INTRODUCTION:

Quality by Design (QbD) was first described by Joseph M. Juran.and applied heavily, particularly in the automotive industry. The fundamental premise behind QbD is that quality can be “designed in” to processes through systematic implementation of an optimization strategy to establish a thorough understanding of the response of the system quality to given variables, and the use of control strategies to continuously ensure quality.

The FDA has recently begun to advocate the QbD methodology for the pharmaceutical sector. In order to describe quality by design, we must first define what we mean by quality. In a 2004 paper, Janet Woodcock (Director for the Centre for Drug Evaluation and Research) defined pharmaceutical quality as a ‘product that is free of contamination and reproducibly delivers the therapeutic benefit promised in the label to the consumer’.This explanation focuses on the QbD for generic drugs. The concept of QbD was mentioned in the ICH Q8 guidance, which states that “quality cannot be tested into products, i.e., quality should be built in by design”. This paper discusses the pharmaceutical quality by design and describes how it can be used to ensure pharmaceutical quality with emphasis on solid oral dosage forms of small molecules. The pharmaceutical industry works hard to develop, manufacture, and bring to market new drugs and to comply with regulatory requirements to demonstrate that the drugs are safe and effective. A new approach to drug development could increase efficiencies, provide regulatory relief and flexibility, and offer important business benefits throughout the product’s life cycle. This topic explores the processes used in developing a market formulation and requisite supportive data, particularly in light of the industry’s current QbD concept as part of its two-year initiative, movement toward submissions based on quality by design (QbD). DA introduced the Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach Pharmaceutical cGMP initiative (also referred to as the pharmaceutical cGMP Initiative or 21st Century Initiative) in 2002. QbD is not a new concept from a pharmaceutical technology perspective. It is, however, a new concept relative to pharmaceutical regulatory review and submission. As a systematic and prospective approach to product design, process design and control, process performance and continuous improvement, QbD designs quality into the manufacturing process. By doing so, QbD encourages innovation, continuous quality improvement, and science-and risk based regulatory processes and ensures the availability of high-quality medicines to the consumer.^1,2,3,4

Design:

Product is designed to meet patient needs and performance requirements. Process is designed to consistently meet product quality attributes. Impact of starting raw materials and process parameters on product quality is understood. Critical sources of process variability are identified and controlled. The process is continually monitored and updated to allow for consistent quality over time.⁵

Quality:

“The degree to which a set of inherent properties of a product, system or process fulfils requirements” (ICH Q9).

“Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.”¹

Definition of QbD [ICH Q8 (R1)]

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.⁵

Definition of PAT [FDA PAT Guidelines, Sept. 2004]

A system for designing, analysing and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of new and in-process materials and processes, with the goal of ensuring final product safety.⁵

Process Analytical Technology

The concept actually aims at understanding the processes by defining their Critical process parameters, and accordingly monitoring them in a timely manner (preferably in-line or on-line) and thus being more efficient in testing while at the same time reducing over-processing, enhancing consistency and minimizing rejects.

The FDA has outlined a regulatory framework for PAT implementation. With this framework–according to Hinze “the FDA tries to motivate the pharmaceutical industry to improve the production process”. Because of the tight regulatory requirements and the long development time for a new drug, the production technology is "frozen" at the time of conducting phase-2 clinical trials.

PAT allows for and encourages continuous process manufacturing improvement. It uses real-time information to reduce process variation and manufacturing capability and demands a solid understanding of the various processes involved in the operation. Simply put PAT is a real-time testing and adjustment based on the complete understanding of how the components and related processes affect the final product. This is in accordance with the fundamental principle that quality cannot be tested but is instead built into the medicinal product by design.⁶

PAT is a system for

· Designing, analysing and controlling manufacturing.

· Timely measurements.

· Critical quality and performance attribute.

· Raw and in-process materials.

· And processes.⁶

Fig.No:1 Proposed Steps to a PAT Implementation⁶

Benefits of QbD:

· QbD is good Business.

· Eliminate batch failures.

· Minimize deviations and costly investigations.

· Avoid regulatory compliance problems.

· Organizational learning is an investment in the future.

· QbD is good Science.

· Better development decisions.

· Empowerment technical of staff.^7,8,9

Opportunities of QbD:

· Efficient, agile, flexible system.

· Increase manufacturing efficiency, reduce costs and project rejections and waste.

· Build scientific knowledge base for all products.

· Better interact with industry on science issues.

· Ensure consistent information.

· Incorporate risk management.^6,8

Fig.No:2 Flow of Quality by Design¹

Fig.No:3 Process, Quality, Design and PAT^5,6

Steps of Quality by Design:

1. Target Product Profile (TPP):

FDA published a recent guidance defining a Target Product Profile (TPP): “The TPP provides a statement of the overall intent of the drug development program, and gives information about the drug at a particular time in development. Usually, the TPP is organized according to the key sections in the drug labelling and links drug development activities to specific concepts intended for inclusion in the drug labelling.” When ICH Q8 says that pharmaceutical development should include “...identification of those attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration”, the consideration of the intended usage and route of administration would be through the TPP.

Identifying Quality Target Product Profile (Qtpp):

“Begin with the end in mind” By Beginning with the end in the mind, the result of development is robust formulation and manufacturing process with an acceptable control strategy that ensures the performance of the drug product. The quality target product profile (QTPP) is “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.” The QTPP is an essential element of a QbD approach and forms the basis of design of the generic product. The quality target product profile (QTPP) is a quantitative substitute for aspects of clinical safety and efficacy.^1,2,5,13

Quality target product profile (QTPP) Includes, but not limited to:

· Dosage form.

· Route of administration.

· Strength.

· Release or Delivery of the drug.

· Pharmacokinetic characteristics e.g., dissolution, aerodynamic performance.

· Drug product quality characteristics for intended use e.g., sterility, purity.^1,2,5

2. Identifying Critical Quality Attributes (CQA):

Definition: ICH Q8 (R1) defines CQAs as physical, chemical, biological or microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality. The International Society of Pharmaceutical Engineers (ISPE) and Product Quality Lifecycle Implementation (PQLI) defines critical quality attributes (CQAs) as physical, chemical, biological or microbiological properties or characteristics that need to be controlled (directly or indirectly) to ensure product quality. CQA has been used by some to describe elements of the QTPP (such as dissolution) while others have used CQA to describe mechanistic factors (such as particle size and hardness) that determine product performance. Thus, CQA is used to describe both aspects of product performance and determinants of product performance. It was stated that the ICH working definition of CQA was: “A CQA is a quality attribute (a physical, chemical, biological or microbiological property or characteristic) that must be controlled (directly or indirectly) to ensure the product meets its intended safety, efficacy, stability and performance”. This CQA definition implies that the intended safety, efficacy, stability and performance are not CQAs. Safety and efficacy clearly fall under the domain of the TPP But if stability and performance are not CQA and not part of the TPP, then what are they? We are thus compelled to acknowledge that there is an intermediate category of product performance (or surrogates for quality) that we have defined as the QTPP.^1,2

3. Critical Process Parameter:

Critical process parameter (CPP) is defined as any measurable input (input material attribute or operating parameter) or output (process state variable or output material attribute) of a process step that must be controlled to achieve the desired product quality and process uniformity. In this view, every item would be a process parameter. Surrogates for quality) that we have defined as the QTPP.

For a given unit operation, there are four categories of parameters and attributes:

· Input material attributes

· Output material attributes

· Input operating parameters

· Output process state conditions.

Critical Process Parameter:

A parameter is Critical when a realistic change in that parameter can cause the product to fail to meet the QTPP. Uniqueness of Critical Process Parameters: Because of the broadness of the CPP definition it is possible for two investigators to examine the same process and come to a different set of CPP. The set of CPP is not unique, but the chosen set must be sufficient to ensure product quality. Different sets of CPP can have several origins. One is that the definition of operating parameters depends on the engineering systems installed on a piece of process equipment.^1,2,10,12

4. Risk Assessment and Design Space:

Quality Risk Management (ICH Q9) indicates that, the manufacturing and use of a drug product necessarily entail some degree of risk. Risk assessment is a valuable science-based process used in science-quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs. Risk assessment is typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained. Risk assessment tools can be used to identify and rank parameters (e.g., process, equipment, input materials) with potential to have an impact on product quality, based on prior knowledge and initial experimental data.

Design space ICH Q8 (R1) defines Design space as, the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Many believe design space and QbD are interchangeable terms. This is incorrect. For generic-drug applications, design space is optional. QbD can be implemented without a design space because product and process understanding can be established without a formal design space. It should be pointed out that implementation of QbD is strongly encouraged by FDA. For some complex drug substances or drug products, implementation of QbD is considered a required component of the application. Submission of a design space to FDA is a pathway obtaining the ability to operate within that design space without further regulatory approval.^1,2,14

5. Defining Control Strategy ICH Q8 (R1):

It defines control strategy as A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.

Minimal and enhanced approaches As in ICH Q8(R), a distinction may be drawn between a minimal and an enhanced control strategy approach. In a Minimal Control Strategy, drug product quality is controlled primarily by intermediate (in process material) and end product testing. In an Enhanced Control Strategy drug product quality ensured by risk-based control strategy for well understood product and process, and quality controls are shifted upstream, with the possibility of real-time release or reduced end-product testing.

Developing the Control Strategy:

Development of a Control Strategy requires a structured process, involving a multi-disciplinary team of experts, linking pharmaceutical development to the manufacturing process, and engineering controls of process equipment.

The PQLI Control Strategy Team has proposed a Control Strategy Model that facilitates understanding and that may be used a cross-functional communication tool.

Personnel at all levels should be able to understand the way control strategy links from CQAs to operational aspects to ensure, for example that:

· Chemists understand in-process controls are established to keep the process inside the design space and seek opportunities for simplification of controls, as knowledge is gained.

· Engineers know how equipment operating conditions impact product quality.

· Quality Assurance professionals know where the highest risks are in the process.^1,5

6. Control Strategy and the Product Lifecycle:

The Control Strategy is related to the level of process understanding at a given time, and evolves as manufacturing experience increases. The originally specified measures, controls or models may be modified or even removed, or the need for additional controls may be identified. Other revisions to the Control Strategy may relate to continual improvement, for example the introduction of improved analyser or control technology. Periodic reviews of risk assessments and mitigation should be conducted to determine the appropriateness of the Control Strategy based on product manufacturing history. Failure or deviations should be investigated and the effectiveness of the control system considered in relation to the identified root cause. Corrective and preventive actions should be applied and the Control Strategy updated as necessary (including any regulatory actions required) in the light of new product and process knowledge. Implementing PAT in the Control Strategy will require the application of process models (multivariate prediction models) that either predicts CQAs or CPPs or a combination of both. These models may require frequent updates, depending on the maturity of the model (e.g., the amount of data and their variability within the model), as well as the kind of data that has been included to reflect variability in scale, equipment, analytical set-up, sampling, and site. A monitoring program for verifying the validity of process models should be established and be based on a risk analysis of the model itself and include possible ways to verify the model by other means. One example would be to compare the predicted CQA value to a conventional analytical method. The monitoring program should include requirements for when a model has to be updated (e.g., change of raw material supplier or deviations resulting in increased knowledge).^1,2,11

CONTINUOUS IMPROVEMENT:

“Continuous improvement is an essential element in a modern quality system that aims at improving efficiency by optimizing a process and eliminating wasted efforts in production. These efforts are primarily directed towards reducing variability in process and product quality characteristics.”

The backbone for Continuous Improvement is the Pharmaceutical Quality System. PQS should facilitate continual improvement and help to: “Identify and implement appropriate product quality improvements, process improvements, variability reduction, innovations and pharmaceutical quality system enhancements, thereby increasing the ability to fulfil quality needs consistently. Quality risk management can be useful for identifying and prioritizing areas for continual improvement. “Continuous improvement is not the same as corrective actions preventative actions (CAPA).^1,11,15

CONCLUSION:

The goal of a well-characterized method development effort is to develop a reliable method that can be implemented with a high degree of assurance to consistently produce data meeting predefined criteria when operated within defined boundaries. QbD can be applied to the development and evaluation of analytical methods. QbD gives an idea about the process development with very detailed analysis of every single part involved in it that can maintain products quality at extreme level. Quality by Design’s steps have accurate understanding of product and process development that can avoid unnecessary variables and problems in manufacturing of product that can evaluate and keep consistency in quality of product.

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Received on 30.04.2022 Modified on 13.05.2022

Asian J. Research Chem. 2022; 15(4):303-307.

DOI: 10.52711/0974-4150.2022.00054