Evaluation of Excipient Variability

Compared to the past few years, pharmaceutical industry has produced a wide variety of excipients, which are available from various sources. Although an excipient is an inert material, it is variable because it is not controlled at the level of individual parameters. Due to the ignorance of variability of excipients, many failed drugs have been recalled. Therefore, it is of great significance for the implementation of control strategies to correctly identify whether excipient variability will adversely affect drug performance and fully understand its impact on drug efficacy. Investigation of the impact of material properties and quantity variability on drug performance will help develop robust final dosage forms. BOC Sciences provides excipient variability assessment services to identify critical excipient properties that may have an impact on drug product performance by providing quantitative physicochemical property data.

Figure 1. Potential variability due to excipient source. (Carlin, B.; et al. 2022)

Variability in the raw materials used in excipient manufacture can arise from causes such as:

• Excipients derived from plants or animals: growing conditions (climate change as well as natural disasters), components related to environmental conditions in different geographical areas (soil, sea), transport processes, raw material processing, packaging, storage and distribution
• Mineral excipients: geographic origin, processing conditions (calcination temperature and type of grinding)
• Synthetics excipients: composition of products derived from crude oil or natural gas feedstocks varies with the content and range of heavy metals, multiphase versus single-phase reactions, distribution of different organic components

Applications of Excipient Variability Studies

• Establish a clear understanding of the variability in relation to specific drug delivery routes or products
• Develop more robust manufacturing processes and products
• Save time and cost in the development of products over longer timescales or large number of batches

Figure 2. Effects of excipient variability. (Zarmpi, P.; et al. 2017)

Excipient Variability Evaluation Services

Multivariate Analysis (MVA)

BOC Sciences supports the employment of various multivariate tools to detect variability in a range of commonly used excipients, tracking and monitoring the variability of excipients over a set time frame. Our experts apply dissolution modeling techniques to track and monitor excipient variability over a set time frame to reveal differences in the release of model drugs using different batches of starting materials.

Quality by Design (QbD)

• Design of Experiments (DoE): DoE is a common tool for studying interactions between different materials. Through establishing a rational experimental design, our experts are able to determine the properties that are affecting the finished drug
• Design Space: At BOC Sciences, based on the results of the DoE and subsequent risk assessment, with full consideration of API/excipient compatibility, our experts build a design space by inputting multidimensional combinations of variables
• Control Strategy: Statistical analysis is used to assess the correlation between properties of excipients and critical quality attributes (CQAs), and a predictive model is built with the application of artificial neural networks (ANN)

Risk Analysis

Based on the production data of multiple batches of excipients, we use statistical analysis methods such as principal factor analysis, to identify the critical material attributes that have potential to alter the performance of the formulation.

Thorough Excipient Characterization

The specific method for excipient characterization depends on the nature of those excipients. At BOC Sciences, our experts carefully select characterization methods based on the needs of the final drug product

• For oral solid dosage forms, we need to pay special attention to the particle size distribution, volume and shunt density and fluidity of excipients.
• For creams and ointments, we characterize the chemical composition of excipients as well as physical properties such as viscosity and melting behavior.

Characterization Methods

• Classical solid-state characterization such as X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR)
• Methods related to surface characterization, including wettability or specific surface area