Services

Dr. Thurston has 30 years of experience pharmaceutical research and development in various therapeutic area focused on characterizing the ADME properties of molecules (both small and large molecule formats) via various routes of administration (IV, oral, SC, inhalation and dermal). 

• GLP Toxicokinetic Analysis and Report Writing

• General ADME Strategy

• Pharmacokinetic Analysis

• Human Dose / PK Prediction

• Clinical PK Analysis / Report Writing

• Regulatory Submission Writing

• Due Diligence Assessments

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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. She was a co-founder of the Computational Toxicology specialty section of the Society of Toxicology and continues to collaborate and publish with other leaders in the field.

• Computational toxicology evaluations conducted in accordance with the ICH M7 guidance

• (Q)SAR analysis using DEREK, Leadscope, and/or MultiCase to predict potential bacterial mutagenicity

• Rule and statistical based methodologies utilized

• Expert review of (Q)SAR data and overall determination of ICH M7 classification

• Regulatory submission quality report

“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.

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The discovery of nitrosamines in some types of drug products led the FDA and other international regulators to conduct a detailed analysis of these impurities in affected APIs and drug products. Following these analyses, the FDA issued a guidance, Control of Nitrosamine Impurities in Human Drugs (Sept 2020). Since then, the guidance has been expanded (Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities, 2023) and now includes a recommended framework for predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that could be present in drug products and recommends acceptable intake (AI) limits for NDSRIs. 

NDSRIs generally form in the drug product through nitrosation of APIs (or API fragments) that have secondary or tertiary amines when exposed to nitrosating agents such as residual nitrites in excipients used to formulate the drug product. NDSRIs often lack carcinogenicity and mutagenicity study data (typically from animal studies) from which an AI limit can be determined. As such, a standardized methodology to determine an AI has been developed through use of structural features of NDSRIs to generate a predicted carcinogenic potency categorization and recommended AI limit for dialkyl N-nitrosamines, and this approach has been termed the carcinogenicity potency categorization approach (CPCA).

Toxicology Solutions can evaluate the potential carcinogenicity of your N-nitroso compound and determine an acceptable intake (AI) value by evaluating the QSAR properties of the structure using in silico software programs using the CPCA, in accordance with the Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities guidance document (2023).

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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. Drs Beilke and Mintie are both board certified toxicologists. Dr. Beilke has many years of experience in large and small pharmaceutical companies and Dr. Mintie has Toxicology Study Direction experience at a large CRO. 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 (subchronic and chronic rodent and non-rodent), carcinogenicity (transgenic and 2-yr bioassay), reproductive toxicity (FEED, EFD, PPND, Juvenile), 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).

• Due diligence evaluation of nonclinical data

• Planning, strategy and interpretation of IND enabling toxicology studies

• Literature reviews and summaries

• Review of GLP and non-GLP study reports

• Quality control (QC) review of documents

• 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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TSI has performed numerous risk assessment evaluations, including those for contamination of drug products and devices, as well as toxicological chemicals of interest and impurities.

• Determination of permissible daily exposure (PDE) / Acceptable daily intake (ADI) values

• Occupational Health Categorizations (OHC)

• SDS writing - Toxicology Section

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We provide clients with DMPK and 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

• Written Safety Pharmacology/Pharmacokinetics/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) 

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.

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