Evaluation of the influence of granulation processing parameters on the granule properties and dissolution characteristics of a modified release drug

Understanding the relationship between high shear wet granulation processing parameters and the characteristics of intermediate and final products is crucial in the ability to apply quality by design (QbD) and process analytical technologies (PAT) to secondary pharmaceutical processes. This research examined a high shear wet granulation process and subsequent manufacturing of a tablet containing a biopharmaceutics classification system (BCS) class II drug, gliclazide (low solubility, high permeability). Previous studies have concentrated on either granulation or tabletting but not both together; this work brings together the analysis as a single large multivariate process. The design of experiment (DoE) was performed according to an L9 Taguchi method with three replications, in total; thirty-six runs were performed. A full statistical analysis relating both granule and tablet properties to selected process parameters were carried out. The research illustrates that mapping a highly multivariate process is possible. Statistically significant critical process parameters were identified for granule hardness, granule density and granule particle size. These granule properties were also identified as contributing to the dissolution release characteristics. Dissolution modeling and prediction was achieved within the DoE structure. Process noise was identified and measured across the entire production and specifically with respect to the milling process.     

Assay Development in Stability Test Methods

Abstract

Stability-indicating analytical methods are developed to monitor the stability of pharmaceutical dosage forms during the investigational phase of drug development, and, once the drug is marketed, for the ongoing stability studies which must be conducted. The development of these methods for pharmaceutical dosage forms forms can be approached from several avenues. Methods can be developed which measure the amount of drug remaining, the amount of drug lost (or the appearance of degradation products), or both.

Traditionally, the analytical methods used to monitor the stability of dosage forms have involved a generally non-specific spectrophotometric or titrimetric procedure for the assay of the active coupled with thin layer chromatography for the estimation of impurities and degradation products. In the last five years, this approach has changed dramatically. Currently, the method of choice for the quantitation of the active and degradation products is rapidly becoming high performance liquid chromatography. This method has obvious advantages since it both separates and measures and it lends itself well to automation. The disadvantages are that, in the absence of automation, the technique can be time-consuming, it is by no means universal, and it is relatively expensive. Recent advances in column technology have reduced some separation times to seconds and, in the next few years, this technique may find even greater utility.

HPLC, however, is not the only way to go. Other chromatographic methods still find a place, particularly gas chromatography when the stability of the component of interest does not pose a problem and thin layer chromatography for the rapid determination of degradation products. Other methods may also be used, including electrometric, e.g., polarography, and spectrophotometric, e.g., fluorimetry or NMR. The choice of an appropriate method must depend on both a scientific and practical evaluation of the drug and its dosage form.

Once an analytical method is chosen, the most important aspect of the development of a stability-indicating procedure is method validation. Validation should include evaluation of the following parameters: specificity, linearity, precision, accuracy, sensitivity, and ruggedness.

There are many other aspects to stability that could also be considered, e.g., the stability of the bulk drug and physical and organoleptic changes in a dosage form. These should be part of a separate discussion. It very often happens that, during the course of product development, analytical methods evolve. As more is learned about the drug and its dosage form, methods can be refined and revised.     

Assay Development in Stability Test Methods

Stability-indicating analytical methods are developed to monitor the stability of pharmaceutical dosage forms during the investigational phase of drug development, and, once the drug is marketed, for the ongoing stability studies which must be conducted. The development of these methods for pharmaceutical dosage forms forms can be approached from several avenues. Methods can be developed which measure the amount of drug remaining, the amount of drug lost (or the appearance of degradation products), or both.

Traditionally, the analytical methods used to monitor the stability of dosage forms have involved a generally non-specific spectrophotometric or titrimetric procedure for the assay of the active coupled with thin layer chromatography for the estimation of impurities and degradation products. In the last five years, this approach has changed dramatically. Currently, the method of choice for the quantitation of the active and degradation products is rapidly becoming high performance liquid chromatography. This method has obvious advantages since it both separates and measures and it lends itself well to automation. The disadvantages are that, in the absence of automation, the technique can be time-consuming, it is by no means universal, and it is relatively expensive. Recent advances in column technology have reduced some separation times to seconds and, in the next few years, this technique may find even greater utility.

HPLC, however, is not the only way to go. Other chromatographic methods still find a place, particularly gas chromatography when the stability of the component of interest does not pose a problem and thin layer chromatography for the rapid determination of degradation products. Other methods may also be used, including electrometric, e.g., polarography, and spectrophotometric, e.g., fluorimetry or NMR. The choice of an appropriate method must depend on both a scientific and practical evaluation of the drug and its dosage form.

Once an analytical method is chosen, the most important aspect of the development of a stability-indicating procedure is method validation. Validation should include evaluation of the following parameters: specificity, linearity, precision, accuracy, sensitivity, and ruggedness.

There are many other aspects to stability that could also be considered, e.g., the stability of the bulk drug and physical and organoleptic changes in a dosage form. These should be part of a separate discussion. It very often happens that, during the course of product development, analytical methods evolve. As more is learned about the drug and its dosage form, methods can be refined and revised.     

Design of experiments (DoE) in pharmaceutical development

At the beginning of the twentieth century, Sir Ronald Fisher introduced the concept of applying statistical analysis during the planning stages of research rather than at the end of experimentation. When statistical thinking is applied from the design phase, it enables to build quality into the product, by adopting Deming’s profound knowledge approach, comprising system thinking, variation understanding, theory of knowledge, and psychology.

The pharmaceutical industry was late in adopting these paradigms, compared to other sectors. It heavily focused on blockbuster drugs, while formulation development was mainly performed by One Factor At a Time (OFAT) studies, rather than implementing Quality by Design (QbD) and modern engineering-based manufacturing methodologies.

Among various mathematical modeling approaches, Design of Experiments (DoE) is extensively used for the implementation of QbD in both research and industrial settings. In QbD, product and process understanding is the key enabler of assuring quality in the final product. Knowledge is achieved by establishing models correlating the inputs with the outputs of the process. The mathematical relationships of the Critical Process Parameters (CPPs) and Material Attributes (CMAs) with the Critical Quality Attributes (CQAs) define the design space. Consequently, process understanding is well assured and rationally leads to a final product meeting the Quality Target Product Profile (QTPP).

This review illustrates the principles of quality theory through the work of major contributors, the evolution of the QbD approach and the statistical toolset for its implementation. As such, DoE is presented in detail since it represents the first choice for rational pharmaceutical development.     

Uncertainty-based internal quality control. Harmonization considerations

Three main quality aspects for analytical laboratories are internal method validation, internal quality control (IQC), and sample result uncertainty. Unfortunately, in the past they have been used in a nonharmonized way. The most universal IQC tool is the mean chart, but some criteria used to fix their control limits do not fit the real nature of analytical results. A new approach for fixing these limits is proposed (the u-approach). The key is the combined uncertainty, u, obtained from the method validation information, also used for estimating the sample result uncertainty. A comparative study on "in-control" simulated, bibliographic, and real laboratory data suggests that the u-approach is more reliable than other well-established criteria. In addition, the u-approach mean chart emerges as an IQC tool, consistent with chemical assays, which harmonizes the validation-control-uncertainty process.     

A Statistical Approach to Blend Uniformity Acceptance Criteria

Recent Food and Drug Administration (FDA) validation guidelines and comments indicate that applying finished product content uniformity specifications to blend testing is unacceptable. The scenario the FDA has presented is one in which disorder increases as the process progresses so that blend test specifications should be more restrictive (tighter) than finished product testing specifications. In other publications, it has been suggested that finished product assay limits be applied as a blend specification along with a lower relative standard deviation value than the current USP content uniformity limit (6.0%). This approach is questionable since assay results are applied to an aggregate finished product sample rather than individual doses. A method is presented in this paper for applying statistical tolerance limits (Sib) to blend data. This procedure provides a 95% confidence level that at least 90% of the values for the entire population are within the calculated limits. These statistical tolerance limits provide an acceptable criterion that is statistically tighter than the application of USP XXIII finished product content uniformity specifications. In addition, this method involves a decision process or multiple-level evaluation based on a statistical comparison of the variance and mean for the blend and finished product. In cases where the calculated STLs are unacceptable, the decision process allows for determining if the out-of-specification values from the first level of testing are due to a true blend failure or if the cause of the aberration is due to other phenomena, which could include sampling technique, thief design, and analytical testing problems.     

Process Validation: A 17-Year Retrospective of Solid-Dosage Forms

The author takes the reader through the various stages, phases, and steps in the product and process development sequence of solid-dosage form design (tablet and capsule) using process validation principles and practices as a guide. The challenge for the pharmaceutical industry as it approaches the next millennium is to streamline and/or simplify validation requirements without sacrificing product quality and process flexibility. Cost-containment pressures in the future will necessitate the use of more process automation and innovative ways of manufacturing products. In the final analysis, these objectives can best be accomplished with the cooperation of a worldwide regulatory commitment to achieving harmonization goals for both good manufacturing practices and process validation.     

Development Pharmaceutics and process Validation

A resume is presented of the guideline on the data required under Part I.A.4. of the Annex to European Directive 75/318/EEC covering the choice of composition of a medicinal product, supported by data on development pharmaceutics. The broad areas of development studies cover the function and compatibility of active ingredients and excipients, the development of liquid, semi-solid and solid dosage forms and the suitability of containers.

The guideline aims also to cover general aspects of process validation. The principles laid down in the Guideline are compared with those of FDA guideline on process validation which are much more detailed, but share the same overall aim.

One of the fundamental aims of the regulatory control of medicinal products is to ensure the correct purity, potency and consistency of manufacture of each product according to the quality appropriate for its intended use. While Good Manufacturing Practice is essential for quality assurance, other factors such as product design and development may also influence quality, and therefore must be studied and controlled. With this in mind, the Regulatory Authorities of the European Community have produced a guideline to the types of studies that should be undertaken in the development of a medicinal product, and which should be presented in support of application for marketing authorisation. A properly presented section on Development Pharmaceutics at the beginning of a dossier is extremely useful, if not essential, in explaining the rationale behind a particular product and giving the reviewer a clearer understanding of the data presented in support of product quality.

Quality Assurance of every product must be demonstrated, and validation is the key to its demonstration, put simply, validation is the act of proving that a process works. Thus the manufacturing methods and controls specified in an application should follow on from the development studies, and be based on valid principles. Demonstration of the validity of the manufacturing process should be provided as should the validation of the analytical methods used to control the process and therefore the product. Thus process validation should be seen as being strongly supported on the one hand by development pharmaceutics, and on the other by analytical validation.     

A Statistical Approach to Blend Uniformity Acceptance Criteria

Abstract

Recent Food and Drug Administration (FDA) validation guidelines and comments indicate that applying finished product content uniformity specifications to blend testing is unacceptable. The scenario the FDA has presented is one in which disorder increases as the process progresses so that blend test specifications should be more restrictive (tighter) than finished product testing specifications. In other publications, it has been suggested that finished product assay limits be applied as a blend specification along with a lower relative standard deviation value than the current USP content uniformity limit (6.0%). This approach is questionable since assay results are applied to an aggregate finished product sample rather than individual doses. A method is presented in this paper for applying statistical tolerance limits (Sib) to blend data. This procedure provides a 95% confidence level that at least 90% of the values for the entire population are within the calculated limits. These statistical tolerance limits provide an acceptable criterion that is statistically tighter than the application of USP XXIII finished product content uniformity specifications. In addition, this method involves a decision process or multiple-level evaluation based on a statistical comparison of the variance and mean for the blend and finished product. In cases where the calculated STLs are unacceptable, the decision process allows for determining if the out-of-specification values from the first level of testing are due to a true blend failure or if the cause of the aberration is due to other phenomena, which could include sampling technique, thief design, and analytical testing problems.     

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization

Objective: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.

Methods: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.

Results: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product’s disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5?seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600?g load).

Conclusions: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.     

Applying GMP to Computerization in a Solid-Oral-Dosage-form-Factory

Quality Assurance and Pharmaceutical security as well must be given a particular consideration both for hardware and software when computerized pharmaceutical industrial operations are concerned

Hardware: The preparation of validation should begin with the design of a computerized system and rely upon specifications and upon defined operational limits

It is suitable to prepare documentation as from the development of the system in order to obtain a fruitful communication between all those concerned with design, implementation, maintenance, validation and auditing

A revalidation procedure should be prepared and maintained updated, in the event of a change in one or several operating conditions

Software: As with hardware, validation of software should be envisioned as early as the development phase. Preparation of test procedures and documentation should start at this very stage. Qualification and validation will be designed to find errors in the program and not to prove that no errors exist. They will be carried out at the operational boundaries of the software and will aim at testing the critical decision paths of the program. Verifications must be repeated a sufficient number of times to demonstrate that the results are repeatable

As with other pharmaceutical manufacturing systems, a formal procedure should exist to support changes made to the software. Vendor supplied software should be verified and documented with the same rigour and details that in-house developed software. Manual back-up systems must be provided for and regularly tested in the event of failure of the automated process. Computerized systems and good manufacturing practices applied to manufacturing of solid oral dosage forms: An application of the above-stated principles is given and illustrated     

Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools

Abstract

The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a ‘One factor at a time (OFAT)’ approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools.     

Development Pharmaceutics and process Validation

Abstract

A resume is presented of the guideline on the data required under Part I.A.4. of the Annex to European Directive 75/318/EEC covering the choice of composition of a medicinal product, supported by data on development pharmaceutics. The broad areas of development studies cover the function and compatibility of active ingredients and excipients, the development of liquid, semi-solid and solid dosage forms and the suitability of containers.

The guideline aims also to cover general aspects of process validation. The principles laid down in the Guideline are compared with those of FDA guideline on process validation which are much more detailed, but share the same overall aim.

One of the fundamental aims of the regulatory control of medicinal products is to ensure the correct purity, potency and consistency of manufacture of each product according to the quality appropriate for its intended use. While Good Manufacturing Practice is essential for quality assurance, other factors such as product design and development may also influence quality, and therefore must be studied and controlled. With this in mind, the Regulatory Authorities of the European Community have produced a guideline to the types of studies that should be undertaken in the development of a medicinal product, and which should be presented in support of application for marketing authorisation. A properly presented section on Development Pharmaceutics at the beginning of a dossier is extremely useful, if not essential, in explaining the rationale behind a particular product and giving the reviewer a clearer understanding of the data presented in support of product quality.

Quality Assurance of every product must be demonstrated, and validation is the key to its demonstration, put simply, validation is the act of proving that a process works. Thus the manufacturing methods and controls specified in an application should follow on from the development studies, and be based on valid principles. Demonstration of the validity of the manufacturing process should be provided as should the validation of the analytical methods used to control the process and therefore the product. Thus process validation should be seen as being strongly supported on the one hand by development pharmaceutics, and on the other by analytical validation.     

Reliability as an added‐value factor in an automotive clutch system

In the present competitive scenario, companies face the challenge of developing new products in a short time period, with superior technology in relation to prior developments and reduced costs to guarantee the survival of their business. Success is directly coupled with client requirements where quality and reliability should be the highest feasible, whereas deadlines and price have to be the lowest possible. This paper discusses tools and methods applied to planning and assurance of quality, which have to be taken into account at the product conception project, which concerns the phase in which quality, reliability and the final price of a product are technically defined. A methodology is presented for this purpose, and it can be extended to any product or system with few adaptations concerning quality, reliability and cost models. The product selected for the case‐study analysis in this work is an automotive clutch. The methodology proposed for the analysis is a combination of the KANO method, target cost and value analysis with respect to the assessment of client requirement compliance levels and the determination of the choice of functions—whose relative costs are above relative needs, therefore offering optimization or elimination potential. Thus, the reliability concepts of statistical distributions and fault tree analysis are employed to locate critical components and quantify design temporary performance. To provide life tests results to the highest failure risk in the system, the planning and deployment of accelerated tests are carried out. The final goal of this paper is the reliability assessment based on critical levels for the analysis of components to be improved or optimized and, mainly, to create a methodology for the development of optimized products. Copyright © 2007 John Wiley & Sons, Ltd.     

The application of atomic absorption spectrometry for the determination of residual active pharmaceutical ingredients in cleaning validation samples

The objective of this work was the development and validation of atomic absorption spectrometric (AAS) methods for the determination of residual active pharmaceutical ingredients (API) in rinse samples for cleaning validation. AAS as an indirect method for the determination of API in rinse samples can be applied when it is in the form of salt with metal ions or when the metal ion is a part of the API's structure. The electrothermal AAS methods (aqueous and ethanol medium) for the determination of magnesium in esomeprazole magnesium and the flame AAS method for the determination of lithium in lithium carbonate in rinse samples were developed. Various combinations of solvents were tested and a combination of 1% aqueous or ethanol solution of nitric acid for esomeprazole magnesium and 0.1% aqueous solution of nitric acid for lithium carbonate were found to be the most suitable. The atomization conditions in the graphite furnace and in the flame were carefully studied to avoid losses of analyte and to achieve suitable sensitivity. The cleaning verification methods were validated with respect to accuracy, precision, linearity, limit of detection, and quantification. In all the cases, the limits of detection were at the microgram level. The methods were successfully applied for the determination of esomeprazole magnesium and lithium carbonate in rinse samples from cleaning procedures.     

Setting up multivariate specifications on critical raw material attributes to ensure consistent drug dissolution from high drug-load sustained-release matrix tablet

The purpose of this study was to describe the raw material variability that influenced the in-vitro dissolution behavior of high drug-load sustained-release matrix tablet and to ensure the consistent quality of the final product. The Panax notoginseng saponins (PNS) – hydroxypropyl methylcellulose – anhydrous lactose – magnesium stearate (57:20:23:0.5%, w/w) was used as the model formulation. PNS extract powders with lot-to-lot and source-to-source differences were collected to cover the common cause variations and their physicochemical properties were characterized by the chromatographic fingerprints and the SeDeM expert system. It was found that the release behavior of active pharmaceutical ingredients (APIs) in PNS from different batches exhibited considerable variations. Latent variable modeling results demonstrated that the physical properties of raw materials played major roles in predicting the drug dissolution. PNS extracts with high specific surface area, the width of particle size distribution and hygroscopicity or low moisture content led to an increase in drug release. In order to perform efficient pass/fail judgments for incoming new materials, multivariate specifications of critical material attributes (CMAs) were established and the multivariate design space in line with the quality by design (QbD) principles was explored to achieve the release target.     

Expediting the method development and quality control of reversed-phase liquid chromatography electrospray ionization mass spectrometry for pharmaceutical analysis by using an LC/MS performance test mix

Mass spectrometry combined with liquid chromatography (LC/MS) has become an important analytical methodology in both pharmaceutical and biomolecule analyses. LC/MS, especially with reversed-phase HPLC (RP-LC), is extensively used in the separation and structural identification of pharmaceutical samples. However, many parameters have to be considered when a new LC/MS method is developed for either separation and structural analysis of unknown mixtures or quantitative analysis of a set of known compounds in an assay. The optimization of a new LC/MS method can be a time-consuming process. A novel kit-LC/MS performance test mix-composed of aspartame, cortisone, reserpine, and dioctyl phthalate has been developed to accelerate the process of establishing a new RP-LC/MS method. The LC/MS mix makes the evaluation and validation of an LC/MS method more efficient and easier. It also simplifies the quality control procedure for an LC/MS method in use.     

Pre-selection of suppliers through an integrated fuzzy analytic hierarchy process and max-min methodology

There are a variety of analytical models for supplier selection ranging from simple weighted techniques to complex mathematical programming approaches. However, these models are specifically aimed at supporting a decision maker in a single phase, especially in the final selection phase and they have failed to consider the supplier selection process from a holistic point of view. Although the methodology presented in this paper primarily focused on the prequalification of potential suppliers, the outputs of the previous phases, namely problem definition and formulation of criteria, are used as inputs in this methodology. The methodology utilises a fuzzy analytic hierarchy process (AHP) method to determine the weights of the pre-selected decision criteria, a max-min approach to maximise and minimise the supplier performances against these weighted criteria, and a non-parametric statistical test to identify an effective supplier set. This information supports decision makers in making the final selection with effective alternative choices. Potential application of the proposed methodology is demonstrated in Audio Electronics in Turkey's electronics industry.     

The Validation Life Cycle Applied to Software Development: New Concept or Simply Good Business

Abstract

The singular, most Important aspect which transforms a control system Into a functioning part of a process is the software applications. The conception, design and implementation of these softwares, in general, are inconsistently applied discipline. Although the need for a methodical process Is clearly evident, every project manager's and project engineer's approach to the problem is quite different. Ultimately, the time and effort Is never circumvented. The concept of “pay me now or pay me later” is very true in this particular area:

The development of software for control applications Is new to some industries which are beginning to automate heavily. However, the concept of “validation” (a significant word in the pharmaceutical industry's vocabulary) is common in the nuclear power industry, petroleum refining and utility systems. Also, unrelated industries such as banking have validation procedures for software. Although the final control elements and processes vary from money to oil to power, the “life cycle approach” of design. Implementation, test and verify are consistent. The methodical processes and good engineering practice are the common links.

The purpose of this paper is to examine the methods, procedures, and concepts used in several industrial environments, and compare them to the current evolution of control software development methods of the batch processing industry. Specifically, we will discuss the life cycle concepts now as applies to the pharmaceutical industry and the validation concepts as imposed by the FDA

The synergy of good development techniques and validation is far more than a coincidence. It is good business. Furthermore, the incentives in manpower, energy and product costs show it is a very profitable experience. This paper is geared for project engineers, project managers, control engineers and programmers. The specific slant will be a “how to” guide for providing a solid validatable system for any project but specifically a pharmaceutical one. The design will be weave the life cycle concept into good design practices.     

Definition and validation of the Design Space for co-milled nasal powder containing nanosized lamotrigine

Objective: Design of Experiment (DoE), that is a tool of Quality by Design (QbD) paradigm, with which experiments can be planned more effectively and provide more information, while after Design Space (DS) can be set up, which assure the quality of the desired product. The aim of this study was to find the optimal drug-excipient ratio and the optimal process parameters (milling time, milling speed) of our previously used dry co-milling method and validate the DS.

Materials and methods: Lamotrigine (LAM), an antiepileptic drug was used as a model API. Poly-vinyl alcohol (PVA) was chosen according to our previous study as a hydrophylic matrix polymer. Milling time, speed, and the API:additive ratio was varied to find out their effect on the product. The optimization was performed on particle size of LAM, its standard deviation and the in vitro dissolution of the samples. Response surface modeling completed the statistical analysis that assessed the effects of independent variables on the responses.

Results: Due to the DS estimation, a more economical sample preparation method was set up. Finally, the sample that was prepared according to the optimized parameters (1.5?h, 400?rpm, 0.8 PVA:LAM ratio) showed around 100?nm drug particles and 97% drug release in five minutes.

Conclusion: From the DS generated by the software, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was a useful and effective tool of understanding the parameters that affect the quality of the desired product.