Process Development Activities Research Articles

Analysis of the Change in Molecular Complexity of Reaction Products in Process Development Activities at AstraZeneca Over Time

Analysis of the Change in Molecular Complexity of Reaction Products in Process Development Activities at AstraZeneca Over Time

Hybrid modeling of T-shaped partial least squares regression and transfer learning for formulation and manufacturing process development of new drug products

T-shaped partial least squares regression (T-PLSR) is a valuable machine learning technique for the formulation and manufacturing process development of new drug products. An accurate T-PLSR model requires experimental data with multiple formulations and process conditions. However, it is usually challenging to collect comprehensive experimental data using large-scale manufacturing equipment because of the cost, time, and large consumption of raw materials. This study proposes a hybrid modeling of T-PLSR and transfer learning (TL) to enhance the prediction performance of a T-PLSR model for large-scale manufacturing data by exploiting a large amount of small-scale manufacturing data for model building. The proposed method of T-PLSR+TL was applied to a practical case study focusing on scaling up the tableting process from an experienced compaction simulator to a less-experienced rotary tablet press. The T-PLSR+TL models achieved significantly better prediction performance for tablet quality attributes of new drug products than T-PLSR models without using large-scale manufacturing data with new drug products. The results demonstrated that T-PLSR+TL is more capable of addressing new drug products than T-PLSR by using small-scale manufacturing data to cover a scarcity of large-scale manufacturing data. Furthermore, T-PLSR+TL holds the potential to streamline formulation and manufacturing process development activities for new drug products using an extensive database.

Evaluating Molecular Complexity with Open-Source Machine Learning Approaches to Predict Process Mass Intensity.

The application of green chemistry is critical for cultivating environmental responsibility and sustainable practices in pharmaceutical manufacturing. Process mass intensity (PMI) is a key metric that quantifies the resource efficiency of a manufacturing process, but determining what constitutes a successful PMI of a specific molecule is challenging. A recent approach correlated molecular features to a crowdsourced definition of molecular complexity to determine PMI targets. While recent machine learning tools show promise in predicting molecular complexity, a more extensive application could significantly optimize manufacturing processes. To this end, we refine and expand upon the SMART-PMI tool by Sheridan et al. to create an open-source model and application. Our solution emphasizes explainability and parsimony to facilitate a nuanced understanding of prediction and ensure informed decision-making. The resulting model uses four descriptors-the heteroatom count, stereocenter count, unique topological torsion, and connectivity index chi4n-to compute molecular complexity with a comparable 82.6% predictive accuracy and 0.349 RMSE. We develop a corresponding app that takes in structured data files (SDF) to rapidly quantify molecular complexity and provide a PMI target that can be used to drive process development activities. By integrating machine learning explainability and open-source accessibility, we provide flexible tools to advance the field of green chemistry and sustainable pharmaceutical manufacturing.

Further accelerating biologics development from DNA to IND: the journey from COVID-19 to non-COVID-19 programs.

The Coronavirus Disease (COVID-19) pandemic has spurred adoption of revolutionary initiatives by regulatory agencies and pharmaceutical industry worldwide to deliver therapeutic COVID-19 antibodies to patients at unprecedented speed. Among these, timeline of chemistry, manufacturing and control (CMC), which involves process development and manufacturing activities critical for the assurance of product quality and consistency before first-in-human clinical trials, was greatly reduced from typically 12-15months (using clonal materials) to approximately 3months (using non-clonal materials) in multiple cases. In this perspective, we briefly review the acceleration approaches published for therapeutic COVID-19 antibodies and subsequently discuss the applicability of these approaches to achieve investigational new drug (IND) timelines of ≤10months in over 60 COVID-19 and non-COVID-19 programs performed at WuXi Biologics. We are of the view that, with demonstrated product quality and consistency, innovative approaches used for COVID-19 can be widely applied in all disease areas for greater speed to clinic.

Accelerated CMC workflows to enable speed to clinic in the COVID-19 era: A multi-company view from the biopharmaceutical industry.

The COVID-19 pandemic has placed unprecedented pressure on biopharmaceutical companies to develop efficacious preventative and therapeutic treatments, which is unlikely to abate in the coming years. The importance of fast progress to clinical evaluation for treatments, which tackle unmet medical needs puts strain on traditional product development timelines, which can take years from start to finish. Although previous work has been successful in reducing phase 1 timelines for recombinant antibodies, through utilization of the latest technological advances and acceptance of greater business risk or costs, substantially faster development is likely achievable without increased risk to patients during initial clinical evaluation. To optimize lessons learned from the pandemic and maximize multi-stakeholder (i.e., patients, clinicians, companies, regulatory agencies) benefit, we conducted an industry wide benchmarking survey in September/October 2021. The aims of this survey were to: (i) benchmark current technical practices of key process and product development activities related to manufacturing of therapeutic proteins, (ii) understand the impact of changes implemented in COVID-19 accelerated Ab programs, and whether any such changes can be retained as part of sustainable long-term business practices and (iii) understand whether any accelerative action(s) taken have (negatively) impacted the wider development process. This article provides an in-depth analysis of this data, ultimately highlighting an industry perspective of how biopharmaceutical companies can sustainably adopt new approaches to therapeutic protein development and production.

Autologous versus allogeneic: the future of manufacturing and standardization in cell therapies

Rupa Pike, PhD is the Senior Director of Technical Affairs for Advanced Therapies, Pharma Services Group at Thermo Fisher Scientific. The Office of Technical Affairs comprises scientific experts that serve as a strategic, innovational and educational leaders in the area of cell-based therapies, plasmids and mRNA therapeutics. In her prior role as the Director of Enterprise Science and Innovation Partnerships, she developed and managed strategic partnerships with global BioPharma, Biotech and Healthcare customers in the area of Cell and Gene Therapy. Prior to this, she was the Head of Technical Operations (Patheon/Thermo Fisher Scientific) where she worked closely with customers to conduct technology transfer and process optimization activities related to GMP manufacturing of cell-based therapies. She has over 15 years of expertise in GMP manufacturing and has successfully led GMP operations, Process Development and MSAT activities, infrastructure buildout, customer relations and business development.Delara Motlagh, PhD the General Manager of Cell Therapy Technologies at Terumo Blood and Cell Technologies, headquartered in Lakewood, Colorado. She is passionate about the cell & gene therapy market and the potential these innovative therapies hold to improve the lives of patients.She brings more than 18 years of experience in biotechnology and healthcare in various therapeutic areas including oncology, cardiology, orthopedics, hematology, and nephrology. Prior to joining Terumo Blood and Cell Therapies in 2017, Delara served in diverse leadership roles at Baxter Healthcare in marketing, research & development, and operations. Her cross-functional background provides a unique perspective and deep understanding of development, cell manufacturing, and commercialization elements in the industry. Delara received a PhD in Physiology and Biophysics from the University of Illinois, fellowship in Vascular Tissue Engineering at Northwestern University, and Executive MBA from Kellogg School of Management.Patrick Hanley, PhD is the Chief and Director of the Cellular Therapy Program and an associate professor of pediatrics at Children’s National Hospital and the George Washington University, respectively. He oversees processing for standard of care stem cell transplantation as well as the development, manufacture, quality, and testing of novel cellular therapies and is responsible for seeking partnerships and commercialization of promising cell and gene therapies. Trained as an Immunologist, Dr Hanley has an extensive background and interest in cellular therapy and is passionate about improving regulations for cellular therapy, training the next generation of cell therapists, and facilitating the translation of new therapeutics. Over the past 15 years he has helped to translate more than 300 products on over 25 cell therapy protocols – ranging from mesenchymal stromal cells to cord blood virus-specific T cells and tumor-associated antigen specific T cells – into the clinic.

R&D Cooperation and Investments concerning Sustainable Business Innovation: Empirical Evidence from Polish SMEs

The empirical literature provides strong evidence supporting the relation of various innovation activities, including business innovation. The literature, however, continues to be limited in the context of developing countries, especially considering different types of business innovations. The aim of the present research is to fill the gap in the literature concerning the impact of research and development (R&D) cooperation and various types of investments in innovation for the creation of sustainable business innovation in small- and medium-sized enterprises (SMEs). Particular emphasis in this study is placed on the differences in types of business innovations. The research is based on cross-sectional data (n = 406) collected by the CATI (Computer-Assisted Telephone Interview) method in a Polish peripheral region (Subcarpathian Voivodeship). To examine the relation between different innovation activities and the creation of business innovation, logistic regression was employed. The results show that the outputs of both R&D cooperation and investments are highly dependent on the innovation type. The outcomes suggest that R&D cooperation might be a driver of the implementation of development activities and organizational innovation, while the expenditures on machinery and equipment lead to a greater probability for the implementation of process innovation and development activities. We also found that expenditures on marketing activities and investments in the implementation of new solutions may have an impact on business innovation implementation.

Sustainability Management Model Based on Risk Analysis and Implementation of the Model

In modern business management, the effective management of organizational structures based on goals within the scope of modern management concepts, as well as the continuous improvement of processes for increasing competitiveness, are critical. The purpose of this study is to discuss the matter of risk identification and analysis, practices that are seen in many different fields within the scope of the notion of sustainable management. It aimed to add the dimensions of targets and risk analysis to the scope of process analysis and development, within this study. The stages, starting with the definition of the processes in the process model through the targets based on the risk analysis, are transformed into a quality assurance cycle and completed with the determination, monitoring, and evaluation of the sustainable process development activities. The performance indicators of the business processes in a textile business were determined, and the identification of a model structure with systematic traceability was provided, in practice. The opportunities and threats encountered in achieving the determined goals were identified. The defined factors were examined within the scope of the failure mode and effects analysis and risk analysis methods. The risk evaluations were performed using fuzzy numbers. The results obtained by fuzzy failure mode effects analysis were evaluated through the MATLAB Fuzzy Logic Design Toolbox model. Risks were ranked as a result of the evaluation, and process development activities were chosen.

Green and sustainable metrics: Charting the course for green-by-design small molecule API synthesis

Sustainable small molecule Active Pharmaceutical Ingredient (API) manufacturing starts at the onset of route development by employing a Green-by-Design strategy. Reliable metrics are imperative for setting targets and measuring process improvements throughout the development cycle. This article reviews some of the many tools and methods established to analyze and assess the greenness and sustainability of a process, each of which highlights different aspects of process efficiency, waste formation or overall environmental impact reduction. Most calculations, such as process mass intensity (PMI), are mass-based and do not consider the types of raw materials used. In contrast, a full life cycle assessment (LCA) offers detailed information about the “cradle to grave” environmental impact of a manufacturing route and its specific resources, but the high data requirements and long timelines are not conducive for multiple processes or repeated assessments during process optimization. To address these challenges, we introduce a Streamlined PMI-LCA Tool, developed in collaboration with the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR), that combines PMI with a “cradle to gate” approach to include the environmental footprint of the synthesis’ raw materials. The frequent re-evaluation of a process continuously highlights areas for improvement and guides the prioritization of process development activities to effectively and rapidly achieve a Green-by-Design commercial synthetic route. The utility of this approach to Green-by-Design is demonstrated with the reduction of PMI for MK-7264 from 366 to 88 over the course of process development.

Abstract 1204: SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels

Abstract Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, has been shown to have a high prevalence, predominantly in gastric and pancreatic cancer. In addition, ectopic expression of CLDN18.2 was described for other cancer types including ovarian, lung, liver and colon, whereas healthy tissue expression is restricted to the stomach. SO-N102 represents a CLDN18.2 targeting antibody-drug conjugate based on a novel proprietary highly specific monoclonal antibody conjugated to a derivative of PNU-159682 using SMACTM technology for the therapy of patients with various CLDN18.2-positive solid tumors, mainly of gastric and pancreatic origin. The CLDN18.2 protein sequence is highly conserved in mammalians with 100% identity in the targeted extracellular loop among rodents, cynomolgus monkey and human. SO-N102 showed excellent specificity for CLDN18.2, strong binding to the target followed by efficient tumor cell killing. Preferential binding to selected patient-derived tumor tissues was observed ex vivo when compared to healthy stomach tissues from mice and cynomolgus monkey. Single-agent therapeutic activity of SO-N102 was demonstrated in 10 patient-derived mouse xenografts models (gastric, pancreatic, liver, colon and lung adenocarcinomas). Complete responses were observed in all models, independent of CLDN18.2 expression levels, ranging from low (IHC1+) to high (IHC3+), with minimum efficacious doses between 0.2 mg/kg and 0.6 mg/kg. An acceptable tolerability profile was observed in preliminary toxicity studies at 10 mg/kg (mouse), 6 mg/kg (rat) and 1 mg/kg (cynomolgus monkey). SO-N102 demonstrated favorable pharmacokinetic properties with half-lives in the range of 8 days and 13 days in cynomolgus monkey and rat, respectively. Stability of SO-N102 without any significant loss of the payload was demonstrated in vitro and in animals. Further toxicology studies in rats and cynomolgus monkeys were initiated, paralleled by process development and manufacturing activities with the plan to initiate the first clinical study with SO-N102 in patients in the first half of 2022. Citation Format: Lenka Kyrych Sadilkova, Iva Valentova, Simona Hoskova, Pavel Vopalensky, Lukas Bammert, Roger Beerli, Ulrich Moebius, Radek Spisek. SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1204.

Finding quality in complexity: how cellular therapeutics are shifting analytical paradigms for clinical supply and product manufacturing

Recent clinical successes of CAR-T cell approaches like Kymriah® or Yescarta® have promoted a boost of clinical trial applications for cellular therapeutics (CT). In terms of quality control, analytical strategies required to assess living cells represent a shift of paradigms compared to how chemical or recombinant biological drugs are typically addressed in a regulated GMP environment. This article elaborates on the corresponding CT-specific challenges and aims to provide standardized strategies for mitigation where available. Furthermore, a generic scheme of critical quality attributes is proposed, which takes into account largely different types of CT, including for example mesenchymal stem cells, CAR immune cells or stem-cell derived cardiomyocytes. Somewhat counterintuitively, rather few analytical core platforms (advanced GMP cell culture, flow cytometry, ddPCR, NGS and microscopy) should suffice to execute the vast majority of the corresponding analytical tasks throughout the product lifecycle. Obviously, internal mastery of these platforms should be achieved in order to ensure proper support of process development activities and product progression throughout clinical development, while other analytical tasks might be prone to be outsourced to contract research organizations.

A Systematic Model for Process Development Activities to Support Process Intelligence

Process, manufacturing, and service industries currently face a large number of non-trivial challenges ranging from product conception, going through design, development, commercialization, and delivering in a customized market’s environment. Thus, industries can benefit by integrating new technologies in their day-by-day tasks gaining profitability. This work presents a model for enterprise process development activities called the wide intelligent management architecture model to integrate new technologies for services, processes, and manufacturing companies who strive to find the most efficient way towards enterprise and process intelligence. The model comprises and structures three critical systems: process system, knowledge system, and transactional system. As a result, analytical tools belonging to process activities and transactional data system are guided by a systematic development framework consolidated with formal knowledge models. Thus, the model improves the interaction among processes lifecycle, analytical models, transactional system, and knowledge. Finally, a case study is presented where an acrylic fiber production plant applies the proposed model, demonstrating how the three models described in the methodology work together to reach the desired technology application life cycle assessment systematically. Results allow us to conclude that the interaction between the semantics of formal knowledge models and the processes-transactional system development framework facilitates and simplifies new technology implementation along with enterprise development activities.

Viral vector production process intensification: analytics, automation, in-line testing and more

<div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/888145b9bcb9494d9523fe80a135ed5f.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name">Susan D’Costa</h3><h5 class="author-title">Senior Director, Technical Program Design, Viral Vector Services, Thermo Fisher Scientific</h5> In her current role, Susan functions as SME for VVS’ viral vector manufacturing platforms and systems providing scientific and technical input for customer programs. Prior to this role, she served as the Head of Process and Analytical Development at Viral Vector Services, Thermo Fisher Scientific, formerly Brammer Bio for over three years. In her role as head of PD/ADA, she provided critical scientific input for projects developed and manufactured at VVS. She has built a robust team for the development, customization, optimization, scale-up and tech transfer of gene therapy vector process and analytics. Susan was also integral to developing robust QC analytics for incoming starting and raw materials and for the release of the clinical vector products in her role as Director of Quality Control at Brammer Bio/Florida Biologix. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/1b65fe190645414eb14a9f6b56f12cbf.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name">Mike Delahaye</h3><h5 class="author-title">Head of Viral Vector Industrialisation, Cell and Gene Therapy Catapult</h5> Michael has almost 15 years of industrial experience within the cell and gene therapy sector. He leads a team of experienced scientists within the Viral Gene Delivery programme, responsible for managing the developmental output of the group within collaborative, commercial and supporting R&amp;D operations. The team’s key focus is the development and delivery of robust manufacturing processes, supported by rapid, high resolution characterisation tools to facilitate the production of AAV based gene therapies. His team is also supporting the development of new adaptive manufacturing approaches by integrating technologies to allow real-time product monitoring and enable feedback control during product manufacture. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/f89a9bee7b7f422f90e20f14ed51c093.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name">Michael White</h3><h5 class="author-title">Senior Scientist, ‎Affinia Therapeutics</h5> Michael is the Head of Viral Vector Industrialisation at the Cell and Gene Therapy Catapult and has almost 15 years of industrial experience within the cell and gene therapy sector. He leads a team of experienced scientists within the Viral Gene Delivery programme, responsible for managing the developmental output of the group within collaborative, commercial and supporting R&amp;D operations. The team’s key focus is the development and delivery of robust manufacturing processes, supported by rapid, high resolution characterisation tools to facilitate the production of AAV based gene therapies. His team is also supporting the development of new adaptive manufacturing approaches by integrating technologies to allow real-time product monitoring and enable feedback control during product manufacture. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/776b16a7bc2e4fbfbe681c777fe42fcd.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name">Franz Gerner</h3><h5 class="author-title">Vice President, Technical Operations, Sio Gene Therapies</h5> Franz Gerner is responsible for process development, manufacturing and analytical activities, including overseeing outsourced activities at CDMOs and CTOs. Prior to joining Sio Gene Therapies, Franz worked at Regenxbio, joining the company at an early stage and building up the Process Development team over the course of 5 years. He started to work in the AAV gene therapy field about 25 years ago. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/c0e2ab70fb724206bfe9ddbb85d6b59f.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name">Jessica Tate</h3><h5 class="author-title">Head of Science &amp; Technology Development, Viral Vector Services, Thermo Fisher Scientific</h5> Jessica Tate has spent the last 15 years producing, purifying, and characterizing various virus modalities, in a combination of industry and academic environments. Currently she leads Thermo Fisher Scientific’s Viral Vector Science and Technology team, who’s mission is to develop and/or employ novel state-of-the-art technologies in the manufacturing of viral vector gene therapies. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/23d387b3f3674a78b57c369bcbcdf517.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name">Jim Warren</h3><h5 class="author-title">Vice President, Pharmaceutical Development, Ultragenyx Pharmaceutical Inc.</h5> Dr. Warren has 27 years of experience in the pharmaceutical and biotechnology industry. At Ultragenyx, he leads a team of over 60 scientists and engineers, responsible for all early and late stage Process and Analytical Development of viral vector gene therapy products as well as Pilot Scale Manufacturing in the Woburn, MA Pilot Plant. Before coming to Ultragenyx Jim held senior CMC leadership positions at Homology Medicines, bluebird bio, and Shire. Earlier in his career, Jim spent 16 years at Merck &amp; Co., Inc., where he led process development, technology transfer, and manufacturing sciences teams responsible for development of several clinical vector and vaccine candidates and the licensure of multiple commercial vaccines (RotaTeq®, Varivax®, ProQuad®, and Zostavax®). </div></div></div>

Methods and Compliance Adopted in Controlling Infectivity of COVID-19/SARS-CoV-2 and facilitating Sample/ Specimen Handling under BSL-2 Containment for Research and Process Development Activities

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has presented the healthcare and scientific research community with an uphill task in testing, controlling, and finding the prevention or cure for the pandemic. A significant amount of challenge related to testing and research activities arise as SARS-CoV-2 is a risk group 3 (RG3) agent and requires for all activities that use live virus for diagnostics, screening, surveillance, process development and scientific research to be handled in the Biosafety Level-3 (BSL-3) biocontainment facility environment. Low availability of the BSL-3 laboratories presents a daunting challenge for health care and research personnel, globally. Therefore, specific sample manipulation followed by risk assessment approach will allow the work to be carried in a Biosafety Level-2 (BSL-2) laboratory with enhanced practices. In the present scenario, this approach will maximize the testing and research activities along with minimizing the risk of infection for personnel involved in this process. The regulatory agencies have laid down interim guidelines for carrying out the work in BSL-2 laboratories but there has been a lot of confusion amongst the research community in adopting those guidelines in their basic science research laboratory set-up. This is due to the interim guidelines being mainly formulated around the way the work should be carried in medical laboratories and not necessarily in the basic science research laboratory environment. The article presents various scientific approaches that can be adopted while planning the work related to SARS-CoV-2 in a BSL-2 basic science research lab environment. This approach will allow simultaneously the health care and research personnel to develop a testing or research benchmark protocol in such a way that majority of the work can be accomplished under the BSL-2 laboratory conditions without having a need of a BSL-3 biocontainment facility environment.

Glycan engineering reveals interrelated effects of terminal galactose and core fucose on antibody-dependent cell-mediated cytotoxicity.

Antibody-dependent cell-mediated cytotoxicity (ADCC) has been identified as one of the potentially critical effector functions underlying the clinical efficacy of some therapeutic immunoglobin G1 (IgG1) antibodies. It has been well established that higher levels of afucosylated N-linked glycan structures on the Fc region enhance the IgG binding affinity to the FcγIIIa receptor and lead to increased ADCC activity. However, whether terminal galactosylation of an IgG1 impacts its ADCC activity is less understood. Here, we used a new strategy for glycan enrichment and remodeling to study the impact of terminal galactose on ADCC activity for therapeutic IgG1s. Our results indicate that the degree of influence of terminal galactose on in vitro ADCC activity depends on the presence or absence of the core fucose, which is typically linked to the first N-acetyl glucosamine residue of an N-linked glycosylation core structure. Specifically, terminal galactose on afucosylated IgG1 mAbs enhanced ADCC activity with impact coefficients (ADCC%/Gal%) more than 20, but had minimal influence on ADCC activity on fucosylated structures with impact coefficient in the range of 0.1-0.2. Knowledge gained here can be used to guide product and process development activities for biotherapeutic antibodies that require effector function for efficacy, and also highlight the complexity in modulating the immune response through N-linked glycosylation of antibodies.

Predictive Modeling Demonstrating a Two-Factor Signature As Early As a Week Prior to Harvest For Chimeric Antigen Receptor (CAR) T-Cell Manufacturing Growth

Background & Aim CAR T-cell therapies have shown remarkable promise in treating patients (PTs) diagnosed with advanced B cell malignancies. CAR T-cell therapies are living drug characterized by robust proliferation and persistence. We reported previously that high T cell expansion ex vivo during clinical manufacturing (MFG) correlated with high in vivo expansion following infusion, which was also associated with favorable clinical outcomes in PTs receiving CAR T-cells to treat chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). There is no known single quantitative parameter can accurately predict high proliferative potential of the T-cells during the clinical MFG process. Therefore, we conducted multivariate analysis of historical data to investigate combinatorial signatures to predict high proliferative capacity during MFG. Methods, Results & Conclusion We pooled data from a total of 297 PTs (n=248 blood cancers, n=49 solid tumors) from 16 different clinical trials receiving autologous CAR T cell products manufactured at the University of Pennsylvania. We evaluated 70 variables including PT data, phenotype of starting material, and MFG performance to determine signatures that could predict with high accuracy when a population doubling level greater than 4 on day 9 of the clinical MFG process (PDL9>4) could be achieved. We performed logistic regression to assess 70 early variables to predict T cell expansion at least 5-7 days ahead of harvest. We successfully identified a 2-factor signature that predicts PDL9>4 with high sensitivity and specificity (S/S) above 79%. The model was validated from 48 available CAR T cell products that were not used for generating the model, resulting in S/S at least 79% and 67%, respectively. This information can be useful in implementing processes/mitigation strategies to increase proliferative capacity ex vivo and MFG success rate for the product itself, provide lead time with potential alternative therapy strategies for PT. Ongoing investigation is assessing the possibility of identifying a signature of factors prior to manufacture and predict clinical response at day 28. This work provides a methodology for further studies for assessing the impact of extrinsic/intrinsic factors on PTs’ CAR T cell growth and efficacy and directing process development activities and decision algorithms in PT candidates for CAR T therapies.

Early integration of Design of Experiment (DOE) and multivariate statistics identifies feeding regimens suitable for CHO cell line development and screening.

In Chinese Hamster Ovary (CHO) cell lines, the establishment of the ideal fed-batch regimen promotes metabolic conditions advantageous for the bioproduction of therapeutic molecules. A tailored, cell line-specific feeding scheme is typically defined during process development (PD) activities, through the incorporation of Design of Experiment (DOE) and late stage cell culture approaches. The feeding during early stage cell line development (CLD) was a simplified "one-fits-all" design, inherited from PD lab, that didn't account for CLD needs of throughput and streamlined workflow. The "one-fits-all" efficiency was not routinely verified when novel technologies were incorporated in CLD and sub-optimal feeding carried the risk of not selecting the most desirable cell lines amenable to late stage PD. In our work we developed the DOE-feed method; a streamlined, three-stages framework for identifying efficient feeding schemes as the CLD technologies evolved. We combined early stage cell culture input data with late-stage techniques, such as statistical modelling, principal component analysis (PCA), DOE and Prediction Profiler. Novel in our DOE-feed work, we deliberately anticipated the application of statistics and approached the method development as an early-stage, continuously updated process, by building iterative datasets and statistically interpreting their responses. We capitalized on the statistical models defined by the DOE-feed methodology to study the influence of feeds on daily productivity and growth and to extrapolate feeding-schemes that improved the cell line screening. The DOE-feed became a methodology suited for CLD needs at AbbVie, and optimized the early stage screening, reduced the operational hands-on time and improved the overall workstream efficiency.

Managing Distributed Product Development Projects: Integration Strategies for Time-Zone and Language Barriers

Distributed product development projects encompass product and process development activities that span organizational and country boundaries. The increasing trend toward globalizing projects requires firms to coordinate development efforts made by team members from various functions within the firm, speaking multiple languages, and working in various time zones. We analyze qualitative data from 70 distributed product development projects that span 14 countries and involve cross-functional team members speaking 10 different languages. We find that commonly discussed integration strategies such as modular product designs and colocating team members by themselves are insufficient to coordinate project work. Rather, our field interviews suggest that firms invest in design information systems (DIS) with specific features to facilitate product design and empower their project managers to integrate the development efforts. Specifically, our interviews suggest that firms often modify the organization by “unifying” the engineering and purchasing functions into a single supply chain integrator function to increase the scope of responsibilities for these managers. We then test our hypotheses on the benefits of these strategies on project outcomes by using survey data from 55 distributed product development projects in 20 firms. Results indicate that the use of DIS is associated with higher quality and relationship performance when there are differences between focal and supplier firm personnel languages. Unifying engineering and purchasing functions into a supply chain integrator is associated with improved response time in the presence of time zone differences. We also find that a unifying strategy is associated with lower cost in the presence of language differences, but is also associated with a worsening of response time. These results provide guidance to product designers in organizations that must coordinate complex work across time zone barriers and languages. The results also provide guidance to researchers, by showing that different integration mechanisms may have differential effects across various coordination barriers and across multiple dimensions of project performance. We conclude by linking these results to integration mechanisms previously discussed in the coordination literature.

The role of standardization at the interface of product and process development in biotechnology

R&D stands for Research and Development and while research is essential for new product development in biotechnology, the development and its integration with research (the transfer from research to development) is underexplored. Without efficient and successful process development, biotech companies would not sustain in the long run as process development is a necessary condition en route to industrial commercialization. Based on qualitative interviews with 31 biotech companies and experts, we test a framework with technological, operational and organizational boundary conditions influencing the transfer between product and process development. Our results uncover two additional dimensions: relational and market determinants. We further identify uncertainties in the transfer and investigate if standardization can mitigate these uncertainties and eventually facilitate the integration of product and process development. We find that standardization is a beneficial mechanism for successful integration of the front end of process development activities. The present investigation contributes to the understanding of standards as a knowledge and technology transfer instrument for complex and critical development activities.

Sustaining an efficient and effective CHO cell line development platform by incorporation of 24-deep well plate screening and multivariate analysis.

Efficient and effective cell line screening is paramount toward a successful biomanufacturing program. Here we describe the implementation of 24-deep well plate (24-DWP) screening of CHO lines as part of the cell line development platform at AbbVie. Incorporation of this approach accelerated the identification of the best candidate lines for process development. In an effort to quantify and predict process performance comparability, we compared cell culture performance in and in shake flasks, for a panel of Chinese Hamster Ovary cell lines expressing a monoclonal antibody. The results in 24-DWP screening showed reduced growth profiles, but comparable viability profiles. Slow growers in 24-DWP achieved the highest productivity improvement upon scaling-up to shake flasks. Product quality of the protein purified from shake flasks and 24-DWP were also compared. The 24-DWP culture conditions were found to influence the levels of acidic species, reduce the G0 N-glycan species, and increase the high-mannose N-glycan species. Nevertheless, the identification of undesirable profiles is executed consistently with the scaled-up culture. We further employed multivariate data analysis to capture differences depending on the two scales and we could demonstrate that cell line profiles were adequately clustered, regardless of the vessel used for the development. In conclusion, the 24-DWP platform was reasonably predictive of the parameters crucial for upstream process development activities, and has been adapted as part of the AbbVie cell line development platform. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:175-186, 2018.