Pharmaceutical Manufacturing Handbook: Production and

BACKGROUND 141
Pisano [3] discusses the management of process development projects in the
pharmaceutical industry. Case studies are used to illustrate the effect of resource
allocation decisions at different stages of a project. While there has been a focus on
product development in the pharmaceutical industry, clearly process development
plays an important role in getting a product to market and lowering the long - term
product manufacturing costs.
3.1.2.2 Batch Reactors
Batch processes present challenging control problems due to the time - varying
nature of operation. Chylla and Haase [4] present a detailed example of a batch
reactor problem in the polymer products industry. This reactor has an overall heat
transfer coeffi cient that decreases from batch to batch due to fouling of the heat
transfer surface inside the reactor. Bonvin [5] discusses a number of important
topics in batch processing, including safety, product quality, and scale - up. He notes
that the frequent repetition of batch runs enables the results from previous runs to
be used to optimize the operation of subsequent ones.
LeLann et al. [6] discuss tendency modeling (using approximate stoichiometric
and kinetic models for a reaction) and the use of model predictive control (linear
and nonlinear) in batch reactor operation. Studies of a hybrid heating – cooling
system on a 16 - L pilot plant are presented.
Various aspects of the effect of process scale - up on the safety of batch reactors
have been discussed by Gygax [7] , who presents methods to assess thermal runaway.
Shukla and Pushpavanam [8] present parametric sensitivy and safety results for
three exothermic systems modeled using pseudohomogenous rate expressions from
the literature. Caygill et al. [9] identify the common factors that cause a reduction
in performance on scale - up. They present results of a survey of pharmaceutical and
fi ne chemicals companies indicating that problems with mixing and heat transfer
are commonly experienced with large - scale reactors.
3.1.2.3
Reaction Calorimetry
The microanalytical methods of differential thermal analysis, differential scanning
calorimetry, accelerating rate calorimetry, and thermomechanical analysis provide
important information about chemical kinetics and thermodynamics but do not
provide information about large - scale effects. Although a number of techniques are
available for kinetics and heat - of - reaction analysis, a major advantage to heat fl ow
calorimetry is that it better simulates the effects of real process conditions, such as
degree of mixing or heat transfer coeffi cients.
Regenass [10] reviews a number of uses for heat fl ow calorimetry, particularly
process development. The hydrolysis of acetic anhydride and the isomerization of
trimethyl phosphite are used to illustrate how the technique can be used for process
development. Kaarlsen and Villadsen [11, 12] provide reviews of isothermal reaction
calorimeters that have a sample volume of at least 0.1 L and are used to measure
the rate of evolution of heat at a constant reaction temperature. Bourne et al. [13]
show that the plant - scale heat transfer coeffi cient can be estimated rapidly and
accurately from a few runs in a heat fl ow calorimeter.
Landau et al. [14] use a heat fl ow calorimeter to investigate feasible pilot plant
operating conditions for the production of a pharmaceutical intermediate. They