Biomedical Engineering Reference
In-Depth Information
Process scale producti
on
(100g - Kg scale)
Lab scale production
(mg scale)
Pilot scale production
(gram scale)
Pre-clinical/
clinical trials
Commercial
product
R & D, initial product
characterisation
Figure 4.9
Scale-up of proposed biopharmaceutical production process to generate clinical trial material,
and eventually commercial product. No substantive changes should be introduced to the production protocol
during scale-up
patients for periods of time longer than the phase III clinical trials. The discovery of more
long-term unexpected side effects can result in subsequent withdrawal of the product from the
market.
Both preclinical and clinical trials are underpinned by a necessity to produce suffi cient quan-
tities of the prospective drug for its evaluation. Depending on the biopharmaceutical product,
this could require from several hundred grams to over a kilogram of active ingredient. Typical
production protocols for biopharmaceutical products are outlined in detail in Chapter 6. It is
important that a suitable production process be designed prior to commencement of preclinical
trials, that the process is amenable to scaling up and that, as far as is practicable, it is optimized
(Figure 4.9). The material used for preclinical and clinical trials should be produced using the
same process by which it is intended to undertake fi nal-scale commercial manufacture. Exten-
sive early development work is thus essential. Any signifi cant deviation from the production
protocol used to generate the trial material could invalidate all the clinical trial results with
respect to the proposed commercialized product. (Changes in the production process could
potentially change the fi nal product characteristics, both for the active ingredient and the con-
taminant profi le.)
4.13.4 Clinical trial design
Proper and comprehensive planning of a clinical trial is essential to the successful development
of any drug. The fi rst issue to be considered when developing a trial protocol is to defi ne precisely
what questions the trial results should be capable of answering. As discussed previously, the terms
safety and effi cacy are diffi cult to defi ne in a therapeutic context. An acceptable meaning of these
concepts, however, should be committed to paper prior to planning of the trial.
4.13.5 Trial size design and study population
A clinical trial must obviously have a control group, against which the test (intervention) group
can be compared. The control group may receive: (a) no intervention at all; (b) a placebo (i.e. a
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