Paul Sharratt

Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Workup, and Isolation of Drug Substance. May 20–21, 2014 Continuous Manufacturing Symposium

This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are.This whitepaper highlights current challenges and opportunities associated with continuous synthesis, workup, and crystallization of active pharmaceutical ingredients (drug substances). We describe the technologies and requirements at each stage and emphasize the different considerations for developing continuous processes compared with batch. In addition to the specific sequence of operations required to deliver the necessary chemical and physical transformations for continuous drug substance manufacture, consideration is also given to how adoption of continuous technologies may impact different manufacturing stages in development from discovery, process development, through scale-up and into full scale production. The impact of continuous manufacture on drug substance quality and the associated challenges for control and for process safety are also emphasized. In addition to the technology and operational considerations necessary for the adoption of continuous manufacturing (CM), this whitepaper also addresses the cultural, as well as skills and training, challenges that will need to be met by support from organizations in order to accommodate the new work flows. Specific action items for industry leaders are: Develop flow chemistry toolboxes, exploiting the advantages of flow processing and including highly selective chemistries that allow use of simple and effective continuous workup technologies. Availability of modular or plug and play type equipment especially for workup to assist in straightforward deployment in the laboratory. As with learning from other industries, standardization is highly desirable and will require cooperation across industry and academia to develop and implement. Implement and exploit process analytical technologies (PAT) for real-time dynamic control of continuous processes. Develop modeling and simulation techniques to support continuous process development and control. Progress is required in multiphase systems such as crystallization. Involve all parts of the organization from discovery, research and development, and manufacturing in the implementation of CM. Engage with academia to develop the training provision to support the skills base for CM, particularly in flow chemistry, physical chemistry, and chemical engineering skills at the chemistry-process interface. Promote and encourage publication and dissemination of examples of CM across the sector to demonstrate capability, engage with regulatory comment, and establish benchmarks for performance and highlight challenges. Develop the economic case for CM of drug substance. This will involve various stakeholders at project and business level, however establishing the critical economic drivers is critical to driving the transformation in manufacturing.

Trends in process analytical technology

Since the promotion of Process Analytical Technology (PAT) by the U.S. Food and Drug Administration (FDA), there has been a flurry of activities happening across related fields. This excitement permeates regulatory agencies, professional societies, academia and industry worldwide. This review surveys the PAT related developments that have taken place in the period 2004–2009. It serves as an introduction to PAT, with highlights on the parallel advances and convergence points across various fields and applications. From this review, five common threads are identified from the underlying trends of the recent global PAT endeavor, namely, organisational objectives, enabling sciences, economic outlook, collaborative efforts and emerging trends. There are also six potential gaps that require further efforts to bridge. The overall PAT venture is promising for delivering an integrated systems approach for quality design, process analyses, understanding and control, continuous improvement, knowledge and risk-based management within the FDA 21st century pharmaceuticalcGMP initiative.

Carbon dioxide mineralization process design and evaluation: concepts, case studies, and considerations.

Numerous carbon dioxide mineralization (CM) processes have been proposed to overcome the slow rate of natural weathering of silicate minerals. Ten of these proposals are mentioned in this article. The proposals are described in terms of the four major areas relating to CM process design: pre-treatment, purification, carbonation, and reagent recycling operations. Any known specifics based on probable or representative operating and reaction conditions are listed, and basic analysis of the strengths and shortcomings associated with the individual process designs are given in this article. The processes typically employ physical or chemical pseudo-catalytic methods to enhance the rate of carbon dioxide mineralization; however, both methods have its own associated advantages and problems. To examine the feasibility of a CM process, three key aspects should be included in the evaluation criteria: energy use, operational considerations as well as product value and economics. Recommendations regarding the optimal level of emphasis and implementation of measures to control these aspects are given, and these will depend very much on the desired process objectives. Ultimately, a mix-and-match approach to process design might be required to provide viable and economic proposals for CM processes.

Systematic Framework for Design of Environmentally Sustainable Pharmaceutical Supply Chain Network

PurposeThe current push towards sustainability has pressurized pharmaceutical companies to reduce greenhouse gas (GHG) emissions in their manufacturing supply chains (SCs). However, the heavily regulated nature of the pharmaceutical industry has necessitated decisions such as sourcing of raw materials including names and addresses of suppliers and siting of plants to be locked early during the registration of a new drug. This could result in SC inefficiencies during the drug commercial life leading to higher than necessary GHG emissions. This paper presents a systematic framework for design of a more sustainable pharmaceutical SC network at the commercial stage that can be performed during the early stages of drug development.MethodsThe framework comprises the following steps. First, basic SC information including process chemistries, outsourcing strategies, and potential supplier and manufacturer sites is consolidated. Next, an analytic hierarchy process (AHP) is performed to identify the most suitable supplier and manufacturer sites followed by mapping the entire SC network by connecting all the sites that have been identified as high priority. Subsequently, a set of indicator metrics—namely, cost, lead time, and GHG emissions—is calculated to evaluate the economic and environmental performances of the network.ResultsThe framework has been applied to an industrially motivated case study. Two network alternatives were proposed and analyzed based on their metrics together with synergies and trade-offs highlighted.ConclusionsThe findings demonstrate the efficacy of the framework in generating different network alternatives and identifying the most sustainable one on the basis of economic and environmental benefits. As such, the framework is applicable to the early stages of drug development where information is very limited.

Integrated Platform at ICES Kilo-Lab for Process Quality by Design

Abstract The paradigm shift that is attempting to change the way pharmaceutical manufacturing is undertaken in the 21 st century has raised practical challenges for the adoption and implementation of the Process Analytical Technology (PAT) framework initiated by the U.S. Food and Drug Administration (FDA). The motive is to engender a science-oriented pharmaceutical manufacturing that is along FDAs pharmaceutical product quality by design (QbD) ideology. One such challenge revolves around the integration of PAT technologies such as varied process analytics (e.g. sensors, spectrometry, chromatography, etc.), multivariate analyses, knowledge management, and process control under a common information exchange and data-logging platform. Such an integrated platform was recently installed and commissioned at the Kilo-Lab in the Institute of Chemical and Engineering Sciences (ICES). Its efficacy was demonstrated through synthesizing 4-D-erythronolactone at kilo-scale using a four-phase hybrid process.