Pharmaceutical Manufacturing Handbook: Production and

are both challenges and opportunities. They are challenges because “ no single
correct method exists to solve signifi cant problems of elegance ” ; they are opportunities
because “ they enable a pharmacist to prepare a product more easily
accepted by the patient ” [4] . Although the most important characteristic of a
dosage form is effi cacy, there are other characteristics that remain important subjects
for the manufacturing of liquid dosage forms such as safety as well as chemical,
physical, and microbiological stabilities. From a pharmaceutical point of view,
stability problems are the main causes of safety complaints. Despite its signifi cance,
some companies decide to outsource stability services [5] . To solve or minimize
stability problems in drug products, it is necessary to analyze and enhance the
development of critical control points in each operation of the full manufacturing
process as well as expected variances and tolerance limits.
Except some aqueous acids, water in aqueous solutions is an excellent media for
microbiological growth, such as molds, yeast, and bacteria. Typical microorganisms
affecting drug microbiological stability are Pseudomonas, Escherichia coli Salmo-
nella , and Staphylococcus
INTRODUCTION 315
[1] . Defi cient methods or an insuffi cient preservative
system may be the principal causes of microbiological contamination in the pharmaceutical
industry of liquid manufacturing [6] .
Chemical instability reactions appear with or without microbiological contribution
through reactions such as hydrolysis, oxidation, isomerization, and epimerization.
Interactions between ingredients and ingredients with container closure
materials are established as the principal causes of these reactions [1] , for instance,
the hydrolysis of cefotaxime sodium, the oxidation of vitamin C, the isomerization
of epinephrine, and the epimerization of tetracycline [7] .
In most cases, physical instabilities are consequences of previous chemical instabilities.
Physical instabilities can arise principally from changes in uniformity of
suspensions or emulsions, diffi culties related to dissolution of ingredients, and
volume changes [6] . For instance, some cases where physical stability has been
affected are cloudiness, fl occulence, fi lm formation, separation of phases, precipitation,
crystal formation, droplets of fog forming on the inside of container, and swelling
of the container [8] .
Although commercial oral solution and emulsion dosage forms rarely present
bioequivalence issues, some bioequivalence problems have been reported for oral
suspensions such as phenytoin [9] . The possibility of microbiological contamination
and physicochemical instabilities during the manufacturing process also needs
to be carefully considered. To approach the stability problems of liquid dosage
forms, in this chapter, the main critical aspects during the manufacturing process
are based on FDA inspection. From physical plant systems to batching management
and packing, the potential sources of microbiological, chemical, and physical instabilities
will be analyzed using defi nitions, case - by - case explanations, and practical
examples.
Final product stability, which determines the therapeutic activity and uniformity
among other characteristics of the fi nal product, refl ects the dynamic of the production
process. Conceptualization of stability issues is important to determine the
changes to enhance the design space as well as protocols of manufacturing and
quality control [3] . An information technology (IT) solution like Enterprice Resource
Planning (ERP) may support the pharmaceutical industry ’ s current challenges of
organization [10] .