We provide professional toxicology consultancy services
Paracelsis operates a toxicology consultancy service primarily serving the Pharmaceutical Industry. However, these services are widely applicable across other Industries such as those involving Chemicals, Cosmetics, Food, Medical devices and Veterinary products. Services include toxicological assessment of active pharmaceutical ingredients (APIs) and/or their metabolites as well as excipients, impurities, degradants and extractables/leachables. Toxicological (hazard and health risk) assessment of metabolites, excipients, impurities, degradants and extractables/leachables is often based on published literature but where reliable information is lacking, Paracelsis can undertake (Quantitative) Structure Activity Relationship ((Q(SAR) assessments to plug any knowledge gaps.
See below for examples of toxicology consultancy services that we offer, or get in touch with us on +44(0)115 7720051 to get started.
APIs: CTAs and MAAs
Paracelsis can provide preclinical (nonclinical) expertise and assist companies, usually in conjunction with their expert regulatory professional, with the preparation of documents to support Clinical Trials Applications (CTAs) and Marketing Authorisation Applications (MAAs). This may involve assessment and summarisation of available pharmacology, ADME and toxicology data on the APIs and preparation of nonclinical overviews as appropriate. A full or partial review of the available literature may also be required to provide necessary background data, help put the data into context, plug knowledge gaps, etc. Paracelsis has experience with a number of conventional (small molecule) APIs as well as peptides, proteins and vaccine antigens. In addition, it can assist with the preparation of other documents such as Investigator’s Brochures and Product Development Plans.
APIs: Nonclinical (preclinical) development plan
Paracelsis can provide advice and recommendations on the nonclinical (preclinical) development plan for pharmaceutical products and supply the necessary documentation for inclusion in a Product Development Plan, Scientific Briefing Document or similar. Furthermore, it can help the customer to ratify the development plan with appropriate regulatory authorities, thereby ‘de-risking’ the development process.
APIs: Health-Based Exposure Limits
When various APIs, such as unlicensed medicinal (‘special’) products or products for use in clinical trials are manufactured within the same facility, there is potential for cross-contamination which may pose a risk to the patient or recipient. In this situation, the setting of health-based exposure limits (HBELs) is used for risk identification and the limits are determined in line with the EMA’s guidance document EMA/CHMP/CVMP/SWP/169430/2012. This is achieved through the derivation of a safe threshold, for example the permitted daily exposure (PDE) representing a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. Paracelsis is experienced in conducting PDE assessments to support its customers manufacturing operations.
The term ‘Excipient’ generally refers to a non-active substance included in a pharmaceutical product to fulfil a specific technological function (e.g. solubiliser, stabiliser, preservative, viscosity enhancer). Paracelsis has experience in supporting the use of conventional excipients as well as novel polymeric excipients such as chitosan and LM pectin. Such support will usually entail hazard and health risk assessment of each excipient with reference to pharmaceutical precedence and published literature. In the case of a novel excipient, summary of available ADME and toxicology data is also crucial to support its inclusion in a pharmaceutical product. In the most recent case, Paracelsis conducted a hazard and risk assessment to support the proposed use of a new excipient in a reformulated medicinal product (due to growing concerns about the safety of an excipient in the licensed medicinal product).
Impurities, degradants and contaminants
As a toxicology consultancy, we are experienced in conducting hazard and health risk assessments on impurities and degradants in APIs and finished pharmaceutical products. Such experience included an evaluation of two impurities/degradants in a finished product which only became evident when the customer conducted QC testing according to revised pharmacopoeial requirements. In another case, the customer proposed to change the supplier of API used in the manufacture of its finished product. The API was found to contain impurities such that the level of total impurities was estimated to be above the finished product specification limit and given that these impurities had historically not been seen, Paracelsis undertook a risk assessment which successfully supported its customers application for a Batch Specific Variation (BSV).
Extractables and Leachables
Pharmaceutical products are in contact with processing, packaging (e.g. vials, bottles, caps, stoppers, seals etc.) and administration (e.g. needles, syringes, catheter tubing, etc.) components during manufacture and use and throughout a products life-cycle, substances can migrate or leach from the various components into the product. This can comprome the quality, efficacy and/or safety of the product. Extractables and leachables studies play a critical role in quality control and monitoring of pharmaceutical products. Extractables are compounds that can be extracted from the various components usually using established solvents and/or exaggerated incubation conditions. Extractables studies are conducted to identify substances that the patient could potentially be exposed to and those that could present a risk and require further confirmation and quantification in a leachables study. The term leachable refers to the substances that leach into the drug product under normal conditions of production, storage and use and thus, leachable studies are performed to identify substances that patients are exposed to. Our toxicology consultancy team are experienced in conducting hazard and health risk assessments which to date have usually been based on leachables data. An example includes an assessment of four leachables in a cytotoxic drug product when used in combination with a Drug Reconstitution and Transfer System. In another assessment, a leachable associated with a container/closure system, in two inhalation products used in clinical trials was conducted.