Quality by Design: A Suitable Methodology in Industrial Pharmacy for Costa Rican Universities

: This review aims to present the Quality by Design (QbD) model as a suitable methodology to perform research in the academic Costa Rican institutions that teach Pharmacy. Pubmed, Science Direct, and Google Scholar databases were screened for original research papers and review papers published not more than ten years ago. Institutional repositories from the different universities were reviewed as well. The QbD model stands out as a great methodology for carrying out research projects regarding Pharmaceutical Sciences, but especially for Industrial Pharmacy, where it has contributed in terms of formulation development, manufacturing, and quality control. Academic research based on this model enables the training and development of practical, scientiﬁc, and leadership skills in Industrial Pharmacy students. The generated knowledge can be shared in classrooms, which represents an ideal environment to communicate research results and to foster collaborative work between researchers, professors, and students. Moreover, research performed through a QbD approach increases the conﬁdence shown by the industrial sector and health regulatory authorities in the quality of the research, products, and knowledge that are developed and created in an Academy. As a result, the implementation of the model has allowed the creation, transfer, and materialization of knowledge from the Costa Rican Academy to different local pharmaceutical industries.


Introduction
Historically, public universities in Costa Rica have taken the lead in research activities; however, only one of them teaches Pharmacy, which is the University of Costa Rica (UCR). On the other hand, the private educational system has played a role in the knowledge economy; i.e., it is a university corporate system that focuses on instrumentalism and marketability. As a result, the private university model in Costa Rica is characterized by academic institutions with little research and personnel dedicated to it [1][2][3][4]. Specifically, these private institutions that offer Pharmacy majors lack a research system properly focused on Pharmacy and Pharmaceutical Sciences.
Every university, either public or private, with a Pharmacy major as part of its academic offer has policies created by the International Federation of Pharmacy (FIP) that can be used as tools for the evaluation, review, and improvement of its educational and scientific standards [5]. Currently, the FIP has focused its efforts on supporting research for Drug Discovery, Drug Development, Pharmaceutical Technology, Natural Products, Pharmacokinetics and Pharmacodynamics, Pharmacology, Personalized Medicine, Biotechnology, Analytical Science and Quality Control, Regulatory Affairs, Drug Metabolism, Pharmacoeconomics, and Pharmacovigilance, among others [6].
A methodology that allows research in some of the mentioned areas, especially the ones related to Industrial Pharmacy, is Quality by Design (QbD). The model is based on an adequate understanding of the sources of variability and the processes involved. All the knowledge about the impact caused by materials and process parameters on the quality profile of the finished product is of great importance [7,8]. The concept of QbD was initially introduced by a quality expert, Joseph Juran, who, in his book Juran on Quality by Design, described it through a dynamic triad, consisting of Quality Planning, Quality Control, and Quality Improvement [9]. Since then, there have been advances in the model, and its benefits in Academies have been demonstrated by high-quality works carried out by Yu et al. [10], Sangshetti et al. [11], and Grangeia et al. [12].
Costa Rican universities that teach the Pharmacy major must follow a strategy that systematically guides the development of scientific research in the industrial field. Therefore, this comprehensive review aims to present the QbD model as an opportunity and suitable methodology for research in Industrial Pharmacy in academic Costa Rican institutions. Pubmed, Science Direct, and Google Scholar databases were screened for original research papers and review papers not older than ten years. Publications were screened by title and abstract. In addition, institutional repositories from different universities were reviewed, and valid guidelines from the International Conference on Harmonization (ICH) and the United States Food and Drug Administration (FDA) related to QbD were considered suitable references due to their relevance to the topic.
To the best of our knowledge, there are no other papers that describe a research system for Industrial Pharmacy in Costa Rican universities or that present a suitable methodology for the promotion of feasible and high-quality research in the field.

University's Research Model in Costa Rica
Bentley et al. stated that universities along with industry and government research entities are the main actors in national research, development, and innovation systems [13]. Nonetheless, the public academic environment possesses the greatest research freedom within society. According to the philosopher Immanuel Kant, generated knowledge has a social impact with a bidirectional behavior, that is, from the world to science, and from science to the world [14].
Research projects from an Academy can influence the theory of a certain phenomenon. The term "Academy" is used to describe a community composed of students and academics, committed to higher education and research as a fundamental activity in the creation of knowledge [15]. A large majority of high-impact publications are the product of the thesis work of master's students and doctoral candidates affiliated with a specific research group from public universities to become trained scientists [16][17][18].
In this sense, the creation of knowledge must be ethical, always emphasizing the quality of research over quantity and avoiding any practice that encourages the opposite. Unfortunately, the latter has not always been put into practice, and it directly affects firstyear Pharmacy students who do not yet know how to validate a scientific reference from the literature [19]. According to the famous library scientist Jeffrey Beall, this student population tends to consult papers from predatory journals for their assignments and evaluations [20].
In addition, Costa Rican private universities where Pharmacy majors are taught have not paid special attention to research activities for the discipline as such; thus, they cannot be considered an Academy yet. This private system, however, is being replaced by a university model with more complex thinking, which seeks to participate in the national social agenda, as well as taking a leading role in the generation of knowledge as the central axis of the research process. Authors such as Egri et al. [21] and Salau et al. [22] have recognized this new model as a means by which research priorities can be organized around strategic areas to bring "non-academia" universities closer to becoming Academies in various countries.
The new vision adopted by the Costa Rican private educational system, besides focusing on the search and design of research methodologies, allows the dissemination of scientific knowledge. The participation of their personnel and students in national and international events (e.g., conferences and symposia) and the production of scientific manuscripts are of great relevance when evaluating the quality of a certain institution [23,24]. According to Pineda et al., these activities give great support to the research program established by the majors and, at the same time, provide prestige to it, its researchers, and the universities [25].
Likewise, some Costa Rican universities have created open-access journals, which facilitate the publication of research without the financial issue that submitting the manuscripts to a large majority of international journals would represent. This open-access model is also a transparent and affordable means of knowledge that also allows the development of collaborative inter-institutional networks, expanding the ideals of the universities [26][27][28].
Nonetheless, despite the consolidated system from the UCR and the great progress experienced by private universities, the establishment of scientific work in both cases is based on the institutional development plan. This promotes the well-defined figure by Berg et al. [2] of the "slow professor", i.e., an individual with few research tasks, either due to little affinity with the research topics or due to poor suitability to participate in them [29]. Similarly, it is important to highlight that not every university is capable of conducting research, or at least, not at the same level. Moreover, not all teaching personnel can be included in the category of academics. In many cases, their research possibilities are reduced due to a lack of resources, economic and political pressures, or unavailability due to overload in teaching [30,31].
Based on the presented overview, the adoption of methodological guidelines or research models for Industrial Pharmacy in Costa Rican universities that teach Pharmacy may improve professor and student integration into research activities. This will not only provide great academic training tools for both, but it will also represent an integral indicator of credibility, compliance, efficiency, and competitiveness of the major and the research system [32][33][34]. The relevance of such parameters also lies in their use as an internal mechanism of evaluation in budgetary control and the prioritization of research [35].

Model's Basic Characteristics
The ICH guideline Q8 (R2) defines the QbD model as a systematic approach to Pharmaceutical Development, which begins with predefined objectives and places special emphasis on understanding the product, the process, and its controls [36]. Moreover, the FDA considers that quality in a Drug Quality System cannot be evaluated or determined in a product but must be introduced and promoted from its design [37].
Despite the aforementioned, the quality of the products has been historically determined through "Quality by Test", i.e., to evaluate the quality of the finished product without prior controls [38]. Nevertheless, the demand to produce medicines of the highest quality and to improve competitiveness within the pharmaceutical, industrial, and health fields forced many institutions to take on new measures to guarantee the quality of their products. Therefore, the adoption of the QbD is of great relevance, as the predictions made by the model are useful in the design of experimental investigations, time management, and the use of resources throughout the process [39].
The QbD model's lifecycle ( Figure 1) [40] is directly related to the different constituent elements, such as the Target Product Profile (TPP), Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Design Space [41,42]. In addition, Quality Risk Management (QRM), Design of Experiments (DoE), and Process Analytical Technologies (PATs) are used as tools to guarantee the quality of the products being developed [43]. These tools also make the QbD model an approach that meets the current demand for research processes, as it is considered cost effective in project development [44][45][46].
The QbD model's lifecycle ( Figure 1) [40] is directly related to the different constituent elements, such as the Target Product Profile (TPP), Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Design Space [41,42]. In addition, Quality Risk Management (QRM), Design of Experiments (DoE), and Process Analytical Technologies (PATs) are used as tools to guarantee the quality of the products being developed [43]. These tools also make the QbD model an approach that meets the current demand for research processes, as it is considered cost effective in project development [44][45][46]. According to the ICH Q9 guideline on Quality Risk Management [47], CQAs, CMAs, and CPPs can be identified through adequate risk management, as it detects those problems in the development of the product and their associated risks [48,49]. In general, nine tools are recommended for risk management. However, among the most widely used tools are Ishikawa's fishbone diagram ( Figure 2) [44] and the Failure Mode and Effects Analysis (FMEA) [48,50,51]. These two tools are thoroughly explained to the Pharmacy students in Drug Analysis courses.
In addition, DoE allows researchers to use their knowledge regarding the product and/or process instead of merely applying the commonly known "trial and error" [52,53]. This tool is used to organize, conduct, and interpret the results of experiments efficiently, guaranteeing the collection of the greatest possible amount of useful information through the execution of a small number of tests. The main objective of an experimental study is to find the relationship between independent variables (i.e., factors) and dependent variables (i.e., responses) that affects a certain process and its final product ( Figure 3) [54]. An adequate DoE can help identify optimal conditions, CMAs, CPPs, and their impact on CQAs [55]. According to the ICH Q9 guideline on Quality Risk Management [47], CQAs, CMAs, and CPPs can be identified through adequate risk management, as it detects those problems in the development of the product and their associated risks [48,49]. In general, nine tools are recommended for risk management. However, among the most widely used tools are Ishikawa's fishbone diagram ( Figure 2) [44] and the Failure Mode and Effects Analysis (FMEA) [48,50,51]. These two tools are thoroughly explained to the Pharmacy students in Drug Analysis courses.  In addition, DoE allows researchers to use their knowledge regarding the product and/or process instead of merely applying the commonly known "trial and error" [52,53]. This tool is used to organize, conduct, and interpret the results of experiments efficiently, guaranteeing the collection of the greatest possible amount of useful information through the execution of a small number of tests. The main objective of an experimental study is to find the relationship between independent variables (i.e., factors) and dependent variables (i.e., responses) that affects a certain process and its final product (Figure 3) [54]. An adequate DoE can help identify optimal conditions, CMAs, CPPs, and their impact on CQAs [55].

Implementation in Academic Research
QbD can be used in any section of the Pharmaceutical Development process, from the drug substance development stages to clinical trials ( Figure 4) [39].

Implementation in Academic Research
QbD can be used in any section of the Pharmaceutical Development process, from the drug substance development stages to clinical trials ( Figure 4) [39].    [63], and others [64,65]. These examples have allowed advances in the Academy, Pharmaceutical Development, and the regulatory en-  Table 1 presents a scientific summarization of the QbD methodology in different areas of the pharmaceutical discipline, such as excipients development [56], analytical methods [57][58][59], dissolution tests [60,61], stability studies [61], bioequivalence development/validation [62], clinical trials [63], and others [64,65]. These examples have allowed advances in the Academy, Pharmaceutical Development, and the regulatory environment, moving from empirical processes to research based on science and risk control [66,67]. Therefore, the application of the model allows tangible results (e.g., pharmaceutical products and analytical methods) of the highest and most reproducible quality to be obtained, which can be easily predicted or anticipated [68].
Moreover, Orozco et al. previously described the Costa Rican innovation system as weak, mainly due to a poorly effective linkage of the universities with the industrial sector [69]. However, a direct benefit of the increase in students and the research groups' practical and scientific skills due to the implementation of the QbD approach is the confidence shown by customers, the industrial sector, and health authorities on the quality of the research, products, and knowledge that are developed and created in the Academy. The empowerment demonstrated by the students during the execution of their graduation projects, and the increase in learning engagement owing to the application of this methodology have also developed leadership and team-work skills, necessary to conduct research [10,11,70]. Liquid chromatography method to evaluate cannabinoid content in cannabis olive oil extracts Quality control of natural products [59] Cell culture in bioreactor for the production of foot-and-mouth veterinary vaccine Biopharmaceutical process development [80] Development of electrospinning coatings for metal microneedles Process optimization [81] As a result, the QbD model has allowed the creation, transfer, and materialization of knowledge from Costa Rican universities to different local pharmaceutical industries, as discussed in the following sections. Different QbD approaches carried out regarding formulation, the manufacturing process design, and the quality control of drugs and natural products are addressed. An emphasis is placed on the different QbD elements and tools employed throughout the research.

Formulation Development
The QbD model satisfactorily deals with the challenges posed by the design and development of pharmaceutical formulations, being also able to accelerate them [82]. The thorough comprehension of CMAs, the assessment of physicochemical compatibility, the application of QRM, the performance of DoE, and the use of PAT to assess and predict stability are responsible for the great success experienced [83].
Castillo et al. employed QbD for the development of different pharmaceutical formulations. In 2017, a collaboration between UCR and the National Laboratory of Nanotechnology (LANOTEC) worked on developing an immediate-release formulation of rupatadine fumarate 10 mg tablets by direct compression. The research involved identifying the TPP in terms of the target population, administration route, posology, potency, composition, and desired performance regarding drug release and physicochemical stability compared to a commercialized reference product, Rupax ® [44]. Later on, knowledge and technological transference to a local pharmaceutical industry resulted in the commercialization of the drug product.
Moreover, an adequate QRM during formulation can provide products of the highest quality and safety, thus becoming an excellent resource for the identification and control of possible quality problems during research [84]. This tool allows for better decision making when quality-related issues arise, making their justification easier and generating greater confidence in the research group [85]. In the rupatadine research, QRM was employed to identify the CMAs and CPPs, and it led to the definition of the CQAs, a safe process, and formulations with no physicochemical incompatibilities. Additionally, spectroscopic and thermal analysis techniques were used to assess the physicochemical compatibility and the suitability of the manufacturing process [44].
Following that, in 2021, another investigation involving students at UCR applied a QbD approach for pharmaceutical formulation development. Hanley et al. developed an oral suspension with anti-ulcer and gastroprotective effects. Remarkably, they reported the thickening agents' concentration as a CMA and the pretreatment of the drug using a wetting agent as a CPP. Once the previous aspects were identified, a DoE was designed and executed to determine the effect of these on the suspension's viscosity, which was defined as a CQA [86]. In general, DoE is conceived as an excellent tool that allows forsystematic manipulation of factors according to a design prior to the establishment of specifications [87,88]. The independent variables are usually formulation factors or manufacturing/test conditions, while the dependent variables are product properties or parameters that indicate the performance of the process [89]. Using this tool, Hanley's research results revealed that only one of the prototype formulations was suitable for development. In this case, the technology was transferred to another local pharmaceutical industry, which is currently in the process of registering the product and commercializing it in the country [86].
At a private university, Universidad Internacional de Las Américas (UIA), Ramírez, et al. developed a sustained-release tablet formulation of a non-steroidal and anti-inflammatory drug (NSAID) to treat chronic pain. In this approach, the research group sought to fulfill the CQAs established by the United States Pharmacopoeia (USP) and the British Pharmacopoeia (BP) for the product. The performed QRM was based on Ishikawa's diagram, FMEA, and the creation of an adequate strategy for risk control and mitigation [90]. Furthermore, other research projects are currently applying this methodology at UIA, such as in the development of a self-emulsifying drug delivery system (SEDDS) to improve itraconazole oral bioavailability and chlorpheniramine/guaifenesin chewing tablets for cold treatment in children.
More recently, collaborative work between the Faculty of Pharmacy of UCR, LAN-OTEC, the Laboratory of Biopharmacy and Pharmacokinetics (LABIOFAR) of UCR, and the Laboratory of Polymers of the National University (POLIUNA) allowed the development of a topical chitosan-based thermo-responsive scaffold loaded with dexketoprofen trometamol (DKT). In this case, the TPP was defined as a function of the intended application for chronic and non-healing wounds caused by different diseases (e.g., diabetes), as well as for local pain and inflammation management. The scaffold was required to provide controlled release of DKT for 24 h use, having a small release rate at or below the normothermia and taking advantage of the local hyperthermia presented in wounds. The latter induces a sol-gel transition in the polymer's structure, which increases the drug's release rate. This QbD approach contributed to the avoidance of excessive DKT loading in the polymer matrix as most conventional drug systems do to achieve a concentration gradient for Fickian diffusion as the main release mechanism [91].

Manufacturing Process Design
In many cases, the definition of scalable and consistent methods of drug preparation or manufacturing is hard to achieve. Nevertheless, a QbD approach can bring solutions to many of the related issues by making use of three key steps: (a) QRM, (b) DoE, and (c) the execution and analysis of studies to determine their impact on the process quality, as well as on the Design Space [92]. In addition, the ICH Q8 (R2) [36], Q9 [47], Q11 Development and Manufacture of Drug Substances [93], Q13 Continuous Manufacturing of Drug Substances and Drug Products [94], and the FDA Guidance for Industry on PAT [95] represent a magnificent framework for the manufacturing of pharmaceutical products [12,96]. In fact, the use of PAT and Continuous Manufacturing has been increasing in QbD-based developments. Both have enabled real-time measurements for process monitoring, higher operational flexibility, reducing batch rejection, faster manufacture, and fewer resources and efforts for regulatory compliance [97]. The reduction in R&D costs and time has also been associated with the implementation of QbD [98].
At UCR, Cantillo et al. designed a film coating process of tablets at a pilot scale for a local pharmaceutical industry. In this case, the group employed a full factorial design to evaluate the impact of the CMAs (friability, density, and tablet dimensions) and CPPs (drum's rotational speed, core bed temperature, and feed rate of the coating solution) on the weight increase and appearance of defects. In conclusion, they reported the drum's rotational speed, the core bed temperature, and the feed rate of the coating solution as the main effects, and created a control strategy for these process parameters [99].

Quality Control
QbD can also be expanded to analytical methods for the quality control of pharmaceutical formulations, also known as Analytical Quality by Design (AQbD), which is different from the classical approach for Analytical Method Development ( Figure 5) [100]. AQbD demands that the goal to be achieved is initially defined, i.e., the analytical target profile, as well as properly selecting the analytical method from the different alternatives that are systematically evaluated. This allows a well-understood method to be obtained that not only exhibits the best performance but also has the possibility to be improved, if necessary. As the next step, a control strategy is designed and established to manage risks and guarantee robustness. Then, the validation of the method is developed, and finally, continuous monitoring is mandatory throughout the lifecycle [101].
Furthermore, AQbD facilitates regulatory flexibility in analytical methods. Given the fact that health regulatory agencies only allow minor modifications, the ease of changing parameters within a method operable design region (MODR) in the AQbD approach provides a multidimensional space based on the factors and settings that provide a suitable method performance [67]. [100]. AQbD demands that the goal to be achieved is initially defined, i.e., the analytical target profile, as well as properly selecting the analytical method from the different alternatives that are systematically evaluated. This allows a well-understood method to be obtained that not only exhibits the best performance but also has the possibility to be improved, if necessary. As the next step, a control strategy is designed and established to manage risks and guarantee robustness. Then, the validation of the method is developed, and finally, continuous monitoring is mandatory throughout the lifecycle [101]. Furthermore, AQbD facilitates regulatory flexibility in analytical methods. Given the fact that health regulatory agencies only allow minor modifications, the ease of changing parameters within a method operable design region (MODR) in the AQbD approach provides a multidimensional space based on the factors and settings that provide a suitable method performance [67].
Recently, at UCR, Murillo et al. developed and validated a bioanalytical HPLC method with a diode array for the simultaneous quantification in human plasma of car- Recently, at UCR, Murillo et al. developed and validated a bioanalytical HPLC method with a diode array for the simultaneous quantification in human plasma of carbamazepine and its active 10,11-epoxide metabolite. The risk assessment focused on the separation and recovery of the analytes from properly preserved human plasma, using a solid-phase component extraction strategy. For this critical parameter, three types of extraction cartridges were evaluated to optimize the process, which allowed more than 95% recovery of the analytes to be obtained. However, validating a bioanalytical method presents some issues posed by the biological matrix. Thus, applying the AQbD approach allowed them to optimize and save reagents and consumables in the execution of the validation process, as well as fulfilling validation criteria in terms of linearity, specificity, precision, and accuracy, among others, to ensure reproducible and reliable results. This was achieved by implementing the use of a 50 mm column with a particle size of 3.5 µm, obtaining good integration and a resolution higher than 2.0 for the chromatographic peaks [102].
QbD has also gained importance in natural product development and quality control due to the current high demand [103]. On top of that, the use of DoE in an AQbD approach for these products implies a higher contribution due to the intrinsic variability that occurs when working with natural raw materials. However, it is important to note that, according to QbD, risk management has priority over DoE [50,51,104].
For instance, Castillo et al. evaluated a sample's mass and temperature impact on the moisture content in Camellia sinensis, Cassia fistula, Chamaemelum nobile, Lippia alba, and Tilia platyphyllos using a gravimetric method developed through a 3 2 full factorial design. A response optimizer was used to define the test conditions that allow results to be obtained according to a target value from a certified method ( Figure 6) [105]. The designed model was able to explain the response variability for all samples based on the R 2 (adj), which led to the definition of the range of mass and temperature for the analyses based on each materials' properties, as well as considering the capacity, precision, moisture range, heating technology, and operational temperature range of the dryer and the available moisture balances.
that occurs when working with natural raw materials. However, it is important to note that, according to QbD, risk management has priority over DoE [50,51,104].
For instance, Castillo et al. evaluated a sample's mass and temperature impact on the moisture content in Camellia sinensis, Cassia fistula, Chamaemelum nobile, Lippia alba, and Tilia platyphyllos using a gravimetric method developed through a 3 2 full factorial design. A response optimizer was used to define the test conditions that allow results to be obtained according to a target value from a certified method ( Figure 6) [105]. The designed model was able to explain the response variability for all samples based on the R 2 (adj), which led to the definition of the range of mass and temperature for the analyses based on each materials' properties, as well as considering the capacity, precision, moisture range, heating technology, and operational temperature range of the dryer and the available moisture balances.

Conclusions
The change in the educational paradigm and the organizational structure of Costa Rican universities has allowed some Pharmacy Schools from these institutions to stand out in terms of scientific research and to seek the consolidation of groups of experts in the industrial field of the discipline. The implementation of research methodologies such as QbD explains the progress achieved in recent years. The QbD model has been exceptional in carrying out research projects in Costa Rican universities regarding Pharmaceutical Sciences since 2017, especially for the formulation, manufacturing process design, and quality control of drugs and natural products. The model has also allowed the creation, transfer, and materialization of knowledge from academic institutions to different local pharmaceutical industries, resulting in a closer linkage between the two sectors. Furthermore, academic research based on this model enables the training and development of practical, scientific, and leadership skills in Pharmacy students. The generated knowledge can be shared in the classroom, which represents an ideal environment for the professors to communicate their results and foster collaborative work between researchers, professors, and students. The participation of all of these sectors allows a high level of commitment to research work, which benefits the scientific advancement of universities and society.