Combating pharmaceutical folklore: No alkyl-sulfonate impurities formed during the synthesis of sulfonate salts.

Whilst an alcohol can be forced to react with a sulfonic acid, this reaction produces minimal ester conversion even under extreme conditions (anhydrous, very low pH) that bear no resemblance to the mild synthetic procedures typically used for the formation of sulfonate salts of basic drugs. The latter involve the addition of a molar equivalent of pharma-grade sulfonic acid to the base form of a drug substance (pKa ≥3.5), dissolved or suspended in an alcohol solvent, normally ethanol (pKa -2).

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of -nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.

Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs).

Low levels of N-nitrosamines (NAs) were detected in pharmaceuticals and, as a result, health authorities (HAs) have published acceptable intakes (AIs) in pharmaceuticals to limit potential carcinogenic risk. The rationales behind the AIs have not been provided to understand the process for selecting a TD or read-across analog. In this manuscript we evaluated the toxicity data for eleven common NAs in a comprehensive and transparent process consistent with ICH M7.

Mutagenic impurities in pharmaceuticals: A critical assessment of the cohort of concern with a focus on N-nitrosamines.

The TTC (Threshold of Toxicological Concern; set at 1.5 μg/day for pharmaceuticals) defines an acceptable patient intake for any unstudied chemical posing a negligible risk of carcinogenicity or other toxic effects. A group of high potency mutagenic carcinogens, defined solely by the presence of particular structural alerts, are referred to as the "cohort of concern" (CoC); aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds are considered to pose a significant carcinogenic risk at intakes below the TTC.

Tolerability of risk: A commentary on the nitrosamine contamination issue.

For decades, regulators have grappled with different approaches to address the issue of control of impurities. Safety-based limits, such as permissible daily exposure (PDE), acceptable intake (AI), threshold of toxicological concern (TTC) and less than lifetime limits (LTL) have all been used. For many years these safety-based limits have been recognized as virtually safe doses (VSDs).

Short commentary on NDMA (N-nitrosodimethylamine) contamination of valsartan products.

A range of generic valsartan products have been found to be contaminated with nitrosamines (principally N-nitrosodimethylamine; NDMA). We present information and discuss various elements of this phenomenon including: actions taken by regulatory agencies, source of the nitrosamine impurities, range of possible risk assessments based mainly on ICH M7 criteria, epidemiological assessment and analytical aspects.

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity?

(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.

Mutagenic impurities in pharmaceuticals: a critique of the derivation of the cancer TTC (Threshold of Toxicological Concern) and recommendations for structural-class-based limits.

The cancer TTC (Threshold of Toxicological Concern) concept is currently employed as an aid to risk assessment of potentially mutagenic impurities (PMIs) in food, cosmetics and other sectors. Within the pharmaceutical industry the use of one default cancer TTC limit of 1.5 μg/day for PMIs is being increasingly questioned.

Guidelines and pharmacopoeial standards for pharmaceutical impurities: overview and critical assessment.

ICH/regional guidances and agency scrutiny provide the regulatory framework for safety assessment and control of impurities in small-molecule drug substances and drug products. We provide a critical assessment of the principal impurity guidances and, in particular, focus on deficiencies in the derivation of the threshold of toxicological concern (TTC) as applied to genotoxic impurities and the many toxicological anomalies generated by following the current guidelines on impurities. In terms of pharmacopoeial standards, we aim to highlight the fact that strictly controlling numerous impurities, especially those that are minor structural variants of the active substance, is likely to produce minimal improvements in drug safety.

Drug substances presented as sulfonic acid salts: overview of utility, safety and regulation.

Objectives: Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients.

Understanding and applying regulatory guidance on the nonclinical development of biotechnology-derived pharmaceuticals.

Biotechnology-derived pharmaceuticals are a well established and growing part of the therapeutic armamentarium. Beginning with recombinant versions of products such as insulin that were previously manufactured by extraction from animal and human sources, licensed biotechnology drugs and those in development now span an ever-increasing range of product types and therapeutic categories. As a consequence of this diversity, both general and product class-specific scientific guidelines have been developed on a regional (e.

Residues of genotoxic alkyl mesylates in mesylate salt drug substances: real or imaginary problems?

Mesylate esters of short-chain (n = 1-3) alcohols are reactive, direct-acting, genotoxic and possibly carcinogenic alkylating agents. Their chemical and biological properties appear to correlate well with Swain-Scott s constants; for example, high S(N)1 character (low s value) is associated with enhanced carcinogenic potential, but also a rapid hydrolysis rate. Concerns over the possible formation of such esters during the preparation of mesylate salt drug substances, by addition of methane sulfonic acid (MSA) to the free base dissolved in an alcoholic solvent, have led regulatory agencies to require applicants to demonstrate that the synthetic method employed does not lead to the presence of detectable levels of alkyl mesylates.

Regulatory immunotoxicology: does the published evidence support mandatory nonclinical immune function screening in drug development?

Recent immunotoxicity guidance documents from the EU CHMP and the US FDA apply significantly different weightings to immune function testing; whereas the former mandates (as a starting point) incorporation of immune function tests (IFTs) to screen for immunotoxic potential in sub-chronic rodent toxicity studies, the more cautious 'for cause' FDA approach recommends the use of IFTs only when warranted by evidence obtained from conventional nonclinical and/or clinical studies. Conclusions from detailed evaluations of several key drugs, including salmeterol and some opioids, challenge the notion that data on these examples support the need for IFTs to detect unintended immunosuppression. Given the virtual absence of convincing pharmaceutical examples and the rarity of unintended immunosuppression, routine immune function testing of all new pharmaceuticals is not considered justified.

An EU perspective on the use of in vitro methods in regulatory pharmaceutical toxicology.

Some in vitro methods such as those used in the assessment of genotoxicity, receptor-binding and QT-prolongation are well established in regulatory pharmaceutical toxicology. In vitro systems to study metabolic profiles, P450 isoforms, drug interactions, etc. or to provide metabolic activation in genotoxicity assays are extremely useful, but are subject to a number of important limitations.

Alternatives models in carcinogenicity testing--a European perspective.

Transgenic mouse strains offer the prospect of significant benefits in the in vivo assessment of carcinogenic potential. The European Regulatory Authorities have been supportive of their inclusion as one of the second-test options in the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human use (ICH). However, there is a concern regarding premature systematic use of these models.