This Women in Pharma® sponsored session features a panel presentation focusing on personal experiences and best business practices when managing business negotiations and operations across borders and age groups. Through this session, you will hear leadership anecdotes of lessons learned, and acquire tools to better manage cultural differences and seamlessly integrate generational perspectives.

As many ATMPs including genetically modified cell-based therapies move swiftly through the CMC process design and development to keep up with an accelerated clinical pathway, the planning to be ready for the critically important Process Performance Qualification (what some refer to as Stage 2B of the Process Validation Lifecycle) must begin early and must be appropriately managed. The employment of a science-driven and risk-based approach has never been more important for managing this process borrowing from lessons learned from previous biopharmaceutical products while also addressing the unique challenges associated with this novel type of product. Alignment of key CMC activities that are pre-requisites for the PPQ including process design and characterization, analytical methods validation, materials (raw/ancillary/starting) qualification and availability, and supply chain logistics (to name some but not all) is of utmost importance to success. In this presentation we will discuss the pre-requisites for the PPQ and how to address the unique challenges faced for the manufacture of a genetically modified cell-based therapy. Examples of custom tools and risk assessments to prepare for the PPQ of a genetically modified cell-based therapy within an ambitious overall project timeline will be detailed.

Along the “Wild Atlantic Way” in the West of Ireland, a unique and established supply chain has been in operation over several years to procure, manufacture and deliver GMP approved clinical therapy (ATMP) products to patients. This involves Galway University Hospital (GUH), Galway Blood and Tissue Establishment (GBTH), the Clinical Research Facility (CRF) and the Centre for Cell Manufacturing (CCMI-REMEDI) at the University of Galway, Ireland.

The Regenerative Medicine Institute (REMEDI) at the University of Galway were instrumental in establishing the Centre for Cell Manufacturing Ireland (CCMI) as part of their translational mission to deliver actual stem cell therapies to the clinic. To that end, after successfully securing regulatory authorisation to manufacture human Mesenchymal Stem Cells (hMSCs) for use in clinical trials, CCMI have delivered on CLI Trial EudraCT. No 2013-003447-37, ADIPOA-2 Trial EudraCT. No 2015-002125 and Nephstrom Trial EudraCT. No 2016-000661-23. The ultimate objective of these clinical programs is to offer patients with debilitating, incurable conditions an alternative treatment through advanced therapies. These State-EU funded treatments were clearly “Not for profit” and the challenge to commercialise such treatments is a pressing goal for all stakeholders in the ATMP – Cell and Gene Therapy space. The intention of this presentation is to offer an insight into the challenges and enablers that may help to commercialise such therapies and is based on experiences gained from delivering such therapies from a Hospital-University setting, albeit these trials were State-EU funded.

National Resilience, Inc. (Resilience) is a first-of-its-kind manufacturing and technology company dedicated to broadening access to complex medicines and protecting biopharmaceutical supply chains against disruption. As a part of this vision, Resilience is developing an advanced end-to- end continuous drug substance manufacturing platform for biological molecules using Siemens gPROMS Formulated Products mechanistic and hybrid modelling platform. To enable robustness, facilitate in silico process characterization, and enable an efficient process control strategy, we are developing a mechanistic model with uncertainty analysis for an integrated and continuous biomanufacturing (ICB) process at Resilience. Described herein are the steps for the development of ICB model. The individual unit operation process models were built separately and then integrated into an end-to-end flowsheet simulation. The model is being used to determine the impact of expected disturbances, deviations, and provide a disturbance divergence strategy to maintain the product quality attribute. With uncertainty analysis, the model can provide the critical level analysis of process parameters along with the identification of failure boundaries on product quality.

Advanced Therapy Medicinal Products are a new treatment modality in the pharmaceutical industry. APC Ltd, Dublin, is one of the world’s leading pharmaceutical process engineering research and development companies. Recently, APC Ltd. developed a scalable manufacturing process for an ATMP, a novel oncolytic vaccine produced in adherent cells. The initial manufacturing process in place was not scalable or commercially viable. APC Ltd. developed a scalable microcarrier based upstream and downstream process. During process development, APC Ltd. overcame the known production challenges with titre recovery and impurity clearance. The scaled process resulted in a 400 % increase in virus production per cell with an impurity profile on target. The number of doses produced was 16 times higher than the previous process with an 8-fold cost reduction per dose and the medicine to patient time was accelerated 3-fold. As a result, more patients could receive this novel advanced treatment option.

How do you prioritize innovation in complex landscapes of competing priorities and finite resources? BioPhorum Technology Roadmapping Phorum have developed an industry vision for biomanufacturing that can help shape strategies and identify key areas of focus. Members of the Phorum leadership team will share this, and also examples of where this has led to innovation collaboration on topics. The roadmap, will be presented alongside recent developments in priority areas agreed by the industry. These developments enable progress for the industry as a whole through identifying technology targets and modelling solutions, for example current work includes proving through concept demonstrators and business case modelling, plug and play hardware, smaller buffer preparation footprints and driving the move for more standard facility design to accelerate capacity builds.

Flexible manufacturing equipment and process flows can now support many distinct production modalities. Multimodal facilities can be designed to accommodate equipment and process flows enabling ease of changeover between entities; concurrent production of more than one product; and ease of future modifications. Distinctions in ATMP facility design are determined by the manufacturing technologies, safety requirements, and regulatory characteristics of the active substance (cell, peptide, or oligo type), delivery vector (viral, vesicle, or molecular), and drug product. Considerations in multi-modal facility design begin with such high-level questions as what in-house manufacturing will be change-over dependant (campaign based), or parallel and concurrent production based. Then such tactical questions can be entertained as the required biosafety level or hazardous area classification; closed, single-use and/or automated processes; straight through processing; and environmental sustainability imperatives. The GMP considerations relating to regulations such as EU GMP Annex 1 and PIC/s Annex 1 are also a critical factor particularly in relation to CT manufacturing. Creative solutions for multi-modal facilities are now supported by such Pharma 5.0 advances as modern building information modelling (BIM) technologies. Such digital architectural tools enable suite and facility designs optimising the desired flexibility in equipment and process flows.

In this presentation Dr. O'Connell will present an introduction to the twin concepts of Lean Manufacturing and the Six Sigma Quality improvement strategy, DMAIC, ending with describing how they can be jointly applied to pharmaceutical manufacturing. The term LSS or Lean Six Sigma is currently used in a number of successful manufacturing companies (both worldwide and in Ireland). This presentation will describe the various forms of non-value add in manufacturing, highlight the benefits, phases of DMAIC and give an overview accompanying tools used for process improvement, specifically the reduction of variability. Lean will focus on enhancing throughput as it involves the elimination of non-value add activities in the manufacturing process.

Many novel biologic-based therapeutics are progressing through the development process toward EMA and FDA filings and future approvals. The long-term viability of these new therapeutics partly depends upon the development of efficient and robust bio-manufacturing processes. Characterization, optimization, and long-term control of these processes is a requirement and development and then implementation of effective predictive models support this requirement. Traditionally, characterization is costly, time consuming, and often no effective predictive models result from these efforts.  We propose by using highly efficient experimental designs and predictive modeling methods from machine learning, cost effective and reliable predictive models can be developed. The models subsequently may be used for scale-down modeling, process characterization, optimization, and identification of critical process parameters for manufacturing control strategies.  Using highly efficient space filling experimental designs combined with a novel method of predictive model developed known as self-validating ensemble modeling (SVEM) combined with artificial neural networks (ANNs) allows for predictive models to be designed that are more representative i.e. predictive.

  No matter if classical biologics or ATMPs – generic methodologies are needed to efficiently identify robust control strategies along the product life cycle.
Digital twins are a means to capture and to deploy knowledge for example for efficient experimental design, prediction of product quality or process events or also for process optimization.
This contribution shows use cases, as to how digital twins can be deployed for various modalities, also including random effects from starting material as this is an inherent challenge for ATMPs.
Last but not least we discuss prerequisites to commercialize digital twin approaches.

ATMP (Advanced Therapy Medicinal Products) facilities are different to the more conventional pharmaceutical facilities, often requiring heightened segregation. Many organizations are evaluating how different modalities may be combined within the same facility having acquired a building, or having constructed an agnostic building. Accommodating multiple modalities in the same facility is therefore becoming an increasingly important requirement and not least during the COVID-19 pandemic when rapidly developing and launching new vaccines. The presentation describes a basic framework and methodology that may be used when evaluating different types of modalities and how they may be accommodated in a new or existing facility. A case study is used to demonstrate how the approach may be applied to an existing facility.

The rapid introduction of a pandemic vaccine created a challenge to the classical sequential approach to process characterization, transfer, and validation at production scale. The lessons learned from this unprecedented opportunity allows for rapid introduction of related variants. Further, the lessons learned influenced decisions in establishing a vaccine platform process which will allow for faster transfer of additional vaccines to market with less onerous process characterization, technology transfer and process validation activities.  Considerations for consumables selection, equipment sizing, batch scale, automation, and digital integration was necessary to ensure a robust platform can be established which would accelerate speed to market while not introducing additional risks that would require rework in the future.

This presentation will cover WuXi Biologics’ new biopharmaceutical contract manufacturing facility in Dundalk, Ireland, which has set industry benchmarks in time to market, scale, and flexibility. A unique approach to the process scope of supply was a key factor in this achievement. WuXi Biologics chose the largest available single use bioreactors (4,000L), a hybrid single-use/stainless steel process design, and an integrated approach for process design, manufacturing, installation, and commissioning. The result is a highly flexible, large-scale process that was turned over only 28 months after start of design, with much of the project occurring during the COVID-19 crisis. In this talk, we provide details of the process scope as well as the project execution approach.

Messenger (m)RNA is increasingly investigated as a platform technology. The delivery of the genetic information offers potentially broad therapeutic applications. For almost all mRNA therapeutics the sequence is introduced by a linear DNA template. Those linear DNA templates can be manufactured via different strategies what comes with additional challenges, but also provides options to affect the behavior of the desired mRNA product.

How does standardization of aseptic filling accelerate drug development? Traditionally aseptic filling processes were developed as a custom solution late in the drug development process, often dedicated to a single drug candidate. That approach is less often successful, as drug candidates can fail, leaving companies with equipment that can’t be used for other purposes. Standardized flexible systems that fill drug into any type of dosage container can solve this problem. The impact of standardization doesn’t stop there. It has benefits other than reducing the risk of unnecessary custom equipment. It allows for lean manufacturing of the equipment, drastically reducing lead times. Standardization allows the development of a shared body of knowledge, allowing end-users to collaborate across companies. A network of standardized systems simplifies technology transfer and even allows the development of common regulatory strategies. This presentation will highlight case studies from several companies that used standard aseptic filling systems to accelerate their drug development.

Effective control of plasmid DNA is paramount since plasmids are critical starting materials for the generation of viral vectors and mRNA used in many cell and gene therapies. In their latest publication, a collaboration of industry colleagues at BioPhorum discuss current best practices and emerging technologies aimed at complementing broader industry efforts to advance release testing of plasmid DNA and the bacterial master cell banks used to produce them.

Following the three presentations by Alfred Penfold, Tom Bannon, Richard Shah, Scott Brady, Aine Brennan and Thomas Page, you'll have the chance you ask your questions.

Global demand for genetically modified therapies like cell & gene therapies along with mRNA vaccines has spiked in the last few years.  With that, plasmid manufacturing market is expected to growth at a CAGR of over 20% in the coming years. To keep pace with the increasing demand, new manufacturing capacity is needed.

The most common production process is based on bacterial fermentation. Even if it is well established, the design and realization of new manufacturing facilities is not exempted of challenges. Factors like production scale (i.e.. batch size), type of plasmid (i.e. drug product vs drug substance vs starting material) as well as GMP requirements (i.e. multi-product, contamination control, risk based approaches) will determine the design and future operations.

We developed a GMP modular continuous processing system that lowers the hurdles of adopting new technologies. This technology was designed to (1) meet drug product demand, (2) provide modular, mobile manufacturing, and (3) reduce environmental impact. Demand for Covid mAbs increased 20X in 2.5 months. To meet such demand, the system increases manufacturing capacity by employing continuous processing. The off-the-shelf system runs any four unit operations simultaneously, resulting in 4X more product. The modular design accommodates different products and processes. Single-use product-contact surfaces allow for quick changes between products. The system is fully closed, can roll through a standard door, and plug into a standard outlet, allowing deployment in various locations. Environmental impact is minimized with compact, single-use equipment, eliminating the need for CIP and SIP systems. Combining four steps shrinks facility footprint requirements another 60%. The system was designed with ease of implementation in mind. Despite operating in a continuous manner, the control strategy ensures batch key process parameters can be maintained in most if not all cases, reducing the burden on process development and process validation activities. This fact, and familiarity of the system by regulatory agencies, reduces unknowns and speeds adoption of this novel technology.

Key challenges in pDNA manufacturing exist around purification unit operations due to its large size, high viscosity, shear sensitivity, and similarities between pDNA and impurities. During this presentation a generic manufacturing template that overcomes these challenges will be discussed based on a comprehensive case study encompassing all downstream unit operations (operations include cell harvest, lysis, clarification, tangential flow filtration, and chromatography).

With demand outstripping supply and the increased focus on access to medicine, the need to maximize production yield and throughput in biopharma remains a high priority. A challenge that spans ERP to the plant floor is having an accurate daily picture of inventory levels throughout all the interconnected production steps. Without this visibility, both scheduling and production personnel are less equipped to make effective decisions that fine-tune operations. This can negatively impact production yield and throughput. Efficient use of materials and energy are also affected, and product traceability becomes more challenging. In this presentation, learn about the latest advances in daily inventory accounting through a dynamic mass balance approach that reconciles all relevant flow, level, composition, density and related measurements to give an accurate picture of the work-in-progress inventory throughout the production process. This approach provides accurate plan vs actual information for scheduling and production, and improves yield, throughput and energy efficiency through more informed corrective adjustments to operating conditions.

Considerations in the design of ATMP Manufacturing Facilities will be outlined and discussed. Design challenges for both Allogenic and Autologous Cell Therapy and Gene Therapy manufacturing will be reviewed. Unique aspects of manufacturing supports such as material controls and sampling requirements will also be outlined including some case studies.

Following the presentations by Celeste Amadei with PAK BioSolutions and Monica Lomeli with Aspen Technology, you'll have the chance you ask your questions.