Principles and Practice of Pharmaceutical Medicine

6.5 Initial nonclinical

considerations

Formulation Aspects

It is desirable to carry out pivotal nonclinical
studies using the proposed clinical route of
administration and with a formulation that best
approximates that anticipated for initial clinical
usage (this is unlikely to be the exact formulation
that is eventually marketed). Factors such as
method of synthesis, excipients and appropriate
vehicles usually evolve from bench-scale drug
supplies and simple vehicles to more sophisticated
pharmaceutical formulations (‘Gallenicals’) as the
program proceeds.
Scale-up of manufacturing processes can result
in bulk drug with different impurity profiles. As
adverse effects may be due to parent drug, meta-
bolites or impurities, this factor must be carefully
considered when preparing preclinical plans to
support human exposure. Furthermore, tablets or
capsules cannot be given to most animal species,
and the nonclinical studies are therefore carried out
using dosing solutions or suspensions. The type of
formulation can affect the pharmacokinetics of the
drug, thus altering the toxicological profile, mak-
ing comparison of animal and human pharmacoki-
netics, in the context of the formulations used, into
a critical element in the evaluation of human safety.

Impurities/stability

Early-stage small-scale synthesis methods will
often create a different profile of impurities or
degradants than drug supplies produced by
scaled-up processes. Every batch of drug used in
nonclinical studies must have a certificate of ana-
lysis that clearly specifies the purity levels and the
quantities of impurities (which may include resi-
dual solvents, unreacted starting materials or
degradants). The impurities must be reviewed in
terms of the potential contribution that they can
make to toxic effects that may be manifested in the
nonclinical studies. There are ICH guidelines that
pertain to impurities and to the extent to which
additional toxicity studies need to be performed

with impurities (Federal Register, 4 January 1996; 19

March 1996). In general, a useful tactic is to conduct

toxicological studies with samples of material that

are intentionally less pure than those to which human

beings will be exposed, so that ceilings for exposure

to both parent molecule and the impurities and may

be simultaneously as high as possible.

Of equal importance is the stability of the drug in

the nonclinical formulation. This can determine

whether the nonclinical formulations must be pre-

pared daily or weekly. If drugs are to be given

orally, it is obvious that they must be resistant to

degradation of gastric acids and must be stable in

the formulation itself (water, carboxymethylcellu-

lose suspensions, etc.). As will be discussed in

more detail later, this requires the availability

of an analytical method at the earliest stages of

development.

Drug requirements

The amount of bulk drug that is typically required

to carry out the nonclinical studies may be a big

surprise in comparison to that needed for initial

clinical studies. Although many biologically

derived drugs may require relatively small quanti-

ties, due to the potency of the material or the

limited number of nonclinical studies that are pos-

sible (see below), a typical program needed for

‘first time in man’drugs that are relatively nontoxic

may require 2–3 kg of active drug. For many com-

panies, this can be difficult from either a manufac-

turing standpoint (small quantities synthesized

prior to scale-up) or cost.

Analytical methods for dose

and plasma determinations

GLP regulations require confirmation of the

potency of all formulations used in nonclinical

studies. Furthermore, current ICH guidelines also

require toxicokinetic data (i.e. animal pharmaco-

kinetics determined at one or more time points

during a nonclinical toxicology study). Both the

potency and the toxicokinetic assays require an

analytical method to determine the parent drug

6.5 INITIAL NONCLINICAL CONSIDERATIONS 65