Jeffrey C. Baker view bio | back to agenda
Deputy Director of the Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA

Real Time Release in Biopharmaceutical Manufacturing

ICH Q8 describes Real Time Release Testing (RTRT) as the ability to evaluate and ensure the quality of process intermediates and/or final product based on process data, typically including a combination of measured material attributes and process controls. RTRT concepts have been in use in commercial biopharmaceutical manufacturing for many years, yet the biotech community continues to explore new and innovative ways to apply RTRT to rapid commercialization, platform development, and lifecycle process monitoring and improvement. This talk will explore the conceptual framework of RTRT as well as issues, and opportunities associated with the application of RTRT to the control of product and processing in biopharmaceutical manufacturing.

Richard D. Braatz view bio | back to the agenda
Edwin R. Gilliland Professor of Chemical Engineering, MIT

A First-Principles Model-based Approach to Real-time Release

Real-time release is the ability to evaluate and ensure the quality of a final drug product based on in-process data. This presentation will describe the use of mechanistic (aka Òfirst-principlesÓ) mathematical models and plant-wide process controls to ensure final product quality for pharmaceutical and biopharmaceutical processes. Specific applications of applying this strategy to the manufacturing of coated tablets and biopharmaceuticals will be described, in collaboration with other researchers at the Massachusetts Institute of Technology.

John Duguid view bio | back to the agenda
Principal Process/Analytical Scientist, Aastrom Biosciences

Rapid Microbiological Methods for Real Time Release of Autologous Cell Therapy Products

Rapid detection of contaminants is essential for autologous cell therapy products with short shelf lives. Integrating quality into the entire process through lot segregation, raw material qualification, environmental control, personnel training, and detailed procedures is critical because final test results for microbiological tests may not be available prior to product release or patient administration. Developing, validating, and implementing rapid microbiological methods can facilitate real-time release of these products, however. Application of a risk-based approach during development mitigates most issues prior to validation and facilitates successful implementation. Proactively removing these obstacles provides convincing evidence that the advantages of using rapid methods outweigh the limitations, garnering support from regulators for implementation as routine product release tests.

René Labatut view bio | back to the agenda
Vice President, Global Manufacturing Technology, sanofi pasteur

Real Time Release Perspective on Vaccines

Vaccines are appropriately considered as partially characterized products having the entire process being totally part of the product definition. It looks, in this condition, that real time release will be a long journey for us. That said, being long doesn’t mean impossible. Different approaches of product, analytic and process design combined with mathematical modeling could be looked at to open up the way to succeed. We have the duty to pursue this for product quality, availability (supply) and economic efficiency (i.e. affordability of the market and financial health of the company) to lead us in the direction of real time release. Let’s briefly have a look at this exciting challenge.

J. Christopher Love view bio | back to the agenda
Associate Professor of Chemical Engineering, MIT

Towards Making Biologics on Demand

The availability of biologic drugs for patients can be limited, if not impossible, in many regions of the world. Patients who could benefit from treatments may live in remote regions, under-resourced areas, or face challenging circumstances such as natural disasters that limit access to life-saving drugs. The current state-of-the-art approaches to manufacture biopharmaceuticals are not compatible with point-of-care, rapid manufacturing of treatments on demand. This talk will present a multi-institutional program aimed at producing biologics on demand called Integrated and Scalable Cyto-Technology (InSCyT).

This platform emphasizes an integrated, milliliter-scale table-top system for (semi)continuous operation, consisting of a parallel set of microbioreactors, filtration of cell debris from secreted product, innovative affinity-based purification, polishing, and finishing, as well as integrated on-line PAT and process control for QbD production and product qualification for release. Examples of the underlying technologies enabling this platform will be presented. Beyond the applications for rapid manufacturing of biologics, the technologies developed here should also address other areas of need in continuous manufacturing identified by large biopharmaceutical companies. This approach to manufacturing should supplement traditional processes to improve global access for this class of drugs, challenge paradigms for real-time release, and ultimately accelerate drug development.

Gunnar Malmquist view bio | back to the agenda
Staff Scientist, GE Healthcare Life Sciences

Towards Real Time Release through Improved Process Understanding

Any journey requires good navigational tools and a detailed map of the terrain. The journey towards Real Time Release Testing (RTRT) for biopharmaceuticals will require improvements both on the tool side (more informative sensors) and on the map side (process understanding). Robust, and potentially adaptive, process control strategies and multivariate data analysis will be key enablers for RTRT given the lack of selective sensors for Critical Quality Attributes suitable for online deployment. Examples of investigational sensors, raw material attribute tracking tools and bioprocess analytics systems will be given.

Peter McDonnell view bio | back to the agenda
Senior Technical Director, Sanofi

Progress toward Real Time Release for a Complex Non-biologics Large Molecule API Produced by Continuous Manufacturing

Genzyme (now Sanofi) in the UK has been producing a high volume API by continuous processing for over 12 years and has been subject to multiple regulatory inspections by FDA and MHRA. The product is a polymer which is largely defined by the process and is not easily characterized by end of line testing. As confidence in processing has increased there has been much less reliance on QC testing and much more on in-line PAT. Many of the lessons learned should be applicable for biologics manufacturing.

Rohin Mhatre view bio | back to the agenda
Vice President, Biopharmaceutical Development, Biogen Idec

Biogen Idec Strategy for Process Control and Parametric Release

The current state of biological process platforms and process understanding has enabled us to develop robust processes that yield consistent product quality. Investment in process technology has resulted in high output processes with a good understanding of levers that control product quality. This presentation will provide an overview of our next-generation processes with automated and adaptive controls that will enable us to predict and assure product quality. Biogen Idec’s plan to leverage process control levers for Parametric release of the product will be also be presented.

Michael O’Connor view bio | back to the agenda
Senior Scientist, Pfizer

Pfizer's Approach to Upstream Sampling and PAT as Future Enablers of Real Time Batch Release

Rapid evaluation and implementation of inline or online technologies are necessary to progress toward real-time release of product batches in the biologics area. These evaluations can be completed more efficiently and effectively when automated offline sampling is performed in conjunction with online or inline methods such as capacitance to measure viable cell density and cell state or RAMAN spectroscopy to monitor glucose, lactate, and amino acid concentrations. Multivariate analyses of these data can lead to more accurate modeling and monitoring for improved process understanding and attribute control. Several challenges have been encountered and overcome in the pursuit of this rapid evaluation framework. Our experience includes collaborations with Bend Research, Inc. for automated sampling, and ABERÕs capacitance probe as well as our recent implementation of RAMAN probes from Kaiser. SIMCA by Umetrics has been used for modeling and multivariate analyses. Together, these technologies have the potential to provide more highly characterized and less variable processes, ultimately enabling Pfizer to validate out many elements of the current release testing regime.

Kripa Ram view bio | back to the agenda
Vice President, Bioprocess and Manufacturing Sciences (R&D), MedImmune

The Use of Mathematical Modeling to Predict and Control pCO₂ Levels in Cell Culture Bioreactors

Successful scale-up of mammalian cell culture based processes to very large scales (greater than 10,000L) has been a challenge to engineers primarily due to the accumulation of CO₂ from cellular metabolism over the course of the culture, coupled with the deleterious effect of high levels of CO₂ (or the resulting reduced pH) on cell growth / protein expression. Conversely, the inability to simulate such pCO₂ profile in small scale bioreactors makes it difficult to predict large scale process performance through small scale experiments.  MedImmune’s effort to develop a mathematical model based on cellular growth/metabolism, bicarbonate buffering kinetics and bioreactor mass transfer characteristics that have allowed better prediction and hence improved control of pCO₂ levels in mammalian cell culture bioreactors will be discussed. 

Rajeev J. Ram view bio | back to the agenda
Professor of Electrical Engineering and Computer Science, MIT

Micro- and Nanotechnologies for Real Time Protein Characterization

The FDA defines Real Time Release Testing (RTRT) as the ability to evaluate and ensure the quality of in-process and/or final product based on process data. This typically includes a combination of measured material attributes and process controls. The traditional tools for characterization of therapeutic protein products include SDS-PAGE and Weak Cation Exchange Chromatography (WCX) to qualify protein ID, size exclusion chromatography (SEC) for identifying protein fragments, and High Performance Anion Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD) for glycoprofiling the protein. These protocols are too time consuming and labor intensive to be part of closed-loop controls for the manufacturing process.

As part of the DARPA Bio-MOD program, the Ram Lab, Strano Lab, and Han Lab at MIT and the Karande Lab at RPI have focused on the development of a suite of new technologies designed to assess critical quality attributes in real-time with minimal labor or materials consumption. The Ram Lab is focused on quantitative Raman characterization of proteins. The Strano Lab is developing Carbon Nanotube based fluorescence-sensors for glycoprofiling. The Han Lab is working on nanofluidic assays for size based separation of proteins. The Karande Lab is developing affinity peptides for use in both CNT and nanofluidic sensors. This suite of new analytics provides orthogonal measures of product quality attributes with the potential for full coverage of the conventional assays. Such an integrated suite of tools could facilitate near real-time product analysis that can guide production processes towards real-time release.

David Sullivan view bio | back to the agenda
Director, Bioprocess R&D Pilot Plants, Pfizer

Real Time Release Testing of Monoclonal Antibodies: Everyone wants it, so what’s taking so long?

Fundamentally, Real Time Release Testing (RTRT) enables the ability to release a batch with no post-manufacturing sampling or QC testing thanks to superior real time process monitoring and control capabilities. Pfizer has successfully implemented RTRT regimes for a number of small molecule products within the last decade; realizing meaningful quality, cycle time, and cost efficiency gains. Many other industry peers have done the same and multiple regulatory agencies have approved the RTRT paradigms for these marketed products. This begs the question - why hasn’t more progress been made for biologics?

Gaps in reliable in situ sensing/monitoring technologies, unit operation based processes heavily reliant on human intervention, slow uptake of multivariate models and/or orthogonal methods, and industry and regulatory culture have all played a role. The good news is that competitive forces, improved process insights, and novel/combination technology innovations are on the cusp of changing all of that.

Jette Wypych view bio | back to the agenda
Scientific Director, Amgen

Approaches and Technologies towards Enabling “Real Time Release Testing” for Biologics

Pharmaceuticals must comply with their approved specifications prior to their release into the market. Historically, compliance with release specifications has typically been established by performing a complete set of lot release tests of the drug substance and the finished drug product. Under certain conditions an alternative strategy to systematic end product testing is possible; this approach has been referred to as Real Time Release Testing (RTRT).

For biologics, we have at Amgen been working towards new strategies and future analytics that allow for better real time control of process and product with less reliance on a complete set of release tests on end product. Such an approach will permit testing on the manufacturing floor while at the same time reducing the footprint of the Quality Control laboratories; in essence, move the testing paradigm of biologics towards RTRT. With a case example, we will share some benefits of the analytics of the future, which provide for a more specific and direct product attribute control.