Drug synthesis Acute and subacute toxicology Preclinical trials Phase I trials
Submit MAA report Phase II trials
Regulatory authority review APPROVAL
Analysis of trial data Phase III trialsFigure 11.1 An example of the activities that are likely to form the critical path for the
development of a drug. MAA is the market authorization application that a company has to
submit in Britain in order to produce and market a drugbecome registered by the appropriate government body. It does not include all
the activities that are necessary to to develop and evaluate a drug. However,
monitoring the critical path does provide a way of making certain the project
remains on schedule.
11.2 Chemical development
The reactions used by research workers frequently use expensive reagents and
only produce sufficient quantities of the drug for very limited biological testing.
In addition, the research routes often involve techniques, such as chromatog-
raphy, that cannot be adapted to large scale production methods. Consequently,
thefirststep in the chemical synthesis development is to find safe, cost effective
alternatives. These alternative reactions should start from cheap readily avail-
able materials, consist of more economical reactions that have high yields and
be capable of being safely carried out on a large laboratory or manufacturing
scale (see section 11.2.4). They should yield sufficient quantities of the lead in an
acceptible purity for the initial activity and toxicology tests. Initially several
large scale synthetic routes will be investigated in order to determine the opti-
mum route. Convergent routes are usually preferred over linear syntheses as
they give better overall yields (see section 10.2). However, in the early stages of
development, speed of production of sufficient amounts of the lead for compre-
hensive testing is often more important than devising a chemically efficient
synthesis. This is because the results of these initial tests will enable the company
managers to decide whether the compound is worth further development.
The progression of the drug through the development process will lead to an
increased demand for larger quantities of the drug. This demand is normally met
by conversion of the most promising laboratory synthesis to pilot plant scale.
Conversion of a synthesis to pilot plant scale, which is effectively a mini-
manufacturing process, may require changes in the synthesis to allow for the
224 DRUG DEVELOPMENT AND PRODUCTION