Research Article: Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch

Date Published: June 22, 2020

Publisher: Springer International Publishing

Author(s): Josip Matić, Amrit Paudel, Hannes Bauer, Raymar Andreina Lara Garcia, Kinga Biedrzycka, Johannes G. Khinast.

http://doi.org/10.1208/s12249-020-01713-0

Abstract

This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-of-the-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation. The predicted optimal process setup can be validated quickly in the pilot plant. Lastly, a transfer of the process to any GMP-certified manufacturing site can be performed in silico for any extruder based on our validated computational framework. In summary, the proposed workflow massively reduces the risk in product and process development and shortens the drug-to-market time for enabling formulations.

Partial Text

Active pharmaceutical ingredients (APIs) are becoming more potent and selective, resulting in increasingly complex formulations, and drug delivery strategies that are precisely tailored to achieve the required PK profile of a drug. Typical examples include poorly soluble APIs that require solubility enhancement (1–3). Moreover, advanced formulation strategies lead to more complex manufacturing processes, which increases the risk of development failure. In general, bringing a new drug to the market involves multiple time-consuming stages, with a go or no-go decision made at each stage. Since the pressure to bring a new drug to the market is immense, originators shy away from risky formulation designs and prefer simple drug delivery systems (DDSs), such as immediate release tablets. In order to counter this trend, our past work focused on de-risking the development and manufacturing stage of new and advanced DDSs. Examples include the development of small-scale formulation screening tools, i.e., the vacuum compression molding (VCM) tool (4), advanced hot melt extrusion (HME) process models, mechanistic studies of biopharmaceutics, and stability aspects of enabling formulations and more, as described in detail in the sections to follow. Hence, we created a toolbox for rapidly developing hot-melt extruded formulations in tandem with the associated manufacturing process.

According to the ICH, quality by design (QbD) is a systematic approach to the development of pharmaceuticals that is based on sound science and quality risk management, with an emphasis on predefined objectives, product and process understanding, and process control (15,16,19–24). In the language of QbD, predefined objectives are reflected in the definition of the quality target product profile (QTPP) with the goal of achieving the intended therapeutic outcome and in the identification of critical quality attributes (CQAs). The importance of this first step cannot be overstated since all of the following product development efforts aim to satisfy the predefined route of administration, delivery system, dosage form and strength, targeted in vivo drug release, and pharmacokinetic profile as part of the QTPP requirements. Moreover, to ensure the desired product quality measured via the CQAs physical, chemical, biological, and microbiological properties should be within the appropriate limits. Preformulation studies, formulation design, and in vitro characterization focus on matching the final product’s QTPP. However, various process-related technological parameters of API and excipients need to be specifically considered as well.

Our approach to developing an enabling ASD formulation for a poorly soluble drug candidate via HME consists of (A) formulation and processability screening, (B) predictive computational and experimental methodologies for assessing biopharmaceutics and stability, and (C) advanced scale-up methods. This includes state-of-the art practices currently applied in industries in combination with emerging knowledge from academia. It should be emphasized that most of the workflow is equally applicable to the ASD development for manufacturing routes other than HME, such as spray drying (SD), milling, congealing, or supercritical fluid technology (Fig. 3).Fig. 3A systematic approach to potential carrier (polymer, surfactant, and combinations) selection for HME-based amorphous solid dispersions

Early phase product development is expected to balance the biopharmaceutics and stability targets and the manufacturability requirement for a given drug molecule. More precisely, the formulation candidates that are transferable from preclinical in vivo studies to first-in-human (FIH) dosing require systematic and thorough preformulation studies, screening and small-scale prototype preparation, which take into account the limited availability of drug candidate and the stringent development timeline. The preformulation screening is intended to provide the relevant information on biopharmaceutics, stability, and processability as early as possible.

As one of the key quality attributes, stability of pharmaceutical products has to be ensured for the patient safety and efficacy. Being able to predict stability by combining the experiments and in silico modeling can drastically shorten the development timeline, while reducing the risk of re-formulation. Although empirical models based on Arrhenius kinetics are widely applied in practice for theoretical shelf-life prediction, they are limited to simple formulations and to cases in which instability can be readily conjectured based on the functional groups involved (e.g., Milliard reaction between lactose and amine-containing drugs). In particular, with regard to ASDs the typical routes of instability are of both physical and chemical nature. On the one hand, amorphous phase separation and nucleation/crystal growth of active components of ASDs eliminate the expected solubility advantages. On the other hand, higher energetics and mobility of amorphous drug molecules in ASD prompt faster drug degradation and drug-excipient chemical interaction. Thus, an accurate prediction of stability in the final dosage forms is still challenging.

Biopharmaceutics of pharmaceutical products contain the most important parameters for ascertaining the success of a given formulation and processing strategy, including the in vivo absorption of drug molecule and the systemic availability. The basis for establishing the biopharmaceutics of a drug product is the dissolution process (and possibly recrystallization due to supersaturation via ASD) in the GI milieu and permeation of the dissolved drug molecules through the GI membrane via active and/or passive transport. These parameters are tested in vitro via biorelevant dissolution testing and drug permeability through the artificial membrane or cell membrane. Biorelevant dissolution testing uses the gastric fluid simulated sequentially over time, followed by the simulated intestinal fluid. The in vitro results, together with in vivo pharmacokinetic data, are used to construct in vitro–in vivo correlations (IVIVC) or to develop a predictive mechanistic physiologically based pharmacokinetic (PBPK) model in vivo.

Drug product development is a complicated and risky endeavor, especially with regard to complex enabling formulations, such as ASDs made via hot-melt extrusion or spray drying. To facilitate it, we developed workflows and platforms for rapid product development that allow a rational design of formulations, process and scale-up/tech-transfer to GMP manufacturing within less than a year. The first step (Fig. 1) is screening the suitable carriers and establishing a detailed understanding of API-carrier interactions, which allow an analysis of long-term stability and biopharmaceutics of the products. Both theoretical tools (e.g., MD simulation, PC-SAFT modeling, Flory Huggins model, Gordon-Taylor equation) and experimental screening methods (DSC, rheology, etc.) form a (semi-) predictive framework for a rational formulation development. Accelerated stability screening and detailed analysis of biopharmaceutical parameters (e.g., biorelevant supersaturation and in vitro dynamic dissolution) are the next logical step. The outcome of these efforts is the selection of suitable carriers for a specific API formulation (for example ASDs). In the past, we demonstrated that such a rational formulation development workflow can be completed within a few months.

 

Source:

http://doi.org/10.1208/s12249-020-01713-0

 

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