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Application of QbD Elements for the Development of Conventional to Lipid Vesicular for Topical Drug Delivery System
CHAPTER 16
Application of QbD Elements for the Development of Conventional to Lipid Vesicular for Topical Drug Delivery System Mahfoozur Rahman*, Sarwar Beg†, Imran Kazmi‡, Abdul Hafeez‡, Vikas Kumar* *
Department of Pharmaceutical Sciences, Shalom Institute of Health and Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences (SHUATS), Allahabad, India † Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Hamdard University), New Delhi, India ‡ Glocal School of Pharmacy, Glocal University, Saharanpur, India
1 INTRODUCTION Overall, formulations composed of active ingredients with excipients, demonstrated safety and efficacy for easy administration in the patient.1 Lacking in product quality may be considered as subtherapeutic drug product, which may not be approved or prescribed.2 According to the center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA), a product is considered as high-quality product when it is free of contamination and delivers the therapeutic benefit as promised on the label to the consumer.3 Ensuring and meeting the requirement of quality is the most important criterion during product development. The protocols being used in pharmaceutical industry which ensures the quality of formulation products,4 are strictly based on the regulations for manufacturing drugs and allows only nonsignificant variation from batch to batch.5 Moreover, number of testing and characterizations would be very effective in identifying the differences from batch to batch in formulation products. Repeated testing of products without identifying the CQAs of the variability would not have much impact in achieving the target quality.5 Therefore, quality should stand on QbD approach instead of much focus on testing of the products. Therefore, it is very important to design and develop formulations and manufacturing processes to ensure predefined product quality.6 Now the FDA and pharmaceutical industry have been widely giving emphasis on QbD terminology in recent years. Therefore, a clear understanding is Pharmaceutical Quality by Design https://doi.org/10.1016/B978-0-12-815799-2.00017-4
© 2019 Elsevier Inc. All rights reserved.
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important before the implementation of concepts of QbD in product developments.6 According to FDA, as per the guidelines of International Conference on Harmonization (ICH) Q8, QbD is defined as a systematic approach which is based on sound science and quality risk management, variable factors with predefined objectives, and clear process understanding.5, 6 Hence, QbD applications have been employed for most pharmaceutical dosage forms.1 However, the present chapter focuses on QbD approaches for the development of conventional-based dosage form and lipid vesicular for topical/transdermal applications. Topical dermatological drug products are formulations meant for topical applications. For a topical formulation a regulatory approval before commercialization of drug products is required.5, 7 In addition, various critical attributes such as the active pharmaceutical ingredient (API), excipients, physiochemical properties of the drug product, container closure system, physical, chemical stability, scalability, and efficacy of the preservatives have been the determining factors in the safety and efficacy of the drug product.5, 6
2 QUALITY BY TESTING (QbT) In QbT, the components that are incorporated into the dosage forms during manufacturing process are tested for their quality.8 Further the raw materials may be utilized for making the formulations if they meet the FDA approved specifications as well as other regulatory standards. These regulatory agencies set strict specifications in the manufacturing process, which ensures the quality of the formulations.3, 8 Beyond the specification limits, the formulations cannot be taken into consideration, which is rejected further. Moreover, the changes can be made only with in the specification limits.3, 8 Furthermore, the quality of formulation products is ensured by an extensive testing of finished drug product.
3 QUALITY BY DESIGN (QbD) This design approach which is intended to optimize the formulation products improves the efficiency of the process and reduces the cost at different stages. While it reduces the time consumed in product launching, simultaneously enhances the quality process through systematic research and development.9 There are FDA guidelines on pharmaceutical development (ICH Q8), quality risk assessment (ICHQ9), pharmaceutical quality systems (ICHQ10), and ICH; these briefly highlight the approach in achieving product quality through QbD. 10 The QbD has developed formulations
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with the identification of critical material attributes (CMAs) and developed robust manufacturing process with the identification of critical process parameters (CPPs) to get predefined product quality.11 The CMAs and CPPs are variables, which play a key role in optimum development of the product.11 Thus, a complete understanding of these variables is known to control these variables in specification to ensure the quality of the product.11 Therefore, the main applications of QbD in formulation development is to create a detailed mechanistic and scientific understanding of the process variability to provide the targeted quality product.10, 11 The physiochemical and biological properties of the ingredient to be used in the designing of formulation is important for the quality of the formulations, which are the so-called CQAs. ICH Q8 (R1) defines CQAs as physiochemical, biological, or microbiological characteristics; these should be within the defined limit to produce the desired quality.11 The CQAs determine the performance of formulation product. Therefore, the manufacturing process involves multiple unit operations and operating conditions for getting the optimized quality of formulations products.12 The process parameter variability must be monitored and controlled at all times, which ensures the process for the targeted quality. Moreover, they can potentially affect the quality of the product and set the data range to produce the same quality product. Therefore, an efficient process design with in-depth understanding of process development and equipment’s and other facilities that help to produce a good quality of product are needed.11, 12 Application of QbD approach through CQAs and CMAs identifies different grades of material. However, QbD paradigm includes design of experiment (DoE), process analytical technology, and risk assessment through which CPPs can be identified.12 Overall, this also gives an idea about the design space for scaling up the process from pilot scale to commercialize the batch size.
3.1 Quality by Design Tools 3.1.1 Design of Experiment The DoE is a method used for determining the relationship between the factors affecting a process and the output of the process.2 The DoE includes Plackett-Burman design, factorial design, and central composite design (CDD). Investigation of every parameter is practically impossible. Therefore, scientists may identify the key input and output variables during the realization of DoE.2 Furthermore, the results of DoE can identify the critical factors associated with CQAs.
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3.1.2 Risk Management According to the ICH Q9 quality risk management, it is the occurrence and severity of harm which is called as risk assessment.4 There are some potential risk management methods that include basic risk management facilitation methods (such as flow charts and check sheets), failure mode effects and critical analysis, fault tree analysis, risk ranking and filtering, supporting statistical tools, etc. ICH Q9 quality risk management indicates the manufacturing defects and the use of such drug products causes some degree of risk.4 Therefore, the risk to quality ratio should be evaluated and linked to the therapeutic benefit of the patient. So, risk assessment studies are important for the manufacturer to decide which studies need to be taken forward to the next step. The risk assessment study revealed about the critical and noncritical variables, which help in establishing a control strategy for processing raw material and final testing.13 3.1.3 Design Space As per ICH Q8, the design space is a multidimensional combination and interaction of input variables and process parameters, which are employed to provide good quality of products. It provides regulatory flexibility for a single unit, multiunit, or the entire process.5, 12 The limitations associated with the design space are the time required and high the cost involved. Furthermore, an altered effect is possible if any critical parameter is not considered or left while constructing the design space.5–12 Manufacturing changes that occur within the FDA approved design space is not considered as a change, but when it occurs beyond the design space is considered as a change5–12 Design space may vary depending on the selection of parameters, formulation design, and on the equipment used for the development of the drug products. 3.1.4 Response Surface Designs (RSD) The screening designs are applied to the identified process variables, which leads to surface optimization.5, 12 Response surface designs (RSD) such as Box-Behnken, central composite, and three level factorial designs can identify the optimum processing conditions. CDDs are most usable because they are robust against missing data and corner and center point trials, which can be included from previously conducted factorial experiments. On the other hand, because of three levels of each factor, Box-Behnken designs are employed to simplify the execution of the experiment.11, 12 Although the limitations associated with the design is a uniform precision, many center
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points are needed. Missing of any single point leads to inconclusive results. Therefore, robust operating space is the range which continuously reproduces a desired quality product within the design space.11, 12 Furthermore, any deviation from the usual process, but that falls within the design space is acceptable. There can be flexibility in regulatory approval only when QbD experimentation is conducted at manufacturing scale.11, 12 A variation that occurs at a laboratory scale level provides valuable information in the design space for a scale-up and commercial batch size. The deviation made between the laboratory-scale equipment and the commercial scale equipment narrows down the processing variability.11, 12 A design space can be made for the formulation product by the identification of CMAs and CPPs. Furthermore, the output variables are always characterized and compared with the target product profile. Finally, if the output is in accordance with the target, there is a need to develop a control strategy for the entire process. 11, 12 Therefore, this is important for both the product as well as the process understanding by close and continual monitoring for the better quality of the product.11, 12 3.1.5 Process Analytical Technology (PAT) It is used for analyzing the variable processing parameters to make sure that the process is within the operating space.14 It is an effective tool to recognize failure during manufacturing processing and the operating parameters, which can be optimized to assure the quality of the product.9, 14 Therefore, it is a system to design, analyze, and control manufacturing with the time measurement to achieve the desired quality of the formulation product. Furthermore, it provides higher flexibility because of its direct and continuous assessment.14 It is also versatile due to its online process monitoring that detect any out of the control situation during manufacturing process.9, 14 Nowadays, continuous monitoring with enhanced and in-depth understanding is an essential application of PAT. Fig. 1 demonstrates a general idea of QbD approach for pharmaceutical product development.
4 TOPICAL DRUG DELIVERY The skin is the largest organ of the human body, which is differentiated into three distinguishable layers; the stratum corneum is the outermost part of the epidermis, which is the rate controlling membrane or the main barrier for diffusion of molecules across the skin.5, 12 The stratum corneum is a heterogeneous two-compartment system, which is composed of keratinized cells
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Designing of topicals
Designing quality– target profile
Identification of CQA
Design of experiments
Design space
Testing and characterization
Targeted quality ? Yes/No Yes Control strategy
PAT
Continual monitoring and improvement
Fig. 1 Illustration of quality by design approach for development of a topical dosage forms.
embedded in a multilamellar lipid matrix of neutral lipids and ceramides.5, 12 Keratin filled dead cells are surrounded by lamellar lipid regions. Most of the drugs are delivered through the intracellular and transcellular pathways of the skin, while the skin appendages, that is, sweat glands and hair follicle play a nonsignificant role.12 Moreover, drug accumulations in dermal layer is critical and topical transport is a potential approach for topical drug delivery.5, 12 Most of the topical products are administered via the topical/transdermal drug delivery systems.
4.1 QbD Approaches for the Development of Generic Topical Dermatological Products For a topical product, an abbreviated new drug application (ANDA) must undergo multiple review cycles cum FDA regulations before the product is
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Table 1 Criteria for the development of topical dosage forms Critical attributes in topical formulations Critical criteria
API Excipients Physical and chemical stability Process conditions for Q3 products Preservatives Packaging
Solubility, particle size, polymorph, melting points Compatibility, solubility, and melting points Crystallization, phase separation, sedimentation, rheology/viscosity change Mixing time, high or low shear homogenization, mixing speed, temperature range Quantity and types of preservatives Types of containers and closure materials
API, active pharmaceutical ingredients.
approved and the sponsors may have to wait for a long time for their decision.10, 12 ICH Q8 describes the generation of a product development report. In designing of topical formulations there are general critical criteria which are summarized in Table 1. The design of equivalence of a generic topical formulation includes meeting the criteria of Q1 and Q2.12 In the development of topical formulations QbD approach is strongly recommended. The DoE is used to determine the products and process spaces for the CMAs and CPPs. The DoE is used to analyze the influence of processing parameters, which can affect the CQAs of the dosage form.12 Furthermore, it can be used to implement a chemistry, manufacturing, and control strategy for evaluating the stability, product performance, and the process control of the dosage form. When DoE is applied to a topical product process, the input factors are the raw materials, attributes and process parameters as mixing time, mixing speed, and method of mixing and the CQAs include pH, uniformity, viscosity, and microscopic structure of the dosage form.12 Therefore, the DoE gives an idea about the optimized manufacturing process within the specification limit to produce quality products more consistently. For example, stability of the final product may be affected by making a variation in the acid value of the excipients and solvents.12 Chang et al. demonstrated 22 factorial design to test the variation in acid value for cetyl ester wax and glyceryl monostearate additive. The above study shows that the low acid value is suitable for low level of impurity under accelerated stability storage condition.12 So, this type of study is a must for the product development with acceptable stability. Therefore, robust process is the optimized process in which a variable is in the acceptable limit and deliver a quality product. In the operating space a CPP sets the upper and the lower limit
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to render a high-quality product.12 Moreover, clear understanding of the role and interaction of CQAs and CPPs ensures a targeted quality product. Overall, the development of a topical dermatological product includes operating parameters such as weighing of the raw material, order of addition of components, mixer speed, mixing time duration, flow rate, heating and cooling rates and heat and pressures are generated during the processing.12 Thus, the significance of variable factors is essentially linked to its effect on the quality of the product. Therefore, the potential operating system (POS) sets the upper and the lower limit for each processing parameter. Critical and noncritical parameters may have been identified and classified by controlling variations in the process parameters. In the research and formulation batches, if the processing parameters fall within the design space, further validation of the design space is required. In other words, if the parameters fall beyond the design space, it is advised to make a new design space to evaluate the role of each processing parameters for a commercial batch, which may be applied as a valuable tool for regulatory approval.12 Moreover, by the identification of proven acceptable ranges and failure edges, the formulation outputs are characterized and compared with the target quality product profile. Further, when the product output satisfies the target, a control strategy is developed by continuous monitoring.6, 12 A general description of QbD approach in the development of topical formulations is depicted in Fig. 1. In the dosage forms and during storage conditions, it is essential to balance the physical and the chemical stability of the product over time, because they can have issues like phase separation, viscosity, change in pH, appearance, crystal formation, and occurrence of chemical reaction.6, 12 Therefore, the optimization of additives is essential before going to finalize a formulation product.
4.2 Excipients There are a number of excipients being used in topical dosage forms. It is very important to study the difference between the active ingredient and excipients and solvents and containers. Variation in the grade of the excipients such as differences in molecular weight and reactive residues leads to unexpected outcomes.13 An additional test such as pharmacology and toxicology studies should be performed. Furthermore, to check whether the excipients of various grades are compatible with the APIs, an excipient compatibility test is recommended. 13 For topical formulations more retaining of
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drug in the skin is an important aspect. For optimum skin retention, viscosity of a formulation should be optimum in addition to other physical properties of the dosage form.13 Other important factors are size of the dispersed particles, size of the dispersed ingredients, interfacial tension, partition coefficient of the active ingredient, product rheology, and process temperature, which ultimately influence the physical properties of the dosage form.13
4.3 Preservatives Antimicrobial agents are essential in aiding the topical formulations to inhibit the growth of bacteria, fungi, and mold.13 The most commonly used preservatives are a combination of methylparaben, it ranges from 0.01% to 0.3%. Other additives like antioxidants which are used in combination with a chelating agent retarded the oxidative issues.13
4.4 Active Pharmaceutical Ingredient The APIs play a significant role in designing of a topical formulation. Selection of API and their compatibility with other ingredients is also a determining factor.13 Stability concern of API and their degradation are valuable tools during the development of a product. In the topical semisolid products, the percentage of the solvent is relatively higher than that in other dosage forms.13 Therefore, a detailed understanding of the API and their degradation pathway via forced degradation studies and validation of the methods are essential to limit the potential degradation routes.13 Thus, the DoE can be exploited for determining or to control the issues of chemical stability.13
4.5 Packaging The container and closure system are used for packaging materials; they must be compatible with the components of the formulation. Leaching is the big problem of the container and closure system, which enhances the degradation of substances as liquids are more prone to degradation.12, 13 Semisolids may also interact with packaging materials, which accelerate instability issues. Another issue arises due to the evaporation of solvent, which leads to changes in the stability, performance, and dermal absorption of the product.12, 13 Thus, it requires QbD approaches in the analysis of packaging materials and their stability.
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5 QbD APPROACHES FOR THE DEVELOPMENT OF LIPID VESICULAR TOPICAL DRUG CARRIERS Since 2007, several research papers have discussed the application of QbD in the development of nanopharmaceuticals. After that, 24 articles are reviewed and all those are based on nanoparticles developed for drug delivery. Among them, large part comes from Asia, in that India contributed 48%, and the United States 33%, whereas QbD analysis is less utilized in Europe, that is, only 11% and in Africa it is only 8%.15 Overall, 62% examinations of QbD research papers revealed that the application of QbD is only restricted to the formulation issues, 29% discussed both formulation and manufacturing aspects, whereas only 9% focused on the identification of critical factors in the production steps of the development process.15 To date, nanopharmaceuticals including lipid-based vesicular topical drug delivery products and their development relies critically on the progression in manufacturing technology to allow scalable processes complying with the process economy and quality assurance.15 Moreover, the relatively high failure rate in the development of topical lipid vesicular formulations with respect to new products on the market is due to the immature bottom-up manufacturing development and resulting suboptimal controls of quality attributes. Now the scenario has changed, and recently, application of QbD in manufacturing of nanopharmaceuticals has undergone an unprecedented change toward process and product development interaction.15 In the context of lipid vesicular-based topicals, QbD implementation enhances increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products.15 Furthermore, the use of microfluidic production approaches provides opportunities for QbD-based manufacturing of said products. Moreover, microfluidics provides unique design flexibility, process control, parameter predictability, and also offers many opportunities for continuous operating production and process control.15, 16 Recently, researchers have developed Diflunisal phospholipidbased complex loaded into nanolipidic carrier for transdermal delivery.17 In the development of formulation they have applied face centered cubic design (FCCD) after screening of variables by L8 Taguchi orthogonal array design. Overall the optimized formulation has found average particle size (188.1nm), entrapment efficiency of 86.77%, and permeation flux with 5.47 μg/cm2/h.17 Moreover, the dermatokinetic studies have shown the higher concentration in Diflunisal in dermis.17 Another researcher worked on the development of aceclofenac loaded nanostructured lipid carriers by
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applications of QbD-oriented approaches and evaluated transdermal penetration potential and stability. Different lipids and surfactants were chosen as CMAs for NLCs.18 A 33 factorial design was applied for optimization of NLCs for different CQAs, viz., particle size, polydispersity index (PDI), zeta potential, in vitro drug release, and entrapment efficiency.18 Moreover, the optimized ACE-NLCs were spherical, nanometric in size with higher drug loading, and entrapment efficiency.18 Topical delivery of lidocaine and prilocaine as local anesthetics has been great area of interest. Researchers have exploited phospholipid modified microemulsion-based delivery systems for effective delivery of lidocaine and prilocaine.18 In the formulation development, QbD (D-optimal mixture design) have been applied for optimization approach. The results found average size of 40.6 nm and better permeability over commercial cream (CC) through abdominal rat skin.18
6 CONCLUSION In the last decade, QbD has gained much attention from pharmaceutical manufacturers. Failure of QbT and emerging out of QbD and its application in formulation development is much used in practice. Applications of QbD help in identifying and understanding of CMAs and CPPs in topical product development. Apart from this, they also played a key role in understanding the role and interaction between these in achieving a target quality product. Overall, their applications also reduce costs at all stages of development and fasten the process of commercializing the products.
REFERENCES 1. Woodcock J. The concept of pharmaceutical quality. Am Pharm Rev. 2004;47(6):1–3. 2. Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781–791. 3. Yu LX, Amidon G, Khan MA, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–783. 4. Lionberger RA, Lee SL, Lee L, Raw A, Yu LX. Quality by design: concepts for ANDAs. AAPS J. 2008;10(2):268–276. 5. Rosas JG, Blanco M, Gonza´lez JM, Alcala´ M. Quality by design approach of a pharmaceutical gel manufacturing process, part 1: determination of the design space. J Pharm Sci. 2011;100(10):4432–4441. 6. Boix-Montanes A. Relevance of equivalence assessment of topical products based on the dermatopharmacokinetics approach. Eur J Pharm Sci. 2011;42(3):173–179. 7. Colombo S, Beck-Broichsitter M, Bøtker JP, et al. Transforming nanomedicine manufacturing toward Quality by Design and microfluidics. Adv Drug Deliv Rev. 2018;128:115–131.
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8. Pramod K, Tahir MA, Charoo NA, et al. Pharmaceutical product development: A quality by design approach. Int J Pharm Investig. 2016;6(3):129–138. 9. Aksu B, De Beer T, Folestad S, et al. Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT). Eur J Pharm Sci. 2012;47(2):402–405. 10. Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J. 2008;10(1):103–109. 11. Huang J, Kaul G, Cai C, et al. Quality by design case study: an integrated multivariate approach to drug product and process development. Int J Pharm. 2009;382(1-2):23–32. 12. Simo˜es A, Veiga F, Figueiras A, et al. A practical framework for implementing Quality by Design to the development of topical drug products: Nanosystem-based dosage forms. Int J Pharm. 2018;548(1):385–399. 13. Dave VS, Saoji SD, Raut NA, Haware RV. Excipient variability and its impact on dosage form functionality. J Pharm Sci. 2015;104(3):906–915. 14. Islam MT, Rodrı´guez-Hornedo N, Ciotti S, Ackermann C. The potential of Raman spectroscopy as a process analytical technique during formulations of topical gels and emulsions. Pharm Res. 2004;21(10):1844–1851. 15. Garg NK, Sharma G, Singh B, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): an improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm. 2017;517(1-2):413–431. 16. Yadav NK, Raghuvanshi A, Sharma G, et al. QbD-based development and validation of a stability-indicating HPLC method for estimating Ketoprofen in Bulk Drug and Proniosomal vesicular system. J Chromatogr Sci. 2016;54(3):377–389. 17. Kaur A, Bhoop BS, Chhibber S, et al. Supramolecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis. Int J Pharm. 2017;533(1):206–224. 18. Garg NK, Sharma G, Singh B, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm. 2017;517(1-2):413–431.
FURTHER READING 19. Kauffman KJ, Dorkin JR, Yang JH, et al. Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs. Nano Lett. 2015;15(11):7300–7306. 20. Negi P, Singh B, Sharma G, et al. Phospholipid microemulsion-based hydrogel for enhanced topical delivery of lidocaine and prilocaine: QbD-based development and evaluation. Drug Deliv. 2016;23(3):951–967.
Application of QbD Elements for the Development of Conventional to Lipid Vesicular for Topical Drug Delivery System Mahfoozur Rahman*, Sarwar Beg†, Imran Kazmi‡, Abdul Hafeez‡, Vikas Kumar* *
Department of Pharmaceutical Sciences, Shalom Institute of Health and Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences (SHUATS), Allahabad, India † Department of Pharmaceutics, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Hamdard University), New Delhi, India ‡ Glocal School of Pharmacy, Glocal University, Saharanpur, India
1 INTRODUCTION Overall, formulations composed of active ingredients with excipients, demonstrated safety and efficacy for easy administration in the patient.1 Lacking in product quality may be considered as subtherapeutic drug product, which may not be approved or prescribed.2 According to the center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA), a product is considered as high-quality product when it is free of contamination and delivers the therapeutic benefit as promised on the label to the consumer.3 Ensuring and meeting the requirement of quality is the most important criterion during product development. The protocols being used in pharmaceutical industry which ensures the quality of formulation products,4 are strictly based on the regulations for manufacturing drugs and allows only nonsignificant variation from batch to batch.5 Moreover, number of testing and characterizations would be very effective in identifying the differences from batch to batch in formulation products. Repeated testing of products without identifying the CQAs of the variability would not have much impact in achieving the target quality.5 Therefore, quality should stand on QbD approach instead of much focus on testing of the products. Therefore, it is very important to design and develop formulations and manufacturing processes to ensure predefined product quality.6 Now the FDA and pharmaceutical industry have been widely giving emphasis on QbD terminology in recent years. Therefore, a clear understanding is Pharmaceutical Quality by Design https://doi.org/10.1016/B978-0-12-815799-2.00017-4
© 2019 Elsevier Inc. All rights reserved.
367
368
Pharmaceutical Quality by Design
important before the implementation of concepts of QbD in product developments.6 According to FDA, as per the guidelines of International Conference on Harmonization (ICH) Q8, QbD is defined as a systematic approach which is based on sound science and quality risk management, variable factors with predefined objectives, and clear process understanding.5, 6 Hence, QbD applications have been employed for most pharmaceutical dosage forms.1 However, the present chapter focuses on QbD approaches for the development of conventional-based dosage form and lipid vesicular for topical/transdermal applications. Topical dermatological drug products are formulations meant for topical applications. For a topical formulation a regulatory approval before commercialization of drug products is required.5, 7 In addition, various critical attributes such as the active pharmaceutical ingredient (API), excipients, physiochemical properties of the drug product, container closure system, physical, chemical stability, scalability, and efficacy of the preservatives have been the determining factors in the safety and efficacy of the drug product.5, 6
2 QUALITY BY TESTING (QbT) In QbT, the components that are incorporated into the dosage forms during manufacturing process are tested for their quality.8 Further the raw materials may be utilized for making the formulations if they meet the FDA approved specifications as well as other regulatory standards. These regulatory agencies set strict specifications in the manufacturing process, which ensures the quality of the formulations.3, 8 Beyond the specification limits, the formulations cannot be taken into consideration, which is rejected further. Moreover, the changes can be made only with in the specification limits.3, 8 Furthermore, the quality of formulation products is ensured by an extensive testing of finished drug product.
3 QUALITY BY DESIGN (QbD) This design approach which is intended to optimize the formulation products improves the efficiency of the process and reduces the cost at different stages. While it reduces the time consumed in product launching, simultaneously enhances the quality process through systematic research and development.9 There are FDA guidelines on pharmaceutical development (ICH Q8), quality risk assessment (ICHQ9), pharmaceutical quality systems (ICHQ10), and ICH; these briefly highlight the approach in achieving product quality through QbD. 10 The QbD has developed formulations
Application of QbD Elements
369
with the identification of critical material attributes (CMAs) and developed robust manufacturing process with the identification of critical process parameters (CPPs) to get predefined product quality.11 The CMAs and CPPs are variables, which play a key role in optimum development of the product.11 Thus, a complete understanding of these variables is known to control these variables in specification to ensure the quality of the product.11 Therefore, the main applications of QbD in formulation development is to create a detailed mechanistic and scientific understanding of the process variability to provide the targeted quality product.10, 11 The physiochemical and biological properties of the ingredient to be used in the designing of formulation is important for the quality of the formulations, which are the so-called CQAs. ICH Q8 (R1) defines CQAs as physiochemical, biological, or microbiological characteristics; these should be within the defined limit to produce the desired quality.11 The CQAs determine the performance of formulation product. Therefore, the manufacturing process involves multiple unit operations and operating conditions for getting the optimized quality of formulations products.12 The process parameter variability must be monitored and controlled at all times, which ensures the process for the targeted quality. Moreover, they can potentially affect the quality of the product and set the data range to produce the same quality product. Therefore, an efficient process design with in-depth understanding of process development and equipment’s and other facilities that help to produce a good quality of product are needed.11, 12 Application of QbD approach through CQAs and CMAs identifies different grades of material. However, QbD paradigm includes design of experiment (DoE), process analytical technology, and risk assessment through which CPPs can be identified.12 Overall, this also gives an idea about the design space for scaling up the process from pilot scale to commercialize the batch size.
3.1 Quality by Design Tools 3.1.1 Design of Experiment The DoE is a method used for determining the relationship between the factors affecting a process and the output of the process.2 The DoE includes Plackett-Burman design, factorial design, and central composite design (CDD). Investigation of every parameter is practically impossible. Therefore, scientists may identify the key input and output variables during the realization of DoE.2 Furthermore, the results of DoE can identify the critical factors associated with CQAs.
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3.1.2 Risk Management According to the ICH Q9 quality risk management, it is the occurrence and severity of harm which is called as risk assessment.4 There are some potential risk management methods that include basic risk management facilitation methods (such as flow charts and check sheets), failure mode effects and critical analysis, fault tree analysis, risk ranking and filtering, supporting statistical tools, etc. ICH Q9 quality risk management indicates the manufacturing defects and the use of such drug products causes some degree of risk.4 Therefore, the risk to quality ratio should be evaluated and linked to the therapeutic benefit of the patient. So, risk assessment studies are important for the manufacturer to decide which studies need to be taken forward to the next step. The risk assessment study revealed about the critical and noncritical variables, which help in establishing a control strategy for processing raw material and final testing.13 3.1.3 Design Space As per ICH Q8, the design space is a multidimensional combination and interaction of input variables and process parameters, which are employed to provide good quality of products. It provides regulatory flexibility for a single unit, multiunit, or the entire process.5, 12 The limitations associated with the design space are the time required and high the cost involved. Furthermore, an altered effect is possible if any critical parameter is not considered or left while constructing the design space.5–12 Manufacturing changes that occur within the FDA approved design space is not considered as a change, but when it occurs beyond the design space is considered as a change5–12 Design space may vary depending on the selection of parameters, formulation design, and on the equipment used for the development of the drug products. 3.1.4 Response Surface Designs (RSD) The screening designs are applied to the identified process variables, which leads to surface optimization.5, 12 Response surface designs (RSD) such as Box-Behnken, central composite, and three level factorial designs can identify the optimum processing conditions. CDDs are most usable because they are robust against missing data and corner and center point trials, which can be included from previously conducted factorial experiments. On the other hand, because of three levels of each factor, Box-Behnken designs are employed to simplify the execution of the experiment.11, 12 Although the limitations associated with the design is a uniform precision, many center
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points are needed. Missing of any single point leads to inconclusive results. Therefore, robust operating space is the range which continuously reproduces a desired quality product within the design space.11, 12 Furthermore, any deviation from the usual process, but that falls within the design space is acceptable. There can be flexibility in regulatory approval only when QbD experimentation is conducted at manufacturing scale.11, 12 A variation that occurs at a laboratory scale level provides valuable information in the design space for a scale-up and commercial batch size. The deviation made between the laboratory-scale equipment and the commercial scale equipment narrows down the processing variability.11, 12 A design space can be made for the formulation product by the identification of CMAs and CPPs. Furthermore, the output variables are always characterized and compared with the target product profile. Finally, if the output is in accordance with the target, there is a need to develop a control strategy for the entire process. 11, 12 Therefore, this is important for both the product as well as the process understanding by close and continual monitoring for the better quality of the product.11, 12 3.1.5 Process Analytical Technology (PAT) It is used for analyzing the variable processing parameters to make sure that the process is within the operating space.14 It is an effective tool to recognize failure during manufacturing processing and the operating parameters, which can be optimized to assure the quality of the product.9, 14 Therefore, it is a system to design, analyze, and control manufacturing with the time measurement to achieve the desired quality of the formulation product. Furthermore, it provides higher flexibility because of its direct and continuous assessment.14 It is also versatile due to its online process monitoring that detect any out of the control situation during manufacturing process.9, 14 Nowadays, continuous monitoring with enhanced and in-depth understanding is an essential application of PAT. Fig. 1 demonstrates a general idea of QbD approach for pharmaceutical product development.
4 TOPICAL DRUG DELIVERY The skin is the largest organ of the human body, which is differentiated into three distinguishable layers; the stratum corneum is the outermost part of the epidermis, which is the rate controlling membrane or the main barrier for diffusion of molecules across the skin.5, 12 The stratum corneum is a heterogeneous two-compartment system, which is composed of keratinized cells
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Designing of topicals
Designing quality– target profile
Identification of CQA
Design of experiments
Design space
Testing and characterization
Targeted quality ? Yes/No Yes Control strategy
PAT
Continual monitoring and improvement
Fig. 1 Illustration of quality by design approach for development of a topical dosage forms.
embedded in a multilamellar lipid matrix of neutral lipids and ceramides.5, 12 Keratin filled dead cells are surrounded by lamellar lipid regions. Most of the drugs are delivered through the intracellular and transcellular pathways of the skin, while the skin appendages, that is, sweat glands and hair follicle play a nonsignificant role.12 Moreover, drug accumulations in dermal layer is critical and topical transport is a potential approach for topical drug delivery.5, 12 Most of the topical products are administered via the topical/transdermal drug delivery systems.
4.1 QbD Approaches for the Development of Generic Topical Dermatological Products For a topical product, an abbreviated new drug application (ANDA) must undergo multiple review cycles cum FDA regulations before the product is
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Table 1 Criteria for the development of topical dosage forms Critical attributes in topical formulations Critical criteria
API Excipients Physical and chemical stability Process conditions for Q3 products Preservatives Packaging
Solubility, particle size, polymorph, melting points Compatibility, solubility, and melting points Crystallization, phase separation, sedimentation, rheology/viscosity change Mixing time, high or low shear homogenization, mixing speed, temperature range Quantity and types of preservatives Types of containers and closure materials
API, active pharmaceutical ingredients.
approved and the sponsors may have to wait for a long time for their decision.10, 12 ICH Q8 describes the generation of a product development report. In designing of topical formulations there are general critical criteria which are summarized in Table 1. The design of equivalence of a generic topical formulation includes meeting the criteria of Q1 and Q2.12 In the development of topical formulations QbD approach is strongly recommended. The DoE is used to determine the products and process spaces for the CMAs and CPPs. The DoE is used to analyze the influence of processing parameters, which can affect the CQAs of the dosage form.12 Furthermore, it can be used to implement a chemistry, manufacturing, and control strategy for evaluating the stability, product performance, and the process control of the dosage form. When DoE is applied to a topical product process, the input factors are the raw materials, attributes and process parameters as mixing time, mixing speed, and method of mixing and the CQAs include pH, uniformity, viscosity, and microscopic structure of the dosage form.12 Therefore, the DoE gives an idea about the optimized manufacturing process within the specification limit to produce quality products more consistently. For example, stability of the final product may be affected by making a variation in the acid value of the excipients and solvents.12 Chang et al. demonstrated 22 factorial design to test the variation in acid value for cetyl ester wax and glyceryl monostearate additive. The above study shows that the low acid value is suitable for low level of impurity under accelerated stability storage condition.12 So, this type of study is a must for the product development with acceptable stability. Therefore, robust process is the optimized process in which a variable is in the acceptable limit and deliver a quality product. In the operating space a CPP sets the upper and the lower limit
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to render a high-quality product.12 Moreover, clear understanding of the role and interaction of CQAs and CPPs ensures a targeted quality product. Overall, the development of a topical dermatological product includes operating parameters such as weighing of the raw material, order of addition of components, mixer speed, mixing time duration, flow rate, heating and cooling rates and heat and pressures are generated during the processing.12 Thus, the significance of variable factors is essentially linked to its effect on the quality of the product. Therefore, the potential operating system (POS) sets the upper and the lower limit for each processing parameter. Critical and noncritical parameters may have been identified and classified by controlling variations in the process parameters. In the research and formulation batches, if the processing parameters fall within the design space, further validation of the design space is required. In other words, if the parameters fall beyond the design space, it is advised to make a new design space to evaluate the role of each processing parameters for a commercial batch, which may be applied as a valuable tool for regulatory approval.12 Moreover, by the identification of proven acceptable ranges and failure edges, the formulation outputs are characterized and compared with the target quality product profile. Further, when the product output satisfies the target, a control strategy is developed by continuous monitoring.6, 12 A general description of QbD approach in the development of topical formulations is depicted in Fig. 1. In the dosage forms and during storage conditions, it is essential to balance the physical and the chemical stability of the product over time, because they can have issues like phase separation, viscosity, change in pH, appearance, crystal formation, and occurrence of chemical reaction.6, 12 Therefore, the optimization of additives is essential before going to finalize a formulation product.
4.2 Excipients There are a number of excipients being used in topical dosage forms. It is very important to study the difference between the active ingredient and excipients and solvents and containers. Variation in the grade of the excipients such as differences in molecular weight and reactive residues leads to unexpected outcomes.13 An additional test such as pharmacology and toxicology studies should be performed. Furthermore, to check whether the excipients of various grades are compatible with the APIs, an excipient compatibility test is recommended. 13 For topical formulations more retaining of
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drug in the skin is an important aspect. For optimum skin retention, viscosity of a formulation should be optimum in addition to other physical properties of the dosage form.13 Other important factors are size of the dispersed particles, size of the dispersed ingredients, interfacial tension, partition coefficient of the active ingredient, product rheology, and process temperature, which ultimately influence the physical properties of the dosage form.13
4.3 Preservatives Antimicrobial agents are essential in aiding the topical formulations to inhibit the growth of bacteria, fungi, and mold.13 The most commonly used preservatives are a combination of methylparaben, it ranges from 0.01% to 0.3%. Other additives like antioxidants which are used in combination with a chelating agent retarded the oxidative issues.13
4.4 Active Pharmaceutical Ingredient The APIs play a significant role in designing of a topical formulation. Selection of API and their compatibility with other ingredients is also a determining factor.13 Stability concern of API and their degradation are valuable tools during the development of a product. In the topical semisolid products, the percentage of the solvent is relatively higher than that in other dosage forms.13 Therefore, a detailed understanding of the API and their degradation pathway via forced degradation studies and validation of the methods are essential to limit the potential degradation routes.13 Thus, the DoE can be exploited for determining or to control the issues of chemical stability.13
4.5 Packaging The container and closure system are used for packaging materials; they must be compatible with the components of the formulation. Leaching is the big problem of the container and closure system, which enhances the degradation of substances as liquids are more prone to degradation.12, 13 Semisolids may also interact with packaging materials, which accelerate instability issues. Another issue arises due to the evaporation of solvent, which leads to changes in the stability, performance, and dermal absorption of the product.12, 13 Thus, it requires QbD approaches in the analysis of packaging materials and their stability.
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5 QbD APPROACHES FOR THE DEVELOPMENT OF LIPID VESICULAR TOPICAL DRUG CARRIERS Since 2007, several research papers have discussed the application of QbD in the development of nanopharmaceuticals. After that, 24 articles are reviewed and all those are based on nanoparticles developed for drug delivery. Among them, large part comes from Asia, in that India contributed 48%, and the United States 33%, whereas QbD analysis is less utilized in Europe, that is, only 11% and in Africa it is only 8%.15 Overall, 62% examinations of QbD research papers revealed that the application of QbD is only restricted to the formulation issues, 29% discussed both formulation and manufacturing aspects, whereas only 9% focused on the identification of critical factors in the production steps of the development process.15 To date, nanopharmaceuticals including lipid-based vesicular topical drug delivery products and their development relies critically on the progression in manufacturing technology to allow scalable processes complying with the process economy and quality assurance.15 Moreover, the relatively high failure rate in the development of topical lipid vesicular formulations with respect to new products on the market is due to the immature bottom-up manufacturing development and resulting suboptimal controls of quality attributes. Now the scenario has changed, and recently, application of QbD in manufacturing of nanopharmaceuticals has undergone an unprecedented change toward process and product development interaction.15 In the context of lipid vesicular-based topicals, QbD implementation enhances increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products.15 Furthermore, the use of microfluidic production approaches provides opportunities for QbD-based manufacturing of said products. Moreover, microfluidics provides unique design flexibility, process control, parameter predictability, and also offers many opportunities for continuous operating production and process control.15, 16 Recently, researchers have developed Diflunisal phospholipidbased complex loaded into nanolipidic carrier for transdermal delivery.17 In the development of formulation they have applied face centered cubic design (FCCD) after screening of variables by L8 Taguchi orthogonal array design. Overall the optimized formulation has found average particle size (188.1nm), entrapment efficiency of 86.77%, and permeation flux with 5.47 μg/cm2/h.17 Moreover, the dermatokinetic studies have shown the higher concentration in Diflunisal in dermis.17 Another researcher worked on the development of aceclofenac loaded nanostructured lipid carriers by
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applications of QbD-oriented approaches and evaluated transdermal penetration potential and stability. Different lipids and surfactants were chosen as CMAs for NLCs.18 A 33 factorial design was applied for optimization of NLCs for different CQAs, viz., particle size, polydispersity index (PDI), zeta potential, in vitro drug release, and entrapment efficiency.18 Moreover, the optimized ACE-NLCs were spherical, nanometric in size with higher drug loading, and entrapment efficiency.18 Topical delivery of lidocaine and prilocaine as local anesthetics has been great area of interest. Researchers have exploited phospholipid modified microemulsion-based delivery systems for effective delivery of lidocaine and prilocaine.18 In the formulation development, QbD (D-optimal mixture design) have been applied for optimization approach. The results found average size of 40.6 nm and better permeability over commercial cream (CC) through abdominal rat skin.18
6 CONCLUSION In the last decade, QbD has gained much attention from pharmaceutical manufacturers. Failure of QbT and emerging out of QbD and its application in formulation development is much used in practice. Applications of QbD help in identifying and understanding of CMAs and CPPs in topical product development. Apart from this, they also played a key role in understanding the role and interaction between these in achieving a target quality product. Overall, their applications also reduce costs at all stages of development and fasten the process of commercializing the products.
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8. Pramod K, Tahir MA, Charoo NA, et al. Pharmaceutical product development: A quality by design approach. Int J Pharm Investig. 2016;6(3):129–138. 9. Aksu B, De Beer T, Folestad S, et al. Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT). Eur J Pharm Sci. 2012;47(2):402–405. 10. Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J. 2008;10(1):103–109. 11. Huang J, Kaul G, Cai C, et al. Quality by design case study: an integrated multivariate approach to drug product and process development. Int J Pharm. 2009;382(1-2):23–32. 12. Simo˜es A, Veiga F, Figueiras A, et al. A practical framework for implementing Quality by Design to the development of topical drug products: Nanosystem-based dosage forms. Int J Pharm. 2018;548(1):385–399. 13. Dave VS, Saoji SD, Raut NA, Haware RV. Excipient variability and its impact on dosage form functionality. J Pharm Sci. 2015;104(3):906–915. 14. Islam MT, Rodrı´guez-Hornedo N, Ciotti S, Ackermann C. The potential of Raman spectroscopy as a process analytical technique during formulations of topical gels and emulsions. Pharm Res. 2004;21(10):1844–1851. 15. Garg NK, Sharma G, Singh B, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): an improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm. 2017;517(1-2):413–431. 16. Yadav NK, Raghuvanshi A, Sharma G, et al. QbD-based development and validation of a stability-indicating HPLC method for estimating Ketoprofen in Bulk Drug and Proniosomal vesicular system. J Chromatogr Sci. 2016;54(3):377–389. 17. Kaur A, Bhoop BS, Chhibber S, et al. Supramolecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis. Int J Pharm. 2017;533(1):206–224. 18. Garg NK, Sharma G, Singh B, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm. 2017;517(1-2):413–431.
FURTHER READING 19. Kauffman KJ, Dorkin JR, Yang JH, et al. Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs. Nano Lett. 2015;15(11):7300–7306. 20. Negi P, Singh B, Sharma G, et al. Phospholipid microemulsion-based hydrogel for enhanced topical delivery of lidocaine and prilocaine: QbD-based development and evaluation. Drug Deliv. 2016;23(3):951–967.