AN OVERVIEW ON QUALITY BY DESIGN IN PHARMACEUTICAL PRODUCT DEVELOPMENT

AN OVERVIEW ON QUALITY BY DESIGN IN PHARMACEUTICAL PRODUCT DEVELOPMENT

P. N. Mallikarjun ^*, Pooja Kumari, S. Manoj Kumar and G. Sowmya

Vignan Institute of Pharmaceutical Technology, Duvvada, Visakhapatnam, Andhra Pradesh, India.

ABSTRACT: The concept of Quality by Design reflects current global regulatory thinking related to pharmaceutical products. The pharmaceutical industry needs to improve its performance. Newer technologies need to be implemented that can effectively reduce the cost and, at the same time, improves product quality. Quality by design (QbD) is the best solution to build quality in all pharmaceutical products. The main objective of QbD is to ensure the quality product resulting from a combination of prior knowledge and new estimation during development. QbD is being widely promoted by the food and drug administration (FDA) and the international conference on Harmony (ICH). Quality by design (QbD) in the pharmacy field is mainly based on the understanding of how materials and process parameters affect the quality profile of final products. In this article, the key elements of QbD viz., Target product quality profile, Critical quality attributes, Risk assessment, Design space, and Control strategy are discussed to understand the performance of dosage forms within the design space. Tools of QbD (DoE, Quality risk management, and process analytical technology) are also discussed in QbD. These reviews underline the importance of QbD in inculcating a science-based approach in pharmaceutical product development.

Keywords: QbD, quality by design, International Conference on Harmonization (ICH), Risk assessment, Design space, Control Strategy, DoE

INTRODUCTION: Pharmaceutical development aims to design a quality product and its manufacturing process to consistently deliver the product's intended performance. It is important to recognize that quality cannot be tested in products. Quality should be built into the process design rather than tested into the final analytical process results ¹. The pharmaceutical market has been considered one of the highly regulated sectors, continuously providing quality drug products for human use to provide pharmacotherapeutic effects for the treatment of diverse ailments.

In 2002, the US Food and Drug Administration [FDA] published a guidance document for pharmaceutical companies. Companies should build Quality, Safety, and Efficacy into their product. This concept is now known as Quality by Design^. In a 2004 paper, Janet woodcock (Director for the Center for Drug Evaluation and Research) defined pharmaceutical quality as a product that is free of contamination. They reproducibly delivered the therapeutic benefit promised on the label to the consumer. The QbD approach is a recent trend in analytical method development, and it helps a lot if it gets properly implemented ².

Pharmaceutical Quality: Pharmaceutical Quality = f (Drug substances, excipients manufacturing, packaging). For quality to increase, it must be built into the product. To do this required understanding how formulation and manufacturing process variables influence product quality; this is the function f in the equation above. RP-HPLC / LC methods were developed and validated by applying the Analytical and Quality by Design approach ³. Quality means customer satisfaction in terms of service, product, and process. Customer demands perfection in quality, reliability, low cost, and timely performances ⁴. Quality, Productivity, cost, cycle, time, and value are interrelated terms. The quality has to be built in the product and service through proper planning ⁵. With the development of the concept QbD “there will be a significant transformation in pharmaceutical quality regulation, from an empirical process to a more scientific and risk-based approach ⁶. QbD also helps create the approach and common language needed to develop the bond necessary for successful outsourcing ⁷. Initially, the concept of QbD was introduced for manufacturing processes, described in four steps ⁸:

• Determination of patient requirements, namely, the Quality Target Product Profile (QTPP).
• Design and development of the manufacturing process.
• Risk assessment and definition of the manufacturing Design Space (DS).
• Implementation of a Control Strategy.

Formulation parameters (independent variables) affect the product's characteristics and are useful in optimizing independent variables to monitor the behavior of dependent variables in producing the optimized product under the given set of conditions. Thus, variables are included in QbD to ease the final best formulation of drug ⁹. QbD is applied to optimize experimental conditions to ascertain the best suitable conditions with limited numbers of experiments ¹⁰.

FIG. 1: SOURCES OF VARIABILITY IN DRUG PRODUCT QUALITY ⁹

Understanding Pharmaceutical QbD:

Quality: Quality by Design (QbD) is defined in the ICH Q8 guideline as a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on Sound Science and Quality risk management ¹¹.

The US Food and Drug Administration initiative to ensure product quality over the whole procedures established in pharmaceutical development of different dosage forms ¹². It is important for all products, including Generics and Biotech.

Purpose and Objectives: QbD encourages process and product understanding to support innovation and efficiency in product development. Moreover, the application of a QbD approach helps to meet FDA.

The benefits of QbD can be translated into an acceleration of product development and a reduction of costs and waste. The quality by Design (QbD) approach to custom 3D printed prostheses can help to ensure that products are designed and manufactured correctly from the beginning without errors ¹³.

The FDA publication defined QbD as:

1. Developing a product to meet predefined product quality, safety, and efficacy.
2. Designing a manufacturing process to meet predefined product quality, safety and efficacy.

FDA accepted this concept in 2004 and detailed description was given in pharmaceutical cGMPs for the 21st century-

• A Risk-Based: The FDA has taken the initiative to guide the pharmaceutical industry on implementing the concept of QbD into its process.
• FDA’s Process Validation: Guidance in Jan 2011 is for companies to continue benefiting from knowledge gained and continually improve throughout the process lifecycle by making adaptations to assure root causes of manufacturing problems are addressed.
• International Conference on Harmonization (ICH): Relevant documents from the international conference on harmonization of the technical requirement for registration of pharmaceuticals for human use. (ICH). US FDA / EMA refers to ICH guidelines Q8, Q9, Q10, Q11 & Q12 for QbD implementation.

• Pharmaceutical Development Q8 (R2).
• Quality Risk Management Q9.
• Pharmaceutical Quality System Q10.

ICH Q8: In the previous decade, the US FDA announced a new pharmaceutical regulatory concept, quality by design (QbD), which has challenged the pharmaceutical industry to design the quality of the final product instead of testing the product. The ICH guideline Q8 definition for QbD is “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management ^14.

Components of Drug Product Given by ICH Q8 ¹⁵:

1. Drug Substances: The physicochemical and biological properties of the drug substances that can influence the performance of the drug product and its manufacturability”.

Example of physicochemical and biological properties  includes:

• Water content.
• Particle size.

The compatibility of the drug substances with excipients should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated.

2. Formulation Development: The formulation's development includes identifying those attributes that are critical to the quality of the drug product and highlighting the formulation design's evolution from the initial concept up to the final design. Comparative in-vitro studies e.g., Dissolution (or) in-vivo studies, e.g., BE, link clinical formulations to the proposed commercial formulation.
3. Container and Closure System

• The choice of materials for primary packaging and secondary packaging should be justified.
• A possible interaction between product and container or label should be considered.

ICH Q9: Provides general guidance and references for some of the primary tools used in Risk assessment. Examples are provided for industry and regulators to evaluate the risk to quality based on scientific knowledge and risk to patient ¹⁶.

Quality risk management, a part of an effective quality system, helps in identifying the probability of occurrence and severity of the risk. It provides a non-exhaustive list of common risk management  tools as follows ¹⁷:

Basic risk management facilitation methods (Ishikawa fishbone diagram, flowchart, check sheets, etc.

• Fault tree analysis.
• Risk ranking and filtering.
• Preliminary hazard analysis.
• Hazard analysis and critical control points.
• Failure mode and effects analysis.

ICH Q10: Pharmaceutical Quality Systems, indicate on an abstract level how Quality by Design acts to ensure drug product quality. Especially for ANDA sponsors, who were not actively involved in the ICH processes ¹⁸.

These guideline applies in the process that help in design, development and preparation of drug substances such as API and drug products which includes biotechnology and biological products, throughout the lifecycle of product ¹⁹.

FIG. 2: QUALITY ATTRIBUTES GOVERNING QUALITY OF DESIRED  PRODUCT ¹⁹

Flow of Quality by Design ²⁰

Regulatory Challenges and Inspection: In a QbD concept, the regulatory burden is less because there are wider ranges and limits based on product and process understanding. Changes within these ranges and limits do not require prior approval. Traditionally, inspections have been conducted using the FDA system-based approach and in accordance with CDER’s compliance program“ Inspection of licensed Bio-logical Therapeutical Drug Product ²¹. During prelicense and preapproval inspections under a QbD concept, the FDA inspection team will assess the implementation and effectiveness of the process design. The inspection will evaluate the quality system and its effectiveness regarding consistent product quality, change in control procedures, and process improvement. Companies Wanted Clarification from the FDA on QbD terminologies, acceptable methods, criteria to select and deselect Critical Quality Attributes, standards to guide adequacy of controls and criteria for analytical method substitution ²².

Benefits of Implementing QbD for FDA ²³:

• Increase Manufacturing efficiency, reduce cost, and project rejections and waste.
• Implementation of a Question-based review (QbD) process has occurred in CDER’s office of generic drugs.
• Implementation of QbD for a biological license application (BLA) is progressing.
• Optimization Design performed using Quality by Design as 2³ full factorial design ²⁴
• Organization learning is an investment in the future ²⁵.

Benefits to Industry:

• Ensure better design of the product with less problems in manufacturing.
• Improve interaction with the FDA deal on a science level instead of a process level.
• Nanocellulose prepared by the QbD approach had better flow property and compatibility

Seven Steps of QbD ²⁷: The best way to assess how to implement QbD in your organization in a simple seven-step process:

Hire an independent Quality design expert.

Audit your organization and processes with the expert conducting a gap analysis.

• Hold a basic QbD workshop with all your personnel – the expert should lead this and design it to speak to multiple levels, from the factory floor to the board room.
• Review the expert's report and recommendations.
• Draft an implementation plan, timelines, and estimated costs.
• Assign the resources.
• Retain the independence expert as your project assurance advisor.

Elements of Pharmaceutical Development: QbD comprises all elements of pharmaceutical development mentioned in the given guideline Q8-

Quality Target Product Profile (QTPP):  ICH Q8 defines 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 ^28.

 Necessary element ²⁹

1. Quality characteristic – Sterility, purity.
2. Pharmacokinetic characteristic – Dissolution
3. Therapeutic effect
4. Target patient population neonates, clinical diagnosis.
5. Shelf life temperature, light conditions, etc.

Desired Elements:

1. Dosage form liquid for injection, solid tablet.
2. Route of administration oral, IV, IM, SC.
3. Clinical setting self or clinic administration.

QTPP leads  ............ CQA definition

Once QTPP has been identified, the next step is to identify the relevant CQAs. A CQA is defined as a physical, chemical, biological or microbiological property or characteristic within an appropriate limit, range, or distribution to ensure the desired product quality ^30. The successful execution of a product development exercise to meet the end objectives always depends on the holistic identification of the QTPP ^31.

Critical Quality Attributes [CQAs] are identified by Quality risk management and experimentation to determine the effect of variation on product quality. The framework for the product design and process understanding is achieved by identifying the CQA ³².

FIG. 3: DECISION TREE TO DECIDE CQAs ³³

Target Product Profile (TPP): FDA gives guidelines for defining Target Product Profile (TPP) ³⁴. As per these guidelines. The TPP is totally correlated to drug development program that provides knowledge of drug during development. Generally, the TPP is useful for developing a link between drug labeling and drug development activities. According to ICH-Q8 (pharmaceutical development), pharmaceutical development should include “Recognition of critical quality attributes of the drug product with consideration of its intended use as well as the route of administration hence it becomes essential to consider the intended usage and route of administration ³⁵.

Critical Material Attributes (CMA): As per ICH, CQA is defined as a quality attribute that comprises physical, chemical, biological, or microbiological characteristics, and it is desired that these attributes should be controlled (directly or indirectly) to give assurance that the product obtained will attain desired safety, efficacy, stability and performance ³⁶. CMAs are the pivotal elements that directly influence the CQAs.

These are defined as the physical, chemical, biological or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of drug products ³⁷. In determining product performance, CQA observes the mechanistic variables such as particle size and hardness. Hence, both the aspects i.e., product performance and product performance determinants, could be explained by using TPQP ³⁸.

Design Space: Design space may be defined as the set of all combinations of a method's input variables that have been proven to assure the quality of the data produced by the method ³⁹. Design space may be constructed for a single unit operation, multiple, or the entire process.

The risk assessment, prior experimentations, and multivariate factor screening methods are used for identifying the criticality of factors and their ranges for establishing a design space. There could be more than one design space in a pharmaceutical product. Ideally, design space is generated using experimental design at lab/pilot scale and extrapolated to exhibit/commercial scale by establishing a correlation with the help of scale-independent parameters ⁴⁰.

FIG. 4: DESIGN SPACE ³⁹

Control Strategy: A control strategy based on extensive knowledge of the process and the product includes control over the CMA of the input materials and intermediates, control of the process parameters, final drug product quality, and final packaging. All these components of control strategy are covered under process analytical technology (PAT) ⁴¹.

Control space should be within the design space; it is an upper and lower limit for raw material (or) a process within which parameters and material are regularly controlled, which assures the quality of the product. Every process has a control strategy right now. Fig 5 shows a simplified quality assurances diagram under the current regulatory evaluation system.

In this system, product quality is ensured by fixing the process to produce the active ingredient, raw material testing, performing the drug product manufacturing process as described in a fixed batch record, in-process material testing, and end-product testing. A factor identified to have risk has to be controlled ⁴².

Control strategy includes the following elements:

• Input material attributes (g., drug substances, excipients).
• Equipment operating conditions.
• In-process controls.
• Finished product specifications.

FIG. 5: CONTROL STRATEGY IN QbD ⁴³

Tools of QbD:

Quality risk management (QRM): FDA defines risk management as a strategic safety program that decreases product risk by using intervention (or) tools. It is a systematic process for the assessment, control, and communication review of risk to the quality of drug across the product life cycle ⁴⁴. Risk management is the joint responsibility of the quality unit, regulatory affairs, production operations, sales and marketing, and clinical department. Two important principles were highlighted in this document for the use of Quality Risk Management ⁴⁵:

1. The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.
2. The level of efforts, formality, and documentation of the quality risk management process should be commensurate with the level of risk.

FIG. 6: OVERVIEW OF TYPICAL QUALITY RISK MANAGEMENT PROCESS ⁴⁵

Design of experiment  (DoE): A structured, organized method for determining the relationship between factors affecting a process and the output of that process is known as“ Design of Experiments” (DoE). With the help of DoE, We can define many factors, create designs, construct models, define responses, evaluate the models, interpret results and hence reach a decision. Traditionally we are used to single variant study DoE help to do multivariate analysis e.g., wavelength, flow rate, concentration in case of HPLC and its impact on retention time, resolution, etc. ⁴⁶. Design of experiment (DoE) is one such structured method that considers the effects of the CMAs and CPPs on the CQAs of the final dosage form ^{47 9, 10}.

It has gained tremendous attention with the introduction of QbD by the FDA in the formulation development of pharmaceutical products ⁴⁸.

PAT as an Important Tool of QbD: PAT is defined as “Tools and systems that utilize real-time measurements, or rapid measurements during processing, of evolving quality and performance attributes of in-process materials to provide information to ensure optimal processing to produce a final product that consistently conforms to established quality and performance standards ⁴⁹. PAT forms a part of the quality by design (QbD) concept, which provides tools to facilitate the quality.

TABLE 1: APPLICATION OF QbD  IN PHARMACEUTICAL PRODUCT DEVELOPMENT

CONCLUSION: Quality by Design (QbD) is increasingly becoming an important and widely used technique in pharmaceutical product development. Provides quality medicines to patients and production improvement. Quality by Design ( QbD ) and its tools indicate the demands of the modern manufacturing process. Quality by design is a cost and time-efficient approach in design and manufacturing. QbD also has wide scope in biotechnological products such as- vaccines, enzymes, monoclonal antibodies, etc. This new Quality by Design (QbD) process provides the opportunity for much greater regulatory flexibility in the future. Moreover, Quality by Design has become a broadly applicable manufacturing model and is going far beyond pharmaceuticals.

ACKNOWLEDGEMENT: We express our sincere thanks to Dr. L. Rathaiah, Chairman, Vignan Group of Institutions, and Dr. P. V. Kamala Kumari, Dr. Y. Srinivasa Rao for providing the necessary facilities to carry out the above review.

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Mallikarjun PN, Kumari P, Kumar SM and Sowmya G: An overview on quality by design in pharmaceutical product development. Int J Pharm Sci & Res 2022; 13(6): 2283-93. doi: 10.13040/IJPSR.0975-8232.13(6).2283-93.

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