INTRODUCTION:

In every product or service, quality is important, but in medicine it is vital as it involves life. Unlike other consumer products, no second quality may exist and does not exist. Therefore analytical methods which are a measure of quality of the drugs play a very comprehensive role in drug development and follow up activities, to assure that a drug product meets the established standard, are a stable and will continue to meet purported quality throughout its shelf life. The number of drugs introduced into the market is increasing every year. These drugs may be either new entities or partial structural modification of the existing one. There is most frequently a lag from the date of marketing of the drug to the date of its inclusion in pharmacopoeia. This arises because of the potential continuous uncertainties and the broader use of these drugs, new toxicity reports (resulting in their removal from the market).

Very often there is a time lag from the date of introduction of a drug into the market to the date of its inclusion in pharmacopieas. This happens because of the possible uncertainities in the continoues and wider usage of these drugs, reports of new toxicities (resulting in their withdrawal from the market). Development of patient resistance and introduction of better drug by compitators. Under these conditions standarads and analytical procedures for these drugs may not be available in the pharmacopiea. It became necessary to develop newer analytical methods for such drugs using QbD pharmaceutical quality^1,2 is assured by understanding and controlling the formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry manufacturing controls (CMC). Review of abbreviated new drug applications (ANDA) in to a science based pharmaceutical quality assessment.

Quality by Design:

As per ICH, QBD describes "a systematic development approach that starts with predefined goals and emphasizes the understanding of goods and processes and process control, based on sound science and risk management of quality." A QBD has numerous instruments, such as Analytical Target Profile (ATP), Critical Quality Attributes (CQA), Risk Assessment, DOE Process Optimization and Development, MODR (Operable Design Area Process), Control Strategy and Risk Assessment, Validation of Analytical QBD System

Pharmaceutical QBD is a systematic, analytical, risk-based, comprehensive and pragmatic approach³ to pharmaceutical production that starts with predefined goals and emphases product and processes understanding and process control. It means designing and developing formulations and manufacturing processes to ensure predefined product quality objectives. From the perspective of patients, QBD defines characteristics that are crucial to quality, converts them into the qualities that the drug product should possess, and decides how the essential process parameters can be varied to deliver a drug product with the desired characteristics consistently. In order to do this the relationships between formulation and manufacturing process variables (including drug substance and excipient attributes and process parameters) and product characteristics are established and sources of variability identified. This understanding is then used to introduce a scalable and stable production process that over time can evolve and produce a consistent product⁴.

Table 1: Pharmaceutical Aspects. Traditional Vs QbD

Featured Desired	Existing State	QbD state
Development	Experimental	Organized
Process	Threebatchesbatches reproducability	Control Strategy developed
Process control	Offline Analysis	PAT (process analytical technologies)
Specification	Based on batch data	Based on product presentation
Control policy	Mainly by middle and finished product testing	Risk based testing
Management throughout life	Immediate to troubles required post approval changes	Continual improvement throughout changes

According to USFDA guidance, QbD approach for analytical methods can be implemented through six steps

Fig. 1: QbD approach for analytical methods

Table 2: Applying QbD principles to Analytical Procedures

Product development	Analytical Procedure Development
Quality Target product profile	Analytical target Profile
Risk Assessment	Risk Assessment
Critical Quality Attributes	Critical procedure Attributes
Design Space	Method Operable Design Region
Control Strategy	Analytical procedure Control strategy
Continued Process Verification	Continued procedure verification

Strategies of Analytical Method Development^5,6

The key application of the quality-by-design (QbD) principles to the development⁵ of the analytical method is concentrated during its development on the theory of the building of quality into the analytical method. Because of this, a systematic approach should be adopted by the actual method creation process for an analytical quality by design (QbD) method. The objective of the development of the QbD method is to comply with predefined goals.

1. Analytical target profile (ATP):

Establishment of ATP can be achieved thorough identification of the analytical target, sample condition and setting up the quantification criteria as per the method intent. The selection of an analytical target is based on the method goal. The purpose of the system signifies the final standard that regulatory authorities want. A thorough survey of literatures and study of chemical properties is vital for selection of a target. QbD is beginning with an analytical target profile, which is a linear to QTPP. Analytical target profile defines the aim of the analytical method development process, relating the results of the method to attain QTPP. ATP describes the method requirements which are expected to be the measurement. The analytical target profile is specifying with the help of knowledge and scientific reason of the analytical process. The ATP defines to what level the measurement is needed (i.e. functioning level characteristics, such as precision, accuracy, range, and sensitivity) and what the method has to measure (i.e. acceptance criteria). Generally, ATP for analytical procedure contains a selection of target analytic (API and impurities), selection of analytical technique (HPLC, HPTLC, gas chromatography, ion chromatography, etc.) and method requirements (assay and impurity profile).

2. Critical quality attributes (CQA):

CQA is the second step of QbD. According to ICH Q8, CQA is defined as a physical, chemical, biological property that should be within an appropriate limit, range to ensure the desired product quality. CQA for analytical method consists of method parameters and method attributes. The analytical technique of CQA can differ from one to another.

· CQA for the GC method is the temperature of the oven and its program, injection temperature, gas flow rate, sample diluents, and concentration.

· CQA for the HPLC method is mobile phase buffer, pH of the mobile phase, column selection, organic modifier, and elution method.

· CQA for HPTLC method is TLC plats, mobile phase, Injection concentration and volume, time taken for plate development, areagent for color development and detection.

3. Risk Assessment:

When CQA has been studied, the next step is to describe the relevant risk assessment, once the technique is identified, analytical QbD focuses on the assessment of the risk associated with variability includes analyst method, instrument configuration, measurement⁷ and method parameters, sample characteristics, sample preparations, and environmental conditions. According to ICH Q9 guidelines, risk assessment is a systematic process for the assessment, control, communication and review of risk to the quality across the product life cycle. Risk identification, risk analysis, and risk evaluation are the three step of risk assessment.

Different steps of Risk Assessment:

The first step is important to identify and prioritize potential risk. These risks include methods of operation of the instrument, characteristics of the reagent and cycle time. It is most desirable to determine a contingent method in case the primary method fails. Flow chart and check list are used to describe the risk factor.

The second step of risk assessment, also called Ishikawa. According to this approaches the risk factor is divides into three categories- high risk factor, noise factor and experimental factor.

4. Method operational Design region:

Once method development and risk assessment have been identified the next step is method operational design region. MODR is used to method development operational region for daily operation. MODR is based on science, risk-based and multivariate approach to measuring the effect of various factors on method performance. It is also used to set up important method control such as system suitability, RRT and RRF.

5. Control strategy:

The control strategy is the control design set. It is calculated from the analyst nature and MODR understanding. The method control strategy can be set up on complete statistical data collected⁸ during the MODR. The control strategy is not forever a onetime practice that is performed during the method development phase but it can get changes with different phases of the method lifecycle. It is noted that the method control strategy of QbD approaches does not differ from conventional approaches.

6. Lifecycle management:

Lifecycle management is the last step of QbD. It is a continuous process of sharing knowledge gain during the method development phase includes the final result of risk assessment; assumption based anterior knowledge, MODR, control strategy CQA and analytical target profile. The lifecycle management of QbD approaches different from conventional approaches.

7. Experimental design:

The experimental design is a statistical approach to systematize the experiments⁹ so that the requisite information is obtained precisely and efficiently, before the conduct of experimental studies. Prior to the selection of an apt experimental design, it is important to demarcate the experimental domain or region of interest within a factor space.

7.1 Design of experiments:

The process of determining the most suited composition and operating conditions is called optimization. The term optimizes literally means to bring something as close to perfection as possible. A number of variables are involved in the design and development of pharmaceuticals. The variables that can be controlled by the manufacturer are called independent variables/ factors and these independent variables have the potential to influence the characteristics of the analytical method and outputs. Levels are the values of the factors. The properties exhibited by finished products are termed as response variables or dependent variables. Any change in independent variables leads to a corresponding change in the dependent variables. DoE has evolved into a powerful tool that elegantly provides a large number of information with the least runs.

Benefits of Implementing QbD For FDA¹⁰:

· Strengthens the theoretical basis for examination

· Using assets to handle greater risks

· Provides better alignment of review, enforcement and inspection during

· Enhances data in regulatory submissions

· Ensures more quality

· Improves review consistency (establishing a QMS for CMC)

· Provides greater decision-making flexibility

· Ensures scientific decisions and not empirical knowledge decisions

· Involves multiple decision-making disciplines

BENEFITS TO INDUSTRY^11-14:

· Ensures improved design of goods and less manufacturing issues

· Reduces the amount of output supplements required for post-market adjustments, based on understanding of process and risk and risk mitigation

· Allows new technologies to be applied to increase quality without regulatory oversight Allows for potential reduction of total production costs-less waste

· Ensures less hassle during evaluation-reduced shortcomings-faster approvals

· Improves contact with the FDA-Scie contract.

Vital Applications of QbD:

Stability indicating methods:

Garg et al.,¹⁵ reported a stability-indicating HPLC method for simultaneous determination of omeprazole and ketoprofen. The paper describes a unique experimental design approach by examining the controllable factors while blocking the uncontrollable factors like system-to-system variability to obtain better resolution between peaks. Pranali Yeram et al¹⁶ reported Stability indicating assay method for the simultaneous estimation of sofosbuvir and ledipasvir in bulk drugs and its formulation the method developed by QbD approach was stability indicating and can be conveniently used for quality control to determine the assay in Sofosbuvir and Ledipasvir. Nand K. Yadav et al¹⁷ reported stability indicating HPLC method for estimation of ketoprofen in bulk drug and proniosomal vesicular system. Acid, alkali, thermal degradation studies have been done. Peak purity and its degradation impurities using water HPLC systems and PDA detector.

Bio analysis of Drugs and Biological Sample Preparation:

Khurana et al.,¹⁸observed QbD-based development and validation of the bioanalytical UPLC method for docetaxel analysis in human plasma has been published. The CMPs, which influenced the responses, were found to be mobile phase ratio and injection length. Peak region, retention time, symmetry factor and theoretical plates. For selective analyte quantification, the QbD method showed optimum chromatographic state. Hasnain et al¹⁹ explained paper detailing the production and validation of the LC-MS / MS bioanalytical system for the quantification of fluoxetine in human plasma has been written. Assessment of responses such as retention time and peak area was carried out for the mobile phase flow rate, pH and mobile phase composition system variables. QbD implementation in this study showed a decrease in variability due to process variables and helped to achieve improved robustness of the system. Beg et al²⁰ studied a novel approach to the implementation of QbD to improve liquid-liquid nevirapine extraction from rat plasma was reported. The CMPs selected extraction parameters such as extraction time, centrifugation speed and temperature to achieve the maximum percentage of nevirapine recovery from rat plasma as a response.

Sample treatment:

Taevernier et al.,²¹ determined the optimal sample treatment protocol for bovine serum albumin containing Franz diffusion cell solutions achieving maximum BSA precipitation, AQbD has been successfully applied. The study showed that the content of formic acid and acetonitrile was found to have the highest effect on BSA sample precipitation.

Quantification of drugs and their impurities:

Ashok K. palakruthi et al.,²²found out a selective quantification of Telmisartan impurities without null, placebo intervention, thus affirming the stability which indicates the nature of the method. Highly selective, reproducible, precise and rapid is the proposed technique. For separation and quantification, the method developed was robust. Karmarkar et al.²³ observed chromatographic separation of amiodarone and its seven impurities, a QbD-based HPLC method was developed. Effects viz. of CMPs. On resolution among all the peaks for the impurities, organic phase composition, buffer pH, and column oven temperature and column lot were assessed.

CONCLUSION:

QBD is the development technique that should be adapted on the basis of product and design complexity and specificity, FDA promotes these methods to be used by the industry in their implementation, using QBD does not bring about any improvement in the regional regulatory process, but offers more versatile scientifically validated approaches to them and for which GMP I adherence is in any case

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Received on 01.10.2020 Modified on 12.03.2021

Research J. Pharm. and Tech 2022; 15(1):436-440.

DOI: 10.52711/0974-360X.2022.00072