Process Systems Engineering for Pharmaceutical Manufacturing

Ravendra Singh, Zhihong Yuan

• Publisher: Elsevier
• Year: 2018
• Print ISBN: 9780444639639
• eBook ISBN: 9780444639660
• Topic: Technik & Maschinenbau
• Subtopic: Chemie- & Biochemietechnik

Process Systems Engineering for Pharmaceutical Manufacturing: From Product Design to Enterprise-Wide Decisions, Volume 41, covers the following process systems engineering methods and tools for the modernization of the pharmaceutical industry: computer-aided pharmaceutical product design and pharmaceutical production processes design/synthesis; modeling and simulation of the pharmaceutical processing unit operation, integrated flowsheets and applications for design, analysis, risk assessment, sensitivity analysis, optimization, design space identification and control system design; optimal operation, control and monitoring of pharmaceutical production processes; enterprise-wide optimization and supply chain management for pharmaceutical manufacturing processes.Currently, pharmaceutical companies are going through a paradigm shift, from traditional manufacturing mode to modernized mode, built on cutting edge technology and computer-aided methods and tools. Such shifts can benefit tremendously from the application of methods and tools of process systems engineering.- Introduces Process System Engineering (PSE) methods and tools for discovering, developing and deploying greener, safer, cost-effective and efficient pharmaceutical production processes- Includes a wide spectrum of case studies where different PSE tools and methods are used to improve various pharmaceutical production processes with distinct final products- Examines the future benefits and challenges for applying PSE methods and tools to pharmaceutical manufacturing

Chapter 1

New Product Development and Supply Chains in the Pharmaceutical Industry

Catherine Azzaro-Pantel Laboratoire de Génie Chimique, Université de Toulouse, CNRS, Toulouse, France

Abstract

The concept of chemical supply chain has received increased attention in the process systems engineering community in the last decade. This chapter discusses the methods, tools, and applications, which are relevant to the pharmaceutical industry. Among the various supply chains that have been studied, pharmaceutical supply chains turn out to be very complex, due to several factors such as long development timelines, high attrition rates in drug development, resource-intensive operations, involvement of multiple stakeholders, among others. A fundamental challenge in managing a pharmaceutical company is identifying the optimal allocation of finite resources across the infinite constellation of available investment opportunities. Specific attention is given here to the modeling and optimization of three key phases in the life cycle of an innovative drug product, namely, product development pipeline management, capacity planning, and supply chain management. The state of the art in these domains is reviewed, some challenges are identified, and opportunities for further research effort are highlighted.

Keywords

Modeling; Optimization; Supply chain; New product development; Capacity production

1 Introduction

The dynamics of innovation of a company can be assessed through the life cycle of its products. Classically, the life cycle of a product includes the phases of development, launch, growth, maturity, and ends with a stage of decline. The typical features of these stages depend on the scope of application in which the company is competing. Whatever the domain, the steps are carried out by a number of functional groups within the company, including R&D, manufacturing and distribution networks, in compliance with environmental, safety, and environmental standards as well as the quality of products developed. In that context, a supply chain has a pivotal role including all the organizational, operational, and value-adding activities needed to manufacture products from development to the marketplace and get them to the customer. So, a pharmaceutical supply chain covers every activity from new product development (NPD) through to delivery to the hospital, retail pharmacy, or patient.

The choices of these entities are guided, among others, by strategic decisions involving the allocation of capital expenditures, economic profitability, marketing strategies, product and technology portfolio management, supply chain design decisions, including the manufacturing and structure of the distribution network as well as the selection of strategic partners. The complexity of this environment stems from the multiple stakeholders and strategic decisions must involve multiple functional units and integrate the tactical and operational levels of the entire product portfolio. In the pharmaceutical context, the problem is made difficult by the presence of several key stakeholders, such as drug manufacturers, wholesale distributors, retail pharmacies, hospitals, managed care organizations, and insurance companies.

The decisions must be taken in an environment in which both external and internal uncertainties are encountered: external pressures and uncertainties include, for example, product demand, price setting, entry of some competitors into the market, suppliers and buyers, overall economic dynamics, whereas internal uncertainties result in particular from unexpected technical problems, production deviation due to the variation in the quality of raw materials, the risks of failure of R&D activities, etc.

This chapter presents the main characteristics of the life cycle of a drug and the decision-making problems faced by a pharmaceutical company. It discusses some relevant solution methods of new product portfolio management and pharmaceutical supply chain design and operation. It identifies the challenges that must be addressed for the integration of the different levels.

2 Typical Features of Pharmaceutical Industry

2.1 Analysis of the Product Development Process

Within the scope of research and development pipeline management problem, several NPD projects compete for a limited pool of various resource types. The discovery and the development of new medicine indeed involve a very long, complex, and expensive process (Lebret et al., 2010). An average duration of 12 years is required for the development of a new drug (Torjesen, 2015). The research and development of molecules in the pharmaceutical industry has thus a central place. The research and development journey of a new drug that make it to market costs around US$2.6 Billion according to a study carried out by the Tufts Center for the Study of Drug Development (Mullard, 2014). These costs particularly increased these last years with the explosion of the costs of clinical trials (60% increase between 2000 and 2005). Every stage of the process requires a series of tasks before product commercialization. The interconnection of these stages leads to a supply chain by which a company transfers its products from development to market with the objective to generate a profit. It includes all the activities of organization, operation, and added value steps that are necessary for product manufacturing and supply to the customer. For a pharmaceutical company, these activities can include the development of the product until the delivery to the hospital, the pharmacy, or to the patient. If a task leads to a failure, the development of the product is stopped, which can entail consequent financial losses. A generic sequence of the various tasks is proposed in Fig. 1.

Fig. 1 Drug development process.

2.2 Life Cycle of a Drug

From an even more macroscopic point of view, three major stages are involved in the life cycle of a medicine, i.e., discovery, development, and marketing.

First of all, the therapeutic targets related to a pathology must be identified. Among the families of targets, there are membrane receptors (with two big families, G protein-coupled receptors (GPCRs) and ionotropic receptors), nuclear receptors, enzymes, pumps, and the ionic channels. There are at present 330 targets among which 270 are coded by the genome and 60 stemming from pathogenic bodies for 6500 potential targets: 3500 enzymes (among which 4% are investigated), 1000 channels (2.5% investigated), and 2000 GPCRs (10% investigated). The exploration of the human genome allowed to increase enormously the potential of new targets these last years, which will contribute to more specific treatments. Once the target is validated, it is necessary to elucidate its biological function. The defined target is then submitted to the action of various substances to isolate the most promising component, according to a “screening” stage. The selected molecule can result from a database, a biomedical research, or from a modification of the structure of a preexistent active ingredient. Then, the chemical and biological assay run follows to demonstrate the selectivity, the safety, and the efficiency of the studied molecule.

The tests are practiced at first in vitro, then studies to the animal (pharmacological, pharmacokinetic, pharmacodynamical, toxicological) are led to investigate the behavior and confirm the harmlessness of the candidate drug.

If all the obtained results are positive, the clinical tests can thus be conducted on healthy volunteers then on first patients. This phase of development involves very important material resources.

• Phase I. In this stage, first clinical trials are carried out and drugs are administered to healthy volunteers. At the same time, acute/chronic and reproductive studies are also conducted in animals (mice/rats). Positive results will allow to the drug to go on the process, whereas an unacceptable behavior in human and animal studies can terminate the study.
• Phase II. The Drug is administered to unhealthy human patients with the disease by using the results of dosing studies from Phase I. Coincident with these studies are long-term oncogenic toxicological studies in animals and market research to obtain sales estimates. If the compound fails to treat the disease or is inferior to competitive products, it is destaged or returned to the discovery phase for modification.
• Phase III. Large-scale clinical studies are carried out on unhealthy human patients. The FDA (Food and Drug Administration) is involved and indicates benchmarks for giving their approval. In addition to confirming the efficiency, these studies identify drug-drug interactions, human demographics, etc. This most ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Chapter 1: New Product Development and Supply Chains in the Pharmaceutical Industry
• Chapter 2: The development of a pharmaceutical oral solid dosage forms
• Chapter 3: Innovative process development and production concepts for small-molecule API manufacturing
• Chapter 4: Plantwide technoeconomic analysis and separation solvent selection for continuous pharmaceutical manufacturing: Ibuprofen, artemisinin, and diphenhydramine
• Chapter 5: Flowsheet modeling of a continuous direct compression process
• Chapter 6: Applications of a plant-wide dynamic model of an integrated continuous pharmaceutical plant: Design of the recycle in the case of multiple impurities
• Chapter 7: Advanced multiphase hybrid model development of fluidized bed wet granulation processes
• Chapter 8: Global sensitivity, feasibility, and flexibility analysis of continuous pharmaceutical manufacturing processes
• Chapter 9: Crystallization process monitoring and control using process analytical technology
• Chapter 10: BioProcess performance monitoring using multiway interval partial least squares
• Chapter 11: Process dynamics and control of API manufacturing and purification processes
• Chapter 12: PAT for pharmaceutical manufacturing process involving solid dosages forms
• Chapter 13: Model-based control system design and evaluation for continuous tablet manufacturing processes (via direct compaction, via roller compaction, via wet granulation)
• Chapter 14: Fast stochastic model predictive control of end-to-end continuous pharmaceutical manufacturing
• Chapter 15: Advanced control for the continuous dropwise additive manufacturing of pharmaceutical products
• Chapter 16: Control system implementation and plant-wide control of continuous pharmaceutical manufacturing pilot plant (end-to-end manufacturing process)
• Chapter 17: Automation of continuous pharmaceutical manufacturing process
• Chapter 18: Implementation of control system into continuous pharmaceutical manufacturing pilot plant (powder to tablet)
• Chapter 19: Monitoring and control of a continuous tumble mixer
• Chapter 20: Flexible continuous manufacturing—based on S88 batch standards and object-oriented design
• Chapter 21: Planning pharmaceutical clinical trials under outcome uncertainty
• Chapter 22: Integrated production planning and inventory management in a multinational pharmaceutical supply chain
• Chapter 23: Optimal production of biopharmaceutical manufacturing
• Chapter 24: Perspective on PSE in pharmaceutical process development and innovation
• Index