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Fully continuous biosimilar manufacturing framework: A case study

Biologics manufacturing has traditionally been in fed batch mode for the last 2 decades. During the early stages of biologics manufacturing, lower cell line productivity and product instability necessitated the usage of perfusion technology. As productivity increased and mabs became more stable, perfusion was replaced by fedbatch technology, as they were simpler to scale up. However, during the past 2-3 years, the perfusion technology is making a comeback due to the novel continuous chromatography technology. Connecting the perfusion bioreactor to the continuous chromatography system creates a continuous flow of drug substance and promises the following advantages

The facility footprint for a continuous manufacturing plant would be substantially lower. Our calculations show that a 10-fold reduction in bioreactor size is possible with continuous bioprocessing. So the capacity of a 2000L Fed batch Bioreactor can be achieved by a 200L continuous bioreactor. This reduces the capex by about five fold.
Consumption of media per amount of DS produced is the same for fedbatch and perfusion, although the cost per liter might be lower for perfusion as it could be a more diluted version of the fedbatch media ,
Another major cost in bioprocessing is the Protein A resin. A significantly smaller Protein A column could be used in the continuous process and the utilization could be maximized by this strategy.
As the process is more dynamic in continuous, automation and in-line analytical tools are essential for the successful implementation.
Enzene Biosciences is on the forefront of the development of the continuous bioprocessing. We are in the processing of building a cGMP plant that would have a fully integrated continuous bioprocess. We have already complete a proof of concept studies in pilot scale (50L)
Recorded Jun 14 2018 68 mins
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Presented by
Samir Varma, Head of Manufacturing, Enzene Biosciences and Lotta Molander, Global Product Manager, GE Healthcare
Presentation preview: Fully continuous biosimilar manufacturing framework: A case study
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  • Project and Portfolio Management as a key tool to manage continuous improvement Sep 6 2018 2:00 pm UTC 75 mins
    Gloria Gadea-Lopez, Ph.D.and Melvin Santos
    Continuous improvement, risk mitigation and adherence to compliance rely on the successful execution of key initiatives aligned with an organization’s strategic imperatives. This article summarizes the Project and Portfolio initiatives at Shire’s Biologics manufacturing facility at Shire, Lexington, MA site. In addition to practical advice, the authors discuss the need for sound business processes, alignment with Finance and budget cycles, and play special attention to the importance of resource allocation and management.
  • Material Understanding for Continuous Manufacturing of Solid Dosage Forms Aug 23 2018 2:00 pm UTC 75 mins
    Dr Yifan Wang, regulatory research scientist, FDA CDER
    In continuous manufacturing of solid dosage forms, continued assurance of process performance and product quality is based on accurate and consistent flow of solid materials. Acknowledging the multidimensionality of material flow properties is often the first step to explore the material knowledge space. In addition, modular operations such as feeding and continuous blending often requires additional material testing for better understanding of process dynamics. As a key element of control strategy, tolerance of incoming material variations needs to be considered. The FDA’s Division of Pharmaceutical Quality Research is working to understand the impact of material properties and explore the material knowledge space for continuous manufacturing of solid dosage forms.
  • Implementing CMC Strategies for scale-up operations in biologics manufacturing Aug 20 2018 9:30 am UTC 75 mins
    Dr Anita Krishnan, Lupin
    Biotechnological products are so complex, that manufacturing biologics which are both cost-effective and with best product quality, is a technical challenge. In the context of biosimilar manufacturing at each step, the sponsor should evaluate the extent to which there is residual uncertainty about the biosimilarity of the proposed product. Often there is remnant quality difference beyond the capability of process to address. In such instances, in-depth understanding of the process, impurities, analytical methods, the mechanism of action (MOA) of the drug substance and clinical relevance of any observed structural differences, will help in implementing novel CMC strategies. This talk will examine the elements of biopharmaceutical development that lead to successful licensure of biotherapeutics.
  • Is India Anywhere Closer to Implementing Continuous Bioprocessing Aug 16 2018 9:30 am UTC 75 mins
    Narasimha Rao Nedunuri, CEO of CLONZ Biotech, and José Castillo, PhD, CTo and co-founder of Univercells
    Continuous processing has been widely employed in many biological manufacturing processes. In recent years it gained the momentum in the field of Biosimilar manufacturing due to an ever-increasing pressure for reduction in manufacturing costs.
    Potentially, the continuous processing offers Lower Cost of Goods, ease of scalability, and lower manufacturing footprint and hence became a topic of interest to many biosimilar players. Ongoing research on various new technologies for continuous operation, both in upstream and downstream processing may potentially be a game changer. Top on the wish list being, integration of all the multiple unit operations into a single continuous process with real time analytical tools.
    Though there are several challenges to develop and adapt continuous bioprocess, the magnitude of potential benefits are currently driving the research programs worldwide. India , being a significant global player in the biosimilar domain, currently making efforts to adapt these novel processes to make the drugs more cost effective.
  • Mixed mode Chromatography in Purifying biologics - Overview Aug 13 2018 9:30 am UTC 75 mins
    Vivek Halan Zumutor Biologics Pvt Ltd, Bangalore, India
    This Webinar will discuss MMC in purifying biologics which includes monoclonal antibodies (mAbs), Bispecific antibodies (BsAbs), antibody fragments (Scfv,Fab) and other recombinant proåteins. My discussion is intended for audience from biopharmaceutical industry as well as active collaborators from academic institutes.
  • Next generation processes: What model works the best in Asia? Aug 9 2018 5:00 am UTC 75 mins
    Ravishankar Kasturi, Reliance Life Sciences
    Compare and contrast the available full scale processing technologies, and discover what works the best for manufacturing next generation therapeutic products in Asia.
  • Subvisible Particles Matter, Developments in Regulations and Low Volume Methods Jul 26 2018 2:00 pm UTC 75 mins
    Dr Satish K Singh, Lonza
    The need to measure and characterize proteinaceous particles in therapeutic protein products has been emphasized by regulators. USP is a new chapter that addresses the limitations of USP for therapeutic proteins in measurement of subvisible particles. USP is a guidance chapter addressing the task of characterization of particles with the emphasis on proteinaceous particles. Furthermore, regulatory authorities require that sponsors understand the submicron particle size range of the products also. This article will look at latest regulatory developments, key aspects of the measurement of subvisible and submicron particles in biotherapeutics, as well as the utility of low volume methods.
  • Quality-By-Design in Spray Drying Processes - Transfer Lab to Production Jul 25 2018 2:00 pm UTC 75 mins
    Sune Klint Andersen, Janssen Pharmaceutica & Filipe Gaspar, Hovione FarmaCiência
    Spray drying is a continuous and scalable manufacturing process commonly used in the pharmaceutical industry. Due to its scalable and continuous nature it is possible to apply Quality-by-Design (QbD) and Process Analytical Technologies (PAT) early on in the development of a spray drying process.
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  • Lifecycle management of single use technologies Jul 25 2018 12:00 pm UTC 75 mins
    Francis Verhoeye, Director Single Use Technologies, GSK Vaccines
    Single-use technologies (SUTs) are one of the key drivers in the biopharmaceutical industry today and are changing the way we are operating and qualifying our bioprocesses, offering more flexibility and increasing efficiency. However, the extended use of those technologies in commercial operations requires a robust and specific lifecycle management approach. In this context, we have built an improved technical lifecycle management approach involving close partnership with key suppliers, enhanced standardization, early involvement of global manufacturing functions and full compliance with item creation process in order to ensure business continuity and value creation.
  • Key components of a comprehensive program for the management of single use techn Jul 18 2018 2:00 pm UTC 75 mins
    John Maguire, Shire
    As a result of the increased adoption of single-use technologies (SUTs) in biotech manufacturing, companies need to develop and implement programmatic approaches for the management of these systems under regulatory compliance. This webinar discusses the key aspects of such programs, with emphasis on collaboration with suppliers, cost management, as well as practical insights about the use of SUTs.
  • Development and Manufacturing of Recombinant Nanoparticle Vaccines Jul 12 2018 9:30 am UTC 75 mins
    Atin Tomar, CPL Biologicals
    A recombinant vaccine technology platform based on highly purified, properly-folded protein antigens in stable well-defined Nanoparticles, enabling efficient and safe manufacture of vaccines against highly pathogenic targets. Nanoparticles are intrinsically immunogenic, producing both durable neutralizing antibodies and cellular immunity. The platform can be utilized for rapid response to potential pandemics as the time from identification of relevant viral gene sequence to final GMP drug product ready for human studies has been demonstrated to take less than 4 months for multiple vaccines.
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    Nobel Vale, Research Scientist II, Bristol-Myers Squibb
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  • Strategies to overcome Low Endotoxin Recovery using the conventional LAL assay Jun 28 2018 2:00 pm UTC 75 mins
    Dr. Ruth Daniels, Janssen & Kevin L. Williams, BIOMÉRIEUX USA, Inc.
    Title: Strategies to overcome Low Endotoxin Recovery using the conventional LAL assay
    Presenter: Dr. Ruth Daniels, Janssen
    This presentation will discuss:
    - Endotoxin hold time studies to identify LER
    - In silico assessment of interfering factors and associated LER mitigation strategies
    - Case study: optimization of product-specific LAL assay to overcome LER

    Title: : Addressing LER at the root, with ENDO-RS® sample preparation (demasking) prior to endotoxin assay of choice
    Presenter: Kevin L. Williams, Senior Scientist Endotoxin - BIOMÉRIEUX
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    Interview with Dr. Günter Jagschies, business advisor for the GE BioProcess teams
    AN INTERVIEW WITH DR GÜNTER JAGSCHIES, OF GE BIOPROCESS TEAMS ON WHAT ARE THE MAIN OPPORTUNITIES AND CHALLENGES IN THE RAPIDLY EVOLVING ASIAN BIOPHARMA MARKETS?

    Demand for better, more precise, and effective medicines is driven by a changing global population and increased economic power in growth economies. Asia and the Sub-Saharan Africa are almost exclusively driving the global population growth. Also, the ageing populations are growing there, resulting in an increased demand on the healthcare systems. But simultaneously, there are also more and more Asian patients who can afford treatment with biologics, which is aided by generally lower price levels and improved economic situations in the region.

    Currently, the Asian biopharma industry is mainly concentrated in China, India, South Korea, Japan, and Taiwan, but the development of these markets is going to be heterogenous as they have, for example, different starting points, local policies and biopharma know-how. However, these countries are likely to face a market fragmentation challenge, because a large number of Asian companies are all focusing on the development of biosimilars for only a very few (5-10) original drugs, while at the same time many multinational companies are also entering the region. This requires more product development and manufacturing innovation from the local players to develop a differentiated position in their markets and to move to original drugs, although access to affordable biosimilars is also critical.
  • Manufacturing strategies for Biosimilar: A case of continuous capture Recorded: Jun 15 2018 74 mins
    Solomon Alva, Biocon & Presented by Yvan Ruland, PhD, Technology Director, Asia/Pacific operations, Novasep Asia
    Presented By Solon Alva Antibody Purification Group Lead, Senior Scientific Manager, Biocon Research Limited
    Continuous manufacturing is an emerging technology in biopharmaceutical industry. The focus of this webinar is a case-study on the benefits of continuous Protein A capture on productivity, capacity utilization and buffer consumption. The potential challenges of adopting the technology such as its integration with cell culture and low pH incubation step has been discussed. There is promise of this technology as an effective platform, and potential of additional savings when considering new generation Protein A resins and in-line concentration technologies.
    Followed by Yvan Ruland, PhD, Technology Director, Asia/Pacific operations, Novasep Asia
  • Fully continuous biosimilar manufacturing framework: A case study Recorded: Jun 14 2018 68 mins
    Samir Varma, Head of Manufacturing, Enzene Biosciences and Lotta Molander, Global Product Manager, GE Healthcare
    Biologics manufacturing has traditionally been in fed batch mode for the last 2 decades. During the early stages of biologics manufacturing, lower cell line productivity and product instability necessitated the usage of perfusion technology. As productivity increased and mabs became more stable, perfusion was replaced by fedbatch technology, as they were simpler to scale up. However, during the past 2-3 years, the perfusion technology is making a comeback due to the novel continuous chromatography technology. Connecting the perfusion bioreactor to the continuous chromatography system creates a continuous flow of drug substance and promises the following advantages

    The facility footprint for a continuous manufacturing plant would be substantially lower. Our calculations show that a 10-fold reduction in bioreactor size is possible with continuous bioprocessing. So the capacity of a 2000L Fed batch Bioreactor can be achieved by a 200L continuous bioreactor. This reduces the capex by about five fold.
    Consumption of media per amount of DS produced is the same for fedbatch and perfusion, although the cost per liter might be lower for perfusion as it could be a more diluted version of the fedbatch media ,
    Another major cost in bioprocessing is the Protein A resin. A significantly smaller Protein A column could be used in the continuous process and the utilization could be maximized by this strategy.
    As the process is more dynamic in continuous, automation and in-line analytical tools are essential for the successful implementation.
    Enzene Biosciences is on the forefront of the development of the continuous bioprocessing. We are in the processing of building a cGMP plant that would have a fully integrated continuous bioprocess. We have already complete a proof of concept studies in pilot scale (50L)
  • Preview of USP’s Informational Chapter , Guidelines on the Endotoxins Test Recorded: Jun 11 2018 61 mins
    Karen Zink McCullough of MMI Associates & Kevin L. Williams of BioMérieux
    Title: Preview of USP’s Informational Chapter, Guidelines on the Endotoxins Test
    Presenter: Karen Zink McCullough, MMI Associates
    The retirement of FDA’s 1987 Guideline on LAL testing left a number of gaps in the written body of knowledge
    on LAL testing. Some of these gaps include: Guidance on RSE:CSE standardization, Guidance on Training,
    Guidance on OOS test results, and Calculation of Endotoxin Limits. The proposed chapter, that will appear in the
    July/August issue of Pharmacopeial Forum, provides information and recommendations on these topics and
    more. This Webinar will provide an overview of the contents of this new informational chapter.

    Title: Regulatory Compliance of Alternative Methods
    Presenter: Kevin L. Williams, BIOMÉRIEUX
    Recombinant Horseshoe Crab Factor C (rFC) tests are endotoxin-specific alternatives to Limulus Amebocyte Lyste
    (LAL). The United States Food and Drug Administration included rFC in their Guidance for Industry in 2012 and in
    2016 the European Pharmacopoeia followed suit. Recently, the Japanese Pharmaceutical and Medical Device
    Agency published a collaborative study demonstrating equivalence between rFC and LAL. This presentation will
    provide an overview of how alternative method validation of rFC methods is conducted in accordance to USP
    chapters < 1225 > and < 85 >.
  • FINDING THE COMMON ROAD TO QUALITY FOR SINGLE-USE MATERIALS Recorded: Jun 6 2018 65 mins
    Dr Trishna Ray-Chaudhuri, Genentech & Dr Hélène Pora of Pall Biotech |
    – GMP requirements touch every single use assembly used in clinical studies to commercial manufacturing. The drug product produced in clinical studies are given to patients.

    – GMP practices followed in producing the single use assemblies will ensure that there is no risk to patients in clinical trials and future commercial products.

    IF WE CAN”T PROVE GMP WHAT HAPPENS?

    -Single use assemblies will not be accepted by regulatory agencies and internal quality departments as an alternative to stainless steel tanks.

    -The perception will continue that there is inadequate quality controls on single use assemblies as GMP practices are not adequately followed.

    – Implementation of single will be inhibited

    Presented by Dr Trishna Ray-Chaudhuri, Senior QC Scientist in Direct Materials in Global Analytical Sciences & Technology / Global QC, Genentech

    DRiIVING QUALITY & RESPONSIVENESS IN SINGLE-USE TECHNOLOGIES

    Single-use technologies require a shift of responsibility from biomanufacturers to suppliers to enable production of safe and reliable drugs. One of the pre-requisites for efficient supply is to have standardized processes to design and manufacture single-use systems.
    Pall has developed a unique design, quality and business tool to drive quality and responsiveness, and to support standardization of single-use technologies. We will take you through the functionalities of this system and demonstrate what benefits it brings to end users when implementing single-use technologies in a regulated environment.

    Presented by Dr Hélène Pora, Vice President Technical Communication & Regulatory Strategy , Pall Biotech
  • Extractable Study Design & Data Evaluation of Polymeric Product Contact Material Recorded: Jun 5 2018 74 mins
    Dr. Ping Wang, Principal Scientist, Janssen R&D & Dr Nixdorf, SGS Group
    Concerns over the safety and drug product qualities due to extractables and leachables (E&L) from polymeric Product Contact Materials (PCM), especially single use systems, in the manufacturing, packaging and delivery of biologics have increased in recent years. Based on surveys and author’s experience, almost all major regulatory agencies require the E&L risk assessment of PCM for new biologics license applications (BLA). To ensure the E&L data are suitable for the assessment of intended application of the PCM, the health authorities are paying close attention to the study design, analytical assays employed, and how the extractable data being used to conduct a safety risk assessment of the materials. The key to the success is to ensure the study design and data interpretation is product and process specific. The lack of relevant E&L data from suppliers presents end-users a great challenge. Strategies of developing relevant extractable data and applying that in the toxicological evaluation will be discussed.
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  • Title: Fully continuous biosimilar manufacturing framework: A case study
  • Live at: Jun 14 2018 8:30 am
  • Presented by: Samir Varma, Head of Manufacturing, Enzene Biosciences and Lotta Molander, Global Product Manager, GE Healthcare
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