Design Of Pharmaceutical Manufacturing Process Research Articles

Robust optimization of a pharmaceutical freeze-drying process under non-Gaussian parameter uncertainties

Model-based design of pharmaceutical manufacturing processes has received much interest in academia and industry. Model parameter uncertainties, however, might deteriorate the predicted process performance. Probability-based robust process design concepts as a countermeasure against uncertainties might be implemented. Here, parameter uncertainties are typically limited to Gaussian parameter distributions. However, parameter uncertainties derived with experimental data can be correlated and arbitrarily distributed. In our previous work, transformation techniques were combined with the point estimate method (PEM) to address non-Gaussian and correlated parameter distributions, but at the cost of additional nonlinearities and approximation errors. In this work, we take advantage of Gaussian mixture distributions (GMD) and decompose the parameter distribution into a finite set of Gaussian distributions using the Expectation-Maximization approach. Combining the GMD with the PEM ensures a proper and effective uncertainty quantification. The improved PEM algorithm is applied to a freeze-drying process (lyophilization) aiming for high-quality products with minimum processing time. Results obtained suggest that the novel GMD-PEM algorithm has the potential to outperform conventional robustification concepts regarding credibility and efficiency.

Introduction to the application of QbD principles for the development of monoclonal antibodies

Quality by Design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody.This chapter introduces a publication series on the application of Quality by Design for biopharmaceuticals, with a focus on the development of recombinant monoclonal antibodies. The development of and overview on the QbD concept applied by Roche and Genentech is described and essential QbD elements are presented.

Integration of QbD risk assessment tools and overall risk management

Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody. This chapter describes how the risk assessments, logic and interactions of the tools are designed to connect the set of QbD tools and elements into an overarching risk management system. The tools allow comparisons of options based on elective decisions that the sponsor could take and reflect relative values of these options. The overall risk management strategy assures product quality from this enhanced set of assessments and employs a science and risk based approach resulting in a consistent and transparent set of process and product controls and a rational monitoring system.

Process characterization and Design Space definition

Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody (MAb).This chapter describes the tools used for the characterization and validation of MAb manufacturing process under the QbD paradigm. This comprises risk assessments for the identification of potential Critical Process Parameters (pCPPs), statistically designed experimental studies as well as studies assessing the linkage of the unit operations. Outcome of the studies is the classification of process parameters according to their criticality and the definition of appropriate acceptable ranges of operation. The process and product knowledge gained in these studies can lead to the approval of a Design Space. Additionally, the information gained in these studies are used to define the ‘impact’ which the manufacturing process can have on the variability of the CQAs, which is used to define the testing and monitoring strategy.

Determination of critical quality attributes for monoclonal antibodies using quality by design principles

Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody. This chapter describes the identification of critical quality attributes (CQAs) as an important first step for QbD development of biopharmaceuticals. A systematic scientific based risk ranking and filtering approach allows a thorough understanding of quality attributes and an assignment of criticality for their impact on drug safety and efficacy. To illustrate the application of the approach and tools, a few examples from monoclonal antibodies are shown. The identification of CQAs is a continuous process and will further drive the structure and function characterization of therapeutic proteins.

QbD implementation and Post Approval Lifecycle Management (PALM)

Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11) [1–3]. An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody. This chapter describes concepts for implementing the control strategy for a monoclonal antibody including a Design Space for routine commercial manufacturing, and the Post Approval Lifecycle Management (PALM) plan that is used to manage any remaining risks during the commercial lifecycle. The PALM plan is part of the submitted dossier in the regional section and serves as a regulatory agreement between the manufacturer and the health authority specifying how process and product attributes are monitored to ensure both remain within a controlled state post-approval, process parameter changes are managed within the design space, and the control system is updated as necessary based on further process and product knowledge.

Establishing a control system using QbD principles

Quality by design (QbD) is a global regulatory initiative with the goal of enhancing pharmaceutical development through the proactive design of pharmaceutical manufacturing process and controls to consistently deliver the intended performance of the product. The principles of pharmaceutical development relevant to QbD are described in the ICH guidance documents (ICHQ8-11). An integrated set of risk assessments and their related elements developed at Roche/Genentech were designed to provide an overview of product and process knowledge for the production of a recombinant monoclonal antibody. This chapter describes the elements and tools used to establish acceptance criteria and an attribute testing strategy (ATS) for product variants and process related impurities. The acceptable ranges for CQAs are set based on their potential impact on efficacy and safety/immunogenicity. This approach is focused on the management of patient impacts, rather than simply maintaining a consistent analytical profile. The ATS tools were designed to identify quality attributes that required process and/or testing controls, or that could be captured in a monitoring system to enable lifecycle management of the control strategy.

Combined simulation–optimization methodology to reduce the environmental impact of pharmaceutical processes: application to the production of Penicillin V

Abstract In this work, we present a systematic method for the optimal design of pharmaceutical manufacturing processes that allows decision-makers to assess economic and environmental concerns in the early stages of the process development. Our approach relies on the combined use of process simulation, multi-objective optimization, economic analysis and life cycle assessment. The pharmaceutical production plant design is mathematically formulated as a multi-objective mixed-integer dynamic optimization (moMIDO) problem, which is solved by a decomposition algorithm that generates as output a set of Pareto optimal solutions. The capabilities of the proposed methodology are illustrated through the production of the antibiotic Penicillin V.