From lab to industrial development of lipid nanocarriers using quality by design approach

Lipid nanocarriers have attracted a great deal of interest in the delivery of therapeutic molecules. Despite their many advantages, compliance with quality standards and reproducibility requirements still constrain their industrial production. The relatively high failure rate in lipid nanocarrier research and development can be attributed to immature bottom-up manufacturing practices, leading to suboptimal control of quality attributes. Recently, the pharmaceutical industry has moved toward quality-driven manufacturing, emphasizing the integration of product and process development through the principles of quality by design. Quality by design in the pharmaceutical industry involves a thorough understanding of the quality profile of the target product and involves an assessment of potential risks during the design and development phases of pharmaceutical dosage forms.

By identifying essential quality characteristics, such as the active ingredients, excipients and manufacturing processes used during research and development, it becomes possible to effectively control these aspects throughout the life cycle of the drug. Successful commercialization of lipid nanocarriers can be achieved if large-scale challenges are addressed using the QbD approach. QbD has become an essential tool because of its advantages in improving processes and product quality. The application of the QbD approach to the development of lipid nanocarriers can provide comprehensive and remarkable knowledge enabling the manufacture of high-quality products with a high degree of regulatory flexibility. This article reviews the basic considerations of QbD and its application in the laboratory and large-scale development of lipid nanocarriers. Furthermore, it provides forward-looking guidance for the industrial production of lipid nanocarriers using the QbD approach.

Highlights

• Lipid nanocarriers offer significant potential for therapeutic payload delivery but face industrial production challenges due to quality and reproducibility issues.
• Pharmaceutical manufacturing has shifted toward quality by design (QbD).
• Applying QbD to lipid nanocarrier development enhances process and product quality, facilitating successful commercialisation and regulatory flexibility.

Introduction

Nanocarriers are currently at their peak in the pharmaceutical industry. The rise of nanocarriers is primarily driven by technological advances that have made it possible to manipulate and study nanomaterials, justifying the time gap between their early scientific introduction and their recent implementation in the pharmaceutical market. Initially, nanocarriers were described as vehicles with measurements ranging from 10 to 100 nm that can attach or encapsulate drugs for delivery (Jeevanandam et al., 2016). As the field progressed, the description has been expanded to cover vesicles with at least one dimension up to 300 nm (Ganta et al., 2014).

Nanocarriers have enormous potential to change the landscape of the pharmaceutical industry by enhancing the efficacy and safety of many of the available drug molecules. Nanocarrier-based drugs offer a promising route to achieve specific characteristics by manipulating the biopharmaceutical and pharmacokinetic properties of the molecule. By reducing unwanted toxicity related to nonspecific administration, improving patient compliance with treatment, and producing positive clinical outcomes, nanocarriers offer great potential for improving disease targeting with therapeutic agents. This approach indirectly alleviates pressure on the healthcare system while developing treatments that are cost-effective and less toxic than traditional approaches (“Nanoscience and nanotechnologies: opportunities and uncertainties, 2022.; Weissig et al., 2014).

Among the wide variety of nanocarriers described, lipid nanocarriers (LNCs) have attracted much interest for the delivery of therapeutic molecules. It is anticipated that LNCs would be a suitable option for clinical use because they are relatively safe and biocompatible (Bandopadhyay et al., 2020). LNCs have gained popularity in therapeutic delivery due to their superior biocompatibility, inherent ability to penetrate tissue, ease of manufacture and nontoxic nature resulting from the use of components generally considered safe. LNCs offer several advantages, including drug protection, enhanced bioavailability, reduced dosing frequency, improved treatment, higher oral bioavailability, and versatile surface modifications [5,6]. In addition, LNCs enable controlled transport of hydrophobic and hydrophilic drugs for optimal therapeutic effects. Their high surface-to-volume ratio enables further modifications using chemical entities such as polyethylene glycol, polyamino acids, fatty acids, and carbohydrates to avoid recognition by the reticuloendothelial system (Lee et al., 2013; Mitchell et al., 2020; Xue et al., 2015).

According to the US FDA, 359 applications containing nanocarriers for drug delivery were submitted between 1970 and 2020, of which 70% involved LNCs (liposomes, nanoemulsions, etc.) (Anselmo et al., 2016; D’Mello et al., 2017). These submissions indicate that many LNCs navigate regulatory agencies.

With ongoing competition on a global scale and the increasing impact of research on drug development, pharmaceutical industries dealing with LNCs urgently need to improve the manufacturing process and the quality of their products (Ohage et al., 2016; “QbD: Improving Pharmaceutical Development and Manufacturing Workflows to Deliver Better Patient Outcomes, 2022.; Rantanen and Khinast, 2015). Numerous obstacles hinder the industrial production and clinical application of LNCs. Firstly, the factors influencing their physicochemical characteristics have not been clearly demonstrated, and their specific in vivo effects have not been clearly demonstrated (Li et al., 2017). Secondly, challenges persist regarding the variability in particle size, unsuitable surface charge, low encapsulation efficiency, and nonuniform shapes that impede large-scale manufacturing remain.

Overcoming these obstacles is essential to comply with good manufacturing practice (GMP) standards. (Kraft et al., 2014). Thirdly, the formulation of some LNCs (i.e., liposomes) is not always simple and cost-effective (Tang et al., 2012). For instance, obtaining a clinically meaningful synthesis procedure for ligand-coated liposomes can be challenging (Fatouh et al., 2021). Fourth, conventional procedures for developing pharmaceuticals that rely on quality testing (QbT) have become obsolete (Cunha et al., 2020b). The QbT approach guarantees product quality by adhering to procedures, including assessing the quality of components (such as drugs and excipients), using consistent manufacturing methods, and conducting product testing. The final product comes into the market only when all the requirements of the regulatory agencies regarding these steps are fulfilled. Otherwise, the manufacturer must restart the process and determine the cause of the failure. In general, identifying the root causes of failure is often challenging because there may be limited comprehension of the process and uncertainty regarding how excipient properties impact the desired product profile (Cunha et al., 2020b). Therefore, the QbT approach is expensive and may not be able to solve problems related to variations that could render the final product less safe and effective.

In 2005, through the ICH Q8 guidelines, the FDA implemented a strategy called “Quality by Design” (QbD) based on risk assessment as an alternative to the conventional QbT approach (GMP Regulation Handbook: Pharmaceutical Development, ICH Q8(R2) | ISPE | International Society for Pharmaceutical Engineering, 2022; Rawal et al., 2019). The FDA defines QbD as “a systematic approach to development that begins with predefined objectives and emphasizes product and process control based on sound science and quality risk management” (“GMP Regulation Handbook: Pharmaceutical Development, ICH Q8(R2) | ISPE | International Society for Pharmaceutical Engineering, 2022). This approach came about when it was realized that more testing does not necessarily improve product quality. Instead, quality must be inherently built into the pharmaceutical product (Sangshetti et al., 2017). Fig. 1 illustrates the differences between the QbT and QbD approaches. QbD is crucial in product development because it involves examining and evaluating all underlying factors that can lead to variations in the final product (Beg et al., 2019a; “ICH Q11 Development and manufacture of drug substances (chemical entities and biotechnological/biological entities) – Scientific guideline, 2022; Pallagi et al., 2015). The QbD approach is needed for designing complex formulations, especially when dealing with well-designed LNCs. Currently, several researchers are applying QbD for the development and optimization of LNCs (Cunha et al., 2020b; Fernández-García et al., 2020; Waghule et al., 2021).

This approach saves time and helps understand the products and design processes by controlling the quality of the final product according to standards. The application of QbD in the development of LNCs holds great promise. Therefore, this review discusses QbD concepts and their applications in developing LNCs. Firstly, the basic considerations of pharmaceutical QbD and their application to the formulation and optimization of LNCs will be outlined. Subsequently, the opportunities and challenges associated with the large-scale production of LNCs using QbD will be discussed.

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Excipients mentioned in the article: Tween® 80, Span® 80, Tween® 20, Miglyol® 812

Aristote B. Buya, Phindile Mahlangu, Bwalya A. Witika, From lab to industrial development of lipid nanocarriers using quality by design approach, International Journal of Pharmaceutics: X, Volume 8, 2024, 100266, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2024.100266.

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