Drug Product Quality Research Articles

Evaluating surfactant effectiveness in preventing antibody adsorption directly on medical surfaces using a novel device

Biopharmaceuticals, specifically antibody-based therapeutics, have revolutionized disease treatment. Throughout their lifecycle, these therapeutic proteins are exposed to several stress conditions, for example at interfaces, posing a risk to the drug product stability, safety and quality. Therapeutic protein adsorption at interfaces may lead to loss of active product and protein aggregation, with potential immunogenicity risks. Non-ionic surfactants are commonly added in formulations to mitigate protein-surface interactions. However, their effectiveness varies with the monoclonal antibody (mAb), and model surface material. Extrapolating findings from model surfaces to real medical surfaces is challenging due to diverse properties.This study pioneers the evaluation of surfactant effectiveness in preventing mAb adsorption directly on medical surfaces at the medical bag/formulation interface, utilizing the ELIBAG device. The adsorption of different protein modalities, mAbs and antibody-drug conjugate (ADC), using three surfactants (PS80, PS20, and P188), was examined across various medical surfaces, IV bags and manufacturing bags, and model surfaces. Our findings reveal that surfactants prevent mAb adsorption depending on the mAb modality, surfactant type and concentration, and surface material. This research underscores the importance of considering real medical surfaces in direct contact with formulations, offering insights for enhancing drug product development and ensuring material-protein compatibility in real world use.

Review on vital role of regulatory affairs in pharmaceutical industry

The burgeoning field of Regulatory Affairs (RA) serves as the foundation for ensuring public health in today's globalized marketplace. In the pharmaceutical industry, regulatory affairs play a crucial role in assuring the safety, efficacy, and quality of drug products, which are essential for the approval of new products entering the market. Emerging from a collective international desire to protect individuals from potentially harmful medications, this profession bridges the gap between pharmaceutical companies and regulatory agencies, ensuring that products meet all necessary legal and scientific standards.Regulatory affairs professionals act as guardians, meticulously ensuring the accuracy and completeness of product information. They navigate the complex labyrinth of regulations, translating them into practical plans for companies to follow. Their expertise encompasses the entire life cycle of a drug, from initial application submission and oversight of clinical trials to ongoing adherence to evolving regulatory requirements. This comprehensive approach guarantees the development, manufacturing, and distribution of safe and effective medications across various fields, including traditional pharmaceuticals, veterinary medicine, medical devices, and complementary therapies.As the pharmaceutical landscape continues to evolve, the demand for highly skilled regulatory affairs professionals remains strong. In India, the Central Drug Standard Control Organization (CDSCO) regulates drug legislation, facilitating drug development from initial research to market approval and post-marketing surveillance.

Real-time prediction of dissolution profiles of coated oral dosage forms

Optical coherence tomography (OCT) has emerged as an in-line monitoring technique for pharmaceutical coating processes based on a representative number of samples. In this study, an approach was developed to correlate the coating thickness measured in-line via OCT with the resultant tablet dissolution profile. This strategy enables prediction of the dissolution profile of coated oral dosage forms for each individual state of the coating process in real-time. Correlation models were developed for a tablet pan coating process and for a pellet fluid-bed coating process. The feasibility of the correlation models was tested using different process parameters and types of coating formulations. This work demonstrated that using the OCT data to predict dissolution could possibly form a unique way of assuring drug product quality and establishing a control strategy within the real-time release testing (RTRT) concept.

PBBM Considerations for Base Models, Model Validation, and Application Steps: Workshop Summary Report.

The proceedings from the 30th August 2023 (Day 2) of the workshop "Physiologically Based Biopharmaceutics Models (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives" are provided herein. Day 2 covered PBBM case studies from six regulatory authorities which provided considerations for model verification, validation, and application based on the context of use (COU) of the model. PBBM case studies to define critical material attribute (CMA) specification settings, such as active pharmaceutical ingredient (API) particle size distributions (PSDs) were shared. PBBM case studies to define critical quality attributes (CQAs) such as the dissolution specification setting or to define the bioequivalence safe space were also discussed. Examples of PBBM using the credibility assessment framework, COU and model risk assessment, as well as scientific learnings from PBBM case studies are provided. Breakout session discussions highlighted current trends and barriers to application of PBBMs including: (a) PBBM credibility assessment framework and level of validation, (b) use of disposition parameters in PBBM and points to consider when iv data are not available, (c) conducting virtual bioequivalence trials and dealing with variability, (d) model acceptance criteria, and (e) application of PBBMs for establishing safe space and failure edges.

Thermal Behavior and Infrared Absorbance Bands of Citric Acid

Citric acid is widely used in the Food and Pharmaceutical Industry. Various issues regarding its thermal behavior and infrared spectrum require clarification. Here, we studied citric acid monohydrate (raw, heated, freeze-dried and recrystallized from D2O) via Differential Scanning Calorimetry, Thermogravimetric Analysis, Infrared Spectroscopy, and antioxidant capacity assay. Also, we used ab initio Density Functional Theory calculations for further supporting the interpretations of the experimental results. Citric acid monohydrate exhibits desolvation inability and upon heating does not dehydrate but esterifies. Nor by freeze drying can it be dehydrated. The heated sample is not anhydrous, it exhibits melting inability, and any fluidization occurs simultaneously with decomposition. In other words, the interpretations regarding the two endothermic peaks in the DSC curve of citric acid that have been attributed to water evaporation and melting are not correct. The increase in the molecular weight due to esterification is most likely responsible for the increased antioxidant/chelation capacity of the heated sample. We concluded that what we call citric acid monohydrate and anhydrous do not exist in a pure form (in the solid state) and actually are mixtures of different compositions of citric acid, water and a citric acid oligomer that is produced through esterification. The esterification reaction seems to be able to proceed easily under mild heating or even at room temperature. The presence of the ester oligomer and water affect the infrared spectrum of citric acid monohydrate and anhydrous and is responsible for the existence of multiple peaks in the C=O stretching region, which partially overlaps with the water H-O-H bending vibration. The insights presented in this work could be useful for optimizing the design, performance and quality of food and drug products in which citric acid is used.

Impact of mixing and shaking on mRNA-LNP drug product quality characteristics

Since the COVID-19 pandemic, the interest in RNA-lipid nanoparticle (LNP) based drug products has increased drastically. While one RNA-LNP drug product, Onpattro, was already on the market in 2018, high volume manufacturing was only initiated end of 2020 with the approval of the mRNA-LNP vaccines, Comirnaty and Spikevax. As such, deep product knowledge for RNA-LNPs is continuously increasing. In this article the effect of large-scale mixing and lab-scale shaking on mRNA-LNP drug product quality characteristics is investigated. It is shown that mixing and shaking can have a profound impact on both LNP size distribution and mRNA encapsulation, suggesting a direct correlation between both quality characteristics, and further supported by a proposed underlying mechanism. An in-depth investigation of different drug product (DP) presentations reveals a consistent effect of headspace volume and LNP content on the shaking stress sensitivity. Results reported in this study are of utter importance for both small- and large-scale manufacturers but also for care givers and patients using these products.

Application of quality by design in optimization of nanoformulations: Principle, perspectives and practices.

Nanoparticulate drug delivery systems (NDDS) based nanoformulations have emerged as promising drug delivery systems. Various NDDS-based formulations have been reported such as polymeric nanoparticles (NPs), nanoliposomes, solid lipid NPs, nanocapsules, liposomes, self-nano emulsifying drug delivery systems, pro liposomes, nanospheres, microemulsion, nanoemulsion, gold NPs, silver NPs and nanostructured lipid carrier. They have shown numerous advantages such as enhanced bioavailability, aqueous solubility, permeability, controlled release profile, and blood-brain barrier (BBB) permeability. This advantage of NDDS can help to deliver pure drugs to the target site. However, the formulation of nanoparticles is a complex process that requires optimization to ensure product quality and efficacy. Quality by Design (QbD) is a systemic approach that has been implemented in the pharmaceutical industry to improve the quality and reliability of drug products. QbD involves the optimization of different parameters like zeta potential (ZP), particle size (PS), entrapment efficiency (EE), polydispersity index (PDI), and drug release using statistical experimental design. The present article discussed the detailed role of QbD in optimizing nanoformulations and their advantages, advancement, and applications from the industrial perspective. Various case studies of QbD in the optimization of nanoformulations are also discussed.

Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

Quality by Design (QbD) Paradigm: An Integrated Multivariate Approach to Transdermal Patch System Development

: The International Council on Harmonization issued quality by design (QbD) guidelines, including Q8 (R2) pharmaceutical development, Q9 quality risk management, and Q10 pharmaceutical quality system, to ensure the quality of pharmaceutical products. For continual and consistent improvement of the quality of pharmaceutical drug products, QbD tools, such as risk assessment, design of experiment, and control strategy, are used, which can solve the narrow areas in product development. Transdermal patch systems (TPS) are gaining attention among scientists and are one of the strong-growing drug delivery systems in the market as a result of numerous benefits, including lowering the dosing frequency, adverse effects and invasiveness, avoiding pre-systemic metabolism, and better patient efficiency and compatibility. Transdermal patch systems are a likable dosage form when compared to other dosage forms. However, several challenges are faced in TPS product development which has hindered enormous products concerning the market status of TPS in comparison to the oral dosage forms. The implementation of the QbD concept was much focused on oral dosage forms. Additionally, the lack of understanding of the development of TPS leads to failure and withdrawal from markets. Therefore, to understand the QbD concepts of TPS, an attempt has been made to review the QbD approach for the development of TPS from the identification of the Quality Target Product Profile to the arrival of design space, which might help the formulator to navigate the sticky areas, in the TPS development.

Identification and Structural Characterization of Degradation Products of Linagliptin by Mass Spectrometry Techniques.

As part of the development and production of pharmaceuticals, the purity of Active Pharmaceutical Ingredients stands as a fundamental parameter that significantly influences the quality, safety, and efficacy of the final drug product. Impurities in Active Pharmaceutical Ingredients are various unwanted substances that can appear during the whole manufacturing process, from raw materials to the final product. These impurities can stem from multiple sources, including starting materials, intermediates, reagents, solvents, and even degradation products resulting from exposure to environmental factors such as heat, light, or moisture. Their presence can potentially compromise the therapeutic effect of the drug, introduce unexpected side effects, or even pose safety risks to patients. This study aims to conduct the forced degradation of linagliptin and subsequently attempt to identify the resulting degradants. The degradation procedures were carried out in accordance with the guidelines of the International Committee for Harmonization. The degradation profile of linagliptin was investigated under various conditions, including acid hydrolysis, alkaline hydrolysis, oxidation, heat, and light exposure, utilizing ultra-performance liquid chromatography connected to a photo array detector. Identification and characterization of the degradation products were achieved using an ultra-performance liquid chromatography coupled with a single quadrupole detector mass spectrometer and also a liquid chromatography coupled with a high-resolution mass spectrometry. The identified degradation products demonstrate that linagliptin is particularly susceptible to degradation when exposed to acid and peroxide. Whereas, no significant degradation effects were observed under alkali, thermolytic, and photolytic conditions.

The impact of diluents on the compaction, dissolution, and physical stability of amorphous solid dispersion tablets

Amorphous solid dispersion (ASD) is an effective approach for enhancing the solubility, dissolution, and bioavailability of poorly water-soluble drugs. However, these metastable forms can transform into more thermodynamically stable but less soluble crystalline forms. Despite this challenge, research on processing ASDs into solid dosage forms, such as tablets, is lacking. This work aims to fill this gap by investigating the impact of common diluents on the tableting behavior, dissolution, and physical stability of ASDs composed of itraconazole and hypromellose acetate succinate. Four widely used diluents found in commercially available ASD tablets were selected for the study: microcrystalline cellulose (MCC), anhydrous lactose, starch, and mannitol. The performance of ASD tablets varied significantly depending on the diluent used. Tablets prepared with MCC exhibited higher mechanical strength than those formulated using other diluents. ASD tablets containing mannitol and lactose revealed a faster release rate than those composed of MCC or starch. Notably, the study highlighted that the physical stability of ASDs within a tablet is not solely dependent on the amount of sorbed water; crystalline diluents like lactose and mannitol were found to facilitate ASD recrystallization within a tablet. In summary, the study underscores the importance of excipient selection, considering factors such as mechanical strength, dissolution rate, and physical stability of ASD tablets. These findings offer valuable insights into the selection of excipients for downstream ASD tablet development, leading to improved manufacturability, physical stability, and the overall quality of ASD drug products.

Patient In-Use Stability Testing of FDA-Approved Metformin Combination Products for N-Nitrosamine Impurity.

Between February 2020 and January 2022, the Food and Drug Administration (FDA) recalled 281 metformin extended-release products due to the presence of N-nitrosodimethylamine (NDMA) above the acceptable daily intake (ADI, 96ng/day). Our previous studies indicated presence of NDMA levels above ADI in both metformin immediate and extended-release products. When metformin products have NDMA impurities, it is indispensable to check for the same impurities in metformin combination products. Therefore, the objective of the present study was to evaluate in-use stability of commercial metformin combination products for NDMA. For this purpose, metformin products in combination with glyburide (GB1-GB12), glipizide (GP1-GP8), pioglitazone (P1-P3), alogliptin (A1, A2), and linagliptin (L1, L2) were repacked in pharmacy vials, stored at 30°C/75% RH for 3months, and monitored for NDMA impurity. The NDMA level varied from 0 to 156.8 ± 32.8ng/tablet initially and increased to 25.4 ± 5.1 to 455.0 ± 28.4ng/tablet after 3months of exposure to in-use condition. Initially, 18 products have NDMA level below ADI limit before exposure which decreased to 7 products (GB5, GP3, GP5, A1, A2, L1, and L2) meeting specification. In conclusion, in-use stability study provides quality and safety risk assessment of drug products where nitroso impurities are detected in the probable condition of use.

Semi-crystalline materials for pharmaceutical fused filament fabrication: Dissolution and porosity

A better understanding of crystallization kinetics and the effect on drug product quality characteristics is needed to exploit the use of semi-crystalline polymers in pharmaceutical fused filament fabrication. Filaments were prepared from polycaprolactone or polyethylene oxide loaded with a crystallization inhibitor or inducer, which was either 10% (w/w) ibuprofen or theophylline. A design-of-experiments approach was conducted to investigate the effect of nozzle temperature, bed temperature and print speed on the printed tablets’ microstructure and dissolution kinetics. Helium pycnometry derived porosity proved an ideal technique to capture significant distortions in the tablets’ microstructure. On the other hand, terahertz time domain spectroscopy (THz-TDS) analysis proved valuable to investigate additional enclosed pores of the tablets’ microstructure. The surface roughness was analyzed using optical coherence tomography, showing the importance of extensional viscosity for printed drug products. Drug release occurred via erosion for tablets consisting of polyethylene oxide, which partly reduced the effect of the inner microstructure on the drug release kinetics. An initial burst release effect was noted for polycaprolactone tablets, after which drug release continued via diffusion. Both the pore and crystalline microstructure were deemed essential to steer drug release. In conclusion, this research provided guidelines for material and process choice when a specific microstructure has to be constructed from semi-crystalline materials. In addition, non-destructive tests for the characterization of printed products were evaluated.

ICH Q14-inspired novel approach to establish an SFC-based purity method for carbamazepine.

The proposed ICH Q14 guideline "Analytical procedure development" describes science and risk-based approaches for development and maintenance of analytical procedures suitable for the assessment of the quality of drug substances and drug products. As a case study, the systematic development and validation of a supercritical fluid chromatography (SFC)-based purity method for carbamazepine is presented. Systematic analytical quality by design (AQbD) principles were applied using the software package Fusion QbD to the method development approach. The relationship between chromatographic parameters and the responses of interest were examined to improve the reliability of the method by understanding, reducing, and controlling sources of variability. Method performance qualification in terms of method robustness was finally carried out with the parameters that were classified as critical after method development and a validation study met previously set acceptance criteria. The developed SFC purity method for carbamazepine demonstrated readiness as a viable alternative to the official HPLC method published in the Ph.Eur. with improved peak resolution, improved peak symmetry, and faster analysis times (3min vs. 80 min for the official method). Its inherent reliability illustrates the superiority of AQbD in method development and application for drug quality assurance.

Development and validation of simultaneous HPLC-PDA analysis method for quality control of Hwang-ryeon-hae-dok-tang: An analytical quality by design approach

This study introduces an advanced analytical method for quality control of botanical drugs, focusing on Hwang-ryeon-hae-dok-tang (HRHDT), a traditional herbal prescription utilized for inflammation, gastritis, fever, and hypertension. Botanical drugs pose a challenge due to their complex composition, requiring reliable and robust analytical techniques. Our step-by-step procedure included defining the analytical target profile, risk assessment, screening and optimizing design of experiment, measuring the design space, and Monte Carlo simulation. The established HPLC-PDA method enables the simultaneous analysis of four major compounds (geniposide, baicalin, palmatine, and berberine) present in HRHDT. The optimized conditions involve a gradient elution with acetonitrile and water, both containing 0.1% trifluoroacetic acid, a 32 °C column temperature, 254 nm detection wavelength, and 1.0 mL/min flow rate. A successful validation demonstrated excellent linearity (R2: 0.9984–0.9989) and accuracy (recovery: 100.61%–102.44%), with precise repeatability and intermediate precision (%RSD: 0.39%–0.83%). These results further confirm the reliability and accuracy of the analytical method. Overall, our design-based approach not only facilitated the development of robust analytical methods but also allowed for flexible operation ranges. Therefore, this methodology holds significant potential for ensuring the quality of botanical drug products within the pharmaceutical industry.

Pre-formulation study of Bisoprolol as fast Dissolve Sublingual Tablet

Fast dissolving drug delivery systems offer a solution for patients having difficulty in swallowing tablets. In this study, an attempt had been made to perform pre-formulation studies of bisoprolol as fast dissolve sublingual tablet, an antihypertensive by direct compression methods using sodium-starch-glycolate, croscarmellose-sodium, & crospovidone as superdisintegrant agent. The basic purpose of the pre-formulation activity is to provide a basis for the formulation approaches, to maximize the chances of success in formulating an acceptable product, optimizing drug product quality and performance. Preformulating activity including drug melting point; analytical wavelength (λ max) detections, drug-excipients physical & chemical compatibility by FT-IR, and Calibration curve of Bisoprolol were studied. It was discovered that the melting point was 100°C, and the UV spectral analysis revealed that the maximum value of λ was between 224 and 273 nm. The physicochemical compatibility studies results indicate that there was no interaction between bisoprolol and the excipients. Strong linear relationship obtained from calibration curve. Based on results, fast dissolving sublingual tablets of Bisoprolol can be prepared successfully by direct compression.

Quality by Design in Pharmaceuticals: A Review of its Impact on Regulatory Compliance and Product Quality.

The pharmaceutical industry has embraced the quality-by-design (QbD) approach as a promising development, formulation and manufacturing strategy. QbD provides a systematic and science-based framework for designing and producing high-quality products, with a particular focus on identifying, assessing and controlling risks throughout the development process. This review aims to assess the benefits of implementing QbD in pharmaceutical processes, evaluate its impact on regulatory compliance and explore its potential to enhance drug product quality. The primary objective of this review is to evaluate the influence of QbD on pharmaceutical development and manufacturing processes. It also seeks to examine the regulatory requirements associated with the implementation of QbD and highlight the advantages of this approach in terms of product quality and cost-effectiveness. Additionally, the review aims to explore the potential of QbD in improving the safety and efficacy of drug products. The QbD approach holds tremendous potential to revolutionize the pharmaceutical industry by optimizing drug development & manufacturing processes, reducing costs and enhancing product quality and consistency. However, implementing QbD requires a comprehensive understanding of the underlying science, as well as strict adherence to regulatory requirements in drug development and manufacturing. In conclusion, by embracing the QbD approach, the pharmaceutical industry can ensure the production of safe, effective and regulation-compliant products while simultaneously improving process efficiency. This strategic shift toward QbD represents a pivotal step in advancing pharmaceutical research and manufacturing capabilities, ultimately benefiting both the industry and more importantly, patients worldwide.

Quality of New Domestic Hand Sanitizer Drug Product Manufacturers During COVID-19.

The FDA initiated a cross-sectional, statistically based sampling and testing study to characterize the quality of marketed alcohol-based hand sanitizer (ABHS) by evaluating the alcohol content and impurities present in ABHS products manufactured by establishments that registered with the FDA during March-April 2020. A stratified sampling design divided the population of manufacturers into independent groups based on each establishment's level of experience with FDA oversight and its geographic location. ABHS products were collected and analyzed by spatially offset Raman spectroscopy and gas chromatography with mass spectrometry (GC-MS). The GC-MS results for 310 products, from 196 newly registered domestic manufacturers, showed that 71.6% (± 5.7%) of these manufacturers had violative products. In 104 (33.5%) cases, the alcohol content did not meet label claim assay specifications but still fell within CDC efficacy ranges. Ethanol ABHS products failed more often overall (assay and impurities) (84.3%) and for impurities (84.3%), than isopropanol ABHS products (11.2% and 6.2%, respectively). Differences in test results across active ingredients were statistically significant. Ethanol ABHS products often (63.5% of cases) failed due to the presence of acetal or acetaldehyde, particularly in products with pH ≤ 6. Other impurities were also detected in several ABHS products, suggesting the use of low-grade alcohol in the manufacture of these products. Evidence was insufficient to conclude that having experience manufacturing FDA-regulated products, or lack thereof, influenced product-level violative results. This study highlights the importance of sourcing and testing active pharmaceutical ingredients to produce quality drug products.

Titanium Dioxide (E171 Grade) and the Search For Replacement Opacifiers and Colorants: Supplier Readiness Survey, Case Studies and Regulatory Perspective

Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others.