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New Active Ingredient Portfolio

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Screening	Optimisation	Pre-Trials Development	Development	Registration
100,000s Candidates	10 Compound Classes	4 Compounds	1 Compound	1 Compound
Ongoing	2 Years	2 Years	3 Years	2 Years
$4.5M	$4.3M	$17.2M	$36.5M	$4.7M
Screening Efficacy Mode of action	Synthesis Efficacy Early Tox	Tox ecotox testing Manufacturing feasibility	Tox Confirmation Formulation Manufacturing development	WHOPES Regulatory Country regs

Whilst the major agrochemical companies follow very similar processes in their AI discovery and development pipelines, the phasing and nomenclature of the pipelines has not reached the level of standardisation that is commonly recognised for drug development phases. In collaboration with our industry partners IVCC has developed a portfolio model to manage the range of projects undertaken by different institutions and companies.

Multiple screening or molecular design projects create optimisation candidates that feed the input to the optimisation phase, after which the best candidates are taken forward in competition with one another. At pre-trials development the portfolio target is to have a choice between four successful candidates per planned development project. Only one candidate is taken forward into development, while the others are held in reserve to replace the lead candidate in the event of failure in the field trials and registration phases. However, the fact that efficacy and toxicity can be tested very early in the insecticide development cycle means that late failures are relatively rare in the development phases, usually only as a result of adverse findings in chronic toxicity studies.

In some cases a partner company may work on several independent routes to creation of lead candidates and these projects will be managed as a miniportfolio in which IVCC and company jointly prioritise the candidates. This approach has been shown by other PDPs to create flexibility and stability within the developing company and provides a commercialisation route to candidates developed by academic institutions. The miniportfolio itself may produce one or several development projects.

The number for projects required at each stage is determined by a calculation of the cumulative probability of success for each project or miniportfolio.

Data Mining and Screening
The Screening phase consists of searching the chemical libraries of chemical companies for insecticidal hits focussing on any data that shows activity against indicative insects. e.g. adult Diptera data, Aedes larval data etc. Compounds showing interesting activity are screened for activity against adult mosquitoes. Mode of action data and evidence for the absence of cross resistance is assessed here.

In addition molecular design and synthesis contributes an alternative approach to innovation at this stage.

This phase takes approximately one year and starts from a library of up to two million chemicals with the expected output of a portfolio of up to ten lead chemical classes.

Optimisation
Optimisation involves intensive analogue synthesis and testing focussed on selected series within the lead areas of chemistry to identify lead molecules in terms of key intrinsic features (entomological activity, safety and environmental impact, production, patentability), and indications of response to improvement via enabling technologies (formulation, application).

This phase can take up to two years and involves reduction of the approximately ten lead chemical classes to four pre-trials development candidates.

Pre-Trials Development
Pre-trials development is analogous to the preclinical phase of drug development and involves all activities designed to determine the final development candidate. In-market field trials, initial chronic toxicology, environmental fate and impact, formulation selection, process development studies and market positioning take place. A small number of candidates are involved.

The aim is to define the compound with the highest probability of meeting the Target Product Profile, and of achieving registration and commercial viability. Many of the studies if successful can contribute to the development study package. This phase takes two years and selects the preferred development candidate.

Trials Development and Registration
This is the full development and registration phase. It involves studies of the chosen molecule/formulations, in previously defined use patterns, including in-country in-house and official trials of the candidate in its preferred formulations, applications, mixtures and sectors, formulation and pack optimisation, development of a full regulatory toxicology and eco-toxicology package, full process development and manufacturing establishment. The aim is to conduct all ability to make and product performance studies and establish production and launch capability of the final formulated products. This is the longest phase, taking between three and five  years and is only undertaken on one candidate.

Registration including WHOPES and Local Registration
This is the registration submission and final vector control product testing and registration phase. The preferred final formulations go through the WHOPES process. After WHOPES recommendation is achieved the product goes through the local registration process. Formulation efficacy testing, toxicology testing and registration occur during this phase.

Phase five  can take up to three years; the timing is determined by the length of the regulatory process and is undertaken on formulations of the new active ingredient.