QUALITY BY DESIGN: CHANGING OUTLOOK OF PHARMACEUTICAL DEVELOPMENT

QUALITY BY DESIGN: CHANGING OUTLOOK OF PHARMACEUTICAL DEVELOPMENT

Sahil Kalyan ^* and Amrita Parle

Department of Quality Assurance, Delhi Institute of Pharmaceutical Sciences and Research, New Delhi -110017, Delhi, India.

ABSTRACT: The concept of quality by design (QbD) justifies the saying that, quality is not an act, it is a habit. This innovative and systematic approach to pharmaceutical development based on scientific principles has been a breakthrough in developing quality products with a high level of reproducibility. The process of QbD is based on risk management which leads to a better understanding of the product and its manufacturing process, resulting in products with required quality, safety, and efficacy. As the quality and reliability requirements of today’s world are constantly increasing, QbD serves as an important tool in outperforming the global competition. This paper comprehensively discusses the concept of pharmaceutical quality by design, elements of QbD; quality target product profile (QTPP), critical quality attributes (CQAs), design space, control strategy, and lifecycle management. Application of QbD across various fields of pharmaceutical development including formulation development, analytical method development, phytopharmaceutical & biopharmaceutical product development are encompassed in the review.

Quality by design (QbD), Quality target product profile (QTPP), Critical quality attributes (CQAs), Risk assessment, Pharmaceutical development

INTRODUCTION: Pharmaceutical industry is rapidly growing, with quality being the most important aspect while developing new products. The goal of pharmaceutical development activities is to design a reproducible high-quality product and efficient manufacturing processes which would fulfill all regulatory and healthcare requirements. Quality by design (QbD) is a new approach in pharmaceutical development which focuses on building quality into the product rather than testing it later.

ICH Q8 defines QbD as “a systematic approach to development that begins with predefined objectives & emphasizes product and process understanding and process control, based on sound science and quality risk management.” QbD essentially involves designing and developing a product and its manufacturing process with predefined quality characteristics. QbD hence establishes an understanding of how material and process variables influence the product quality ^{1, 2, 3}.

Objectives of Quality by Design: Pharmaceutical QbD has the following objectives:

• To establish a better understanding of product and process.
• To achieve a higher degree of assurance of drug product quality.
• To reduce product recall and rejects.
• To accelerate product development and manufacturing activities.
• To make regulatory filings and post-approval changes easier.
• To implement innovative changes throughout the product life cycle.

FIG. 1: DIAGRAMMATIC REPRESENTATION OF QbD

History of QbD: Dr. Joseph M. Juran was known as ‘Father’ of quality, first described the term Quality by Design in 1992 to achieve breakthroughs in new products, services and processes ⁴. Later QbD was implemented by automobile, technology, telecommunications, aeronautics, and medical devices industry. Emerge of pharmaceutical quality by design began in 2002, when FDA announced in a concept paper, a new initiative “Pharmaceutical cGMPs for the 21^st century”. This encouraged pharmaceutical manufacturers to explore QbD ⁵. In 2004, the final report on “Pharmaceutical cGMPs for the 21^st century-A risk-based approach” was published by FDA and then progress report followed up in May 2007. ⁶

Milestone activities that took place after the initiation of Quality by Design approach are:

• Pharmaceutical quality assessment system (PQAS) was established in the FDA’s Office of New Drug Quality Assessment (ONDQA) which emphasizes on quality by design in the evaluation of critical aspects of pharmaceutical quality.
• Pharmaceutical manufacturers were encouraged to submit New Drug Applications demonstrating the use of QbD and in 2006 Merck’s Januvia became the first product approved based on QbD application.
• International Council for harmonization of technical requirements for pharmaceuticals for Human Use (ICH) described the principles of QbD in its quality guidelines 1.
• On November 1^st, 2013 Roche’s Gazyva became first QbD approval including design space for a biologic license application.

A process of QbD: ⁷ Pharmaceutical quality by design is a systematic approach in which product specification, manufacturing process, and critical parameters are identified.

The traditional approach for ensuring product quality and performance known as pharmaceutical quality by testing (QbT) includes raw material testing, a fixed drug product manufacturing process, in process material testing and end product testing which significantly differs from QbD.

QbD implements a flexible and robust manufacturing process that is adaptable and yield reproducible results. Knowledge management and quality risk management play a crucial role in the development and implementation of QbD.

FIG. 2: STEPS INVOLVED IN QBD PROCESS ⁸

Elements of Quality by Design: ^{1, 9} In a QbD approach to product development there is the identification of characteristics that are critical to quality from the patient’s perspective.

QbD consists of the following elements:

1. Defining the quality target product profile (QTPP) which relates to quality, safety, and
2. Identifying potential critical quality attributes (CQAs) of the drug product for studying and controlling those product characteristics which have an impact on product quality.
3. Identification of critical material attributes (CMAs) and critical process parameters (CPPs) and linking of CMAs and CPPs to CQAs.
4. Defining a control strategy that includes specifications and controls for each step of the manufacturing
5. Product lifecycle management and continual improvement.
6. These elements provide a more systematic approach to pharmaceutical development facilitating innovation.

Quality Target Product Profile: ICH Q8 describes quality target product profile (QTPP) as “A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.” It includes:

• Therapeutic use,
• Dosage form,
• Route of administration,
• Dosage strength,
• Pharmacokinetics,
• The container closure system, etc.

Critical Quality Attributes: A critical quality attribute (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.” It includes but not limited to:

• Assay,
• Dissolution/Drug release,
• Sterility,
• Degradation products,

Risk Assessment: Risk assessment is linking material attributes (Density, particle size distribution, moisture content, etc.) and process parameters (Temperature, the rate of drying, mixing speed, etc.) to drug product’s CQAs. Risk assessment is a scientific process which comes under quality risk management; it facilitates in identifying which material attributes and process parameters potentially affect product CQAs. After parameters are identified mathematical tools are utilized to achieve a higher level of process understanding.

Design Space: Design space is an essential element of QbD, it describes the relationship between the process inputs (material attributes and process parameters) and the critical quality attributes.

• A design space is either described in terms of ranges of material attributes and process parameters or using complex mathematical relationships.
• A design space is a better way to represent the established process of
• Operations within the design space results in products with desired quality characteristics.

Control Strategy: The role of the control strategy is to ensure that the products of the required quality are developed consistently. It consists of:

• Input material controls (Drug substance, excipients, packaging material, etc.)
• Control for maintaining the predefined product specifications.
• Control for critical process parameters.
• Real-time release testing.
• Overall monitoring program.

Product Lifecycle Management and Continual Improvement: Continual improvement is the essence of the QbD process. Over the lifecycle of a product, certain process changes are required for further improvisation. It is necessary that the improvisation is being carried within the design space. With the help of data collected throughout the product lifecycle, innovative approaches can be applied to improve product quality.

Quality by Design in Formulation: When QbD principles are applied, it results in a better understanding of the process which ultimately leads to a robust formulation with predefined quality characteristics. QbD is applied to various aspects of formulation development which are described below:

Novel Drug Delivery System: Developing new dosage forms is a challenging process, and huge money is invested in R & D. Using QbD ensures a quality product right from the beginning which saves time and effort in developing the desired formulation. A case study carried out by Kan et al., described the preparation of Naproxen enteric coated pellets by fluidized bed coating using the QbD principle. Acid resistance and cumulative drug release were identified CQAs, based on which design space was established. Confirmation tests showed that the predicted and the response values of the formulations with different variables were similar, thus the validity of the model was established and all the parameters were robust within design space ¹⁰.

TABLE 1: RECENTLY DEVELOPED NOVEL DRUG DELIVERY SYSTEM BASED ON QbD ^13-22

A recent paper by Porfire et al. illustrates the use of a QbD approach for the development of lyophilized liposomes of simvastatin. Formulation factors mainly PEG proportion, cholesterol concentration, cryoprotectant to phospholipids molar ratio are identified. Two process parameters, the no. of extrusions through 100 nm polycarbonate membranes and freezing conditions prior lyophilization are also taken into account. Among the formulation factors, the cholesterol concentration had a significant effect on the CQAs of the product, and hence lyophilized liposomes with predictable quality were developed ¹¹. Recently developed novel drug delivery system based upon QbD are summarised in Table 1.

Coating Process Optimization: Variability in the coating thickness is a common problem during tablet coating; it alters the aesthetics and taste masking properties. QbD approach can be applied to optimize the coating process thus reducing coating variability. The approach consists of achieving an optimal set of operating conditions which includes the amount of coating material, pan rotation speed, spray rate, and spray temperature. Appropriate CQAs are identified, and the optimum ranges of these parameters are established which leads to improved coating process, examples of which are given in Table 2.

Enhanced Manufacturing Process: QbD provides a thorough understanding of the manufacturing process; all critical factors of variability are identified and explained. QbD emphasizes on controlling process output using real-time release testing which enables continuous tracking of the process. QbD is encouraging the use of new technologies to improve manufacturing processes like the use of morphologically directed imaging, in which imaging technology and spectroscopy are combined to provide chemical identification and physical measurements of the material under process ¹². Table 3 describes how QbD resulted in designing an efficient manufacturing process.

TABLE 2: APPLICATION OF QbD IN COATING PROCESS OPTIMIZATION ^23-27

TABLE 3: QbD APPROACH IN ENHANCING MANUFACTURING PROCESS ^28-32

Quality by Design in Phytopharmaceuticals: Quality by Design for the development of herbal products is comparatively new but has expanded over a few years. Quality of phytopharmaceuticals is a concern not only for the safety of patients but also for the standardization of herbal products. It plays a significant role in increasing the confidence of patients in the quality of plant-based products. The main challenge of applying QbD approach in herbal products is the natural variation in the plant species due to the genetic and environmental factors. Thus, well-defined quality standards and process knowledge are essential in developing a robust, reproducible phytopharmaceutical products. Development in the field of quality by design in phytopharmaceuticals is summarized in Table 4.

TABLE 4: SIGNIFICANT ADVANCES IN APPLICATION OF QBD APPROACH TO PHYTO-PHARMACEUTICALS ^33-36

Analytical Quality by Design: Quality by design finds great application in analytical method development, the aim of analytical QbD (AQbD) is to develop a robust method which is applicable throughout the life cycle of the drug product and on similar products containing the same active ingredient. Analytical QbD provides flexibility in the analysis of API, drug impurities and biological metabolites. Table 5 summarizes recent applications of AQbD.

Analytical Target Profile (ATP): Analytical target profile is parallel to QTPP, defining the goal of the analytical method development process. The Pharmaceutical Research and Manufacturers of America (PhRMA) and European Federation of Pharmaceutical Industries and Associations (EFPIA) define ATP as “A statement that defines the method’s purpose which is used to drive method selection, design and development activities.” ATP consists of identifying target analytes and selecting the suitable analytical technique for carrying out process ³⁷.

Method Operable Design Region (MODR): MODR is the analog of “design space” in analytical QbD. It describes the operating range for critical input variables to achieve the ATP ³⁷. Working in MODR provides flexibility in changing the method input variables without any post-approval changes.

The process of Analytical QbD: ³⁸ Process of analytical QbD broadly consists of:

• Defining the objectives of method development, laying emphasis on product and process understanding and establishing an analytical target profile (ATP).
• Performing experimental design which consists of a selection of analytical technique, obtaining method understanding and performance optimization and designing MODR.
• Finally, risk assessment and method verification are performed to prove that method is applicable throughout the product lifecycle with robustness and ruggedness.

FIG. 3: ANALYTICAL QbD PROCESS ³⁹

TABLE 5: RECENT APPLICATIONS OF ANALYTICAL QUALITY BY DESIGN ^40-44

Quality by Design in Biopharmaceuticals: A biopharmaceutical also known as a biologic or biological is a pharmaceutical product that originated from biological sources. In September 2004, the United States Food and drug administration published process analytical technology (PAT) Guidance, PAT-A framework for innovative pharmaceutical development, manufacturing, and quality assurance ⁴⁵. These publications encouraged the use of QbD for biological products. QbD principles are being adopted by the biotechnology industry to develop safe and effective biologics ⁴⁶. QbD provides a systematic way of development of biologicals to prevent lot failures and to reduce variability in product quality. As cost is an important factor while developing biologicals, thorough product, and process understanding, proves to be more efficient and cost-effective.

Challenges in implementing QbD to Biologics: ⁴⁷

• Biologics are complex, and there is a limited understanding of CQAs and CPPs
• Biotechnological processes consist of many process variables and a large number of raw materials
• Scale-up and technology transfer is difficult to predict
• Lack of harmonization and clarity across different regulatory bodies

Steps to Overcome Challenges:

• Increased understanding of the impact of quality attributes on safety and efficacy is required.
• Regulatory bodies have to work more towards framing clear-cut guidelines on QbD for Biologics.
• Use of advanced statistical and analytical tools to achieve results in less time.
• Encourage manufacturers to develop QbD based biologics by simplifying the application process.
• More pilot programmes are needed to demonstrate the significant benefits of QbD.

CONCLUSION: Quality by design approach leads to the development of efficient and cost-effective product and its manufacturing process in a shorter period. Reproducible products with required quality attributes are achieved through QbD. Though the concept of QbD is in a growing phase and still requires worldwide harmonization; the Pharmaceutical industry is embracing QbD concepts and implementing this approach in the product development process due to its significant benefits. It is also pivotal to comply with emerging technologies & upcoming regulatory requirements. Thus, QbD has a promising future in the development of quality pharmaceuticals.

ACKNOWLEDGEMENT: Nil

CONFLICT OF INTEREST: None declared.

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    How to cite this article:

    Kalyan S and Parle A: Quality by design: changing outlook of pharmaceutical development. Int J Pharm Sci & Res 2019; 10(9): 4100-08. doi: 10.13040/IJPSR.0975-8232.10(9).4100-08.

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