Extractables and Leachables (E&L) USA 2023 Conference

Hello again it’s me Dr Candice Johnson. The E&L conference took place on May 17th – 18th and it was so nice meeting colleagues and hearing about all the developments in the E&L field.

The E&L community is eagerly anticipating the changes that the ISO-10993-17 standard and the ICH Q3E guideline will bring. Several presentations highlighted the importance of defined procedures for the identification and toxicological evaluation of E&L. Instem delivered a presentation on the chemical classification of E&L chemicals and identified chemical classes which are the most commonly seen as E&Ls as well as the prevalence of mutagens and potent skin sensitizers in the dataset. This work reproduces an important finding by Parris et al.1, that the prevalence of potent sensitizers in E&L is very low using an expanded dataset of E&L structures. Further, the degree of structural classification of E&L chemicals opens an interesting area of research on the feasibility and utility of setting class-based limits.  

Please get in touch if you would like to hear more about this work or receive a recording of a presentation summarizing our activities related to E&L (candice.johnson@instem.com).

  1. Parris et al., Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis (2022) being submitted

Read-across collaborative working group

Instem will be starting a new working group on the application of In Silico models to support read-across for the derivation of a point of departure for data poor substances. Read-across is being increasingly adopted to support a wide variety of applications including the assessment of non-genotoxic impurities, E&L (extractables & leachables), NIAS (non-intentionally added substances), occupational safety, to name a few.

In a recent publication, we showed how a combination of read-across alongside computational models was successfully used as part of a regulatory submission to assess a degradant within a drug product.1 An additional example was presented at this year’s SOT meeting discussing how an expert review of In Silico results for acute toxicity can be supported using read-across approaches.2

Despite many read-across publications, there is a still a need for a transparent and easy-to-adopt framework. Such a framework should be accepted by regulators and industry alike, as well as tailored to the specific application areas. It is important to address the justification of a suitable analog(s) (often referred to as the source chemicals) taking into consideration the general structural similarity, the similarity of the physico-chemical properties, at the same time as the biological similarity using either experimental data and/or In Silico predictions of biological properties or mechanistic profiles. This information needs to be assessed in a consistent and defendable manner, based on the weight of the evidence.

Furthermore, such a framework needs to address how you can read-across available experimental data of the chemical analogs on to the test (or target) chemical. One of the major elements here is the availability, relevance and reliability of the experimental data on any identified analogs, that needs to be evaluated in light of the application context.

This initiative is being led by Dr. Arianna Bassan and is focusing on specific read-across applications and case studies, thus building on the earlier published framework and examples.

Would you like to contribute to this activity or like to learn more about this new collaborative working group? If so, please get in touch with Glenn Myatt, PhD, glenn.myatt@instem.com


  1. A. Bassan et al., In silico approaches in organ toxicity hazard assessment: current status and future needs in predicting liver toxicity, Comput. Toxicol. 20 (2021) 100187. https://doi.org/10.1016/j.comtox.2021.100187
  2. G. Myatt et al. Predicting the Acute Toxicity 6-Pack to Support Health, Safety, and Environmental Product Stewardship (3671/ P156), Poster presented at the Society of Toxicology 2023 annual meeting
  3. https://www.instem.com/

Data, data, data, data…now what? (Guest Author Dr. Brenda Finney)

This week, we are pleased to welcome Dr. Brenda Finney, Instem’s Vice President of Translational Sciences, as a guest contributor to the blog:

You only have to consider the amount of data that tech companies are collecting about us as we move around an app or the internet to realize how other industries view the value of data. So, when you are working in drug or chemical discovery, development and regulatory or clinical testing, what do you do with your data? Does it disappear into a black hole of storage if the program or compound is cancelled? Does it contribute to a submission and then go into an archive – where again, it never sees the light of day?

Let us think about it in a different way:

What kind of things could you do if you could not only access all of your old data, but some of everyone else’s data as well?

What kind of improvements could you make to your strategy if you could review preclinical and clinical data in a single space?

What if there was a tool that helped to start making translations between medical terms used for clinical events and preclinical observations?

My goal at Instem is to help answer those questions.

Building on the work accomplished by the eTRANSAFE consortium, we are bringing Centrus™ (formally known as ToxHub) to the wider community of pharma and chemical companies. This platform will make data more accessible both within companies by providing a private data repository, and across companies with a shared database. There is also a mechanism for sharing data with some details anonymized to preserve company confidential information, but still add useful information to scientific discourse.

It provides a translation ontology, customizable visualization and analytics tools, allowing researchers to explore and interpret data in a user-friendly manner. These tools help researchers identify trends, patterns, and correlations, enabling data-driven decision making and more efficient R&D processes. We want this system to foster an interdisciplinary collaborative environment by offering features such as data sharing, data visualization and modeling, making a space for knowledge sharing, and innovation among researchers, ultimately leading to more effective drug development.

If you would like to discuss this project, please contact me (Brenda Finney, brendy.finney@instem.com).


  1. https://etransafe.eu/ 
  2. https://www.instem.com/

(Q)SAR and veterinary medicinal products

One of the most widely used applications of (Q)SAR is to support the assessment of pharmaceutical impurities aligned with the ICH M7 guideline1. Such assessments include the use of two complementary (Q)SAR methodologies alongside an expert review to assign the impurities to a specific class (classes 1 to 5 are outlined in the guideline). To support such implementation, Instem (through the Leadscope solution) developed bacterial mutagenicity and carcinogenicity databases, (Q)SAR models, and workflow tools2. We also developed a number of position papers, through cross-industry collaboration, to address issues related to the practical implementation of the ICH M7 guideline, including what should be addressed as part of an expert review and how to handle out-of-domain results.3,4,5,6

In 2020, a similar guideline was issued to support the assessment and control of DNA reactive (mutagenic) impurities in veterinary medicinal products by the European Medicines Agency5. Although there are some differences to ICH M7, the guideline adopts similar recommendations on the use of (Q)SAR approaches.

If you would like to discuss this application of (Q)SAR methods, please get in touch via glenn.myatt@instem.com.


  1. ICH, M7 (R1) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, 2017. https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf.
  2. Myatt, G.J., et al., 2022. Implementation of in silico toxicology protocols within a visual and interactive hazard assessment platform. Comput. Toxicol. 21, 100201. https://doi.org/10.1016/j.comtox.2021.100201
  3. E. Ahlberg, et al., Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity, Regul. Toxicol. Pharmacol. 77 (2016) 1–12. https://doi.org/10.1016/j.yrtph.2016.02.003.
  4. Amberg, A., et al. (2018) Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity? Mutagenesis 34, 67–82. 10.1093/mutage/gey020
  5. Amberg, A., et al., 2016. Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses. Regul. Toxicol. Pharmacol. 77, 13–24. https://doi.org/10.1016/j.yrtph.2016.02.004
  6. A. Amberg, et al., Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses, Regul. Toxicol. Pharmacol. 102 (2019) 53–64. https://doi.org/10.1016/j.yrtph.2018.12.007.
  7. Guideline on assessment and control of DNA reactive (mutagenic) impurities in veterinary medicinal products, 2020. Guideline on assessment and control of DNA reactive (mutagenic) impurities in veterinary medicinal products (europa.eu)

Society of Toxicology 2023 Meeting

We have just got back from this year’s Society of Toxicology meeting. It was an enjoyable and productive meeting, and great to see everyone there.

Thanks to everyone who attended Instem’s exhibitor hosted sessions on “Implementation of a Weight of Evidence Carcinogenicity Assessment Aligned with ICH S1B” and “Assessing N-nitrosamine Potency Classes”. There were a lot of interest and questions around the preparation of regulatory submissions to address these important topics. Unfortunately, the room was not large enough to accommodate all who wanted to attend; however, we will have the recording of the session available in the near future.

Thanks also to all who stopped-by the nine posters that Instem was a co-author on.1

Please get in touch if you would like us to send the recording of the sessions or to discuss the above in more detail (Glenn Myatt; glenn.myatt@instem.com).


  1. In Silico Insider – Nine Instem Posters at the 2023 SOT Meeting

Polo-like kinase 4 (PLK4) safety review – distilling the risks with a rapid augmented intelligence approach (Guest Author Dr Frances Hall)

Hello there! My name is Frances Hall PhD and I started my career at Instem in the GeneTox Team, enabling CROs, Pharma Companies, Universities and Research Institutes to gain value from the software solutions Instem provides for the genetic toxicology market, such as Comet Assay IV and Cyto Study Manager.

More recently, I’ve been working closely with clients on Target Safety Assessments (TSAs) as part of our KnowledgeScan TSA service team and I’ve learnt two things:

  1. People resonate with visuals in the form of colourful pictures, infographics, charts and graphs.
  2. People appreciate a recently assessed and relatable target example.

So, when it’s time to show an example document, I always pick an engaging target to discuss, and for the purpose of this blog I would like to discuss PLK4 – Polo-like Kinase 4. PLK4 is a great target for us to focus on, we used 72 PLK4 synonyms (alternative target names) and we found over 500 records in PubMed. The KnowledgeScan production team searched across the literature landscape, cross referencing PLK4 publications with our library of organ and adverse outcome terminology, and we identified 32 risks across 23 different organs.

PLK4 has an essential role in centriole duplication. The protein localizes to centrioles and regulates centriole duplication during the cell cycle. PLK4 turn-over must be strictly controlled to prevent centriole amplification. Therefore, PLK4 inhibitors have potential in cancer treatment; rendering cells unstable and more sensitive to chemotherapy. Given the role and cancer-focussed fame of PLK4, you might think that risks were limited to carcinogenesis, cell proliferation and ciliogenesis, however, this was not the case. Although we detected risks in those three areas, the most popular organs for risks were eye and lung.

Within the PLK4 corpus (collection of information), the amount of cancer-related literature does dominate the dataset, but this is a very typical (and real) target. The PLK4 TSA is an excellent discussion starter, where we can talk about how the KnowledgeScan platform handles larger, more complex, more weighted datasets.
Going back to my first point, PLK4 also has some immense Instem-developed infographics. In particular the Expression Topography and the Iris Plot are two excellent examples of how we can display large amounts of information succinctly and beautifully. When viewing the graphics, themes and stories are instantly revealed, and the observer can start asking appropriate questions.

If you’d like to see these PLK4 graphics and more, you can find my poster discussing this target at the upcoming SOT (Society of Toxicology, March 19-23, Nashville, TN, USA) meeting: 3096:202: Polo-like kinase 4 (PLK4) safety review – distilling the risks with a rapid augmented intelligence approach.

Alternatively, email me (frances.hall@instem.com) and I’ll gladly send you a copy.


  1. https://www.instem.com/news/articles/0601-sot-2023-events.php

Assessing carcinogenicity risk of nitrosamines and supporting the ICH S1B guideline

At this year’s SOT in Nashville (March 19-23, 2023), Instem will be organizing two workshops related to cancer assessments.1

In the first workshop, to be held on Tuesday, March 21, 4:30 PM – 5:30 PM (CT) in Room 101B, we will discuss carcinogenicity assessments aligned with the ICH S1B guideline2, specifically focusing on the weight of evidence (WoE) factors outlined in the addendum. The workshop will describe a new collaborative working group to develop a framework and pragmatic consensus procedure to support these WoE factors, which is being coordinated by Dr. Arianna Bassan, Principal Consultant at Innovatune. In addition, Dr. Frances Hall will outline a recent project undertaken at Instem to support an ICH S1B regulatory submission and review different ways to collaborate with Instem on this important topic.

The second workshop, Assessing N-nitrosamine Potency Classes, will be held on Wednesday, March 22, 12:00 PM – 1:00 PM (CT) in Room 101D.  Dr. Kevin Cross will review recent regulatory and industry updates in the assessment of N-nitrosamine potency classes based on various international collaborations. The workshop will outline new defendable methods, including SAR and read-across approaches, based on a mechanistic understanding of N-nitrosamine carcinogenicity. Dr. Arianna Bassan will also present an example of how in silico approaches can be used to support risk assessment of nitrosamines.

If you are unable to attend these workshops, please get in touch (Glenn Myatt; glenn.myatt@instem.com) and we would be happy to discuss these projects.


  1. https://www.instem.com/news/articles/0601-sot-2023-events.php
  2. https://database.ich.org/sites/default/files/S1B-R1_FinalGuideline_2022_0719.pdf

Nine Instem Posters at the 2023 SOT Meeting

Instem will again have a large presence at this year’s Society of Toxicology meeting in Nashville.1 As part of the scientific program, we will be co-authoring on nine posters covering the spectrum of scientific topics where we are undertaking research and development activities. This work supports many regulatory mandates and guidelines, including SEND, carcinogenicity risk assessment (as part of nitrosamine analysis and ICH S1B), target safety assessment, and occupational hazard and risk evaluation. The titles of these posters (along with abstract and poster numbers) are:

  • Challenges in SEND Conversion of Embryo Fetal Development (EFD) Studies in Compliance with the SENDIG DART v1.1 and Practical Examples Addressing the CDISC SEND Conformance Rules v4.0 (3172/P287)
  • Application of in Silico Methods for the Definition of Occupational Exposure Banding (3176/ P291)
  • Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Carcinogenicity (3233/ P350)
  • Polo-Like Kinase 4 (PLK4) Safety Review: Distilling the Risks with a Rapid Augmented Intelligence Approach (3096/ P202)
  • In Silico Approaches in Carcinogenicity Hazard Assessment: Case Study of Pregabalin, a Nongenotoxic Mouse Carcinogen (3058/ P163)
  • EMA Mutamind: Data Gap Analysis of N-Nitrosamines for Structure-Activity Relationship (3692/ P177)
  • Predicting the Acute Toxicity 6-Pack to Support Health, Safety, and Environmental Product Stewardship (3671/ P156)
  • Risk (Re)Assessment of N-Methyl-N-Nitrosophenethylamine for Use in Computing Acceptable Intake Levels of N-Nitrosamine Drug Substance-Related Impurities (4477/ P351)
  • A protocol to support weight-of-evidence assessments in the ICH S1B guideline (5152/P253)

If you are unable to attend the meeting, please get in touch (Glenn Myatt; glenn.myatt@instem.com) and we would be happy to share copies of the posters and review these projects in detail.


  1. https://www.instem.com/news/articles/0601-sot-2023-events.php

Final meeting of the current eTRANSAFE consortium

The eTRANSAFE project1 is a strategically important project that has been developing a translational technology infrastructure to support drug safety assessments. The project started around 5 years ago and has been jointly funded by the European Innovative Medicines Initiative alongside the pharmaceutical industry. The partners on the project include representatives from the pharmaceutical industry, academia, and technology companies.

The project focused on the sharing and integration of thousands of proprietary pre-clinical studies leveraging the SEND (Standard for the Exchange of Nonclinical Data) format. This allows the review of study data from different pharmaceutical companies, harmonizing the toxicity studies. The studies have been integrated into a technology platform coupled with additional solutions, including search and data visualization capabilities, predictive modelling, tools to support the handling of treatment-related findings, databases with clinical findings, and translational ontologies, to name a few.

The policies, strategies and technologies developed as part of this project will have a significant impact in enhancing the speed and quality of drug safety assessments as well as supporting the 3Rs and streamlining program planning activities in the preclinical and clinical space.

The final open meeting2 of the current consortium is scheduled for 22-24 February 2023 and will include speakers from regulatory authorities, industry, and academia. It will highlight the progress to date and will provide a roadmap to the future of translational research.

Representatives from Instem will be attending this meeting and happy to discuss collaborative opportunities. However, if you are unable to attend and would like to discuss, please contact Brenda Finney (brenda.finney@instem.com).


  1. https://etransafe.eu/
  2. Latest advances in drug safety – eTRANSAFE Final Meeting (linkedin.com)

FDA Modernization Act 2.0

The U.S. Congress recently passed the FDA Modernization Act 2.01 which permits the use of alternatives to animal studies as part of the FDA’s regulatory approval process. The new legislation explicitly identifies in silico models as one of these alternatives.

This legislation is an important step forward in the use of alternative methods and will encourage the use of scientifically valid alternative methods to support the assessment of a drugs’ efficacy and safety. Since many of these alternative methods, especially in silico models, generate results rapidly, they can be deployed strategically throughout the drug discovery and development process to accelerate product development.

Please reach out to me if you would like to discuss in silico toxicology models in more detail (glenn.myatt@instem.com).


  1. https://www.congress.gov/bill/117th-congress/senate-bill/5002