The pharmaceutical market has long been regarded as one of the most strictly regulated industries, consistently producing high-quality drug products for human consumption with the desired pharmacotherapeutic effects for the treatment of a wide range of ailments 1. However, over the last few decades, the pharmaceutical industry has faced on going challenges in delivering high-quality drug products 2. The primary goal of drug development is to assure safety, quality, and efficacy; however there are other issues to consider, such as drug recalls, the cost of manufacturing failure, scale up, and regulatory load. End product testing is a traditional method of guaranteeing product quality. This is why regulatory authorities are now focusing on QbD implementation to reduce process variability and improve process quality. As a result, QbD offers a systematic and modern way to assuring constant product quality across time. Quality by Design is a concept pioneered by Joseph.M.Juran in a number of books. In his book Quality by Design, Juran highlights the elements that contribute to customer pleasure and the dependability of such features. He also proposed a Juran's triology, which defined three quality pillars: planning, control, and improvement. It is the current approach to pharmaceutical quality 3 and it contains the components of management, statistics, psychology and sociology 4.

According to ICH advice Q8 (R2), QbD is "a systematic approach to pharmaceutical development that begins with established objectives and stresses product and process understanding and process control, based on strong science and quality risk management. It emphasises a fundamental concept of QbD: quality cannot be tested into goods it must be built in by design 5. According to Janet Woodcock (2004), "QbD means the product and process performance characteristics are scientifically created to suit specified objectives, rather than merely empirically obtained from test batch performance." QbD is all about building an appropriate process and understanding process performance for the target product performance 6. Simultaneous QbD operations in synthetic and analytical development will result in the highest quality product while minimising risks 7 . To assure quality, the full implementation of QbD necessitates process control of essential phases 8 . Its overall purpose is to incorporate quality into pharmaceutical products in order to preserve patient safety 9 . The advancements under QbD were listed in Table 1 . Currently, no regulatory authorities have defined standards for AQbD (Analytical Quality by Design) and PAT in analytical development.

The concept of QbD can be extended to the development of analytical methods, which is known as AQbD 10. Analytical QbD is defined as a science and risk-based paradigm for analytical method development that aims to understand the predefined objectives in order to control the critical method variables that affect the critical method attributes in order to achieve enhanced method performance, high robustness, ruggedness, and flexibility for continuous improvement 11 . It can help improve certain analytical methods that are currently utilised for quality control and analysis. AQbD is a more advanced way to develop analytical techniques based on QbD concepts. The analytical development phase is essential for characterising drug substances as well as for analysing drug(s) in dosage forms, biological matrices, and stability samples. Due to the high level of criticality seen during method development, validation, and transfer, analytical methodology is, thus a crucial component of pharmaceutical development. ICH Q14 guidelines offer scientific approaches to analytical procedure development and to give principles relevant to the description of the analytical procedure development process. These new recommendations are intended to improve regulatory communication between industry and regulators in order to promote more efficient, solid scientific and risk-based approval, as well as post-approval change management of analytical methods.

The implementation of AQbD 12 is expected to strengthen the concept of "right analytics at right time," which is important in drug product development 13 . A few months ago, the FDA approved a few NDA’s that supported AQbD and emphasised the importance and application of QbD in analytical method development. It activates the analytics role in the product 14 . Furthermore; there is a need of transition from traditional checklist implementation requirements to a method validation approach that should provide a high level of assurance of method reliability in order to adequately measure the drug product's critical quality attributes (CQAs) 15. Scientific and regulatory knowledge, as well as quality control requirements, are all considered in AQbD. While most applications have focussed on using design of experiments (DOEs) and statistical screening for method parameter operational spaces in order to consider method robustness, a systematic approach has also been advocated 16. However, much more work is needed to perfect the AQbD procedures and spread the concept to all methods, from clinical to commercial, as well as lifecycle management 1.

QbD- Quality by design; AQbD-Analytical quality by design; ICH-International conference on harmonisation; FDA-Food and drug association; ANDA-Abbreviated new drug application; NDA- New drug application; ATP-Analytical target profile; CQA- Critical quality attributes; CMP- Critical method parameters; CMV- Critical method variables; QTMP- Quality target method profile; QTPP- Quality target product profile; CAA- Critical analytical attributes; DoE- Design of experiments; MODR- Method Operable Design Region; QRM- Quality risk management; AQbD strives to achieve the predefined analytical

Traditional validation methods are typically evaluated only once. As a result, the possibility of method failure during transfer is always present high. Furthermore, the performance variables are not thoroughly investigated and comprehended. Figure 1 summarises the comparison of traditional and AQbD approaches, with the goal of addressing the flaws of the traditional approach based on scientific comprehension and knowledge repository 17. More than just developing more robust methods, applying AQbd Approach to analytical methods will optimise the methods of risk assessments as well as the control assignment strategies. Using the AQbD, methods will be developed in a risk-based manner, ensuring quality assurance in all of the processes. This is a superior alternative to traditional approaches 18.

The rationale for applying QbD principles to analytical techniques stems from the fact that multitude of variables tends to influence method outputs. These factors include sample properties, equipment settings, procedure parameters, and calibration model selection. The number of variables involved in chromatographic procedures, which are the most often used analytical tools in pharmaceutical quality control, is large. The analytical method development phase is quite similar to the formulation development phase. Implementing QbD allows for regulatory flexibility, but it demands a high level of resilience, product quality, and understanding of the process, product, and analytical procedure 20. On the ground, the implementation of the AQbD exercise may be completed effectively by following the five critical phases 21 outlined below:

AQbD begins with an analytical target profile (ATP), which is analogous to QTPP. ATP specifies the purpose of the analytical method development process, tying the technique's outcomes to QTPP. ATP was recently defined as "a statement that describes the method's purpose and is used to drive method selection, design, and development processes." Once the regulatory authorities approve the ATP statement, ATP is an important metric in AQbD that allows for higher continual improvement of analytical methods and their selection 22. ATP is the core of any analytical technique established using QbD principles, and it is quite similar to the quality target product profile, whereas adopting QbD for pharmaceutical goods includes the goal of analytical procedures and quality criteria to allow for predictable results about material properties. The identification of ATP provides a defined direction for technique development, validation, and transfer, as well as future flexibility; operating within a known acceptable region PAR.

The next phase in pharmaceutical QbD is the identification of critical quality attributes. CQA refers to the chemical, physical, biological, or microbiological features or characteristics of a pharmaceutical product (in-process or finished) that must meet particular criteria in order to be considered high-quality. Identity, assay, content, uniformity, degradation, products, residual solvents, medication release or dissolution, moisture content, microbiological limits, and physical qualities such as colour, shape, size, and friability may all be considered in CQA. QTPP potential CQA is used to assist product and process development. In order to achieve CQA and QTPP, Critical Material Attributes and Critical Process Parameters must also be identified. Analytical Method Performance Characteristics are defined to satisfy the needs of ATP. AMPC is divided into two categories based on the source of error: a) systematic (bias) variability, which includes accuracy, specificity, and linearity; and b) random variability, which includes precision, limit of detection, and limit of quantification. Furthermore, range and robustness can be mentioned in the AMPC definition. It is always advised to include a joint requirement of technique features (at the very least, accuracy and precision) in ATP. Analytical technique selection (for example, chromatographic, spectrophotometric, or microbiological assays).

According to ICH Q9, risk assessment consists of three steps: risk identification, risk analysis, and risk evaluation. Risk identification defines all of the procedure parameters based on their potential influence on the CAAs. Furthermore, "critical few" CMPs impacting CAAs and method performance are discovered. The primary strategy generally used to offer a thorough awareness of the total risks associated with distinct CMPs while altering CAAs of the analytical method is quality risk management (QRM). CMPs are significant input factors or independent variables related to instrument settings, column chemistry and dimension, sample preparation, and so on, whereas CAAs comprise the output responses or dependent variables. The cause and effect relationship on the potential CAA of analytical methods is represented below in Figure 2

The use of DoE principles permits strong scientific knowledge of the numerous technique factors and variables that tend to effect CAAS utilising little testing to give the most information, while minimising the prevalence of (any) interactions and lowering complexities. DoE can also be used to optimise experimental conditions using many variables. Knowledge of CAAs, CMPs, their ranges, and optimal fitting of the mathematical model (s) is required for the successful execution of the DoE research.

Nowadays, computer-aided techniques and software are employed to optimise parameters and their corresponding reactions. MODR or ADS of any analytical approach, also known as proven acceptable range. PAR is the multidimensional integration and interaction of input variables (i.e., CMPs during analysis) that has been established to offer assurance of quality.

A designed set of controls for all conceivable variations ensures that ATP requirements are satisfied throughout analytical method transfer and routine use. This is achievable by constant monitoring of CAAs or system appropriateness criteria. Control strategy is not necessarily a one-time effort, and it should be developed across all crucial stages of the method development life cycle in order to achieve continual improvement. Even after going through all of the QbD aspects for a specific analytical method, method validation, verification, and transfer are the important activities that assure the method's suitability for its intended application.

This comes after the development of an analytical method for quality control or routine testing. Once a method has been developed for normal usage, its performance should be tracked over time to ensure that it remains in compliance with the defined ATP criteria. It is represented in the pharmaceutical industry by using control charts or other tools to track system suitability data and method-related investigations. For example, by tracking system appropriateness data with control charts or other tools, conducting method-related research, and so on. Periodic fit for purpose re-verification trials can also be carried out if necessary. This continuous monitoring enables an analyst to detect, identify, and address any abnormal or out-of-trend analytical method performance. Existing methods should be re-evaluated on a regular basis to address any gaps or improvement possibilities identified in the current methodology, either by refining the methodology or by incorporating a new technology as analytical technologies develop. The analytical method's role in control strategy is critical, and it starts with raw material testing (before manufacturing) and ends with stability testing (after marketing),

Quality risk management and knowledge management are two of the most important QbD enablers. They are extremely important in QbD development and implementation they are helpful in reaching product realisation, creating and retaining control, and lastly allowing for continuous improvement.

Figure 1

Figure 2

The essential axioms of QbD revolve around a complete knowledge of a process, product, or purpose that has been specified prior to the start of a process. Quality by Design (QbD) has become an essential idea for the pharmaceutical business since it was first introduced by the United States Food and Drug Administration (FDA) in its "Pharmaceutical cGMPs for the twenty-first century 28 .”Previously, until 2005, the US Food and Drug Administration (FDA) required manufacturers to provide chemical, manufacturing, and control (CMC) information as part of a new drug application (NDA). The ICH Q8, Q9, and Q10 guidance documents, on the other hand, imposed stricter requirements for meeting a drug product's quality standards. Although the ICH Q8 (R2) guideline has not primarily addressed the analytical method development perspective in the context of design space, it has been extended to MODR with the goal of on-going improvement in method robustness for enhanced analytical comprehension. Adopting AQbD as a control method during the production process would, as a result, ensure process performance and product quality 29.    

The implementation of AQbD is expected to strengthen the concept of "right analytics at the right time," which has enormous potential in drug product development. The reliance of pharmaceutical development and manufacturing on reliable analytical data demonstrates the value of QbD-guided analytical method development as the current domain of attention and implementation. Recent FDA approvals of AQbD-supplemented NDA applications tend to stimulate and emphasise the importance and use of QbD in analytical method development. The USFDA and USP require system appropriateness assessment for an analytical technique in order to ensure continuing functioning of an analytical system and related methodologies. The USFDA and USP require system appropriateness assessment for an analytical technique in order to ensure continuing functioning of an analytical system and related methodologies. However, recent modifications to the USP - NF and European Pharmacopeia have allowed for flexibility in changing analytical techniques without requiring revalidation. There is currently no regulatory guidance dedicated to the systematic development of analytical methods. The next ICH Q14, "Analytical Procedure Development," as well as the revision of the ICH Q2 (R1) Guidelines on Validation of Analytical Procedures: Text and Methodology are encouraged to provide analytical technique validation criteria that match the ATP standards.

With the rising desire for the incorporation of systematic techniques and quality tools into analytical science, the popularity of AQbD has spread to numerous domains of analytical testing 30

Impurity profiling and identification of degradation products in bulk drugs and finished products are highly essential for maintaining product quality, safety, and efficacy. Requirement of a highly sensitive analytical method along with critical monitoring of chromatographic conditions, in this regard facilitate estimation of impurities and degradation products, and controlling their levels within the acceptance limits for regulatory approval 40. QbD concepts can also be applied in developing an appropriate control plan 41.

Use of non-destructive tools is gaining high importance for saving time during pharmaceutical analysis of drug substances in bulk and finished products. New - Age spectroscopic techniques such as near infra-red and Raman are used for non-destructive analysis to identify impurities or counterfeit drug analysis for the purpose.

As a relatively new concept to analytical scientists, AQbD possess implicit challenges for implementation, particularly when it is not a strict regulatory requirement. There is no expectation of technology transfer or method validation, so a paradigm shift from traditional information-rich dossiers to scientifically sound and knowledge-rich documents is expected. Furthermore, worldwide harmonisation of AQbD terms and ideas, such as MODR, ADS or PAR, and ATP or QTMP, is required. Another problem in effectively harvesting QbD principles in the analytical arena is training human resources at the industrial and regulatory levels, necessitating specific criteria on recording of knowledge gained during method development. By using AQbd, the analytical technique makes it easy to acquire the optimum values, making further drug analysis easier. The present article is a humble attempt on our part to give essential yet comprehensive information on the growing concept, to strengthen existing comprehension of the concept, and to provide the required boost toward its fruitful implementation in the pharmaceutical environment. In many ways the success of companies in the near future may be a direct by-product of their ability to integrate the concepts of QbD. Such a systematic approach can enhance achieving the desired quality of the product and help the regulators to better understand a company’s strategy.