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Engineering First Principles: Applications to Pharmaceutical Manufacturing

Within the pharmaceutical industry, creating a robust Operational Control Strategy (OCS) is a key step to accomplishing the goals of Quality by Design (QbD). Along the way to developing this robust Operational Control Strategy many problems will be encountered that need to be solved. The use of a First Principles based approach provides value because it improves the effectiveness and efficiency of our problem solving, thereby leading to solutions that are more likely to work without unintended consequences and were created in a faster and more cost effective manner. Based on the author’s experience, a clear definition of what First Principles are will be given (and what they are not!). Areas of opportunity where the application of First Principles is likely to be successful will be described. An outline of a high-level process for implementing a First Principles based approach will be presented. Finally an example of the application of First Principles in the pharmaceutical industry will be briefly described.
Recorded Aug 24 2020 65 mins
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Presented by
Bernard McGarvey, PhD Chemical Engineering
Presentation preview: Engineering First Principles: Applications to Pharmaceutical Manufacturing
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  • Designer Sterile Filtration in Aseptic Processing Using Single Use Technology Nov 4 2020 3:00 pm UTC 90 mins
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    As the number of cell and gene therapy products grow it is important to consider aspects of gene therapy production process robustness, and one key characteristic is the variability of incoming raw materials. Understanding and controlling raw material variability is an important aspect of process development, characterization and commercialization. In the recent history of therapeutic protein production with cell cultures, many problems caused by raw material variability were only discovered post-commercialization, and failure to understand and address key raw material variability during process development led to costly underperformance and batch failure. In this article, we consider some known sources of raw material variability and specifically, those that have been known to impact cell culture production processes. Trace element impurity variation, particularly iron, copper, manganese and zinc, are candidates for high process impact risk. Compositional variation of undefined material (i.e., fetal bovine serum [FBS]) is another important potential failure mode. This includes known nutrient components, such as amino acids and cholesterol, as well as unidentified components, such as growth factors. Cell and gene therapy processes also include relatively new materials for cell culture, such as plasmid DNA and the transfection agent polyethyleneimine, the understanding of the variability of which must be considered.
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    Thorsten Lorenz studied Biochemistry at the University of Bochum in Germany. He performed his PhD work at the Max Planck Institute for Medical Research in Heidelberg and afterwards joined Novartis as postdoctoral fellow. In 2011, he took the lead for the buildup of a laboratory for protein characterization and pre-formulation assessment. After taking roles of increasing responsibility in the unit, Thorsten was appointed Team Head Developability Assessment in 2017, responsible for the assessment of molecular properties, downstream process and stability characteristics as well as immunogenicity and in vivo stability risks for the Novartis Biologics pipeline at the transition from Research to Development.
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    Follolwed by an Industry perspective presented by Renee Tobias, Director of Marketing, Halo Labs
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    3.        Key consideration of mAb industry in China
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    Followed by Biosimilar development—how to deal with the similarity challenge

    Presented by Sarah (Xuyu) Wang, Head of Segment Marketing, Biosimilars and Bioconjugations at Sartorius Stedim Biotech

    Globally we have more than 1000 biosimilars in the pipeline till the beginning of 2019, Sales of mAb biosimilars is also taking up as popular targets being approved both in Europe and US. With the 3rd wave of the biosimilar coming the challenges is still ahead---how to keep the similarity from the beginning of the development to the manufacturing stage and cover the whole lifecycle? With the evolving cell line development platform, good analytical strategy and QbD implementation better similarity will be achieved step by step.
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    Defining the role of MES in using technology to achieve compliance.
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    Organizational strategies to leverage the Power of technology by implementing MES.
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    Michelle Raikes, M.S., Scientist IV and Dr. Fredrik Nordstrom, Sr Research Fellow at Boehringer Ingelheim
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    Presented by Michelle Raikes, M.S., Scientist IV and Dr. Fredrik Nordstrom, Sr Research Fellow at Boehringer Ingelheim

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    Presented by Robert Dimitri

    Robert Dimitri is a Director in Takeda’s Business Excellence group for the Biologics Operating Unit as the Digital Transformation and Innovation Lead. Previously he led the Digital and Data Sciences group in Manufacturing Sciences at Takeda’s Massachusetts Biologics Site leading a team for the implementation of digital tools used for the analysis of internal manufacturing operations data, used to support the production of biologic drugs to treat rare diseases. He has over 15 years of experience in this field, having worked previously as a process engineer and developing software to perform process data analytics. Robert has a B.S. degree in Chemistry and Computer Science, an M.S. in Computer Science, and an M.B.A.

    Followed by an Industry Perspective by Pep Gubau, CTO and co-founder, Bigfinite
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    Followed By A Presentation From Kevin L. Williams, Microbiological Test Development at bioMérieux
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    Karen Zink McCullough, Owner, Principal Consultant at MMI Associates and Veronika Wills, Manager, Technical Services
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    The Bacterial Endotoxins Test is not a test for pyrogens (fever causing agents). It is not a test for the presence of Gram negative bacteria. Based on extensive comparisons of endotoxins activity in the BET and fever rabbits executed in the 1970s and 1980s, we may say that the BET is a test for levels of Gram negative bacterial endotoxins activity that may be predictive of a fever in mammals.

    The various methodologies that are described in the harmonized in the harmonized chapter use the primary Reference Endotoxin Standard (RSE) or secondary Control Standard Endotoxin (CSE) to prepare assay standards, perform suitability testing as instructed in the chapter and inoculate positive product controls. These standards are relatively pure preparations of lipopolysaccharide. However, the utility of the compendial assay for non-compendial applications is limited. Our discussion will focus on the compendial uses of these BET assays.
  • A Comprehensive Approach to Assess the Impact of Microbial Impurities on Pat... Recorded: Sep 16 2020 80 mins
    Dr Friedrich von Wintzingerode, QC Lead iNeST Project at Roche and Shabnam Solati, CEO & Co-Founder at CTL-MAT
    FULL TITLE: A Comprehensive Approach to Assess the Impact of Microbial Impurities on Patient Safety and Product Quality of Biologics

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    Large-scale Production of Biologics is susceptible to microbial contamination because many manufacturing steps occur under non-sterile conditions in aqueous systems at ambient temperature or 2-8 °C under substantially neutral pH conditions. Regardless of where in the Drug Substance (DS) manufacture (manufacture of the Active Pharmaceutical Ingredient), or Drug Product (DP) manufacture (manufacture of the Final Drug, e.g. formulated mAbs filled in vials or syringes) they occur, microbial contaminations can have a significant impact on product quality and patient safety. Even after bioburden removal by 0.2 µm filtration subcellular microbial components like toxins, lipopeptide/lipoproteins, flagellin, bacterial and fungal DNA, cell wall polysaccharides, extracellular proteases or endoglycosidases remain in the product. Those microbial components potentially lead to toxic, allergic or inflammatory responses in humans or product degradation or modification. The Case-by-Case Assessment of Bioburden (CCAB) approach described here enables a comprehensive assessment of these risks.
  • Analytical Strategies for Comparability in Bioprocess Development Recorded: Sep 15 2020 52 mins
    Dr Christine P. Chan, Director in Global Manufacturing Science & Technology at Sanofi
    Bioprocess changes can impact quality attributes of biologics and may affect efficacy and safety of the product. During development and throughout the product lifecycle, when process improvements are implemented, it is essential to gather sufficient data to support the conclusion that product safety and efficacy has not been adversely affected. This demonstration exercise requires careful planning of the comparability studies and is based on the background knowledge of protein structure, biological function, and clinical attribute profiles of the product accumulated during development.

    In this webinar, I will discuss the key concepts of establishing product quality profiles, and the hierarchical assessment approach to demonstrating comparability of biopharmaceuticals in support of process changes.
  • Mapping Future Technology Needs For Real Time Release Testing Recorded: Sep 14 2020 51 mins
    Dr Udayanath Aich, Associate Director at Bristol-Myers Squibb
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    Presented by Dr. Udayanath Aich Associate Director at Bristol-Myers Squibb

    Dr. Udayanath Aich has an extensive experience and management skills in analytical chemistry, and CMC analytical strategies for early, late and commercial biologics products. He then decided to move to M.I.T to gain extensive skills in the area of Biopharmaceutical characterization and drug development. Dr. Aich joined at Thermo Fisher Scientific in the chromatographic and mass spectrometric division to broaden his extensive analytical skills. Then Dr. Aich worked as Investigator at GlaxoSmithKline in the area of protein and glycans characterization, process analytics, CMC analytical strategies as ATL and structure-function study. Finally, before joining at Bristol Myers Squibb, Uday was working at Sanofi related to high throughput technologies, process analytical technologies (PAT), Analytical method harmonization, multi-attribute method Dev, analytical method dev, robustness, qualification and transfer for early and late stage product including 2nd generation commercial product as part of life-cycle analytics.
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  • Title: Engineering First Principles: Applications to Pharmaceutical Manufacturing
  • Live at: Aug 24 2020 4:30 am
  • Presented by: Bernard McGarvey, PhD Chemical Engineering
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