INTRODUCTION:

The word quality was derived from the Latin word ‘Qualitus’ that suggests excellence or totally different feature. Quality is nothing however the suitableness of either a drug substance or product for its desired purpose.¹ Quality is one in all the vital aspects while developing a new product in the pharmaceutical industry.²

To design quality product and its production technology are one of the main motives of pharmaceutical product development for continuously delivering desired performance of the product.³ In earlier days, the quality of the pharmaceutical products was solely supported its testing. From an entire batch of the pharmaceutical product, randomly a little quantity of the sample was taken for the aim of testing and then the results were analyzed and hence the quality of that product was taken under consideration. However, the quality of every unit of the dosage form is extremely vital in respect to the end user’s intended purpose. So, currently the concept of ‘Quality by design’ is to be initiated so that the quality is inbuilt by design.^4,5

Quality by design:

Quality by Design (QbD) is a current, scientific approach that standardizes product design, streamlines troubleshooting and automates manual testing. Rather than counting on finished product testing alone, QbD allow insights upstream throughout the development process. QbD requires the recognition of all critical formulation attributes and process parameters in addition as determinant the extent to that any variation may impact the quality or standard of the finished product.⁶

Definition [FDA PAT Guidelines, Sept. 2004]:

A method for planning, evaluating, and managing production through timely measurements (during processing) of vital quality and performance characteristics of novel and in-progress materials and processes, with the aim of assuring the safety of the finished product.^7,8

Definition [ICH Q8 (R1)]:

a methodical approach to development that starts with predetermined goals and places an emphasis on process control, product and process understanding, and reliable science.⁸

Objectives of Quality by design:

The main objective of QbD is to attain the standard quality products. Other objectives

are:

· To guarantee combination of product and process knowledge gained throughout the development.

· To bring off positive performance testing.⁹

· To increase product development and production efficiencies.

· To enhance product capability and scale back variability.

· To enhance root cause analysis and post-approval modification management.¹⁰

· To facilitate innovation and continuous improvement throughout the product life cycle.

· To offer regulative flexibility for specifications setting and post-approval changes.

· To come through significant product quality specifications that’s supported clinical trials

History:

Dr. Joseph M. Juran, Father of Quality describe the term Quality by Design (QbD) in 1992. Then in early 2002 the FDA announced a new initiative (cGMP for the 21stcentury: A risk-based approach). In addition to this, two vital instructions documents were bring out as a part of international conference on harmonization (ICH) guidelines: which are Q8 pharmaceutical development and Q9 quality risk management.

Figure No.1: Quality by design

QbD needs a comprehension of how product and process variables affects the quality of product. This initiative planned to update the FDA’s regulation of pharmaceutical quality and set up a new regulatory framework targeted on QbD, risk management and quality systems.¹²

Foundations of QbD:

ICH Guidelines Q8 for Pharmaceutical Development, Q9 for Quality Risk Management, Q10 for Quality Systems are foundation of QbD.^13-16

Figure No.2: Foundation of QbD

Regulatory Aspects to QbD:

According to ICH Q8 (R), Step two “QbD is that the systematic approach to development that begins with predefined objectives and highlights on product and process understanding and process control that is predicated on sound science and quality risk management”. The regulatory agency expects that drug substances, container closure systems, excipients, manufacturing processes and all other aspects which are condemnatory to product quality should be defined and control strategies should be established. Regardless of the information and the data which is gained throughout pharmaceutical development studies, producing experience should provide scientific understanding to initiation of the design space, specifications, and manufacturing controls. It is important to note that quality can’t be tested into product rather than it should be built by design. Changes in manufacturing and formulation process throughout development and lifecycle management should be focus upon as opportunities to realize further knowledge and more support the institution of the design space.¹⁷ Also, the information gained through the experiments, is useful for incorporation. ICH Q8, Q9, Q10 offers necessities regarding the quality of the pharmaceutical Product.

The concept of QbD has been implemented in the pharmaceutical industry by initiatives such as the FDA’s current good manufacturing practice (cGMP) for the 21st century and process analytical technology (PAT). Implementation of Analytical Quality by Design [AQbD] is forecast to make up the concept of “right analytics at right time” that plays a vital role in the process of development of the drug product. Couple of months ago, the FDA had made approval for a few NDA assisted AQbD and referred the significance and utilization of QbD in the analytical method development.¹⁸

It activates the role of analytics in the process of product development cycle for comprehensing drug excipient interactions and to compute the critical quality attributes (CQAs) during experiment, process, control and also continuous process verification so as to monitor tendency within the product quality. ICH Q8 (R2) guidelines do not discuss analytical method development in association with design space; also, it recognizes that the concept can be applicable to analytical design space and continuous development in method robustness and understanding. Quality assurance personnel trust that AQbD is very important to avoid Out of Trend and Out of Specification and hence the chances of failure of methodology. Due to the above cited reason the analytical method development by using QbD approach is an important area of center and needs to be accomplished. The increase in dependence of pharmaceutical development and manufacture on study analytical data intensifies the need for rigor in analytical method development and ultimately increases in an AQbD.¹⁹

Elements of QbD:

Figure No.3: Elements of QbD

1. Quality Target Product Profile [QTPP]

2. Critical Quality Attributes [CQA]

3. Risk Assessment

4. Design Space

5. Control Strategy

6. Lifecycle Management

1. Quality Target Product Profile:

FDA recently published a guideline which defines a target product profile [TPP]. The target product profile has been defined as a “prospective and active summary of the quality characteristics of a drug product that preferably will be attained to secure that the desired quality and hence the safety and efficacy, of a drug product is realized”.²⁰ The Target Product Quality Profile (TPQP) is a terminology that is a natural augmentation of TPP for product quality. It is nothing but the quality characteristics that the drug product should possess in order to consistently deliver the therapeutic effect which is expressed in the label claim. It includes dosage form, dosage form strength, route of administration, therapeutic moiety release or delivery and pharmacokinetic characteristics relevant to the drug product dosage form being established and drug product-quality standard relevant for the intended marketed product.²¹ TPQP is related to identity, assay, dosage form, purity, stability in the label claim.²²

2. Critical Quality Attributes:

A CQA is defined as physical, chemical, biological or microbiological characteristics that need to be within an appropriate limit to secure the specified product quality. When the QTTP has been recognized then the step ahead to be taken is to point out for the relevant CQAs. The CQA is that the crucial part in the QbD and it is usually correlated with the intermediate, raw materials and the drug products. It’s a subgroup of the QTTP that makes modifications with the change within the completely different variables of the formulation.^23,24

3. Quality Risk Management:

It is very foremost to decide the manufactures for study that to be conduct. It helps in connecting the quality attributes as well as process parameters to CQAs. The assessment of the quality risk should be construct on the both scientific knowledge as well as therapeutic benefit to the patient.25

Various tools that are involved in Risk Assessment are as follows:

· Failure mode effects analysis (FMEA)

· Fault tree analysis (FTA)

· Failure Mode, Effects and Criticality Analysis (FMECA)

· Hazard analysis and critical control points (HACCP)

· Probabilistic Risk Analysis [PRA]

· Hazard and Operability Analysis [HAZOP]

· Decision Trees [DT]

· Root Cause Analysis [RCA]

4. Design Space:

A design space is a multidimensional amalgamation and interlinkage of input variables that have been indicated to provide assurance of quality. The relation between the process inputs and critical quality attributes is explained in the design space. Risk assessment can lead to realize the interconnection and effect of process parameters and material attributes on product and range for variables with in which uniform quality can be achieved. These variables or characteristics are chosen to be included in the design space. Examination of historical data can allow the set up for demonstrating a design space. How a design is established, it is anticipated that operation within the design space will result in a product should meet its quality.²⁶

Design space is suggested by applicant is subjected to regulatory evaluation and approval to ICH Q8. The applicant can select to demonstrate independent design space that crosses numerous operations. A design space, the applicant should consider the desired level of operational flexibility. A design space can be established at any scale. When design space is clarified then we are capable to plan control process.²⁷

5. Control Strategy:

Control strategy is a set of control, that is acquired from present product and process understanding that secures the process performance and quality of product. It helps in eluding defect and maintains preferred quality. Control strategy is essential to make sure that material and process are within its specified limits.²⁸ A control technique integrates the information material controls, process controls and noticing structure space throughout individual or numerous unit activities, as well as specific item determinations used to assurance the specified quality.^29,30

The Control strategy consists of the process and input material control and

monitors the design space to identify the final product that ensures the desired quality.³¹

Components of control strategy are as follows:

· Procedural control

· Comparability testing

· In-process controls

· Constancy testing

· Batch release testing

· Process monitoring

6. Life Cycle Management:

In the QbD model, process modification within the design space will not need scrutiny or assent. Therefore, process development during the product life cycle with respect to process uniformity and productivity could take place with hardly any post approval submissions. In addition to regulatory pliability, the increased comprehension of the manufacturing process would permit more well-informed risk evaluation as per ICH Q9 concerning the affects of process modifications and manufacturing divergence on the product quality^32-34

Continuous development is a crucial component in modern quality system. QbD concentrates on quality into the product, as well as continuous process development depletion of variability³⁵

QbD in Analytical Method Development and Validation:

Analytical Quality by Design (AQbD) is a systematic approach to design the methods that begin with describing the separation goals and target method profile. Comprehension of method parameters and controls, build on sound science and quality risk management are the focus of attention in Analytical Quality by Design.³⁶ Analytical procedure is fully unified into the QBD paradigm and is a crucial step in developing technique which used for applications. The primary goal is to interpret the motive of the analytical method that begins with validation and its measure of fitness. A method validation is a three-stage proposition. Method design explains requirements and conditions and identifies critical controls. Method qualification certifies that the method is capable of meeting its design purpose. Continued method verification gains ongoing assurance to make sure that the method remains in a state of control during routine use.

Following steps are involved in QBD to an analytical approach:

1. Analytical target profile

2. To determine the critical quality attributes (CQAs)

3. Risk assessment

4. To design and implement the control strategy

5. Management of product life cycle and continual improvement.³⁷

Importance of adopting QbD for analytical method

· It gives more transfer success when the method is transferred from research level to quality control department.

· It allows greater concurrence with regulatory authorities.

· Design space idea eludes the post-approved changes which may cause to pay a higher interest for any of the firm.

· The development method will be more robust which gives more confidence in case of variation in conditions.

^·It helps for increase comprehension of the method.³⁸

Analytical QbD Method Validation^39-41

A QbD method validation proposition is that the validation of analytical method over a distinct API batch. It uses Design of Experiment and Method Operable Design Region understanding for designing method validation for all types of API manufacturing modification without revalidation. It allows the required ICH validation components and information on interactions, measurement uncertainty, control strategy, and continuous improvement. This approach requires less resource than the traditional validation approach without adjusting the quality.

QbD can be enforced for various analytical methods which consist:

1. Chromatographic techniques like HPLC for forced degradation studies, method development, and determination of impurities in pharmaceuticals.

2. Moisture content can be determined using the Karl Fischer titration.

3. Vibrational spectroscopy for identification and quantification of compounds e.g., UV method.

4. Chromatographic techniques like HPLC for stability studies, method development, and termination of impurities in pharmaceutical.

5. To Biopharmaceutical processes.

6. Dissolution studies.

7. Hyphenated technique like LC-MS.

8. Advanced techniques like mass spectroscopy, UHPLC, capillary electrophoresis.

9. Analysis of genotoxic impurity.

Tools of Quality by Design:

The tools of Quality by Design are as follows:

1. Design of Experiment [DOE]:

Design of experiments (DOE) is an integrated and organized method to set on the correlation among factors that affects outputs of a process. Application of DOE in QbD aid in acquiring more information from a smaller number of experiments. It has been recommended that DOE can provide returns that are four to eight times more than the price of putting the experiment in a part of the time. As each unit operation has many independent and dependent variables as well as process parameters, it is not feasible to experimentally examine all of them. DOE can support to recognize optimal conditions, the crucial factors that mostly affect CQAs and those who do not.^42-45 Choosing the best experimental design should observe several aspects, such as specified objectives, number of independent variables and interactions to be considered, and statistical rationality and effectiveness of each design. In order to allow a better knowledge of DoE application, experimental designs may be divided into two types:

a. Screening designs

^b.Optimization designs^46-48

a) Screening Design:

Two-level full factorial designs fractionate factorial designs, and Placket-Burman designs are the most commonly used screening design due to the advantage of their cost effectiveness. Two-level full factorial designs are one of the most powerful screening designs, as it allows to evaluate main effects of input factors and their interactions on output responses. The main restriction of two-level full factorial designs is that it depends on the large number of experiments required as compared to the fractionate factorial designs and Plackett-Burman designs. Fractionate factorial designs are one the most commonly used for screening purposes, because these designs allow the estimation of large number of independent variables with a decreased number of experiments required. Screening designs are frequently used in the first step to Design of Experiment in order to select the most important input factors and reject the unimportant ones. Pareto charts are helpful mechanism to attain this objective because they permit to put the input factors (and their interactions) in order of significance.

b) Optimization Design:

Three-level full factorial designs, central composite designs, and Box-Behnken designs are the most commonly used optimization designs because they permit modeling complex response surface. The most important restriction of screening designs are that it depends on the fact that they only permit modeling first order (linear) response surface, because they have only two level for each input factor. Optimization designs uses three to five levels of each input factors, which permit modeling second order (quadratic) response surface. Box-Behnken design are distinct types of three-level fractionate factorial designs, which permit modeling first and second order response surfaces. These designs are more cost-effective as compared to the three-level full factorial designs, specifically for large number of input factors.

Defining Design Space [DS]/Method Operable Design Space [MODS]:

Design Space (DS) is a multifaceted combination and interaction of input factors (usually Critical Material Attributes and Critical Process Parameters) that had been proved to allow assurance of quality and subsequently safety and the efficacy. Moving the independent variables in the design space regions are not examined a modification subject to notification, which secures regulatory pliability.⁴⁹ In analytical QbD, Method Operable Design Region (MODR) is the multifaceted combination and interlinkage of analytical conditions that have been indicated to allow assurance performance of analytical method.⁵⁰

2. Process Analytical Technology [PAT]:

PAT is a progressive tool for designing, analyzing and controlling Pharmaceutical Manufacturing Process through timely estimation of Critical Quality and performance attributes for raw material and in process materials and processes with the aim to secure specified product quality. Concept is based on recognition and control of risks during the production of drug product.⁵¹ For the purpose of comprehension scientific, risk-managed pharmaceutical development, manufacture and quality assurance many tools are accessible in the Process Analytical Technology framework. These tools can be classified as follow:⁵²

1. Multivariate tools for design, data acquisition and analysis

2. Process analyzers

3. Process control tools

4. Tools for knowledge management and ongoing improvement.

Different levels of PAT Implementation:

Primary stage is to capture the Manufacturing Process Parameters. Scale up stage is the estimation of process parameters data. Provisional Stage is Process Understanding. Permanent Stage is real process monitoring and process control by executing PAT Tools.

Importance of PAT:

It successfully constructs quality into products; also abolish the process variation resultant into process safety. It also aids to recognize the production process and its control in totality.

PAT Analysis is preferred over conventional Laboratory Analysis:

There are some of the reasons which explain why the Process Analytical

Technology is preferred over the conventional laboratory analysis that are as follows:

· Faster or online results are available, which helps to take the decision to release the batches for the consumption

· PAT eliminate the Human error

· It is safe to product, Human and Environment

· It increases the productivity

· During analysis sample integrity exists^53,54

One Factor at a time vs QbD in Analytical Method Development:

In present practices, chromatographic methods are more often working as right analytics at all the stages during the product life cycle. In present days, method failure is becoming more usual mostly during method transfer as well as in the quality control departments. It is supposed to be due to the anomaly given for robust test compliance by ICH Q2 guidelines. Ordinary analytical methods for content uniformity, assay, impurity profile, and stability indicating assay are based on High Performance Liquid Chromatography or Ultra Performance Liquid Chromatography or rapid resolution liquid chromatographic methods (RRLC). On the other hand, in current practice, the executed analytical methods were based on one-factor-at-a-time (OFAT), in which one parameter alone is optimized for the anticipated response while others remained constant.⁵⁵ The present technique of analytical method i.e., one-factor-at-a-time development has high risk in method negligence and consistently requires revalidation protocol after method transfer or alternative method development; hence it has been increasing the cost of the method. The Analytical Quality by Design inspect scientific understanding in method implementation sequences and starts with product quality that relates the risk assessment in method choice and then between method parameter and anticipated method results and finally a region for high study and economical approach.

CONCLUSION:

Quality by design is based on guidance and some reference documents to enhance process knowledge. These documents help in understanding how formulation and manufacturing process variables influence product quality and it ensures the product quality with effective control strategy. Pharmaceutical Quality System (PQS) is the foundation for ongoing improvement. It helps to identify and implement appropriate product quality improvements, process, improvements, variability improvements, thereby enhancing the capability to satisfy the quality. QbD is required for improved product and process design and understanding and its more efficient regulatory oversight. In that all quality attributes are the targeted elements of drug product which achieved through good quality management system appropriate design, manufacturing and development, QbD tools also helpful for drug development and design without defects it ensures the well economical manufacturing method for coherent production of quality drugs.

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Received on 05.04.2023 Modified on 13.06.2023

Asian J. Pharm. Ana. 2023; 13(3):190-196.

DOI: 10.52711/2231-5675.2023.00031