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1.
Regul Toxicol Pharmacol ; 110: 104524, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31734179

RESUMO

Regulatory Guidance documents ICH Q3A (R2) and ICH Q3B (R2) state that "impurities that are also significant metabolites present in animal and/or human studies are generally considered qualified". However, no guidance is provided regarding data requirements for qualification, nor is a definition of the term "significant metabolite" provided. An opportunity is provided to define those categories and potentially avoid separate toxicity studies to qualify impurities. This can reduce cost, animal use and time, and avoid delays in drug development progression. If the concentration or amount of a metabolite, in animals or human, is similar to that of the known, structurally identical impurity (arising from the administered test material), the qualification of the impurity on the grounds of it also being a metabolite is justified. We propose two complementary approaches to support conclusions to this effect: 1) demonstrate that the impurity is formed by metabolism in animals and/or man, based preferably on plasma exposures or, alternatively, amounts excreted in urine, and, where appropriate, 2) show that animal exposure to (or amount of) the impurity/metabolite is equal or greater in animals than in humans. An important factor of both assessments is the maximum theoretical concentration (or amount) (MTC or MTA) of the impurity/metabolite achievable from the administered dose and recommendations on the estimation of the MTC and MTA are presented.


Assuntos
Contaminação de Medicamentos , Preparações Farmacêuticas/metabolismo , Animais , Biotransformação , Humanos , Testes de Toxicidade
2.
Mutagenesis ; 34(1): 67-82, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189015

RESUMO

(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class. This article analysed a series of publicly available aromatic N-oxide data in search of supporting information. The article also used a previously developed structure-activity relationship (SAR) fingerprint methodology where a series of aromatic N-oxide substructures was generated and matched against public and proprietary databases, including pharmaceutical data. An assessment of the number of mutagenic and non-mutagenic compounds matching each substructure across all sources was used to understand whether the general class or any specific subclasses appear to lead to mutagenicity. This analysis resulted in a downgrade of the general aromatic N-oxide alert. However, it was determined there were enough public and proprietary data to assign the quindioxin and related chemicals as well as benzo[c][1,2,5]oxadiazole 1-oxide subclasses as alerts. The overall results of this analysis were incorporated into Leadscope's expert-rule-based model to enhance its predictive accuracy.


Assuntos
Óxidos N-Cíclicos/química , Dano ao DNA/efeitos dos fármacos , Mutagênicos/química , Relação Quantitativa Estrutura-Atividade , Óxidos N-Cíclicos/toxicidade , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos/toxicidade
3.
Regul Toxicol Pharmacol ; 102: 53-64, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30562600

RESUMO

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation.


Assuntos
Contaminação de Medicamentos , Guias como Assunto , Mutagênicos/classificação , Relação Quantitativa Estrutura-Atividade , Indústria Farmacêutica , Órgãos Governamentais , Mutagênicos/toxicidade , Medição de Risco
4.
Regul Toxicol Pharmacol ; 84: 116-123, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28038978

RESUMO

Management of organic non-mutagenic impurities (NMIs) in medicinal products is regulated by the ICH Q3A, B and C guidelines that are applicable at late stages of clinical development (Phase III onwards) and as a consequence there is no guidance for the assessment and control of NMIs in early clinical trials. An analysis of several key in vivo toxicology databases supports the ICH Q3A defined concept that a lifetime dose to 1 mg/day of a NMI would not represent a safety concern to patients. In conjunction with routine (Q)SAR approaches, this 1 mg/day value could be used as a universal qualification threshold for a NMI during any stage of clinical development. This analysis also proposes that modification of this 1 mg/day dose using an established methodology (i.e. Modified Haber's Law) could support 5 mg/day or 0.7% (whichever is lower) as an acceptable limit for a NMI in a drug substance or product in early clinical studies (<6 months). Given the controlled nature of clinical development and the knowledge that most toxicities are dose and duration dependent, these proposed NMI limits provide assurance of patient safety throughout clinical development, without the requirement to commission dedicated in vivo toxicology impurity qualification studies.


Assuntos
Ensaios Clínicos como Assunto , Contaminação de Medicamentos , Descoberta de Drogas , Compostos Orgânicos/efeitos adversos , Segurança do Paciente , Preparações Farmacêuticas/análise , Animais , Ensaios Clínicos como Assunto/legislação & jurisprudência , Relação Dose-Resposta a Droga , Descoberta de Drogas/legislação & jurisprudência , Controle de Medicamentos e Entorpecentes , Regulamentação Governamental , Política de Saúde , Humanos , Nível de Efeito Adverso não Observado , Compostos Orgânicos/análise , Segurança do Paciente/legislação & jurisprudência , Formulação de Políticas , Controle de Qualidade , Medição de Risco , Fatores de Risco , Níveis Máximos Permitidos , Fatores de Tempo , Testes de Toxicidade/métodos
5.
Regul Toxicol Pharmacol ; 90: 22-28, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28822875

RESUMO

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.


Assuntos
Contaminação de Medicamentos/prevenção & controle , Testes de Mutagenicidade/normas , Mutagênicos/toxicidade , Preparações Farmacêuticas/normas , Tecnologia Farmacêutica/normas , Simulação por Computador , Humanos , Testes de Mutagenicidade/métodos , Preparações Farmacêuticas/síntese química , Guias de Prática Clínica como Assunto , Controle de Qualidade , Relação Quantitativa Estrutura-Atividade , Medição de Risco
6.
Regul Toxicol Pharmacol ; 81: 201-211, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27569203

RESUMO

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."


Assuntos
Produtos Biológicos/efeitos adversos , Produtos Biológicos/química , Liberação Controlada de Fármacos , Preparações Farmacêuticas/química , Segurança , Produtos Biológicos/administração & dosagem , Segurança Química , Humanos
7.
Regul Toxicol Pharmacol ; 77: 1-12, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26879463

RESUMO

Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data. Primary aromatic amine mutagenicity was selected as a case study because this chemical class is often encountered in pharmaceutical impurity analysis and mutagenicity of aromatic amines is currently difficult to predict. As part of this analysis, a series of aromatic amine substructures were defined and the number of mutagenic and non-mutagenic examples for each chemical substructure calculated across a series of public and proprietary mutagenicity databases. This information was pooled across all sources to identify structural classes that activate or deactivate aromatic amine mutagenicity. This structure activity knowledge, in combination with newly released primary aromatic amine data, was incorporated into Leadscope's expert rule-based and statistical-based (Q)SAR models where increased predictive performance was demonstrated.


Assuntos
Aminas/toxicidade , Mineração de Dados/métodos , Bases de Conhecimento , Mutagênese , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Aminas/química , Aminas/classificação , Animais , Simulação por Computador , Bases de Dados Factuais , Humanos , Modelos Moleculares , Estrutura Molecular , Mutagênicos/química , Mutagênicos/classificação , Reconhecimento Automatizado de Padrão , Relação Quantitativa Estrutura-Atividade , Medição de Risco
8.
Regul Toxicol Pharmacol ; 77: 13-24, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26877192

RESUMO

The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript.


Assuntos
Testes de Carcinogenicidade/métodos , Dano ao DNA , Mineração de Dados/métodos , Mutagênese , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Toxicologia/métodos , Animais , Testes de Carcinogenicidade/normas , Simulação por Computador , Bases de Dados Factuais , Fidelidade a Diretrizes , Guias como Assunto , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Mutagenicidade/normas , Mutagênicos/química , Mutagênicos/classificação , Formulação de Políticas , Relação Quantitativa Estrutura-Atividade , Medição de Risco , Toxicologia/legislação & jurisprudência , Toxicologia/normas
9.
Regul Toxicol Pharmacol ; 73(1): 367-77, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26248005

RESUMO

The ICH M7 guidelines for the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals allows for the consideration of in silico predictions in place of in vitro studies. This represents a significant advance in the acceptance of (Q)SAR models and has resulted from positive interactions between modellers, regulatory agencies and industry with a shared purpose of developing effective processes to minimise risk. This paper discusses key scientific principles that should be applied when evaluating in silico predictions with a focus on accuracy and scientific rigour that will support a consistent and practical route to regulatory submission.


Assuntos
Testes de Mutagenicidade/métodos , Testes de Mutagenicidade/normas , Simulação por Computador/normas , DNA/química , Contaminação de Medicamentos/prevenção & controle , Mutagênicos , Relação Quantitativa Estrutura-Atividade
10.
AAPS PharmSciTech ; 16(3): 664-74, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25511807

RESUMO

The effective management of leachables in pharmaceutical products is a critical aspect of their development. This can be facilitated if extractables information on the materials used in a packaging or delivery system is available to assist companies in selecting materials that will be compatible with the drug product formulation and suitable for the intended use. The Extractables and Leachables Safety Information Exchange (ELSIE) materials working group developed and executed a comprehensive extraction study protocol that included a number of extraction solvents, extraction techniques, and a variety of analytical techniques. This was performed on two test materials, polyethylene (PE) and polyvinyl chloride (PVC), that were selected due to their common use in pharmaceutical packaging. The purpose of the study was to investigate if the protocol could be simplified such that (i) a reduced number or even a single extraction technique could be used and (ii) a reduced number of solvents could be used to obtain information that is useful for material selection regardless of product type. Results indicate that, at least for the PVC, such reductions are feasible. Additionally, the studies indicate that levels of extractable elemental impurities in the two test materials were low and further confirm the importance of using orthogonal analytical detection techniques to gain adequate understanding of extraction profiles.


Assuntos
Polietileno/química , Cloreto de Polivinila/química , Contaminação de Medicamentos , Embalagem de Medicamentos/métodos , Preparações Farmacêuticas/química , Projetos Piloto , Solventes/química
11.
J Pharm Sci ; 112(12): 3005-3011, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37805074

RESUMO

N-Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation of the DNA-alkylating diazonium ion. Following up on the in-silico identification of thousands of nitrosamines that can potentially be derived from small molecule drugs and their known impurities described in a previous publication, we have now re-analyzed this dataset to apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with the 16th revision of their Q&A document for Marketing Authorization Holders. We find that the majority of potential nitrosamines from secondary amine precursors belongs to potency categories 4 and 5, corresponding to an acceptable daily intake of 1500 ng, whereas nitrosamines from tertiary amine precursors distribute more evenly among all categories, resulting in a substantial number of structures that are assigned the more challenging acceptable intakes of 18 ng/day and 100 ng/day for potency categories 1 and 2, respectively. However, the nitrosative dealkylation pathway for tertiary amine is generally far slower than the direct nitrosation on secondary amines, with a direct nitrosation mechanism suspected only for structures featuring electron-rich (hetero)aromatic substituents. This allows for greater focus towards those structures that require further review, and we demonstrate that their number is not substantial. In addition, we reflect on the nitrosamine risk posed by secondary amine API impurities and demonstrate that based on the ICH Q3A/B identification threshold unknown impurities may exist that could be transformed to relevant amounts of NA. We also demonstrate that the analytical sensitivity required for the quantification of high potency nitrosamines can be problematic especially for high dose APIs. In summary, the regulatory framework rolled out with the latest Q&A document represents a substantial improvement compared with the previous situation, but further refinement through interaction between manufacturers, regulators, not-for-profit and academic institutions will be required to ensure patient access to vital medicines without compromising safety.


Assuntos
Nitrosaminas , Humanos , Nitrosaminas/química , Aminas/química , Preparações Farmacêuticas
12.
J Pharm Sci ; 111(5): 1421-1428, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34673095

RESUMO

The purpose of this publication is to show how an elemental impurities excipient database can be used in assisting the execution of a drug product elemental impurities risk assessment as required by the ICH Q3D guidelines. As a result of this exercise, we have demonstrated that the database, used in conjugation with other sources of information, is a credible source of elemental impurity levels in excipients therefore, a valuable source of information in completion of drug product risk assessments. This useful collection of data helps to reduce the burden of analytical testing for elemental impurities in excipients.


Assuntos
Contaminação de Medicamentos , Excipientes , Bases de Dados Factuais , Contaminação de Medicamentos/prevenção & controle , Preparações Farmacêuticas , Medição de Risco
13.
AAPS J ; 24(6): 101, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36168002

RESUMO

This publication provides some industry reflections on experiences from the Chemistry, Manufacturing, and Controls (CMC) development and manufacture and supply of vaccines and therapies in response to the COVID-19 pandemic. It integrates these experiences with the outcomes from the collaborative work between industry and regulators in recent years on innovative science- and risk-based CMC strategies to the development of new, high-quality products for unmet medical needs. The challenges for rapid development are discussed and various approaches to facilitate accelerated development and global supply are collated for consideration. Relevant regulatory aspects are reviewed, including the role of Emergency Use/Conditional Marketing Authorizations, the dialogue between sponsors and agencies to facilitate early decision-making and alignment, and the value of improving reliance/collaborative assessment and increased collaboration between regulatory authorities to reduce differences in global regulatory requirements. Five areas are highlighted for particular consideration in the implementation of strategies for the quality-related aspects of accelerated development and supply: (1) the substantial need to advance reliance or collaborative assessment; (2) the need for early decision making and streamlined engagement between industry and regulatory authorities on CMC matters; (3) the need to further facilitate 'post-approval' changes; (4) fully exploiting prior and platform knowledge; and (5) review and potential revision of legal frameworks. The recommendations in this publication are intended to contribute to the discussion on approaches that can result in earlier and greater access to high-quality pandemic vaccines and therapies for patients worldwide but could also be useful in general for innovative medicines addressing unmet medical needs.


Assuntos
COVID-19 , Vacinas , COVID-19/epidemiologia , COVID-19/prevenção & controle , Humanos , Pandemias/prevenção & controle , Vacinas/uso terapêutico
14.
Mutat Res ; 724(1-2): 1-6, 2011 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-21645632

RESUMO

Boronic acids and their esters are important building blocks in organic syntheses including those for drug substances and for which, as far as it can be determined, there are no published reports of testing for genotoxicity. A number of boronic acids have now been tested in this laboratory using Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA(pKM101). Twelve of the 13 structures presented here were found to be mutagenic. All the compounds except one were active only in TA100 and/or WP2uvrA(pKM101), did not require S9 activation and produced relatively weak responses, i.e. no more than seven times the concurrent solvent-control values at >1000µg/plate. The single exception was also weakly mutagenic for TA1537 in the presence of S9. Results with two compounds mutagenic for both TA100 and WP2uvrA(pKM101) showed no evidence of DNA-adduct formation detectable by (32)P-postlabelling. It appears that boronic acids represent a novel class of bacterial mutagen that may not act by direct covalent binding to DNA. However, their mechanism of action remains to be elucidated and it cannot yet be determined whether or not they present a real genotoxic hazard.


Assuntos
Ácidos Borônicos/toxicidade , Mutagênicos/toxicidade , Animais , Biotransformação , Cricetinae , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Humanos , Testes de Mutagenicidade/métodos , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética
15.
J Pharm Biomed Anal ; 48(5): 1339-44, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18996665

RESUMO

An automated sample preparation and analysis procedure was developed to monitor the formation of ethyl methane sulfonate from reaction mixtures containing ethanol and methane sulfonic acid. The system is based on a liquid handling robot combined with a static headspace module. The formed ethyl methane sulfonate is analysed after derivatisation with pentafluorothiophenol using static headspace-gas chromatography-mass spectrometry (SHS-GC-MS). Using the automated reaction-derivatisation-headspace GC-MS system, the formation of ethyl methane sulfonate can be monitored in different reaction mixtures under different reaction conditions, including temperature, water content and pH. Excellent linearity, repeatability and robustness were obtained, allowing the system to be used in kinetic studies.


Assuntos
Etanol/química , Metanossulfonato de Etila/síntese química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Mesilatos/química , Metanossulfonato de Etila/química , Estrutura Molecular , Padrões de Referência , Reprodutibilidade dos Testes , Robótica/métodos , Temperatura , Fatores de Tempo
16.
J Pharm Sci ; 107(9): 2335-2340, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29679706

RESUMO

To support the practical implementation of the International Council for Harmonisation (ICH) Q3D guideline, which describes a risk-based approach to the control of elemental impurities in drug products, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of 26,723 elemental determinations for 201 excipients and represents the largest known, and still rapidly expanding, collection of data of this type. Analysis of the database indicates good coverage of excipients relevant to real-world drug product formulations and tested element profiles consistent with ICH Q3D recommendations. The database includes the results from multiple analytical studies for an excipient and thus incorporates within it an indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The data confirm the findings of earlier smaller studies that elemental impurity concentrations in excipients are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk. The database is now in active use as one line of evidence in ICH Q3D risk assessments.


Assuntos
Química Farmacêutica/normas , Bases de Dados Factuais/normas , Contaminação de Medicamentos/prevenção & controle , Excipientes/normas , Preparações Farmacêuticas/normas , Química Farmacêutica/métodos , Excipientes/análise , Humanos , Preparações Farmacêuticas/análise
17.
J Pharm Sci ; 99(7): 2948-61, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20112423

RESUMO

The issue of controlling genotoxic impurities in novel active pharmaceutical ingredients (APIs) is a significant challenge. Much of the current regulatory concern, has been focused on the formation and control of genotoxic sulfonate esters. This is linked with the withdrawal of Viracept (Nefinavir mesilate) from European markets in mid-2007, over concerns about elevated levels of ethyl methanesulfonate (EMS). This issue has resulted in calls from European regulators to assess risk mitigation strategies for all marketed products employing a sulfonic acid counter-ion to ensure that the sulfonate esters that could be potentially formed are controlled to threshold of toxicological concern (TTC)-based limits. This has even led to calls to avoid sulfonic acids as salt counter-ions. However, sulfonic acid salts possess a range of properties that are useful to both synthetic and formulation chemists. Whilst sulfonate salts are not a universal panacea to some of the problems of salt formation they do offer significant advantages as alternatives to other salt forming moieties under certain circumstances. This review thus sets out to define some of the advantages provided through utilization of sulfonic acids, explaining the importance of their retention as part of a thorough salt selection process.


Assuntos
Descoberta de Drogas , Sais/química , Ácidos Sulfônicos/química , Animais , Humanos , Sais/farmacologia , Ácidos Sulfônicos/farmacologia
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