Garry Scrivens

Opportunities for Lean Stability Strategies

The International Conference on Harmonization (ICH) has provided practical guidance on the amount and type of stability data needed to support marketing applications (International Conference on Harmonization Guideline Q1A(R2), 2003; International Conference on Harmonization Guideline Q1C, 1996; International Conference on Harmonization Guideline Q7A, 2001). Additional guidance has been issued by the World Health Organization (WHO, 2009). Recent scientific advances and practices have resulted in improved scientific understanding of the chemical and physical attributes that contribute directly or indirectly to drug substance and drug product stability. Combining this improved understanding with the science- and risk-based approaches detailed in ICH Q8–Q11 allow for alternative and more scientifically driven approaches to meet the scientific and regulatory objectives for drug substance and drug product stability (International Conference on Harmonization Guideline Q8(R2), 2009; International Conference on Harmonization Guideline Q9, 2005; International Conference on Harmonization Guideline Q10, 2008; International Conference on Harmonization Guideline Q11, 2012). This paper follows and expands on the concept and application of the lean stability strategies that were introduced for drug substance (Colgan et al., J Pharm Innov 7:205–213, 2012). Herein, proposals are presented to more fully leverage enhanced product knowledge to design and prosecute improved stability strategies throughout the developmental lifecycle. The chemical and physical attributes that could impact stability and the tools that can be leveraged in pursuit of optimized stability strategies are discussed. Dove-tailing these stability strategies into regulatory filings for products with extensive product knowledge and the reception of these strategies by regulatory authorities in both major and emerging markets are summarized.

Electrochemical oxidation coupled with liquid chromatography and mass spectrometry to study the oxidative stability of active pharmaceutical ingredients in solution: A comparison of off-line and on-line approaches

Stability studies of pharmaceutical drug products and pharmaceutical active substances are important to research and development in order to fully understand and maintain product quality and safety throughout its shelf-life. Oxidative forced degradation studies are among the different types of stability studies performed by the pharmaceutical industry in order to understand the intrinsic stability of drug molecules. We have been comparing the use of electrochemistry as an alternative oxidative forced degradation method to traditional forced degradation and accelerated stability studies. Using the electrochemical degradation approach the substrate oxidation takes place in a commercially available electrochemical cell and the effluent of the cell can be either a) directly infused into the mass spectrometer or b) injected in a chromatographic column for separation of the different products formed prior to the mass spectrometry analysis. To enable the study of large numbers of different experimental conditions and molecules we developed a new dual pump automated electrochemical screening platform. This system used a HPLC pump and autosampler to load and wash the electrochemical cell and deliver the oxidized sample plug to a second injection loop. This system enabled the automatic sequential analyses of large numbers of different solutions under varied experimental conditions without need for operator intervention during the run sequence. Here we describe the system and evaluate its performance using a test molecule with well characterized stability and compare results to those obtained using an off-line electrochemistry approach.

Modeling of in-use stability for tablets and powders in bottles

Abstract A model is presented for determining the time when an active pharmaceutical ingredient in tablets/powders will remain within its specification limits during an in-use period; that is, when a heat-induction sealed bottle is opened for fixed time periods and where tablets are removed at fixed time points. This model combines the Accelerated Stability Assessment Program to determine the impact on degradation rates of relative humidity (RH) with calculations of the RH as a function of time for the dosage forms under in-use conditions. These calculations, in a conservative approach, assume that the air inside bottles with broached heat-induction seals completely exchanges with the external environment during periods when the bottle remains open. The solid dosages are assumed to sorb water at estimable rates during these openings. When bottles are capped, the moisture vapor transmission rate can be estimated to determine the changing RH inside the bottles between opening events. The impact of silica gel desiccants can also be included in the modeling.

The application of electrochemistry to pharmaceutical stability testing--comparison with in silico prediction and chemical forced degradation approaches.

The aim of this study was to evaluate the use of electrochemistry to generate oxidative degradation products of a model pharmaceutical compound. The compound was oxidized at different potentials using an electrochemical flow-cell fitted with a glassy carbon working electrode, a Pd/H2 reference electrode and a titanium auxiliary electrode. The oxidative products formed were identified and structurally characterized by LC-ESI-MS/MS using a high resolution Q-TOF mass spectrometer. Results from electrochemical oxidation using electrolytes of different pH were compared to those from chemical oxidation and from accelerated stability studies. Additionally, oxidative degradation products predicted using an in silico commercially available software were compared to those obtained from the various experimental methods. The electrochemical approach proved to be useful as an oxidative stress test as all of the final oxidation products observed under accelerated stability studies could be generated; previously reported reactive intermediate species were not observed most likely because the electrochemical mechanism differs from the oxidative pathway followed under accelerated stability conditions. In comparison to chemical degradation tests electrochemical degradation has the advantage of being much faster and does not require the use of strong oxidizing agents. Moreover, it enables the study of different operating parameters in short periods of time and optimisation of the reaction conditions (pH and applied potential) to achieve different oxidative products mixtures. This technique may prove useful as a stress test condition for the generation of oxidative degradation products and may help accelerate structure elucidation and development of stability indicating analytical methods.

Sample preparation composite and replicate strategy for assay of solid oral drug products.

In pharmaceutical analysis, the results of drug product assay testing are used to make decisions regarding the quality, efficacy, and stability of the drug product. In order to make sound risk-based decisions concerning drug product potency, an understanding of the uncertainty of the reportable assay value is required. Utilizing the most restrictive criteria in current regulatory documentation, a maximum variability attributed to method repeatability is defined for a drug product potency assay. A sampling strategy that reduces the repeatability component of the assay variability below this predefined maximum is demonstrated. The sampling strategy consists of determining the number of dosage units (k) to be prepared in a composite sample of which there may be a number of equivalent replicate (r) sample preparations. The variability, as measured by the standard error (SE), of a potency assay consists of several sources such as sample preparation and dosage unit variability. A sampling scheme that increases the number of sample preparations (r) and/or number of dosage units (k) per sample preparation will reduce the assay variability and thus decrease the uncertainty around decisions made concerning the potency of the drug product. A maximum allowable repeatability component of the standard error (SE) for the potency assay is derived using material in current regulatory documents. A table of solutions for the number of dosage units per sample preparation (r) and number of replicate sample preparations (k) is presented for any ratio of sample preparation and dosage unit variability.

Sample Preparation for Solid Oral Dosage Forms

Development of extraction and sample preparation methods for solid oral dosage forms for potency and purity analysis can be challenging. Complete extraction of drug and impurities is required using reasonable extraction and sample preparation conditions, and the final prepared sample must be compatible with the analysis method. A systematic approach for the development of extraction and sample preparation methods for potency and purity analysis of solid oral dosage forms is presented. Key steps of the process include the selection of an appropriate diluent to allow complete extraction and solubilization of the analytes of interest and the selection of an appropriate mechanism to disperse the dosage form to facilitate extraction of the analytes. Each step of the method development process is discussed and potential problem areas are highlighted.

Strategies for Improving the Reliability of Accelerated Predictive Stability (APS) Studies

Abstract The reliability of Accelerated Predictive Stability (APS) studies to satisfactorily predict long-term stability behavior can be improved by increasing prediction precision and prediction accuracy. Prediction precision is improved by increasing experimental and analytical precision, and various strategies for achieving this are presented. It is suggested that the main causes of prediction inaccuracy are associated with having multiple conversion processes, which may be physical or chemical in nature. These processes may be reversible and may occur consecutively or competitively with each other, leading to substantial challenges deconvoluting the mechanisms that lead to the overall degradation process. Particular problems are encountered when the individual processes have very different temperature and humidity sensitivities. The use of milder conditions can improve both prediction accuracy and prediction precision, but the drawback is that this requires longer study durations. Other strategies are presented for mitigating the effects of these sources of inaccuracies. Firstly, ensuring that the physical state of the sample under accelerated conditions remains representative of those under long-term conditions, through understanding the potential changes that may occur and applying physical characterization methods to the API or APS stability samples. Secondly, by confirming the shape of the degradation profiles is consistent across different conditions.

Theory and Fundamentals of Accelerated Predictive Stability (APS) Studies

Abstract The aim of accelerated predictive stability (APS) studies is to predict long-term stability behavior on the basis of short-term stability assessments that comprise multiple different accelerated conditions. The effects of temperature and humidity on the rate of degradation are modeled using a humidity-modified Arrhenius equation. APS methods require that an expression for the rate of degradation (k) be obtained for each stability condition; this chapter outlines various methods used to calculate “k” if the degradation profile is not linear. Finally, various methods for data processing and assessing the goodness of fit of the model are discussed.

The Humidity Exposure of Packaged Products

Abstract In order to predict the shelf life of packaged products, it is necessary to know the humidity levels inside the packaging. This chapter provides a comprehensive description of the methods used to simulate the humidity inside packaging, and provides the library data on packaging permeability and the moisture sorption properties of excipients necessary to carry out the simulation. Case studies are presented to demonstrate the accuracy and reliability of the approach, and some of the numerous benefits and applications of performing these simulations are discussed.

A Systematic Approach for Investigating Aberrant Potency Values

Accurate potency and purity data are critical in the development of drug products. These results are used to make decisions regarding formulation development/selection, formulation stability, and process robustness, and are used to release clinical supplies and set clinical use periods. Sometimes aberrant potency values (e.g., assay values, content uniformity results, stratified core test results) are obtained and significant efforts are spent investigating these issues to identify the root cause, which may be manufacturing or method related. This chapter discusses a systematic approach for investigating aberrant potency values from the analytical method perspective. In addition, several case studies are described.