Pharmaceutical Product Toxicological Support

In recent years we have experienced a considerable increase in demand for our consultancy services from those operating in the pharmaceutical sector. This includes assistance with the toxicological assessment of the actives (and their metabolites), excipients, impurities, contaminants, degradants and extractables/leachables (E&Ls).

We consider ourselves the regulatory professional’s ideal partner when the knowledge required goes beyond the specifics of a particular regulation or guideline into the more nuanced territory concerned with risk assessment.

Active Pharmaceutical Ingredients (APIs)

With the guidance of expert regulatory professionals, bibra has assisted companies in summarising the available toxicity/ADME/pharmacology data on their APIs and in preparing (non‑clinical) overviews. In addition to a number of “traditional” pharmaceutical APIs, bibra has generated supporting toxicity/ADME/pharmacology reports for inclusion in marketing authorisation applications submitted to the UK MHRA for breath-operated nicotine inhalers and, more recently, an e-cigarette submission.

 

Examples of specific API assessments

  • Actives – hazard assessments of active substances e.g. for due diligence purposes and marketing authorisation applications (e.g. the UK MHRA and US FDA). Health risk assessment of proposed modifications to the active molecule e.g. changes in counter ions. Review of the available pharmacological and pharmacokinetic data.
  • Occupational controls – determinations of worker exposure controls (e.g. OELs or banding) based on toxicological studies or clinical data, or (where data are lacking) a “read-across” approach from structurally-related compounds.
  • API cross contamination – setting health-based exposure limits for use in risk identification when various APIs are manufactured within the same facilities. Limits determined in line with the EMA’s guidance document EMA/CHMP/CVMP/SWP/169430/2012.
  • Expert role – acting as (Non-Clinical) Expert fulfilling responsibilities relating to assessment of non-clinical toxicity data for submissions, in line with Annex I Part I 1.4 of Directive 2003/63/EC.
  • Elemental impurities – provision of supporting information for the risk assessment / risk management of metal impurities arising in drug products from a variety of sources, in line with the ICH Q3D Guideline for Elemental Impurities (EMA, 2016; ICH, 2014).
  • Occupational controls – determinations of worker exposure controls (e.g. OELs or banding) based on toxicity data or (where data are lacking) a “read-across” approach from structurally-related compounds.
  • Expert role – acting as Expert (Non-Clinical) fulfilling responsibilities relating to assessment of non-clinical toxicity data for submissions, in line with Annex I Part I 1.4 of Directive 2003/63/EC.

 

Non-actives (e.g. excipients, impurities, and E&Ls)

Our advice is regularly sought on the toxicological risks posed by non-active substances present in pharmaceuticals.

Bibra scientists are experts in identifying existing relevant information on toxicity and ADME. While toxicity data may be plentiful for excipients and certain extractables/leachables, they are often insufficient or absent for impurities/degradants, making our expertise invaluable in the application of (Quantitative) Structure Activity Relationship ((Q)SAR) considerations and the Threshold of Toxicological Concern (TTC) concepts.

Pharmaceuticals are administered by various routes including intravenous injection, by mouth, by inhalation or dermally. We are experienced in the application of available data (often generated by the oral route) to other routes of administration. Genotoxic or potentially genotoxic impurities and contaminants can pose a particular challenge to risk assessment, and we can apply EMA/ICH guidance (including M7) and make best use of the TTC concept. In addition, our risk assessors are familiar with the guidelines and draft guidelines from the US Product Quality Research Institute (PQRI) on extractables and leachables in drug products.

 

Examples of specific (non-API) assessments

  • Excipients – hazard and health risk assessment of substances included in pharmaceutical products to perform a specific technological function (e.g. propellants).
  • Manufacturing impurities/degradants – health risk assessment of substances that arise during manufacture and/or storage; these are often structurally related to the active molecule. Development of proposals for modified Qualification Thresholds. Some impurities may be significant mammalian metabolites (and thus, under EMA guidance, be qualified). Determination of mutagenicity status and ICH M7 class based on genotoxicity data (including read-across), SAR analysis (using Leadscope, Toxtree, Toolbox and Derek-Nexus) and expert review. Use of ICH M7 guidance to assess the potential cancer risk associated with intermittent and/or less‑than-lifetime exposure to DNA-reactive mutagens.
  • Extractables/leachables – health risk assessment of substances contaminating pharmaceutical products as a result of leaching from processing equipment or containers/closures during production, storage or use.

 

Read more about our work on “Extractables and Leachables in the Pharmaceutical sector

 

Recent work in this field

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