Application of Quality by Design for the Development of Biopharmaceuticals

CHAPTER 18

Application of Quality by Design for the Development of Biopharmaceuticals Amit Kumar Nayak*,¶, Syed Anees Ahmed†,¶, Sarwar Beg‡, Mohammad Tabish§,¶, Md Saquib Hasnain¶ *

Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, India Department of Pharmacology, Hygia Institute of Pharmaceutical Application and Research, Lucknow, India ‡ Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Hamdard University), New Delhi, India § Department of Pharmacology, College of Medicine, Shaqra University, Shaqra, Kingdom of Saudi Arabia ¶ Department of Pharmacy, Shri Venkateshwara University, Gajraula, India †

Abbreviations ANDA BLA CPP CQA CMA CPP DoE FDA FMEA ICH NDA PAT QbD QbR QTPP QTPP

abbreviated new drug applications biological permit applications critical process parameters critical quality attributes critical material attributes critical quality parameter design of experiments food and drug administration failure mode effect analysis international conference on harmonization new drug applications process analytical technology quality by design question base review quality target product profile quality target product profile

1 INTRODUCTION In pharmaceutical companies, the quality of products plays an important role, nowadays. From the time when all the people have gathered globally to synchronize, to guide, and to practice the Food and Drug Administration (FDA) recommended the good manufacturing practices—cGMP. In the 21st century, awareness of the pharmaceutical products is growing significantly with respect to the product quality.1 All the regulatory bodies have Pharmaceutical Quality by Design https://doi.org/10.1016/B978-0-12-815799-2.00019-8

© 2019 Elsevier Inc. All rights reserved.

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kept the product quality as their top priority. The meaning of quality for a customer is fulfillment with regard to the product. The process and various quality linked activities show the requirement for an organization to surpass the expectations globally. Consumer desires excellence in reliability, quality, and affordable price. The user loyalty can be accomplished in two different manners, features and deficiency-free goods. Properties like performance, reliability, strength, convenience, and workableness need to be employed in manufacturing the goods and such goods ought to be deficiency-free products. Quality, profitability, price, and time are the terms, which are interrelated to each other. The pharmaceutical companies are continuously catering to the tricky demands of the patients. The uninterrupted demand to decrease price is adding to the case to enhance the work frame for the development of drug molecules and advancement of improvement in the process.2,3 In order to minimize the regulatory barriers to novelty, creativity, and the developmental cost, the International Conference on Harmonization (ICH) and FDA have already started promoting “Quality by design” (QbD) in the pharmaceutical companies.4, 5 Quality regulations are required to identify the quality issues adequately, without any compromise in the quality, schedule, or cost. Importance must be given not only to the quality issues, but also to the safety measures. Quality can be the main impetus to engage results in different parameters. Thus, the quality must be ensured in the manufactured products and in services by appropriate planning in order to minimize/avoid failure of the product. The investigation of the product development, to be finalized until the quality of product is planned. The idea of QbD was briefed by an outstanding expert in quality— J. M. Juran; “He believed that quality could be planned and that most quality associated problems have their origin in the way which quality was planned in the first place.” The ideologies of QbD have been utilized for the product advancement and the quality process in all the industries. As a result of the need of potent drug molecule having safe profile parameters, pharmaceutical companies are investing billions in discovery of new drug molecule and attempt to design the quality product with consistency in the manufacturing procedure to give the expected product performance. The data knowledge and information obtained from the pharmaceuticals and manufacturing industries give a base to the systematic conception to establish manufacturing control, space design, and its specifications. Data from the pharmaceutical advancement studies can be a root for the risk of quality management. In the formulation and manufacturing processes, the life cycle management allows the changes during its development process and provide further opportunity to increase awareness. This also provides support for the design

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space establishment. The design space planned and submitted by the applicant goes through an assessment and approval by the regulatory bodies.

2 BACKGROUND HISTORY The FDA got 5000 supplements in 2007, which was really a striking factor in bringing up the quantity of manufacturing supplements to applications of abbreviated new drug applications (ANDAs), biological permit applications (BLAs), and new drug applications (NDAs). The FDA has documented an increased lapse of ANDA or NDA entries by the organizations; generally a number of supplemental applications for each manufacturing change were received. In both the submitted original applications and supplements, the information was mainly concerned with the chemistry and least importance was given to the development of product. In 2005, the United States Food and Drug association (USFDA) requested the firms to use the QbD design format. Question base review (QbR) makes the arena of QbD guideline.6 Later in the meeting with Nick in 2011 along with Lawrence Yu Deputy Director, Science and Chemistry, FDA demonstrated and cautioned that 2013 is the due date for generics to execute QbD. The idea of QbD is “The quality cannot be tested into the manufactured product; however, it ought to be built-in within the product.” The design space is characterized as manufacturing zone of the product including equipment, material, and operators and manufacturing conditions. The design space ought to be very much characterized prior to the regulatory approval. Working with design space is not considered as a change, yet working out of designed space is considered as a change. Characteristic factors are observed for their impact on the product quality, when the manufacturing is done out of designed space.7,8 Each of these factors are evaluated and concluded so that it fulfills the requisite tool for QbD. Each of these data and information are incorporated into the regulatory dossier. The formulation of pharmaceutical products is developed, which is based on the information obtained from the product development studies (Fig. 1).

3 QbD ELEMENTS In the process of formulation designing and development, QbD plays an important role, ensuring the prerequisite specifications of the product.2,9 Some advantages of QbD are presented in Fig. 2. As per ICH guidelines Q8, Q9, and Q10, the QbD elements are quality target product profile (QTPP), process analytical technology (PAT), critical process parameters

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Fig. 1 Steps involved in QbD product development.

Good business Better development decisions

Technical staff empowerment

Minimize deviations

Advantages of QBD

Avoid regulatory compliance problems

Good science Organizational learning

Fig. 2 Advantages of QbD.

Minimize costly investigations

QbD for the development of biopharmaceuticals

Table 1 Different QbD elements Sl. no. QbD elements

1 2

Critical process parameters (CPP) Quality target product profile (QTPP)

3

Design of experiments (DoE)

4

Critical quality attributes (CQAs)

5

Design space

6

Process analytical technology (PAT)

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Importance

In designing and understanding of the process and affects upgrade process It forms the basis of QbD; helps to attain performance needed to obtain clinical advantage; important for discovery drug development process It enables creation of design space and used in optimization studies; to study the effects of interaction of several factors at a time It affects the quality of product and scale-up process; influenced by properties of input materials It provides quality assurance, improved process and product perceptive to support sciencebased approach Adopted in scheduled manufacturing to monitor process, reduce release testing control and control product quality

(CPP), QTPP, design of experiments (DoE), risk assessment, control strategy, and design space (Table 1). The data and information gained from the pharmaceutical development studies and the manufacturing acquaintance give scientific approach in establishing specifications and manufacturing controls.10–12

4 STEPS FOR PHARMACEUTICAL QbD IMPLEMENTATION For the development of new pharmaceutical product the following procedure is followed by applying the implementation of QbD practically13-15: 1. The product’s desired performance is defined by indentifying the QTTPs 2. CQAs identification 3. Recognition of probable CPPs and CMAs 4. Association of DoE with CMAs and CPPs to CQAs in order to obtain adequate data and how these variables affect QTPP. Then, define the design space, leading to an end product with preferred QTPP

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5. Spot out the variability sources and its control from raw materials and the manufacturing process 6. Persistently monitoring manufacturing process and improving to assure reliable product quality

5 TOOLS OF QbD The idea of QbD has two parts—the manufacturing science and the space design science. The most commonly used tools in QbD are risk assessment, DoE and PAT.12

5.1 Risk Assessment There is a possibility of innate component of risk in all the products as well as processes.16 An efficient quality risk management (QRM) is intended to be imposed in an organization, and a reasonable “risk” definition must be given due to excessive number of collaborators in the pharmaceutical companies and their relating varied interests.8 For risk identification, the risk management plan is used.16 QRM is defined as a technique by which the evaluation, communication, control, and risk assessment of the drug quality can be done via the manufactured goods life cycle to achieve decisions at any point in the process.8 The relation between the critical quality attributes (CQAs) and the input process variables form the risk assessment. There are different risk assessment tools such as fishbone diagram or Ishikawa diagram, Pareto analysis, and failure mode effect analysis (FMEA). For the purpose of identification of each and every potential variable the fishbone diagrams are used. The potential variables are instrumental factors, raw materials, and environmental factors, which have an impact on CQAs. In order to rank the variables on the basis of risk, the FMEA are used. FMEA are also used to choose the process parameters having higher risk to study the effects on CQA in order to gain a greater understanding.10 The purpose of the method development using the chromatography is compound separation and its identification. The robust and rugged methods are given emphasis in the QbD approach in the course of risk assessment. ICH guidelines Q8 and Q9 are the basis for risk-based approach. The minute alterations in the process parameters are included in risk assessment. These are laboratories, instruments, reagents, analyst, temperature, days and humidity. The tools available for analyzing the data are method system analysis (MSA) and

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DoE. The frequently used methods for the risk assessment management are check sheets, process mapping, and Flow charts.17

5.2 Design of Experiments (DoE) In the DoE approach, the process variables are primarily screened in order to establish a significant result like type of excipients and disintegration time. The other one is optimization, which is important for the determination of variables. The design mixtures are being used in altering the composition mixtures and involve determination of changes, which are affecting the mixture properties.18–21 The DoE is a competent process for the experiment planning in order to get data, which may be analyzed to get suitable objective conclusions. A well thought-out and planned process for establishment of association between factors, which affects a process and the amount produced out of that process is called as DoE. While performing an experiment, we intentionally vary one or more factors and examine the alterations occurring with a change in the response variables. The statistical DoE is a wellorganized process for experiments planning, so that the data obtained can be analyzed to yield valid and objective conclusions. Steps involved in DoE present in Fig. 3. The DoE begins with determining the objective

Fig. 3 Steps involved in DoE.

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Fig. 4 Advantages of DoE.

of an experiment and selecting the process factors for the study.4,22,23 Advantages of DoE are presented in Fig. 4. Benefits of DoE: • DoE involves manipulation of variables, which are independent in order to see its effect on the dependent variable. • Control over the independent variables, as the person performing experiment try to get rid of surplus variables, which are irrelevant. • Control over the irrelevant variables, which is generally more as compared to the research methods. • The person performing experiment may check the results by the repetition of the same experiment. Experiments done by doing replication of samples is advantageous as the obtained results boosts up the confidence.

6 APPLICATIONS OF QbD The QbD is a widespread systematic approach in the development and manufacturing of pharmaceuticals. There are various fields such as biopharmaceuticals, pharmaceuticals, genetics, clinical, and biotechnological products, where QbD has been applied.

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6.1 In Pharmaceuticals In pharmaceuticals, the QbD is applied for quality design and manufacturing of a product in order to ensure the constant drug delivery and enhance its performance. The drug delivery from the product is expected to be delivered at the site with an appropriate rate, potency, and purity. There are certain regulatory bodies regarding pharmaceutical product development, which ensure the safety of human beings from the unwanted side effects, which was common in the early 20th century. Therefore, the Q8 guidelines for pharmaceutical development aim at a quality design and manufacturing of a product. The QbD is applied to different dosage form in the development of pharmaceutical products.

6.2 In Solid Oral Dosage Forms The principle of QbD is to develop and design the formulations and manufacturing processes to make sure a predefined quality. The QbD challenge is to develop the functional relationship precisely and quantitatively. The relationship is between CQAs and CPPs. Its impact is on the finished dosage forms.24 Surface area, porosity, and density are correlated quantitatively to mechanical properties of capsules or tablets. It is used as control key variables in the development and manufacturing process. Now, the QbD approach has been accepted by the industries and is working on its implementation into their processes. According to the principal consultant of Parexel, Siegfried Schmitt, the QbD approach needs rigorous studies before its implementation for batch validation, not just for higher validation success rate, but also to ensure a good control over the manufacture of pharmaceutical solid dosage forms.24,25 That is why the QbD ensures enhanced control, understanding, and continuous performance. The considerate properties of drug in the formulation and design process of solid dosage forms are explained using QbD. It uses tools which increase the process development.24,25

6.3 In Gel Manufacturing The pharmaceutical manufacturing of gel comprises of the QTPPs identification from the past values for earlier batches, which were manufactured and the CQAs for the process such as pH and viscosity used to construct a D-optimal experimental design.26 The QbD and PAT are widely used in manufacturing of pharmaceutical dosage forms.

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6.4 In Nanomedicine In the development of the pharmaceutical nanomedicinal product, that is, PEIm/pDNA, its characterization, and biological activity as well as stability of the product, QbD approach is applied nowadays. The formulation of nanomedicine is as per the FDA’s QbD approach.27

6.5 In Modified Release Products The modified release products describe that the QbD provides a better assessment of comparable drug by the introduction of QTPP. The immediate release tablets are used to observe the impact of variation in properties of excipient material on the quality attributes.

6.6 In Biologicals After the publication of PAT guidance by FDA, QbD got a place in the industry in the field of biotechnology. PAT is a framework for innovative pharmaceutical manufacturing and quality assurance in 2004. Worldwide approval of QbD and PAT standards are reflected in the contents of the ICH quality rules: ICH Q8 Pharmaceutical Development, ICH Q9 QRM, and ICH Q10Pharmaceutical Quality System.7,8,28 QbD for biologicals needs technologies and processes for its development and implementation of QbD in biopharmaceutical companies.29

7 CHALLENGES IN APPLICATION OF QbD TO BIOPHARMACEUTICAL PRODUCTS Director of FDA’s Office of Pharmaceutical Science, Helen Winkle, have contributed in improvement of quality of product and its regulation and the faced the challenges and the opportunities in the implementation of QbD for biotech products.30 The FDA has made some progress toward improving pharmaceutical product quality by the application of QbD since 21st century.31 Initially, the QbD approach was designed for small molecule drugs; but now, it has found its application in biotechnological products. Now, there is uncertainty and discrepancy in the company over the application of QbD in the biotechnological products related to the data type required for defining design space for biotechnological products. On the basis of current publications and reports, the total data being recently submitted in favor of QbD is more than required. More emphasis has been given to the design space of processes, thorough the multivariate

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Fig. 5 Factors impacting the QbD application in biopharmaceutical industry.

analyses and several DoE studies.32–34 The factors impacting the QbD application in biopharmaceutical industry are shown in Fig. 5.

8 CONCLUSION The QbD is a vital part of the current approach to the biopharmaceutical and pharmaceutical quality. The QbD is now replacing the conventional/traditional approach and is decisively making a higher impact on the pharmaceutical companies. Accurately, if QbD implementation is adopted, along with the recent advances globally, the harmonization of regulations and risk should be taken for what it has to offer, rather than its concerns. The QbD has achieved the significant importance in the field of biopharmaceutical and pharmaceutical processes like development of drug molecule, drug formulations, and analytical method.

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