The gene therapy revolution is gaining momentum, and consequently, the demand for clinical-grade viruses is following the same path. Continuous manufacturing offers a paradigm shift and new opportunities for improving manufacturing efficiency. The present talk will highlight some of the challenges  and lessons learned during the development of a continuous purification process for gene therapy products, such as AAVs.

This talk will focus on selection of a suitable resin for the integrated continuous capture step and design of an automated, dynamic control strategy for load volume.

Viral production using conventional technologies presents several limitations including high costs of manufacturing, capacity constraints as well as process complexity. These challenges are today responsible on one hand for worldwide vaccine supply shortage and on the other hand for holding back the deployment of affordable gene therapy products for previously unmet indications. Technology innovation can become a strong solution in breaking down those barriers. In this presentation we will discuss how it can successfully improve both vaccine and gene therapy development and manufacturing with two specific examples representative of those sectors.  

ICH Q13 will be a new ICH guidance document that will be titled “Continuous Manufacturing of Drug Substances and Drug Products." An informal Working Group was formed with members from the industry and regulators and this team met in November 2017 to finalize the Concept Paper and a Business Plan to support the development of this guidance document. ICH Management Committee approved the concept paper and the Business Plan resulting in forming the Expert Working Group to develop the guidance document. This presentation will share with the participants the status of the development of the guideline, its impact on continuous manufacturing in the biopharmaceutical industry and some of the key highlights of the document and the ICH process.

Buffers & media are one of the largest constituents by volume used in the production of most modern biopharmaceutical products. This presentation will give an overview of innovative new technologies like single use powder packaging and in-line dilution which can help reduce facility footprint, labor hours and overall cost-of-goods.  

This presentation will illustrate a model-based approach to combine the chromatographic and process models for evaluating and optimizing the operation conditions for multicolumn continuous chromatography, such as CapureSMB, AKTA pcc and BioSMB. A software platform and some artificial intelligence methods will also be introduced to accelerate the data treatment. The results indicate that model-based approaches are useful for process development and rational control for continuous process.

Understanding of propagation of process disturbances of an integrated process will be requested by the regulatory agencies (draft guideline of FDA on continuous biomanufacturing). RTD of the process is the basis to estimate critical process properties, such as the duration of the startup and shutdown phases, the propagation of possible disturbances, and the propagation of fluctuations throughout the process. Approaches how to establish an RTD model for a continuous antibody process will be shown. 

Current trends in the biopharmaceutical industry indicate a move towards continuous production which leads to a constant demand of reconstituted process materials, but there is no continuous reconstitution from solids available, and buffers and media are typically reconstituted batch-wise. This leads either to large vessels if buffers are constituted on a low frequency, or high personal costs if the reconstitution is done regularly. We therefore developed a proof-of-concept for a continuous reconstitution of media and buffers from solids in lab-scale to be directly connected to any upstream or downstream unit operation with continuous demand.

This presentation describes the design and assembly of an end-to-end continuous monoclonal antibody manufacturing testbed at MIT. The testbed is fully automated and includes extensive inline and at-line process analytical technology, including Raman spectroscopy, high-performance liquid chromatography (HPLC), and liquid chromatography-mass spectrometry (LC-MS). The presentation describes use of the testbed for the evaluation of data analytics and machine learning methods, the validation of mechanistic models, and real-time feedback control of CQAs.

Higher formulation concentrations and continuous manufacturing of biopharmaceuticals have created significant challenges for the UFDF process. Tight process control, made possible by process analytical technology (PAT), is essential to monitor and achieve desired excipients concentrations and solution viscosity. We employ FTIR and variable pathlength OD measurement for in-line real-time monitoring of protein and excipients concentrations. The PAT data aligns well with offline analytics, demonstrating that PAT has potential for real-time process control.

Raman spectroscopy has moved into the mainstream as a Process Analytical Technology (PAT) application in Upstream biologics development. As models have evolved for glucose, lactate and other analytes, so too has the opportunity to utilize Raman in a real-time feedback control loop. This added layer of complexity presents new challenges as well as the ability to tailor feed schedules on time scales that were not possible with daily feed events.