Pilot Equivalence Study Comparing Different Batches of Topical 0.025% Capsaicin Emulsion: Product Microstructure, Release, and Permeation Evaluation

The European Medical Agency (EMA) has issued a draft guideline on the quality and equivalence of topical products. The equivalence for complex semisolid formulations involves several steps: the same quantitative content, the same microstructure, the same release, and permeation profile. In this paper, several batches of a low strength topical product, which we used as a reference/comparator product, were evaluated according to the recommendations of the EMA draft guideline. The batches were 0.025% capsaicin emulsions from the same manufacturer that were evaluated in terms of droplet size, X-ray diffraction patterns, rheology, release, and permeation profile. The generated data revealed a large batch-to-batch variability, and if the EMA guideline was applied, these batches would not be considered equivalent, although they were produced by the same manufacturer. The result of this work illustrates the difficulties in obtaining equivalence according to the current draft guidelines. It also highlights that the equivalence guidelines should consider the variability of the comparator product, and in our opinion, the guidelines should allow for claiming equivalence by comparing the limits in the variability of the data generated for the comparator product with the limits in the variability of the data generated for the intended equivalence product.

Multiple Sclerosis International Federation guideline methodology for off-label treatments for multiple sclerosis

Background A total of 2.8 million people are living with multiple sclerosis and due to disparities in access to medicines, the ability to treat this condition varies widely. Off-label disease-modifying therapies are sometimes more available or affordable in different health systems. Appropriate methodology is integral in creating high-quality and trustworthy guidelines. In this article, we outline Multiple Sclerosis International Federation’s (MSIF) approach to creating guidelines for off-label treatments for multiple sclerosis. Methods We use the Guidelines International Network (GIN)-McMaster Guideline Development Checklist and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Evidence-to-Decision (EtD) framework. We developed detailed health descriptors for health outcomes and the panel drafted PICO (Population, Intervention, Comparator, Outcome) questions and prioritised outcomes. We collaborate with independent organisations, which systematically review and collate the information. We are actively engaging stakeholders and consulting with relevant organisations, boards, working groups and individuals. Results The draft guideline recommendations will be published for open comment and stakeholders will be encouraged to endorse and disseminate the guidelines. Our methodology ensures integrity and transparency in the criteria, evidence and judgement used to make recommendations. Conclusions This approach will facilitate transparent creation of high-quality and trustworthy guidelines, and allow the global guidelines to be adopted or adapted into national settings.

Recommendations for the content and management of Certificates of Analysis for reference standards from the GCC for bioanalysis

The 13th Global CRO Council (GCC) closed forum for bioanalysis was held in New Orleans, LA, USA on 5 April 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. While ICH M10 will cover requirements for reference standards, one of the biggest challenges facing the CRO community is the lack of consistency and completeness of Certificates of Analysis for reference standards used in regulated bioanalysis. Similar challenges exist with critical reagents (e.g., capture and detection antibodies) used for assays supporting biologics. The recommendations provided in this publication are the minimum requirements for the content that GCC members believe should be included in Certificates of Analysis for reference standards obtained from commercial vendors, sponsors and compendial suppliers, for use in regulated bioanalytical studies. In addition, recommendations for internal standards, metabolites and critical reagents are discussed.

Statistical Methods for Quality Equivalence of Topical Products. 0.5 mg/g Betamethasone Ointment as a Case-Study

This study examines the statistical implications, and their possible implementation, of the “Draft guideline on quality and equivalence of topical products” issued by the European Medicines Agency in 2018, with particular focus on the section devoted to quality equivalence of physical properties. A new confidence interval to conduct the quality equivalence test and a way to cope with the multiplicity of quality parameters are presented and discussed. As an example, the results and the statistical analysis of a study on betamethasone 0.5 mg/g ointment are presented. It is suggested that the equivalence limits proposed in the draft guideline are overly strict: It is as difficult to declare quality equivalence between two packaging formats of the same reference product as to declare quality equivalence between the reference and the test product.

Challenges of Regulatory Environmental Risk Assessment for Human Pharmaceuticals with Focus on Antibiotics

Just recently the problem of pharmaceutical residues in the environment has been emphasized by OECD. Especially antibiotics are of concern due to their widespread use and diverse modes of actions including ones that can affect the photosynthetic activity of primary producers and subsequently primary biomass production and carbon dioxide fixation. The EU regulatory authority, the European Medicines Agency (EMA), has therefore proposed to implement a new tailored environmental risk assessment scheme, published in a new draft guideline 2018. Threshold effect levels to three fixed representative species of green algae and cyanobacteria will be required. This article reviews and compares the contamination of waters with antibiotics in Switzerland and Germany and also presents an overview of published effect data on eukaryotic algae and prokaryotic cyanobacteria in order to discuss the representativeness of the selected species. Since no full datasets as demanded by the EMA were publically available yet, the gaps for four antibiotics have been experimentally completed. In summary the results support the species selection of the EMA published in the revised draft guideline, however it remains unclear whether diatoms should also be considered.

European Bioanalysis Forum feedback on draft ICH M10 guideline on bioanalytical method validation during the Step 2b public consultation period

Once released, the ICH M10 Guideline on bioanalytical method validation will become one of the most important milestones in the history of regulated bioanalysis, closing a chapter on intense discussions among the industry and health authorities started in Crystal City in 2001. In this manuscript, the European Bioanalysis Forum community reports back on their feedback on the ICH M10 draft guideline gathered during the public consultation period. The comments given are intended to contribute to a guideline that combines several decades of experience and current scientific vision. They should provide future generations of bioanalytical scientist a regulatory framework so their bioanalytical work can contribute to safe, effective and high-quality medicines, which can be developed and registered in the most resource-efficient manner.