Capabilities

 

We offer a variety of services with excellent turn around time and responsive client service.

 

 
I had the pleasure of working with Lisa during the preparation of an NDA submission for a novel polymeric therapeutic. Lisa’s broad experience not only in general toxicology, but also her specific insights regarding the evaluation of impurities, were invaluable. Her positive personality, attention to detail, careful planning and timely execution were major assets to the writing team.
— Jamie Cope, Vice President Biology & Research, Tricida, Inc.

Toxicology

TSI can provide toxicology support and strategy planning for therapeutic programs spanning the breadth of early research through product registration (NDA). We have extensive experience working with contract research organizations (CROs) and have developed trusting relationships with many. TSI can act as the sole interface with the CRO or work with your project management staff to coordinate the work effort.  

Any study types are supported including early single dose PK and dose escalation MTD studies, repeat dose range-finders, repeat dose GLP (28 day, 13 week, 26 week rodent and non-rodent), carcinogenicity (transgenic and 2-yr bioassay), reproductive toxicity (Segment I, II, III), phototoxicity (in vitro and in vivo), genetic toxicology (Ames, chromosome aberration, micronucleus) and safety pharmacology (cardiovascular, respiratory, CNS, GI) including ion channels (hERG, Na, Ca).

General

  • Due diligence
  • Planning, strategy and interpretation of IND enabling studies
  • Review/write research manuscripts, position papers and white papers
  • Literature reviews and summaries
  • Subject-specific literature searches
  • Review of GLP study reports
  • Quality control review of documents

Non-clinical Study Planning and Management

  • Bid solicitation and contract laboratory (CRO) selection
  • Protocol development
  • Study design/planning
  • Data and report review
  • On-site study monitoring and preparation of study monitoring reports
  • Central point of contact for study-related communication
  • Development and maintenance of timelines and budgets for preclinical programs
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Genotoxic impurities strategy

Excipient expert review

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In Silico Toxicology

In silico software programs to predict toxicity combine biology and chemistry with modeling and computational science in order to increase the predictive power in the field of toxicology.   Since the finalization of ICH M7 in 2015 (Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk), structures should be tested in at least 2 different in silico software programs, followed by a computational analysis of the in silico data.

The ICH M7 guidance also speaks of expert review of the in silico data, and states that “if warranted, the outcome of any computer system-based analysis can be reviewed with the use of expert knowledge in order to provide additional supportive evidence on relevance of any positive, negative, conflicting or inconclusive prediction and provide a rationale to support the final conclusion.”  

TSI has a proven track record of successful regulatory submissions of computational reports in both the U.S and Europe (EMA). We offer analysis via the most up to date and widely used in silico tools, including both rule and statistical based programs. Dr. Beilke is also active in the field of computational toxicology through collaborations with Leadscope and recent publications.

 

DEREK Nexus
DEREK software was developed by Lhasa Limited, an organization that specializes in the development of expert computer systems for toxicity and metabolism predictions.  DEREK is a knowledge and rule based predictive toxicology software program that makes qualitative estimations of endpoint risk.  A knowledge based system is a computer program that contains expert knowledge rules in toxicology and applies the rules to make predictions about the toxicity of chemicals, usually when no experimental data is available.  The qualitative estimations of risk are categorized, in descending order of probability, as ‘certain’, ‘probable’, ‘plausible’, ‘equivocal’, ‘doubted’, ‘improbable’ or ‘impossible’.  A negative prediction for bacterial in vitro mutagenicity was also introduced into the software, where an 'inactive' call can be made and non-alerting compounds are evaluated to identify unclassified and misclassified features.  

The most common use of DEREK is to screen for potential mutagenicity, but several other endpoints are available, such as: Carcinogenicity, Genotoxicity, Irritation, Miscellaneous Endpoints, Neurotoxicity, Organ Toxicity, Reproductive Toxicity, Respiratory Sensitization, and Skin Sensitization.

DEREK Example: Aflatoxin B1
Mutagenicity in vitro in bacterium is PLAUSIBLE

Leadscope
Leadscope® FDA Model Applier software is statistical based and uses QSAR models to provide a quantitative predictive probability for the potential toxicity of chemicals. In addition to mutagenicity in the Genetox Suite, several other toxicity endpoint suites are available, such as Developmental Toxicity, Human Adverse Cardiological Effects, Human Adverse Hepatobiliary Effects, Human Adverse Urinary Effects, Neurotoxicity, Reproductive Toxicity, and Rodent Carcinogenicity.

The Leadscope® Genetox Expert Alerts Suite is also offered.  This is a new expert rule-based in silico system to predict the results of a bacterial mutagenesis.  The Genetox Expert Alerts are based on well-defined mutagenicity structural alerts from the literature.  Over 200 distinct alerts were identified and these alerts were further validated against a reference database of over 7,000 chemicals with known bacterial mutagenesis results.

Expert Alerts Example: Aflatoxin B1

 

MultiCase

CASE Ultra is a QSAR software for modeling and predicting toxicity of chemicals designed to uncover the relationship between the structure of the chemicals and their activity in a specific biological assay.  It has been designed to deal with “noncongeneric” databases, that is, databases consisting of structurally unrelated molecules that are not normally amenable to treatment with traditional Quantitative Structure-Activity Relationship (QSAR) type techniques. CASE Ultra utilizes suites of models to assess various endpoints. The ICH M7 suite consists of statistical (Gt1_A7B and GT1_AT_ECOLI) and rule-based (GT_EXPERT) models.

The GT1_A7B model covers mutagenicity in S. typhimurium bacteria in strains TA97, TA98, TA100, TA1535 and TA1538 with a database size of 3,979 compounds. The GT1_AT_Ecoli model covers A-T base pair mutations in E. coli (WP2 uvrA and pkM101 strains) and S. typhimurium TA102 strain, with a database size of 1,199 compounds. The GT_Expert alert is a model for mutagenicity and contains 10,777 compounds.

Case Ultra Prediction Summary

 

Leadscope Toxicity Database
The Leadscope Toxicity Database is a data mining tool that contains over 180,000 chemical structures with over 400,000 toxicity study results. Evaluation of the experimental data can allow read-across for structural comparison. Sources of toxicity data include:

  • FDA PAFA Database
  • National Toxicology Program (NTP) Chronic Database
  • Registry of Toxic Effects on Chemical Substances (RTECS)
  • DSSTox Carcinogenicity Potency Database (CPDB)

Covers acute, multiple dose studies including subchronic liver, carcinogenicity, genetic toxicity, reproductive and irritation

Lisa ran a complete in-silico genetox assessment of the process related impurities and degradation products in our API under a tight time line and she delivered it ahead of schedule and made herself available to discuss the results on short notice which was very helpful. I would absolutely consult with her again and would recommend her services to my colleagues.
— Jeff Barker, Vice President Pharmaceutical Sciences, Trius Therapeutics, Inc.

Regulatory Services

We provide clients with toxicology support for their regulatory interactions (FDA, Europe and Japan) through written documentation, oral communication, and face-to-face meetings. Areas covered include:

  • FDA correspondence interpretation and regulatory guidance
  • FDA meeting and teleconference participation
  • Safety Pharmacology/Toxicology Sections of Regulatory Submissions
    • INDs and NDAs (can include Section 2.4 Nonclinical Overview)
    • Preparation of CTD Tabular Sections (2.6.3, 2.6.5, 2.6.7)
    • Investigator Brochures (IBs)
    • Special Protocol Assessments (SPAs) 
    • FDA meeting packages
Thanks again for your high quality report and responsiveness in helping us get our regulatory filing finalized quickly for submission.
— Trevor Charvat, ChemoCentryx

EHS & Risk Assessment

We help clients evaluate occupational and environmental health risks from manufacturing and research activities and communicate these risks via activities such as:

  • Occupational Health
    • Safety Data Sheet (MSDS) writing
    • Occupational Health Categorization
    • Plan/design/Conduct of worker safety studies
  • Leachable and Extractables safety evaluation
  • Technical Reporting of the safety of process solvents, degradants,

Intermediates with calculation of Permissible Daily Exposure (PDE)

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