Determination of ICH-Q3D Elemental Impurity Leachables in Glass Vials by Inductively Coupled Plasma Mass Spectrometry.

Container closure systems that are used for packaging pharmaceutical products are required to satisfy numerous safety requirements. Maximum permitted limits on the concentrations of numerous toxic elemental impurities that potentially leach from the packaging are one such requirement. The implementation of ICH-Q3D Guideline for Elemental Impurities, in conjunction with the 2018 publication of USP <232> Elemental Impurities-Limits and USP <233> Elemental Impurities-Procedures, requires a critical risk assessment of all container closure systems to evaluate their contribution of certain elemental impurities to the enclosed drug product. ICH-Q3D has established limits for each specific elemental impurity that considers relevant toxicological data and administration route (oral, parenteral, or inhalation) and presents them as permitted daily exposures based on the maximum daily dosage of the final drug product. A study was undertaken to assess the degree of elemental impurity leaching from one type of pharmaceutical glass vial under specific, fixed environmental controls. Multiple buffer systems representing a broad spectrum of possible parenteral drug product formulations were used in the study. Resulting buffer solutions that had been in contact with a single type of glass vial under specific conditions were subsequently analyzed using an inductively coupled plasma mass spectrometry (ICP-MS) method developed and validated specifically for the purpose of quantifying elemental impurity leachables in a variety of parenteral formulations. Results indicated that the degree of elemental impurity leachables imparted by the specific type of glass vial evaluated during this study posed no risk to patient safety, regardless of the drug product buffer formulation. Following this evaluation, the ICP-MS method developed for the determination of elemental impurities leachables has been successfully applied to the assessment of elemental impurities in a number of different biological parenteral drug product formulations currently under development. These data can be leveraged for inclusion in elemental impurities component ICH-Q3D risk assessments to satisfy the container closure system contribution.

First-Principles and Empirical Approaches to Predicting In Vitro Dissolution for Pharmaceutical Formulation and Process Development and for Product Release Testing.

This manuscript represents the perspective of the Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) and of two focus groups of the American Association of Pharmaceutical Scientists (AAPS): Process Analytical Technology (PAT) and In Vitro Release and Dissolution Testing (IVRDT). The intent of this manuscript is to show recent progress in the field of in vitro predictive dissolution modeling and to provide recommended general approaches to developing in vitro predictive dissolution models for both early- and late-stage formulation/process development and batch release. Different modeling approaches should be used at different stages of drug development based on product and process understanding available at those stages. Two industry case studies of current approaches used for modeling tablet dissolution are presented. These include examples of predictive model use for product development within the space explored during formulation and process optimization, as well as of dissolution models as surrogate tests in a regulatory filing. A review of an industry example of developing a dissolution model for real-time release testing (RTRt) and of academic case studies of enabling dissolution RTRt by near-infrared spectroscopy (NIRS) is also provided. These demonstrate multiple approaches for developing data-rich empirical models in the context of science- and risk-based process development to predict in vitro dissolution. Recommendations of modeling best practices are made, focused primarily on immediate-release (IR) oral delivery products for new drug applications. A general roadmap is presented for implementation of dissolution modeling for enhanced product understanding, robust control strategy, batch release testing, and flexibility toward post-approval changes.

Enhancing tablet disintegration characteristics of a highly water-soluble high-drug-loading formulation by granulation process.

The objective of this study was to improve the disintegration and dissolution characteristics of a highly water-soluble tablet matrix by altering the manufacturing process. A high disintegration time along with high dependence of the disintegration time on tablet hardness was observed for a high drug loading (70% w/w) API when formulated using a high-shear wet granulation (HSWG) process. Keeping the formulation composition mostly constant, a fluid-bed granulation (FBG) process was explored as an alternate granulation method using a 2(4-1) fractional factorial design with two center points. FBG batches (10 batches) were manufactured using varying disingtegrant amount, spray rate, inlet temperature (T) and atomization air pressure. The resultant final blend particle size was affected significantly by spray rate (p = .0009), inlet T (p = .0062), atomization air pressure (p = .0134) and the interaction effect between inlet T*spray rate (p = .0241). The compactibility of the final blend was affected significantly by disintegrant amount (p < .0001), atomization air pressure (p = .0013) and spray rate (p = .05). It was observed that the fluid-bed batches gave significantly lower disintegration times than the HSWG batches, and mercury intrusion porosimetry data revealed that this was caused by the higher internal pore structure of tablets manufactured using the FBG batches.

Correlating bilayer tablet delamination tendencies to micro-environmental thermodynamic conditions during pan coating.

OBJECTIVE: The objective of this study was to determine the impact that the micro-environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions. MATERIALS AND METHODS: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed. RESULTS: The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R(2 )= 0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets' propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers. CONCLUSION: The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage.

Development of a fluid bed granulation design space using critical quality attribute weighted tolerance intervals.

The fluid bed granulation and drying unit operation were used as a case study for control systems implementation. This single processor was used to blend, granulate, dry, and cool the materials. The current study demonstrated control of each of the phases using a fully automated, hybrid control system that incorporated first-principle modeling, empirical design of experiments (DOE), and process analytical technology to assure the production of constant product quality. The system allowed data to be collected efficiently for the development of a rigorous design space that combined formulation factors, process factors, and their interactions to define a tolerance surface where risk of future product failure was significantly reduced. The DOE incorporated microcrystalline cellulose and lactose monohydrate, excipients with substantially different wetting properties, to elucidate the relationship between the critical process parameters of the unit operation and the material properties of the formulation components. The extended analysis of covariance model enabled these factors and their interaction terms to be described in a single model. The results indicate that the development of a tolerance interval-based weighted design space can enhance product understanding and thereby help to assure future product quality.