Challenges and Successes in Externalization of the ADC Supply Chain
Sourcing for the manufacture and control of Antibody-Drug Conjugates (ADCs) used in clinical trials requires strategic planning, establishment of a specialized support network, and execution of several interdependent tasks. ADCs are complex molecules, a fusion of a biological, the monoclonal antibody (mAb), and of small molecules, the linker and the toxic payload. Facilities of acceptable standards for the handling of high potency materials need to be engaged, and there is a limited supply currently. This is further complicated by the fact that there is not one contract facility that has fully integrated services, a “one-stop shop” capable of mAb production, linker and/or payload synthesis, conjugation of mAb to linker-payload to make the Drug Substance, and finally, formulation of the ADC to make the Drug Product. Strategizing the best outsourcing practices for producing and testing ADCs, and establishing guiding principles for externalization to ensure the selection of the right CMOs for ADC outsourcing and technology transfer, will be further discussed.
RecordedFeb 14 201774 mins
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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.
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.
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.
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.
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.
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.
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.
Knowledge gained from QbD e.g. Design-of-Experiments (DoE) and PAT increases process understanding and the knowledge can be readily applied when scaling up the process and in production scale application of PAT i.e. especially with respect to the control strategy.
The Webinar will discuss the application of QbD early in the development and how the obtained knowledge can be used to optimize transfer of the spray drying process to production scale including PAT strategy.
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.
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.
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.
The GMP drug substance manufacturing process for the platform largely utilizes single-use technologies. Single-use-technologies and recombinant platform enables the utilization of same manufacturing facility for multiple products with rapid change-over.
Nobel Vale, Research Scientist II, Bristol-Myers Squibb
Raman spectroscopy has been seen as spectroscopic tool used in bioprocessing to monitor and control cell metabolism to optimize quality and yield of titer. This is due to Raman’s insensitivity to water and ability to analyze samples without manipulation. However there are certain challenges for Raman when analyzing a complex and dynamic sample such as a cell culture. This article will describe the different challenges in analyzing in-line Raman data and how to mitigate changes in samples that include changes in fluorescence background, presence of cells/debris in samples, and spectral interference.
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
Scientific studies have demonstrated that biologics typically containing protein in high concentrations and non-ionic surfactants, are likely to change the aggregate state of endotoxin in such a way that it is no longer accessible for detection with Factor C-based endotoxin detection methods (LAL and rFC). The ENDO-RS® endotoxin recovery method developed by Hyglos - a bioMérieux company, is a unique toolbox of dedicated reagents for demasking (recovering) endotoxin prior to detection, also for conventional LAL. This presentation covers the mechanism of LER, regulatory requirements, work principle of ENDO-RS, the demasking services of bioMérieux, as well as method application data.
Dr Hung Fai Poon, President, QuaCell Biotech Ltd and Floris De Smet, Sartorius Stedim Biotech
Discover strategies to move candidate molecules through development
Building consistent, straightforward processes with low variability
Exploring the possibility of using single use, high throughput bioreactors in the upscaling process
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.
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
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)
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 >.
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
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.
The Journal for Asia's Pharmaceutical and Biopharmaceutical Industry
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