Integration of the Green Analytical Chemistry (GAC) Principles and Quality-By-Design (QBD) Steps for Sustainable Analytical Methods: A Systematic Review

The public and private sectors have recently given the ideas of green chemistry a great deal more attention and are putting them into practice. These methods seek to improve the quality of life for both people and wildlife by lowering environmental contamination that affects the soil, air, and water. Green chemistry is defined as the creation of chemical products and processes that minimize or completely do away with the usage and production of hazardous compounds ^{[1, 2].} The goal of the current investigations is to utilize less solvents and other contaminants. Tools like the Green Analytical Procedure Index (GAPI), Analytical Eco-Scale, Analytical GREEnness (AGREE), and the National Environmental Methods Index (NEMI) are commonly used to assess how environmentally friendly analytical techniques are. In particular, this study uses AGREE, GAPI, and Analytical Eco-Scale to evaluate the methodology's greenness. There isn't much research that uses AGREE and GAPI for these kinds of evaluations ^[3-9].

The time-consuming, trial-and-error approach is the traditional strategy for optimizing one method factor at a time ^[10-18]. The QbD methodology, on the other hand, provides a methodical approach development process that starts with identifying possible risks that can result in failures. The next step is to identify the method critical parameters (CMPs) and use the design of experiment (DoE) to optimize them. Understanding the individual and combined effects of method critical parameters (CMPs) is also made easier by the QbD technique.

The use of environmentally friendly and sustainable procedures, reagents, solvents, and techniques in the analytical determination of different analytes is examined in this review ^[19]. The application of methods and strategies that reduce or do away with the use of hazardous compounds in manufacturing, products, byproducts, solvents, and reagents in order to lower risks to the environment and public health is known as "green chemistry" ^{[20, 21].} Green chemistry is primarily concerned with the design of materials or chemical processes, with particular attention paid to four of the twelve key principles ^[22]. The growing quantity of scientific papers and citations in a variety of domains shows how quickly all sciences—including chemistry and chemical engineering—are developing. This is also true of analytical chemistry, where contemporary techniques provide hitherto unheard-of possibilities. Alongside these advancements, a significant trend in analytical chemistry is "green analytical chemistry," which refers to the focus on minimizing the adverse environmental effects of new techniques while increasing their safety ^[23].

The approach entails a methodical review of the literature to identify developments in the integration of Quality by Design (QbD) techniques with Green Analytical Chemistry (GAC) principles. The review starts by outlining how GAC helps reduce its negative effects on the environment by using waste-reduction tactics, eco-friendly solvents, and miniaturization techniques. It then explores QbD principles, emphasizing Analytical Target Profile (ATP), risk assessment (Ishikawa diagrams), and optimization using Design of Experiments (DoE) to ensure method robustness and sustainability. The article also compares and contrasts the efficacy of several greenness evaluation instruments, including AGREE, GAPI, NEMI, and Analytical Eco-Scale, in measuring the environmental impact of analytical techniques.In order to illustrate the real-world application of these ideas, case studies from a variety of industries—including pharmaceutical, food, and environmental analysis—are also examined. The methodology provides a thorough overview of the development of green and QbD-based analytical methods by identifying obstacles, potential research avenues, and the necessity of regulatory harmonization.

Principle of Green chemistry

Figure 1: Green Chemistry

In their 1998 book, Green Chemistry: Theory and Practice, EPA scientists Paul Anastas and John Warner expanded on the twelve tenets of green chemistry. In order to reduce hazards to the environment and public health, these principles concentrate on minimizing or eliminating hazardous compounds in the synthesis, manufacture, and use of chemical products. Although it is difficult to apply all twelve principles (Figure 1) at once when designing a green chemistry process, every attempt is made to include as many of them as feasible at various synthesis phases. ^[24]

1. Prevention

Preventing waste generation is more effective and sustainable than dealing with waste after it has been produced. The main principle of green chemistry is garbage avoidance, which is not only more cost-effective than treating and dumping waste once it is produced but also better for the environment and human health. Halogenation, oxidation, alkylation, nitration, and sulfonation are common processes that generate this kind of waste and are utilized extensively in many different industrial sectors. ^[25]

Waste prevention has previously been neglected by the chemical industry and other businesses, but reducing waste output is the main goal of green chemistry. However, as no raw material can be fully exploited, waste elimination is nearly unattainable. In the production-consumption cycle, waste signifies a permanent loss of valuable resources when it is wasted. Any attempt to reintegrate these elements into the cycle is therefore profitable. It's crucial to first ascertain whether trash generation can be avoided and, if not, to devise plans to maximize the quantity of waste produced during manufacturing that is recycled or otherwise put to good use. ^[26]

It is seen to be better to manage or lessen the impacts of waste, toxic, explosive, hazardous, and bio-accumulative compounds than to try to regulate or stop their production completely. ^[27]

2. Atomic Economy

Minimize the loss of raw materials by designing or carrying out the chemical process in a way that guarantees a sizable portion of the reactants are present in the finished product. Atom Economy (AE), sometimes known as Atom Efficiency, is a synthetic efficiency. This was a serious issue. In the 1990s, a new "green" method of producing ibuprofen was found that only needed three stages. With a yield of up to 99%, this innovative method allowed for material regeneration and reuse while producing nearly flawless conversion of each intermediate element into the finished product.^[28]

Use the following formula to find the atomic efficiency percentage: (Mr of the target product/Mr of all reactants) x 100 is the percentage of atomic efficiency.^[29]

3. Less hazardous synthesis

Selecting safer reagents and solvents that are less corrosive or poisonous is one method of achieving less hazardous synthesis. For example, less hazardous organic solvents like benzene or chloroform can be substituted with water or ethanol. Furthermore, the possibility of producing dangerous byproducts or using harsh chemicals can be decreased by creating gentler response conditions, such as reduced heat and pressures. ^[30]

Using different, environmentally friendly catalysts that are more selective and less toxic is another strategy that can reduce unintended side reactions that result in hazardous materials. Furthermore, creating processes that are more efficient in terms of atom economy—that is, in which a greater percentage of the starting materials are absorbed into the final product—can also reduce the formation of hazardous waste. In the end, less hazardous chemical synthesis results in a safer workplace, cheaper disposal and regulatory expenses, and a smaller environmental impact. This idea emphasizes the larger objectives of green chemistry, which include making chemical manufacturing safer for all parties involved as well as more sustainable.

This idea encourages the creation of synthetic processes that put the usage and production of materials with little or no toxicity to the environment and human health first. Biological enzymes can be used as a substitute for dangerous chemicals in industrial processes to increase efficiency and save costs. ^[31]

4. Designing safer chemicals

One of the biggest difficulties in designing safer products and processes is decreasing toxicity without jeopardizing a product’s usability or efficacy

Since danger is recognized as a flaw in molecular design that must be corrected from the start, success in toxicology requires creative ways to chemical characterization. The inherent hazard of elements and compounds is a crucial chemical characteristic that needs to be recognized, assessed, and managed as part of a comprehensive, systems-based approach to chemical design.

Using molecular biology to comprehend the mechanisms behind toxicity, toxicology is rapidly evolving. An understanding of these mechanisms provides the foundation for developing design principles that chemists may use to focus their efforts on creating safer compounds. We are ready to pave the path for a safer and nourishing planet as we begin a new chapter. ^[32]

5. Safer solvents and auxiliaries  

Auxiliary compounds (solutes, separating agents, etc.) should not be dangerous and should be used sparingly or not at all.

According to the "Safer Solvents and Auxiliaries" approach, auxiliary chemicals should be avoided wherever possible and the synthesis process should be streamlined. These substances ought to be non-hazardous if their use is required. Choosing suitable alternatives to conventional organic solvents in line with the principles of green chemistry should prioritize the process's long-term viability, worker safety, process security, and environmental protection.

Based on their applicability, conventional solvents can be categorized as suitable, usable, or undesirable (Table 1).

Table 1: Solvent selection is based on their intended uses

One viable approach at the moment is to use recyclable substitutes, such as ionic fluids, in place of conventional organic solvents. These are the salts that remain liquid at room temperature. Because ionic liquids have a low vapor pressure and do not evaporate as readily as volatile organic compounds, they offer safer chemical processes. ^[33]

6. Design for energy efficiency

Energy requirements in chemical processes have significant economic and environmental effects that must be recognized and addressed. Synthetic processes ought to be performed at room temperature and pressure wherever feasible. In reaction to the 1973 oil crisis, a number of energy-saving methods were created to optimize the efficiency of every kilojoule used in production. Adherence to the Principle of Energy Efficiency, also referred to as Design for Energy Efficiency, is necessary to minimize energy usage. ^{[34, 35]}

7. Use renewable feedstock

Both technically and economically, renewable raw resources should be used whenever possible in place of non-renewable ones. The seventh principle of green chemistry emphasizes the use of renewable feedstocks whenever feasible. For instance, using renewable materials is typically more beneficial than using various waste-producing polymers. This has led to the development of biodegradable polymers. Because of a number of factors, including global demand for agricultural and energy resources, political developments, and legislative changes, biodegradable packaging is becoming increasingly important in the food industry. ^[36]

8. Reduce derivatives

The employment of blocking groups, protection and deprotection procedures, or short-term adjustments to chemical or physical processes are all examples of needless derivatization that must be minimized or avoided. These procedures might result in waste production and frequently call for more reagents. One of the fundamental principles of green chemistry is the reduction of the use of chemical derivatives. According to this concept, physicochemical processes that involve the releasing and preventing of groups during synthesis should be avoided if feasible. ^[37]

9. Catalyst

The catalysis concept promotes the use of biodegradable catalysts to aid in environmental protection. These catalysts limit water use or waste, prevent the production of organochlorine chemicals, and lower energy use. Enzymes stay unaltered and can be utilized repeatedly during this process. They don't change the reactants' energy levels. Although biocatalysts have advantages over non-biological catalysts, such as higher selectivity and faster reaction rates, they may be constrained by stability and heat sensitivity problems. ^[38]

10. Design for degradation

Because they don't decompose, organic contaminants like halogenated chemicals can accumulate in the environment. As much as feasible, swap out harmful chemicals for ones that decompose more rapidly when exposed to water, UV light, or microbes.^[39]

11. Real-time pollution prevention

According to the design for degradation principle, chemical products must be made to decompose into innocuous compounds for the environment after their intended use is over. By varying auxiliary chemicals utilized at different phases of manufacturing and adjusting technological parameters during process management, this requirement can be met. The objective is to increase the recycling of waste materials for use in production while reducing the development of hazardous byproducts. ^[40]

12. Safer chemistry for accident prevention

Working with chemicals is never completely risk-free. Nonetheless, risk can be reduced with effective hazard management. There are obvious connections between this concept and several other principles that address dangerous materials or goods. Processes should, if feasible, be structured to minimize risks in the event that eliminating exposure to hazards is not feasible. ^{[41, 42]}

The steps involved in fostering an ecological mindset in analytical labs are as follows:

Table 2: Increasing Environmental Consciousness in Analytical Labs

An increase in analytical wastes and a discernible change in laboratories' attitudes toward the consequences of their residues were the outcomes of the increased analysis activity on unfavorable environmental factors and environmental samples. Concerns about the detrimental effects of growing reagent consumption and waste creation have propelled the development of environmental consciousness in analytical laboratories (Table 2) ^[43].

Green Analytical Chemistry's Objectives:

• Decrease in the use of chemical components
• Appropriate garbage disposal
• Stops pollution
• Reduction in energy usage
• Prevent the harmful solvent from release
• Reduce the amount of dangerous materials
• Making effective use of raw materials

Quality by Design

Figure 2: QbD principles

Quality by Design and Analytical Chemistry

As the main technique of technology and product quality control in the business sector, analytical chemistry is mostly utilized by chemists and chemical engineers as a measurement tool to monitor chemical technological processes. Analytical chemistry's process monitoring and control capabilities are incorporated into Process Analytical Technology (PAT), mainly for product composition analysis and troubleshooting. Its goal is to create and preserve technological procedures that guarantee the manufacturing of superior products. This strategy is consistent with the Quality by Design (QbD) principle. Leading the way in applying QbD to improve technical procedures, the pharmaceutical sector has influenced PAT and analytical techniques. According to the literature, creating dependable chemical processes is facilitated by integrating the QbD technique with Risk Analysis and Experiment Design. To guarantee product quality, these procedures include suitable analytical monitoring and control techniques. ^{[43, 44]}

Sustainable production, which requires incorporating green aspects into each step of the process, can also be depicted using a fishbone diagram.

Figure 3: Ishikawa diagram for analyzing how possible variables can affect process based on knowledge from pilot studies

Since QbD is now the main focus of pharmaceutical development, analytical chemistry is being studied in great detail. Analytical Quality by Design seems that modern approaches to process development in chemistry and pharmacy are increasingly using the quality-by-design philosophy. Priority one for that is the assessment of the performance profile of the desired product. ^[45]

Analytical reagents

It is crucial to recognize and make use of the wide variety of analytical methods, procedures, and instruments that are accessible, matching them to the particular goals of the investigation. This method entails a methodical development process that begins with clearly stated objectives, concentrating on product and process understanding as well as process control, all based on scientific principles and quality risk management, in accordance with ICH Guidelines Q8(R2) on Quality by Design.

The growing application of Quality by Design (QbD) in analytical evaluation processes is highlighted in a thorough analysis by T. Tome et al. ^[46] that cites over 70 studies. This trend is giving rise to the term "Analytical QbD" in the field of analytical chemistry. One significant benefit of using QbD to develop process analytical systems is that it increases regulatory flexibility over the method's lifetime. This is achieved by prioritizing the method's overall performance goals over stringent instrument specifications.

Although there aren't many publications on the topic, research shows that incorporating Green Chemistry principles into analytical processes can improve environmental sustainability while preserving the precision of particular techniques.

Three important factors should be considered when evaluating an analytical procedure's greenness: the specimen prior to treatment, the efficiency of the analytical instruments, and the application of appropriate waste treatment methods in addition to disposal material reductions. Choosing the right solvent is typically the first step in making an analytical method more ecologically friendly, and there are established selection guidelines available to assist with this process. For bases and acids, separate selection criteria have been developed. When assessing supplement chemicals used in analytical procedures, these guidelines are helpful.

Figure 4: AQbD environment's analytical method development procedure.

An Analytical Target Profile establishes the objectives of an analytical procedure and details the exact measurements to be made as well as the success criteria, such as accuracy, precision, and range that must be reached ^[47]. It should be decided before the method's development starts, stating its objective without identifying the analytical methodology.

Response Modelling and Response Surface Design

Several experimental layouts, including the Central Composite Design, Box-Behnken Design, Doehlert Design, and three-level full factorial design, are examples of response-surface designs. Based on a Central Composite Design, Figure 5 shows how experiments are distributed in three dimensions. A D-optimal design can be utilized to cover an asymmetrical experimental domain when factor levels are limited. These designs require substantially more experiments for a comparable number of parameters than screening approaches. Since they can predict responses for particular combinations of factors, they are used to identify the combination of elements that predicts the optimal response. ^{[48, 49]}

Greenness assessment for developed method

All three elements are crucial to the development of procedures, and the approach incorporates tri-combinations for the analysis of two drugs. Without being properly evaluated using the right approaches, a solution cannot be said to be ecologically friendly. The AGREE-Analytical Greenness Metric, the AGMS-Analytical Method Greenness Score, the GAPI-Green Analytical Procedure Index, and the NEMI-National Environmental Methods Index were the four assessment instruments used to evaluate the method's environmental impact. A variety of features, restrictions, and assessment methods are provided by each of these products. The best environmentally friendly design and the evaluation technique to use will be decided by the outcomes of each assessment tool. Despite the fact that this review process employed a number of technologies, all of the results were presented in an environmentally conscious way. The methodology was evaluated as follows: the total volume could not exceed 50 milliliters. The third quadrant was tinted green because the recycling procedure results in minimal loss. The method's principal NEMI image. ^[50]

NEMI

One well-liked qualitative evaluation technique for green chemistry is NEMI as seen in (Figure 4). At initially, it was the sole tool available for evaluating GAC efforts. Despite developing new tools for the GAC assessment, NEMI has benefits when considering the green analytical method. NEMI is represented by a sphere-shaped symbol with four quadrants and corresponding colors (green and colorless). According to the Toxicity Regulatory Inventory list, the PBT is responsible for managing the Persistent Bio-accumulative Toxic chemicals in quadrant one.

On the other hand, quadrant two's work focuses on the Toxicity substances Regulation Inventory list of PBT substances. This quadrant is green because the components used in this process are not part of PBT.Hazardous compounds are mainly controlled and fall within the second quadrant of the RCRA.

The second quadrant is shown as green due to the substances that this method also found to be on the RCRA list. The pH levels of the mobile phase, ethanol plus phosphate buffer, must be 60:40%, and the pH levels of the analytical solutions must be below a specific threshold. The third region is a green zone since it meets these requirements. The fourth quadrant is about waste.  The most important parameter combinations were then confirmed. ^[51]

Figure 5: NEMI Diagram

With its eleven classes and use of red, yellow, and green to indicate hazard, tolerance, and environmental friendliness, GAPI is a slightly modified NEMI. Through the creation of publicly available software, procedure simplifies the use of GAO for evaluation in research projects. The method specifics that need to be assessed must be entered into the program, which contains 11 easy steps to achieve the result. ^[52]

Figure 6: GAPI Diagram

Agree with Metrics

All twelve of the green analytical principles are included in the new Green Assessment tool, AGREE WITH METRICS. The significance of the distinct principles score that each person's authorities provided was underlined. Which indicated the overall outcome, which was 1. The individual principles score, which is based on each person's rights, has been given priority. The procedure's greenness is indicated by a value that is closer to one. The total outcome is displayed in (Figure 6) once the method's details have been entered into the application. The approach's environmental consequences have been described as "long-term sustainable" and "extremely benign." Five distinct methodologies or processes are used to analyze the greenness of an approach; the primary objective was to ascertain the method's level of sustainability. Regardless of their tactics, every methodology showed that this strategy is environmentally safe and easily adaptable to future green assessments.

Figure 7: The outcomes of the suggested green assessment technique are shown by the AGREE metric.

The AMGS was separated into three sections: equipment, solvent energy, and environmental health and safety. The method's overall score, which is the sum of all three ratings, should be as low as practical in order to account for making the method as environmentally friendly as possible. (Figure 7) ^[53]

Figure 8: AMGS Diagram