University Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Chhatrapati Sambhajinagar. India
A methodical, risk- and science-based approach to pharmaceutical development, Quality by Design (QbD) places an emphasis on incorporating quality into products rather than depending just on end-product testing. It entails creating a Design Space backed by risk assessment and statistical tools like Design of Experiments (DoE), as well as defining the Quality Target Product Profile (QTPP), identifying Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), and Critical Process Parameters (CPPs). To make sure that analytical procedures are reliable, repeatable, and appropriate for their intended use, the Analytical Target Profile (ATP) is the first step in the Analytical Quality by Design (AQbD) architecture. regulations, support the QbD strategy for the creation of both products and analytical methods, including ICH Q8–Q14, allowing for continual improvement throughout the course of the lifetime. Greater product quality, less variability, economic effectiveness, and greater regulatory compliance are just a few benefits of using QbD principles. The historical development, essential elements, instruments, and procedures of QbD and AQbD are highlighted in this study, along with their significance in developing reliable analytical techniques that satisfy contemporary pharmaceutical quality requirements.
“A systematic approach to development that begins with predefined objectives and emphasises product and process understanding and processcontrol, based on sound science and quality risk management” [3]The basic concept of QbD is “The Quality cannot be tested into the product, but it should be built into it.” The design space is defined as a manufacturing area of the product, including Equipment, Material, and Operators and Manufacturing Conditions. The design space should be well defined prior to regulatory approval. [1]The pharmaceutical market has been considered as one of the highly regulated sectors, which has been continuously providing quality drug products for human use to provide desired pharmacotherapeutic effects for the treatment of diverse ailments. For the past few decades, however, the pharmaceutical industry has been continuously facing challenges in delivering quality drug products.[10]Quality has different definitions, which are often muddled. According to the FDA, pharmaceutical quality is attained when the product delivers clinical performance as mentioned in the label claim, no additional risk is introduced due to unexpected contaminants, and a robust manufacturing system is ensured. To ensure this, the FDA brought in the concept of “quality by design” (QbD) in the early 2000s. This concept came into being when it was realized that increased testing does not mean the enhanced quality of the product. Albeit, quality must be built into the pharmaceutical product.[1]In Quality by Design, Quality is important word. So Quality is “standard or suitability for intended use.” This term includes such attribute of the identity, potency, and purity.[2]The conception of “Quality by Design” (QbD) was outlined as an approach which covers a better scientific pharmaceutical industry aware of product Quality, Safety, and Efficacy. Product quality has been increasing by implement scientific tools known as QbD (Quality by Design).[3]USFDA has released specific QbD guidance for immediate and extended-release drug products as well as biotechnological products. Regulatory authorities are always proposing the implementation of ICH quality guidelines such as Q8, Q9, Q10 & Q11.[3]Quality has different definitions, which are often muddled. According to the FDA, pharmaceutical quality is attained when the product delivers clinical performance as mentioned in the label claim, no additional risk is introduced due to unexpected contaminants, and a robust manufacturing system is ensured. To ensure this, the FDA brought in the concept of “quality by design” (QbD) in the early 2000s. This concept came into being when it was realized that increased testing does not mean the enhanced quality of the product. Albeit, quality must be built into the pharmaceutical product.[3]
The Quality by Design (QbD) principle has its roots in the 1950s, while the core principles of quality management began to make waves in the 1970s with Joseph M. Juran formally introducing the QbD philosophy. In September of 2002, the USFDA embraced the QbD philosophy in its current Good Manufacturing Practices (CGMP). A year hence, in September 2003, the FDA released a progress report entitled Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach, and then the final report in September 2004. The FDA released the PAT (Process Analytical Technology) guidance within the same year, providing a guideline for innovative drug development, manufacturing, and quality control.In March 2005, the European Medicines Agency (EMA) released its Roadmap to 2010, which included strategic plans for regulation in the future. The International Council for Harmonisation (ICH) released Q8: Pharmaceutical Development and Q9: Quality Risk Management in November 2005 and Q10: Pharmaceutical Quality System in June 2008. In November 2009, ICH Q8(R2) updated the initial Q8 guidance. Concurrently, in January 2011, industry guidance on process validation was issued by the FDA, and in March 2011, the pilot scheme for parallel EMA-FDA assessment of QbD submissions was started.An ICH-endorsed guide to applying Q8, Q9, and Q10 was published by December 2011, followed in February 2012 by further considerations by the ICH Quality Implementation Working Group (IWG). Real-time release testing (RTRT) guidelines were launched in March 2012, previously referred to as parametric release. Subsequently, in April 2012, the FDA issued an example of QbD for Abbreviated New Drug Applications (ANDAs) on immediate-release dosage forms and, in May 2012, issued guidance on drug substance development and manufacture. The FDA and the EMA strengthened their partnership in August 2013 by launching a pilot program of parallel review of QbD applications. Guidelines for process validation describing data for filing purposes were released in February 2014. ICH Q14 was suggested in September 2017 to harmonize analytical method development following industry comments. The MHRA released a strategy for the incorporation of QbD principles in UK pharmaceutical guidelines in January 2018.In August 2020, ICH Q14 was published for public consultation, and by June 2021, the final ICH Q14 guidelines were formally set, looking to harmonize scientific approaches to analytical method development throughout the pharmaceutical industry. [6]
1) Steps in QbD for analytical method development
QbD- Quality by design; AQbD-Analytical quality by design; ICH-International conference on harmonization; 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; A QbD strives to achieve the predefined analytical.[6]
1) Analytical Target Profile (ATP)
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. [6]Analytical methods were designed using the quality by design methodology, and the analytical target profile (ATP) was utilized to specify the method performance requirements for the development and validation of analytical processes. An analytical target profile that is parallel to QTPP is the first step in QbD.[3]An ATP associate degree ATP would develop for every of the attributes outlined with in the management strategy. The Analytical Target Profile defines what the method has to measure and to what level the measurement is required (i.e. performance level characteristics, such as precision, accuracy, working range, sensitivity, and the associated performance criterion). Any method conforming to the ATP is considered suitable. The ATP will be regarded as the focal point in all stages of the analytical life cycle.[3]
2) Critical quality attributes (CQA)
A pharmaceutical manufacturing process is usually comprised of a series of unit operations to produce the desired product. A unit operation is a discrete activity that involves physical changes, such as mixing, milling, granulation, drying, compaction, and coating. A physical, chemical or microbiological property or characteristic of an input or output material is defined as an attribute. Process parameters include the type of equipment and equipment settings, batch size, operating conditions (e.g., time, temperature, pressure, pH, and speed), and environmental conditions such as moisture. The quality and quantity of drug substance and excipients are considered as attributes of raw materials. During process development, raw materials. The purpose of these studies is to determine the critical raw material attributes, process parameters and quality attributes for each process, and to establish any possible relationships among them. Critical quality attributes (CQA) are physical, chemical, biological, or microbiological property or characteristic that must be controlled directly or indirectly to ensure the quality of the product.[8]Factors that directly affect the quality and safety of the product are first sorted out, and their possible effect on method development is studied. Understanding the product and method will help to sort the CQA. If a drug product contains an impurity that may have a direct effect on the quality and safety of the drug product it is being considered the critical quality attribute for the HPLC method development of that particular drug compound. [9]
3) Critical material attributes (CMA)
A CMA-based DS is sufficient to assure pharmaceutical quality since fluctuations of CPPs affect CQAs through CMAs. While the CMA is not defined by ICH, there is a description for the practical contribution of in-process material attributes to CQAs in ICH Q8(R2): ‘‘CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) and drug product’’.[15]It is necessary to identify the quality attributes that are critical, i.e. those defining purity, potency and surrogate for Bioavailability Criticality etc. It is based on the impact of quality attribute/ parameter on the safety, efficacy & quality (manufacturability) of the product.[1]A material attributes is critical when a practical change in that attribute can significantly impact the quality of the output material. CPPs are responsible for ensuring the CQAs & it is identified from a list of potential CPPs using risk assessment. A process parameter is critical when it has a high impact on a critical quality attribute.[3]
4) Critical process parameters (CPP)
This implies that any quantifiable information or result of a strategy step should be overseen to accomplish the necessary item quality and technique consistency. Everything in this read would be a strategy boundary. This is the way it'd work. The parameters are inspected previously or during systems that can affect the completed product's appearance, virtue, and yield.[11]
1. RISK IDENTIFICATION: by Ishikawa Fishbone
2. RISK ANALYSIS: by Relative Risk based Matrix Analysis
3. RISK EVALUATION:by Failure Mode Effective Analysis. [13]
The ICH guidance Q8 [6] defines the design space as “the multidimensional combination and interaction of input variables and process parameters that have been demonstrated to assure quality.” Further, it is stated that: “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.” [4]Design space is a multidimensional region of interest within the region of operability (also known as knowledge space). It is constituted of the levels of CMAs with the CQAs. Both mathematical and graphical approaches can be used for submitting the design space to the regulatory agencies. There can be multiple variants of design space such as laboratory scale, pilot scale, and commercial scale design space. However, the commercial scale design space is the one that has real regulatory importance. Within the design space, a narrower and more constrained region is identified in-house for tighter control on product and process parameters, which is also called the control space. However, the control space has no regulatory importance with respect to the review process and acceptance. illustrates the interrelationship among various spaces like knowledge, design, and control spaces.[10]Design space is described as a “multidimensional combination and interaction of input variables, a design space may be generated for a single operation, multiple operations, or the whole process (e.g. material attributes and process parameters) that have been demonstrated to provide quality assurance.” According to FDA guidelines, defining design space is optional since product and process understanding can be defined without one. However, the above approach can aid in better understanding and overall system control.[7]
A control strategy outlines the measures needed to maintain product quality. It includes monitoring systems, specifications, and operational controls to ensure processes remain within the design space.[14]It is important that the set method performs as intended and consistently gives accurate results, for that purpose control of the method is required. A factor identified to have risk has to be controlled. More attention is given to the high-risk factors. System suitability, the risk assessment can also help identify a specific control strategy.[9]
Based upon CONTINUAL RISK REVIEW & RISK COMMUNICATION BETWEEN PLANT, QA, QC, RA, R&D, AR&D during routine commercial manufacturing experience.[13]Life cycle management is a control strategy used for implementation of design space in commercial stage. CMM is final step in A QbD life cycle it is an continuous process of sharing knowledge gained during development and implementation of design space. This includes results of risk assessments, assumptions based on prior knowledge, statistical design considerations and bridge between the design space, MODR, control strategy, CQA, and ATP. Once a method validation completed, method can be used for routine purpose and continuous method performance can be monitored. This can be performed by using control charts or tracking system suitability data, method related investigations etc. CMM allows the analyst to proactively identify and address any out-of-trend performance. [8]The life cycle approach differs from that of the traditional approach of method development. According to More field, it includes continuous improvement of method performance and the design space allows flexibility for Continuous improvement in the analytical method can be done without prior regulatory approval because of design space made previously. [9]
|
Product Quality By Design (Qbd) |
Analytical Quality By (Aqbd) |
|
|
1 |
Definition of the quality target product profile (QTTP) |
Definition of the analytical target profile (ATP). |
|
2 |
Critical quality attributes (CQA) |
Critical performance attributes (CPA) |
|
3 |
Risk assessment of crucial process parameters and material characteristics |
Risk assessment of the critical method parameters and attributes |
|
4 |
Experimentation design and design space development |
Designing of Experiments and Development of Method Operable Design Region (MODR) |
|
5 |
Validation of manufacturing processes |
Analytical method validation |
|
6 |
Implementation of control strategy |
Implementation of control strategy |
Role Of Qbd Analytical Method Development
Analytical method development is the process of creating procedures to accurately measure compounds or properties. QbD in analytical method development involves designing methods that are reliable, reproducible, and suitable for their intended purpose.[14]Implementation of QbD helps to develop rugged and robust/strong method that helps to go with ICH guidelines hence for that reason pharmaceutical industries are adopting this concept of QbD. This approach facilitates continuous improvement in method.[3]The QbD approach must accurately map product attributes to process parameters by ensuring the product’s area of design’, a space with several dimensions consisting of various qualities, is identified and explained.[19] numerous ideas related to analogous concepts in creating analytical methodologies can be associated with quality by design (QbD) in the manufacturing process [16, 17]. Analytical QbD (AQbD commences with the analytical target profile (ATP), which outlines the measurement’s intended purpose. It then highlights the importance of fully comprehending the analytical system through a detailed examination of the critical method parameters (CMPs), which are founded on multifaceted analysis and evaluation of risk methods. The multidimensional region of the CMPs’ successful operating ranges, which pro duces the intended values for the critical method attributes (CMAs), is known as the design space (DS). [12]
Tool &Technique In Qbd For Analytical Method Development
Scientific approaches can offer the clear and sufficient knowledge from product development to manufacturing. These QbD tools will minimize the hazard by increasing the output and quality. Nowadays QbD approach has been successfully enforced in common formulation development.[3]Semiquantitative tools for risk ranking include fail are mode and effects analysis (FMEA/FMECA), relative ranking, and failure mode effects and criticality analysis. In ICH Q9, various kinds of tools for risk assessment are mentioned, including failure mode and effect analysis (FMEA), comparison matrix (CM), risk estimation matrix (REM), hazard operability analysis (HAZOP), and hazard analysis critical control points (HACCP), REM and FMEA are the methods most frequently used in product development. While, FMEA uses scoring on a scale of 1–10 for risk ranking based on severity, occurrence, and detectability, REM uses different risk levels, i.e., low, medium, and high-risk ratings depending on their severity and occurrence.[5]
|
Stage /Tool. |
Purpose |
|
Analytical Target Profile (ATP) [1,2] |
Clearly outlines the goals, performance traits, and acceptability standards of the analytical approach. |
|
Risk Assessment (CQA / CMP mapping) [3,4] |
Identifies critical quality characteristics (CQAs) and critical method parameters (CMPs) that most influence method performance. |
|
Design of Experiments (DoE) [5,6] |
Statistically organize and plan trials to effectively investigate the connection between CMPs and CQAs. |
|
Response Surface Methodology (RSM) [6,7] |
builds mathematical models to maximize several outputs at once and assess factor-response correlations. |
|
Method Operable Design Region (MODR) [2,8] |
identifies the multifaceted operational environment in which the technique reliably satisfies ATP requirements. |
|
Control Strategy & Continuous Method Monitoring (CMM) [1,9] |
creates monitoring, control, and check systems to guarantee that method performance stays within predetermined bounds during its lifecycle. |
|
Software & Chemometrics [7,10] |
supports data modeling, prediction, and optimization through the use of statistical software and multivariate analysis tools. |
Design of experiments (DOE) is a structured and organized method to determine the relationship among factors that influence outputs of a process. When DOE is applied to pharmaceutical process, factors are the raw material attributes (e.g., particle size) and process parameters (e.g., speed and time), while outputs are the critical quality attributes such as blend uniformity, tablet hardness, thickness, and friability. As each unit operation has many input and output variables as well as process parameters, it is impossible to experimentally investigate all of them. Scientists have to use prior knowledge and risk management to identify key input and output variables and process parameters to be investigated by DOE. DOE results can help identify optimal conditions, the critical factors that most influence CQAs and those that do not, as well as details such as the existence of interactions and synergies between factors. Based on the acceptable range of CQAs, the design space of CPPs can be determined. When considering scale-up, however, additional experimental work may be required to confirm that the model generated at the small scale is predictive at the large scale. This is because some critical process parameters are scale dependent while others do not. The operating range of scale dependent critical process parameters will have to change because of scale-up. Prior knowledge can play a very significant role in this regard as most pharmaceutical companies use the same technologies and excipients on a regular basis. Pharmaceutical scientists can often take advantage of past experience to define critical material properties, processing parameters and their operating ranges1.[8]
MODR (Method Operable Design Region):
Method operable design region (MODR) is used for establishment of a multidimensional space based on method factors and settings MODR can provide suitable method performance. It is also used to establish meaningful method controls such as system suitability, RRT, RRF etc. Further method verification exercises can be employed to establish ATP conformance and ultimately define the method operable design region. [8]
Process Analytical Technology (PAT)
PAT has been defined as “A system for designing, analyzing, and controlling manufacturing through measurements, during processing of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality”. The goal of PAT is to “enhance understanding and control the manufacturing process, which is consistent with our current drug quality system: quality cannot be tested into products; it should be built-in or should be by design.” The design space is defined by the key and critical process parameters identified from process characterization studies and their acceptable ranges. These parameters are the primary focus of on-, in- or at-line PAT applications. In principle, real-time PAT assessments could provide the basis for continuous feedback and result in improved process robustness. NIR act as a tool for PAT and useful in the RTRT (Real Time Release Testing) as it monitors the particle size, blend uniformity, granulation, content uniformity, polymorphism, dissolution and monitoring the process online, at the line and offline, thus it reduces the release testing of the product. [17]
The pharmaceutical industry and regulators can evaluate and manage risks by using well-known risk management tools and/ or internal procedures such as,
• Basic risk management facilitation methods (flowcharts, check sheets etc.);
• Failure Mode Effects Analysis (FMEA);
• Failure Mode, Effects and Criticality Analysis (FMECA);
• Fault Tree Analysis (FTA);
• Hazard Analysis and Critical Control Points (HACCP);
• Preliminary Hazard Analysis (PHA);
• Risk ranking and filtering. [17]
Ensures better design of products with fewer problems in manufacturing
Better development decisions & Empowerment of technical staff [19]
QbD is a methodical and proactive approach to the development and production of pharmaceuticals. By integrating quality into the design of processes and products, QbD offers numerous advantages that extend beyond mere compliance with regulatory standards. These advantages include enhanced product quality, cost savings, improved efficiency, and better risk management. Let’s explore these benefits in detail.[14]
Advantages Of Qbd For Industry:
The design space principle eliminates post-approval modifications, which may result in a high price for all of the firm’s products.When transferring a system from the study level to the quality control department, this technique has a higher success rate.Continuous manufacturing offers several key advantages over batch manufacturing including streamlined manufacturing timeline, flexible production volumes, enhanced product quality and reduced manufacturing costs. These merits make continuous manufacturing a promising technology that can overcome challenges, such as unnecessary product recalls and drug shortages, and modernize pharmaceutical manufacturing. However, due to the difficulties in understanding disturbance propagations in integrated processes, quality assurance has been a challenge of continuous manufacturing.[15]
Advanced Technologies: Integration of Advanced Analytical Tools and Technologies:
Integration of Advanced Analytical Tools:
Role in QBD:
- Integration: Advanced analytical tools, such as high-throughput screening, omics technologies (genomics, proteomics, metabolomics), and sophisticated spectroscopic methods, play a pivotal role in QBD.
- Enhanced Understanding: These tools enable a more comprehensive understanding of critical quality attributes (CQAs) and critical process parameters (CPPs). The integration of real-time monitoring tools enhances the ability to analyze complex data sets, providing insights into the relationships between variables.[16]
QbD transforms analytical method development by providing a structured, scientific approach that enhances method reliability, robustness, and efficiency. By focusing on understanding and controlling critical variables, QbD ensures that analytical methods meet the highest standards of quality and performance. The applications of QbD in analytical method development span various techniques, including chromatography, spectroscopy, biopharmaceutical assays, and dissolution testing. Through systematic experimentation, risk assessment, and continuous improvement, QbD enables the development of methods that are well-suited to their intended purposes, compliant with regulatory requirements, and capable of delivering consistent results. As industries continue to adopt QbD principles, the benefits of enhanced quality, efficiency, and innovation will drive success and competitiveness in an increasingly demanding global market.The Quality by Design (QbD) approach represents a paradigm shift from traditional analytical method development by emphasizing the integration of quality into the design phase rather than relying solely on end-product
REFERENCES
Abhijeet Pawar*, Hamja Pathan, Dr Shushama Vaishnav, Dr Preeti Sable, Dr Praveen Wakte, Quality by Design and Analytical Quality by Design in Pharmaceutical Analytical Method Development: Principles, Tools, and Regulatory Perspectives, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 2, 126-135. https://doi.org/ 10.5281/zenodo.18454195
10.5281/zenodo.18454195
