Computer-Aided Applications in Pharmaceutical Technology

Jelena Duris

• Publisher: Woodhead Publishing
• Year: 2013
• ISBN:
  9781908818324
• Topic: Informatica
• Subtopic: Bioinformatica

Research and development in the pharmaceutical industry is a time-consuming and expensive process, making it difficult for newly developed drugs to be formulated into commercially available products. Both formulation and process development can be optimized by means of statistically organized experiments, artificial intelligence and other computational methods. Simultaneous development and investigation of pharmaceutical products and processes enables application of quality by design concept that is being promoted by the regulatory authorities worldwide. Computer-Aided Applications in Pharmaceutical Technology covers the fundamentals of experimental design application and interpretation in pharmaceutical technology, chemometric methods with emphasis of their application in process control, neural computing (artificial neural networks, fuzzy logic and decision trees, evolutionary computing and genetic algorithms, self-organizing maps), computer-aided biopharmaceutical characterization as well as application of computational fluid dynamics in pharmaceutical technology. All of these techniques are essential tools for successful building of quality into pharmaceutical products and processes from the early stage of their development to selection of the optimal ones. In addition to theoretical aspects of various methods, the book provides numerous examples of their application in the field of pharmaceutical technology.

• A comprehensive review of the current state of the art on various computer aided applications in pharmaceutical technology
• Case studies are presented in order to facilitate understanding of various concepts in computer-aided applications

1

Quality-by-design in pharmaceutical development

Jelena Djuris, Svetlana Ibric and Zorica Djuric, Department of Pharmaceutical Technology and Cosmetology Faculty of Pharmacy University of Belgrade

Abstract:

This first chapter introduces the concept of quality-by-design (QbD) and its role in pharmaceutical product development. QbD assures the quality of a pharmaceutical product through scientific development and risk management tools, and will eventually enable real-time release, regardless of the formulation type. Several guidelines on pharmaceutical development, quality risk management, and pharmaceutical quality systems are presented that are applicable throughout the product lifecycle. Design space appointment and control strategies for risk management are introduced. The meaning of the QbD concept is presented from both regulatory and manufacturers’ points of view. Several illustrative examples are provided to facilitate the understanding of the QbD concept and ease of its application.

Key words

quality-by-design (QbD)

design space

risk management tools

control strategies

1.1 Introduction

The pharmaceutical industry is one of the most strictly regulated and its products are of excellent quality. However, there are issues suggesting that pharmaceutical development and manufacturing can be improved. These facts are especially noticeable in cases of batch failures and reworks, regulatory issues, implementation of new technologies, etc. The current state of the pharmaceutical industry, in terms of yield and defects (e.g. relation of quality and productivity), is not comparable to some of the more advanced industries (e.g. the semiconductor industry). Defects in pharmaceutical product quality can be encountered such as low manufacturing process yield or, more dangerously, some which may affect the therapeutic performance of the drug (or both). For some products, waste can be as high as 50%. Furthermore, the effects of scale-up on the final product are often not understood and reasons for manufacturing failures are not analyzed (Shah, 2009). The quality of a pharmaceutical product can be defined as an acceptably low risk of failing to achieve the desired clinical attributes of the drug (Shah, 2009). It is recognized that reasonable product quality in the pharmaceutical industry sometimes comes with the price of great effort and cost.

Quality-by-design (QbD) is a concept introduced by the International Conference on Harmonization (ICH) Q8 guideline, as a systematic approach to development, which begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. Predefined objectives make up the quality target product profile (QTPP), that is, the summary of the drug product quality characteristics that ideally should be achieved. According to the ICH Q8 guideline, QTPP is a prospective summary of the quality characteristics of a drug product to ensure the desired quality, taking into account safety and efficacy of that drug product. Through the scientifically based process of product development, critical process parameters (CPPs), and critical quality attributes (CQAs) of the product are identified. CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CPP is a process parameter whose variability has an impact on a CQA. The identification of a CQA from the QTPP is based on the severity of harm to the patient if the product falls outside the acceptable range for that attribute. QTPP is initially defined, based upon properties of the drug substance, characterization of the reference product (if it exists), and intended patient population. It is important to emphasize that QTPP does not necessarily need to include all of the product specification tests. A QTPP for immediate release tablets may include the following requirements: assay, content uniformity, and dissolution should be in accordance with the specifications to assure safety and efficacy during the shelf life; tablets should be robust in order to withstand transport and handling, and a suitable size to aid patient acceptability and compliance. According to the defined QTPP, CQAs may include assay, content uniformity, dissolution, and degradation products, whereas CPPs could be the compression force and speed used for tableting.

The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality is denoted as the design space. The emphasis of the ICH Q8 guideline is to shift pharmaceutical product development from the empirical, trial-and-error approach, to the scientifically based process of design space appointment. Definition of design space also requires implementation of various risk management tools, as well as definition of specifications and manufacturing controls. Figure 1.1 shows a diagram of a QbD approach, combining design space development and risk management tools.

Figure 1.1 QbD approach, combining design space development and risk management tools

Implementation of the QbD concept is important for all products, including generics and biotechnological products (Nasr, 2011). There are detailed reports on pharmaceutical QbD (Lionberger et al., 2008; Yu, 2008). The reader is advised to consult relevant textbooks on regulations and quality in the pharmaceutical industry (Gad, 2008), QbD concept in chemical engineering in the pharmaceutical industry (Am Ende, 2010), application of QbD in biopharmaceuticals (Rathore and Mhatre, 2009), QbD issues in process understanding for scale-up and manufacture of active ingredients (Houson, 2011), as well as upcoming reviews on QbD in pharmaceutical and biopharmaceutical development (Herwig and Menezes, 2013; Reklaitis, 2013). Furthermore, links between process analytical technology (PAT) and QbD are elaborated on (Bakeev, 2010), with special emphasis on biopharmaceuticals (Undey et al., 2012).

1.2 ICH Q8 guideline

The ICH Q8 guideline on scientifically based pharmaceutical development serves to provide opportunities for pharmaceutical manufacturers to seek regulatory flexibility and mitigation of some activities required for product registration and/or subsequent post approval change process. The ICH Q8 guideline describes good practices for pharmaceutical product development. Working within the defined design space is not recognized as the change that would require regulatory approval. This paradigm can be used to significantly improve productivity and quality assurance in the pharmaceutical industry. Even though the primary intention of the ICH Q8 document, and QbD itself, was to provide guidance on the contents of section 3.2.P.2 (Pharmaceutical Development) for drug products defined in the scope of Module 3 of the Common Technical Document (CTD), this concept is now broadened to the whole drug product lifecycle. It is often emphasized that the quality of a pharmaceutical product should be built in by design rather than by testing alone. Development of the manufacturing process should include its continuous verification, meaning that rather than one-time process validation, an alternative approach should be employed whereby the manufacturing process performance is continuously monitored and evaluated. The ICH Q8 guideline suggests that those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality, should be determined and control strategies justified. If an adequately organized development study is conducted, it is possible for the pharmaceutical manufacturer to gain reduction in both post-approval submissions and reviews/inspections by the regulatory authorities. Furthermore, real-time quality control is recommended, leading to a reduction of end-product release testing. Some of the tools that should be applied during the design space appointment include experimental designs, PAT, prior knowledge, quality risk management principles, etc. More details on quality risk management tools are provided in the ICH Q9 guideline. QbD and quality risk management tools are often linked to form a pharmaceutical quality system (ICH Q10 guideline).

PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. PAT brought the possibility to evaluate and ensure the acceptable quality of in-process and/or final product based on the measured process data, allowing real-time release of the products. The ICH Q8 annex provides examples of implementation of QbD concepts. Elements of pharmaceutical development (QTPP, CQAs, risk assessment tools) are defined in more detail. Pharmaceutical manufacturers are encouraged to describe the design space in their submission by using a variety of terms, for example, ranges of materials attributes and process parameters, complex mathematical relationships, time dependent functions, multivariate models, etc. Furthermore, independent design spaces can be defined for one or more unit operations or a single design space can be established that spans the entire manufacturing process. In order to en...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of figures
• List of tables
• List of abbreviations
• About the editor
• About the contributing authors
• Introduction
• Chapter 1: Quality-by-design in pharmaceutical development
• Chapter 2: Computer-aided formulation development
• Chapter 3: Experimental design application and interpretation in pharmaceutical technology
• Chapter 4: Chemometric methods application in pharmaceutical products and processes analysis and control
• Chapter 5: Neural computing in pharmaceutical products and process development
• Chapter 6: Computer-aided biopharmaceutical characterization: gastrointestinal absorption simulation
• Chapter 7: Computational fluid dynamics: applications in pharmaceutical technology
• Appendix
• Index