Understanding pharmaceutical stability is of fundamental importance to the industry.
Stability studies at varied temperature, humidity and purposeful degradation experiments using chemical and thermal methods are widely applied to study the stability and degradation of active pharmaceutical ingredients and formulated drug products. Many pharmaceutical degradation reactions occur by REDOX mechanisms and with the availability of electrochemical (EC) flow-cells, a fast and convenient method of studying these reactions is now available. By online coupling of EC cells with LC-MS, immediate identification and quantification of the degradation product profiles under varied experimental conditions becomes possible.

In this lecture examples will be shown were Electrochemistry was used to generate oxidative degradation products of pharmaceutical compounds. The compounds were oxidized at different potentials and pH using an electrochemical flow-cell. The oxidative products formed were identified and structurally characterized by LC/MS/MS. Results from electrochemical oxidation were compared to those from chemical oxidation and from accelerated stability studies. The electrochemical approach (in electro) proved to be very useful as an oxidative stress test as all of the oxidation products observed under accelerated stability studies could be generated. In comparison to chemical degradation tests electrochemical degradation has the advantage of being much faster and does not require strong oxidizing agents. Moreover, it enables the study of different operating parameters in short periods of time and optimisation of the reaction conditions to achieve different oxidative products mixtures. This technique proved to be very useful as a stress test condition for the generation of oxidative degradation products.

Furthermore, the use of electrochemical degradation allows for immediate up scaling and production of mg quantities of degradants (electrochemical synthesis), to generate sufficient reference material for full characterisation by other spectroscopic techniques (NMR, IR) or toxicity studies.

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An ASAP study was performed on an orally administered enteric coated formulation in a gelatin capsule. The aim of the study was to compare ASAPprime™  generated stability prediction model against data generated during a conventional ICH stability study.  ASAP studies were performed to assess differences in predicted stability of different strength capsules prepared from a common batch of granules. The study also demonstrated that the gelatin capsule material does not play a key role in protecting the test material from chemical degradation under the accelerated conditions employed in the study and that ASAP studies can successfully be performed on the capsule fill material. The predicted stability of the drug product in various packaged forms was subjected to an ANOVA study to determine the statistical significance of applying for approval in an alternate ICH climatic zone.

ASAP (Accelerated Stability Assessment Program) is gaining acceptance across the pharmaceutical industry as a powerful tool for predicting the effects of temperature and humidity on pharmaceutical stability.  In this presentation, the theory and fundamentals of ASAP will be discussed covering the science behind the technique and also considerations for its implementation.

In this presentation, we will show how risk-based predictive stability studies have been used to adapt the formulation strategy for one of our compounds in development in our infectious diseases and vaccine portfolio. The target product profile for this drug product was an oral suspension. However, forced degradation studies demonstrated that the drug substance was highly sensitive to hydrolysis, so the development team adapted their strategy and initially developed a powder for reconstitution formulation. Risk-based predictive stability studies were subsequently used to evaluate the stability behaviour of the reconstituted suspension. By modelling the accelerated stability data, it was demonstrated that the suspension was stable at room temperature and had potential to be developed as final formulation for commercialization

Chemical stability of an active pharmaceutical ingredient in drug products is a key quality attribute as a measure of efficacy and safety. During the early phase of formulation and process development degradation chemistry is commonly assessed in solution. Since an API’s chemical stability and the identity of products in the solid-state can differ significantly from that in solution-state the latter data can be of limited usefulness. Although the preferred dosage form is most commonly a solid-state formulation knowledge and methods to predict long term solid-state stability in the pharmaceutical community are rare. Conventional industrial screening includes physical mixtures of drug with excipient(s) and/or water at elevated temperatures/relative humidity (RH) which often turn out to be over-simplistic. For example, elevated temperatures might shift the degradation towards reactions that require a high activation energy or trigger degradation reactions that do not take place at room temperature. Unrealistically high RH can strongly facilitate or inhibit degradation reactions.

The present initiative of stability by design (SbD) aims towards applying material science at molecular, particulate, bulk and surface level to establish rational predictive methodologies for long term stability of solid-state pharmaceuticals. To this end, various empirical and mechanistic theoretical approaches are combined with advanced solid-state characterisation to gain systematic knowledge of drug-excipient reactions, drug-reactive impurities reaction, drug-moisture/oxygen reaction etc. We present a case study investigating the factors governing reactions between crystalline drugs and citric acid (excipient) in the solid-state. Using crystal surface properties derived from molecular dynamics (MD) simulation in combination with accelerated stability studies, we attempt to rationalise the role of different factors in solid-state degradation. In addition, the characterisation of micro and mesoscopic structures of drug powders from small- and wide-angle X-ray scattering are discussed as a means to understand the impact of disorder and heterogeneity on drug degradation in the solid-state.

The quality of stability predictions – that is, their accuracy and precision – depends on a variety of factors including: the experimental design (the “protocol”); the analytical variability (and how these uncertainties propagate through the modelling); and the validity of several assumptions. This talk will illustrate – using pictures and not equations – some important and interesting aspects of these predictions.

During the presentation the use of risk based predictive stability (RBPS) in regulatory filings will be discussed. Last year during the SOS conference, the regulatory sub-team of the IQ consortium Working Group around RBPS presented the results of a survey sent out to 17 pharmaceutical companies to get a sense of to what extent RBPS stability was used in regulatory filings along with the regulatory experience. The past months, the regulatory sub-team has been working on a template on how we should present the RBPS results in a clinical trial application. Also, some case studies (pre- and post-approval) have been gathered from within the industry. These case studies as well as the template will also be part of the presentation. Any update will also be provided by the predictive modelling sub-team of the IQ consortium Working Group.

Forced degradation studies generate a large amount of scientific knowledge about how a drug degrades. For unstable drug substances in particular, degradation chemistry information is often critical for designing a stable drug product. Understanding degradation mechanisms in detail can inform drug product development and help achieve a targeted shelf life and desirable long-term storage conditions. This talk will present a case study in which the degradation chemistry of an unstable drug substance was investigated. The laboratory experiments performed and the actions taken to control degradation in the drug product, including accelerated stability modeling studies, will be discussed.

Precise measurement and control of humidity in stability test applications has challenged the humidity instrumentation community for many years.  Regulatory requirements have driven improved standards of measurement and the development of traceable calibration procedures.  Determination of uncertainty is a structural method of defining performance in measurement and control applications, and is a fundamental requirement of ISO17025 accredited laboratories.  In any Quality System, continual improvement is also a fundamental requirement, so in combination with the necessity to demonstrate traceability, instrumentation performance and calibration is under close scrutiny.  In this presentation, typical measurement techniques are reviewed together with their uncertainty in use, including at elevated temperatures.

Oxygen is a well-known source of degradation of many packaged products including pharmaceuticals. Packaged drugs are exposed to oxygen that is contained in the container headspace or enters the container from the outside atmosphere during shelf storage. It may cause adverse effects on the quality and durability of medicines. There are several ways to prevent drugs from damaging effect of oxygen, including antioxidants or specific coatings. The alternative may be an oxygen scavenger used in the drug packaging.
There are several types of oxygen scavengers used for a variety of applications, mostly in the food packaging. Traditional oxygen scavengers are based on iron metal powder, enzymes, or ascorbic acid. Their major drawback is the need of moisture to perform properly. This requirement precludes their use in a dry packaging environment of food products as well as drug, as moisture is another major reason of degradation of the drug product. In the case of traditional iron based scavengers, oxygen present in a package’s headspace is consumed when the iron reacts with the moisture and oxygen.
The developed oxygen scavenger is based on ZVI (zerovalent iron). It has not only a high oxygen absorption capacity, but is characterised by much higher rate of oxygen uptake due to its high refinement and developed surface area. Moreover, the most important distinction is that ZVI does not need moisture to actively react with the oxygen contained in the package. Preliminary research results with its use are very encouraging.

Foltynowicz, Z., Bardenshtein, B., Sängerlaub, S., Antvorskov, H., Kozak, W.,
Nanoscale, zero valent iron particles for application as oxygen scavenger in food packaging
Food Packaging and Shelf Life, 11 (2017) 74–83; DOI: 10.1016/j.fpsl.2017.01.003

Case studies are presented for two applications of accelerated predictive stability studies within pharmaceutical development: (a) assessing the risk from unplanned temperature excursions, and (b) rapidly predicting the long-term stability of newly formulated and manufactured drug products.

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The stability of porous pharmaceutical products like tablets strongly depends on temperature and relative humidity. The compaction pressure defines the porosity of tablets. In general, the adsorption of water vapor on solid surfaces induces a relaxation of the surface molecules and causes swelling. In mesoporous materials capillary condensation occurs at relative humidities below saturation causing a second deformation effect. We apply the concept of disjoining pressure DP – which is by definition the pressure tensor in z-direction between two phases. The sum of all known pressure components acting in a sorption system is an adequate descriptor for the overall DP [1]. Thus, the first adsorbed layers are described by the ESW (Excess Surface Work). This simple transformation of the experimental isotherm delivers directly the monolayer capacity and loss of energy of the adsorbed molecules. ESW has been already successfully applied on APIs in correlation with solvation effects [2]. In order to describe capillary condensation and evaporation a second part is added based on the Derjaguin approach and extended Kelvin equation [3]. A third component within the DP approach describes deformations. These are treated through Hook’s law. The assumption of complete wetting allows avoiding the usage of interfacial energy of solid adsorbent. The result of the model is a system of self-consisting equations describing the deformation and the adsorbed amount simultaneously. Experimental results for swelling and shrinkage, pore size changes, surface energies as function of relative humidity will be presented and analysed with DP approach.

1. Adolphs, J., Chemie Ingenieur Technik 88 274–281 (2016)
2. Becker, A., Generics (UK) Limited, Patent WO/2008/026012 – Water vapor sorption on APIs (2008)
3. Kolesnikov, A.L., Uhlig, H., Möllmer, J., Adolphs, J., Budkov, Y.A., Georgi, N. Enke, D., Gläser, R.: Micropor. Mesopor. Mat. 240, 169 (2017).
Acknowledgement: The author thanks BMWi (AiF-ZIM ZF4129902GM5) for financial support.

Multivariate analysis of spectral measurements in the near infrared (NIR) and FTIR regions have successfully been used in a wide range of applications in the pharmaceutical industry as a means of monitoring certain pharmaceutical processes. In this study changes in the physical and chemical stability of a range of novel ibuprofen formulations were monitored using NIR, FTIR, pXRD and HPLC analytical methods. Principal component analysis was performed on each of the datasets to determine whether ibuprofen degradation could be successfully monitored using multivariate control charts as an aid in formulation screening.

An example of how ASAP studies have been utilised to support the development of a tablet formulation will be presented. ASAP studies were performed to support a change from a wet granulation process to roller compaction and then later in development to support the introduction of a lower strength tablet formulation. In both cases the ASAP studies focused on chemical degradation but also included dissolution studies. The presentation of the results in a regulatory submission will also be discussed.

Oxidative degradation of drugs is frequently encountered and is often a shelf-life limiting stability problem. Oxidative degradation can occur via a variety of pathways, and these pathways can be complex and intertwined. This presentation will provide an overview of pharmaceutically-relevant oxidative degradation pathways, and techniques for predicting and controlling. Relevant examples of various oxidative degradation pathways will be provided, and principles for designing effective and predictive forced degradation studies will be discussed.

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Abstract – The applications of a range of predictive stability tools during early development will be presented. These will include in-silico tools such as bond dissociation energy predictions and Zeneth, based purely on the molecular structure and used to determine potential drug substance degradants and excipient interactions. Applications of Accelerated Stability Assessment Program (ASAP) studies across both drug substance and product will also be discussed along with packaging predictions for bottles, blisters and bulk pack configurations. A number of case studies involving different formulation types will be used to demonstrate the impact of these tools and how they can be utilised together to understand the overall stability characteristics and risks for a new drug. The impact of the predictions on the control strategy will be discussed along with how the predicted stability data was presented in regulatory submissions.

Many new drugs in the development pipeline have high permeability but low solubility; this confers a low oral bioavailability, which reduces their developability into medicines. A frequently reported approach for enhancing a drug’s kinetic solubility and increasing dissolution rate is to render the drug into an amorphous or disordered physical form. However the barrier to market for medicines containing an amorphous drug is both poor physical and compromised chemical stability. The presentation will use two novel freeze dried formulations developed within my research group to illustrate how common analytical techniques may be adapted to probe the mechanisms which confer stability within amorphous formulations.

ASAPprime® has been used to model the impact of temperature and relative humidity (RH) on the stability of products. While this models oxidation reactions accurately when the oxygen level remains constant at atmospheric levels (21%), in some cases, packaging can be used to reduce the oxygen level and increase the stability for both liquids and solids. A general model for such processes is presented which explicitly accounts for temperature, RH and oxygen. This is incorporated into a packaging model that accounts for oxygen consumption by the oxygen-dependent reaction, initial oxygen level and packaging permeability.

While ASAPprime® modelling of accelerated stability data has successfully been used to project the shelf-life of products, in some cases, stability modelling cannot be done since degradation is not observed at the accelerated conditions. With more companies using accelerated stability to assign shelf-lives, an acceptable process is needed for assigning a minimum shelf-life in these situations. The proposed process involves first determining the minimum shelf-life at each condition based on the maximum rate of degradation that could have occurred at the condition and yet not show any change beyond the limit of detection. This is projected based on the specification limit and the fitting form (usually defaulted to linear). A second step is to use an observed product distribution of activation energies and humidity sensitivities (B-terms) to assign limits based on two standard deviations against the means. This allows for a minimal shelf-life based on each condition projected to the storage temperature and relative humidity, with the overall shelf-life being the greatest of the values from all the conditions.

The rate of drug degradation and the impurities formed are influenced by physical form. The solid-state reaction pathway involved in the decomposition of organic compounds, as described by Paul and Curtin, involves loosening of the molecules at the reaction site, molecular change, solid-solution formation and separation of the product phase from the reactant.1 Molecular loosening plays a critical role in that it results in greater molecular mobility and reactivity of the molecule. Mechanism(s) involved in decomposition can change throughout a study or the product’s shelf life as a result of physical transformation. Physical form transformations commonly observed involve polymorphism, hydration state, and acid/base dissociation (or disproportionation) reactions. Understanding the roll that moisture, temperature, and acidity/basicity of the formulation microenvironment play in influencing molecular mobility is extremely valuable in the rational design of a pharmaceutical product. This presentation will highlight a number of cases where solid form transformation played a significant role in drug degradation. The use of molecular modelling in a complement to experimentation will also be discussed.

1.) Paul, Iain C.; Curtin, David Y. Thermally induced organic reactions in the solid state. Accounts of Chemical Research (1973), 6(7), 217-25.

It has long been observed that capsules and tablets with lower drug loads, i.e. with higher excipient ratios typically exhibit more rapid rates of degradation.  An extensive investigation into this phenomenon has been conducted on several different API – excipient mixtures comprising a wide range of drug loads.  In this presentation, these studies are described and a model is proposed that is able to quantitatively link degradation rate to the drug load for all the products investigated; this model appears to be equally applicable to tablets, blends and lyophiles.  In addition, the combined effects of drug load, temperature and humidity have been explored and an over-arching model is proposed.

The use of the Arrhenius approach for understanding the effect of temperature and for estimating shelf-life of solution-phase drug products is already reasonably well established, since the solution phase is homogenous and, as a result, generally presents fewer problems than solid-phase products.  In addition to temperature, the pH and concentration of solution are usually the most significant quality attributes that affect the stability of solution-phase products.  In this presentation, a simple accelerated stability protocol and approach for modelling the effects of temperature, pH and concentration is described and discussed; this approach can provide enhanced stability predictions and enable the effect of batch-to-batch variability in pH of formulation to be quantified.  Case studies are presented which demonstrate the applicability of this approach.

Excipients in a drug formulation are chosen based on different often contradictory abilities; among properties worth highlighting are process and manufacturability, bioavailability and ability to obtain toxicologically safe and stable formulations. This presentation focus will be on the design to obtain safe and stable formulations however keeping the other properties in mind. Common excipient interactions, both chemical and physical interactions, with pharmaceutical ingredients will be stressed.  The setup of forced degradation studies is discussed in order design excipient compatibility experiments that is fit for purpose. Forced degradation studies can be made both experimentally and in silico, both these approaches will be discussed. The design of compatibility studies will be discussed with different approaches highlighted.

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