by experts. This market share is expected to increase in future as the demand for MCSGP in the biologics market increases. Conclusion As the Mabs market gets more saturated and fragmented with multiple competitors and manufacturers, big biopharmaceutical manufacturers would move into innovative biologic drugs such as Bispecific Mabs, which have a higher effectiveness and require lower dosage requirements as compared to normal Mabs. With the significant impacts shown by Bispecific Monoclonal antibodies in the treatment of Cancer, Bispecific Monoclonal Antibodies are expected to bring a revolution in the oncology market in the near future. According to Evaluatepharma, some BsMabs such as Catumaxomab have already shown significant growth in revenue in the recent past and the trend is expected to continue in the near future. As the demand for innovative antibodies increases, so will be the demand for advanced purification techniques used in downstream processing. Traditional purification techniques have shown limitations in their usage in Bispecific Monoclonal Antibody purification. As companies venture into Bispecific Monoclonal Antibodies as their major blockbusters in future, they would require the usage of more advanced chromatography technologies such as the Multi Column Solvent Gradient Chromatography systems. With better contract structures being developed in the downstream biologics industry, procurement models are expected to undergo alterations and generate more worth to biologics clients. As lesser known contract manufacturers launch Bispecific Mabs in the market using optimized supply chains and process flows, big biopharmas are bound to adapt and adopt with the changing manufacturing environments in the near future. Case Study Catumaxomab Catumaxomab is the first tri-functional Bispecific monoclonal antibody to be approved by the EMA for marketing in Europe. Catumaxomab is manufactured by Trion Pharma and marketed by Fresenius Biotech in the European Union. The drug was approved by the EMA in April 2009, and is in trial stages in the United States. The drug is used for treating malignant ascites, a condition occurring in patients with metastasizing cancer. 11 Copyright Beroe Inc., All Rights Reserved

12 (Source: According to Evaluatepharma, the Catumaxomab market has grown at a very high CAGR of 58% between 2009 and 2012 and is expected to show a similarly high growth rate till The demand for Catumaxomab is expected to remain consistently high in the near future primarily due to its higher effectiveness in cancer treatment as compared to other Normal Mabs. and Supply Chain Complications in Catumaxomab : Low stability and yield of the Master Cell Bank and Working Cell Bank used for preparing the clones. Presence of impurities in the cell culture used in the upstream process. The formulated drug has to be maintained at a low temperature of 2-8 C. Stability issues exist for the formulated drug. Packaging of drug into vials and syringes has to be done at the same facility due to the stability issues of the product. Downstream Processing Issues in the Process: In the bulk medicinal manufacturing stage, the formulated drug substance solution is resorted to sterile in-line filtration, and various chromatography steps. The yield and purity of the formulated drug is low, which also increases the cost of manufacturing of the drug. Solution Optimization of supply chain issues The company needs to revamp its supply chain by the introduction of newer technologies in the different stages of manufacturing process of Catumaxomab. One of the best methods, the company can adopt is to introduce advanced chromatography techniques in the downstream processing stages of Catumaxomab manufacturing. Newer purification techniques such as the Multi Column Solvent Gradient Purification process would ensure a higher yield and purity of the BsMabs. Optimization of the supply chain and improvement in cold chain logistics would ensure that the transition of the drug from 12 Copyright Beroe Inc., All Rights Reserved

13 the manufacturing plant to the customer is smooth and risk-free. The lead time of BsMabs which is presently pretty large, would also improve, once the loopholes in the supply chain are removed. Now that the Multicolumn Countercurrent Solvent Gradient Purification Chromatography System (MCSGP) has been introduced into the market, and companies such as Chromacon AG willing to take up contract purification services for biologic companies, it can be expected that more drugs such as Catumaxomab would be seen in the market within a short time with lower cost of manufacturing and better and optimized supply chains. Appendix Market overview of Monoclonal Antibodies The global Mabs market grew at a significantly high growth rate of 31% between 2002 and 2008 and is expected to grow at a CAGR of 13% to 14% between 2008 and 2017 to reach a value of USD 68 Billion in The oncology and autoimmune diseases segments are expected to drive the maximum demand for Mabs in future. (Source: According to Fiercebiotech.com, Avastin (Bevacizumab) and Humira (Adalimumab) are expected to be the top selling Monoclonal Antibody in 2014, with a market share of 15% of the global Monoclonal Antibody market. 13 Copyright Beroe Inc., All Rights Reserved

14 (Source: The other major Mabs expected to dominate the Mabs market in 2014 are Rituxan, Herceptin and Remicade. Remicade was the top selling monoclonal antibody in However, the market share of Remicade has fallen since and is expected to further drop as it approaches patent expiry. Patent Details of Top Mabs in the market: Brand Company Global Annual Sales (Billion USD) E Patent Approved Date Patent Expiry Date CAGR ( ) Humira Abbott / Eisai December December % Avastin Roche February April % - 7% Rituxan Roche / Biogen December 1997 April % Herceptin Roche September 3% - 29 April % Regulatory Structure for Bispecific Monoclonal Antibodies: 14 Copyright Beroe Inc., All Rights Reserved

15 The BsMabs industry is governed by the same regulatory structure as other biologic products. The approval process for Biologic products such as BsMabs is a long drawn process and happens primarily in 5 stages: Regulatory compliance comparison between US, EU, and emerging economies: USA: Present Regulatory Effectiveness: High Extremely strict regulations. BsMabs have to go through all trial stages, similar to Normal Mabs before being approved by the FDA. Future Regulatory Effectiveness: Medium Regulations would get more liberal with time as pharmaceutical companies start manufacturing BsMabs at a more massive scale. European Union: Present Regulatory Effectiveness: Medium Strict regulations. However, the regulatory framework is comparatively less strong than the American regulations. The governing body for Biologic drugs in the EU is the EMA. Future Regulatory Effectiveness: Medium The regulations in Europe are expected to be less stringent in the future. EMA has shown more tolerance in acceptance of Biologic drugs as compared to FDA. China: Present Regulatory Effectiveness: Low Chinese regulatory agencies such as the SFDA are extremely liberal and counterfeiting of drugs remains one of the major issues in China. BsMabs research is still in nascent stages of developments in China due to high quality specifications of the product. Future Regulatory Effectiveness: Medium-Low China would have more difficulty in reforming the regulatory system due to the sheer size of the country s economy and extreme inequality between cities and rural areas. Therefore, regulatory reforms would be slower. India: Present Regulatory Effectiveness: Medium-Low 15 Copyright Beroe Inc., All Rights Reserved

16 Liberal regulations. Bispecific Monoclonal Antibodies and other Mabs can be easily introduced into the market. The governing authority for Biologic drugs in India is the Central Drugs Standard Control Organization or CDSCO. Future Regulatory Effectiveness: Medium With the development and growth in economy in India, regulations are bound to get stricter and the Mabs markets would get more organized and controlled. Brazil: Present Regulatory Effectiveness: Medium-Low Liberal regulatory environment. Brazil has already been facing issues due to their repeated violations of the TRIPS agreement and the government's support to generic manufacturers. Big pharma manufacturers are hesitant to introduce a new product such as BsMabs in the Brazilian pharma market. The governing authority for Biologic drugs in Brazil is the Anvisa. Future Regulatory Effectiveness: Medium Brazil has already started implementing reforms in the pharmaceutical sector and strengthening its regulatory mechanism for new drugs. The regulatory situation in the country is expected to improve in the future. Authors: Analyst Name Senior Research Analyst Disclaimer: Strictly no photocopying or redistribution is allowed without prior written consent from Beroe Inc. The information contained in this publication was derived from carefully selected sources. Any opinions expressed reflect the current judgment of the author and are subject to change without notice. Beroe Inc. accepts no responsibility for any liability arising from use of this document or its contents. For more information, please contact info@beroe-inc.com. 16 Copyright Beroe Inc., All Rights Reserved