Consequences of New Approach to Chemical Stability Tests to Active Pharmaceutical Ingredients (original) (raw)
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Consequences of New Approach of Chemical Stability Tests of Active Pharmaceutical Ingredients (APIs)
Frontiers in Pharmacology
There is a great need of broaden look on stability tests of active pharmaceutical ingredients (APIs) in comparison with current requirements contained in pharmacopeia. By usage of many modern analytical methods the conception of monitoring the changes of APIs during initial stage of their exposure to harmful factors has been developed. New knowledge must be acquired in terms of identification of each degradation products, especially volatile ones. Further research as toxicology prediction during in silico studies of determined and identified degradation products is necessary. In silico methods are known as computational toxicology or computer-assisted technologies which are used for predicting toxicology of pharmaceutical substances such as impurities or degradation products. This is a specialized software and databases intended to calculate probability of genotoxicity or mutagenicity of these substances through a chemical structure-based screening process and algorithm specific to a given software program. Applying of new analytical approach is proposed as the usage of PAT tools, XRD, HS-SPME GC-MS/MS, LC-MS/MS for stability testing. Described improvements should be taken into account in case of each drug existing already in the market as well as being implemented as new one.
In silico' toxicology methods in drug safety assessment
Arhiv za farmaciju
While experimental animal investigation has historically been the most conventional approach conducted to assess drug safety and is currently considered the main method for determining drug toxicity, these studies are constricted by cost, time, and ethical approvals. Over the last 20 years, there have been significant advances in computational sciences and computer data processing, while knowledge of alternative techniques and their application has developed into a valuable skill in toxicology. Thus, the application of in silico methods in drug safety assessment is constantly increasing. They are very complex and are grounded on accumulated knowledge from toxicology, bioinformatics, biochemistry, statistics, mathematics, as well as molecular biology. This review will summarize current state-of-the-art scientific data on the use of in silico methods in toxicity testing, taking into account their shortcomings, and highlighting the strategies that should deliver consistent results, whi...
Regulatory Toxicology and Pharmacology, 2006
Starting materials and intermediates used to synthesize pharmaceuticals are reactive in nature and may be present as impurities in the active pharmaceutical ingredient (API) used for preclinical safety studies and clinical trials. Furthermore, starting materials and intermediates may be known or suspected mutagens and/or carcinogens. Therefore, during drug development due diligence need be applied from two perspectives (1) to understand potential mutagenic and carcinogenic risks associated with compounds used for synthesis and (2) to understand the capability of synthetic processes to control genotoxic impurities in the API. Recently, a task force comprised of experts from pharmaceutical industry proposed guidance, with recommendations for classification, testing, qualification and assessing risk of genotoxic impurities. In our experience the proposed structure-based classification, has differentiated 75% of starting materials and intermediates as mutagenic and non-mutagenic with high concordance (92%) when compared with Ames results. Structure-based assessment has been used to identify genotoxic hazards, and prompted evaluation of fate of genotoxic impurities in API. These two assessments (safety and chemistry) culminate in identification of genotoxic impurities known or suspected to exceed acceptable levels in API, thereby triggering actions needed to assure appropriate control and measurement methods are in place. Hypothetical case studies are presented demonstrating this multi-disciplinary approach.
International Journal of Pharmaceutics, 2018
Different regulatory guidelines recommend establishing stability profile of pharmaceuticals at the time of drug development. The expiry date, retesting period and storage conditions of active drugs or products are established through stability analysis. Different regulatory guidelines exist for stability testing of pharmaceuticals. Mostly, ICH stability guidelines are followed in practice. ICH guideline recommends to validate stability indicating method using forced degradation samples that contains all possible degradation impurities. ICH guidelines provide general recommendations for inclusion of stability indicating parameters in a stability testing protocol. However, those guidelines do not provide specific requirements and experimental methodology to be followed for stability studies. Due to this gap, often confusion arises in the scientific community in designing stability testing protocol. Therefore, significant variations are observed in reported literature in selection of stability indicating parameters. Procedural dissimilarity amongst reported stability studies is also evident. This review discusses the regulatory guidelines and procedures to follow in performing stability testing of pharmaceuticals. Scope of this review also includes recommendations on practical approaches for designing stability testing protocol to fulfill current regulatory requirements for drug substances and their formulations.
Organic Process Research & Development, 2015
This paper outlines strategies in alignment with ICH M7 for systematically assessing the potential risk posed by mutagenic degradants in active pharmaceutical ingredients (API) and formulated products. A mutagen risk assessment (MRA) process that involves degradation should include results from focused drug substance and drug product stress testing experiments (e.g., at elevated temperature, a wide pH range in solution, oxidative, and photolytic stress) as well as accelerated and long-term stability studies in the solid-state. While the MRA may include hypothetical (theoretically predicted) degradation products from computer based and/or knowledge-based approaches, investigations for numerous hypothetical degradation products whose significance have not been verified experimentally should not be initiated based on these results alone. Drug substance and drug product stress (forced degradation) studies should be designed to generate a comprehensive range of potential degradants that encompass all degradation products likely to form under typical ICH storage conditions. As a result of the absence of definitive regulatory guidance covering stress testing (including strategies for impurity identification/elucidation) there are different approaches used within the industry. Three general strategies for triggering structure elucidation of degradants (and hence inclusion in a MRA) are outlined, all of which are consistent with the approaches outlined in ICH Q1A, Q3A/B, and M7. The first approach for triggering structure elucidation is centered around long-term and accelerated stability and ICH Q3A/B thresholds; the second approach focuses on the "major" degradation products and pathways observed during stress testing using an algorithm for defining the threshold for "major" degradation products; the third approach focuses on those degradation products observed during stress testing that meet criteria derived from thresholds that have been scaled from ICH Q3A/B identification thresholds. Regardless of the chosen strategy, it is proposed that only those major degradation products observed at significant levels in stress testing, ICH accelerated, or long-term stability studies be included in the MRA process as this reflects the degradants most likely to be seen in marketed products. Such an approach is consistent with ICH M7. The overall strategy should be based on a risk assessment, where potential degradation products are determined to be either relevant and addressed or irrelevant and excluded from further consideration. The approaches described herein provide an appropriate framework to assess the risk posed by mutagenic impurities (MIs) arising as a result of either drug substance and/or drug product degradation.
Development of stability indicating studies for pharmaceutical products: an innovative step
A stability study is a routine procedure which ensures the maintenance of pharmaceutical product safety, quality and efficacy throughout the shelf life. These pharmaceutical products are followed by the guidelines issued by International Conference on Harmonization (ICH), World Health Organization (WHO) or other agencies. Stability testing provides evidence that the quality of a drug substance or drug product under the influence of various environmental factors changes with time. Importance of various methods followed for stability testing of pharmaceutical products, guidelines issued for stability testing and other aspects related to stability of pharmaceutical products have been presented in a concise manner in the present review. This review article includes introduction about stability studies types of stability studies and chemical reactions takes place during degradation etc. This article also includes the forced degradation studies and shelf life estimation of pharmaceutical products.