Pharmaceutical Manufacturing Handbook: Production and

APPROACHES 319
To apply QbD as a systemic approach, the company starts by understanding,
step by step, the space design, the design of the dosage form, the manufacturing
process, and the critical process parameters to be controlled in order to reach the
new building block which is the expectation of variances within those critical
process parameters that can be accepted. This approach allows the establishment
of priorities and fl exible boundaries in the process [3] . Infl exible specifi cations
allow uncontrolled small variances that can follow the butterfl y effect of the theory
of chaos by producing unpredictable large variations in the long - term behavior of
the product shelf - life [18, 19] . In contrast, fl exibility, with knowledge of potential
variances, reduces changes in the approved spaces and manufacturing protocols
[3, 17] .
According to the FDA [6] , critical parameters during the manufacturing process
of nonparenteral liquid dosage forms may appear in the design of physical plant
systems, equipment, protocols of usage and maintenance, raw materials, compounding,
microbiological quality control, uniformity of suspensions and emulsions, and
fi lling and packing [6] .
Process isolation and installation of an appropriate air fi ltration system in the
physical plant may reduce product exposition to chemical and microbiological
contaminations. In addition, the use of a suitable dust removal system as well as
a heating, ventilation, and air conditioning system (HVACS) may help to repress
product chemical instabilities [6] .
The equipment of sanitary design, including transfer lines, as well as appropriate
cleaning and sanitization protocols may reduce chemical and microbiological contaminations
in the fi nal product. Chemical instabilities may be reduced by weighting
the right amount of liquids instead of using a volumetric measurement, avoiding the
common use of connections between processes, and using appropriate batching
equipment [6] .
Particle sizes of raw materials are critical to control dissolution in solutions as
well as uniformity in suspensions and emulsions. Temperature control during compounding
is important since heat helps to support mixing and/or fi lling operations,
but, in contrast, high - energy mixers may produce adverse levels of heat that affect
product stability. Too much heat may cause chemical and physical instabilities such
as change of particle size or crystallization of drugs in suspensions, dissolution and
potency loss of drugs in suspensions, oxidation of components, and activation of
microbiological growth after degradation of compounds as well as precipitation of
dissolved compounds in solution [20] . In addition, uniformity of suspensions depends
on viscosity and segregation factors while solubility, particle size, and crystalline
form determine uniformity of emulsions. Application of pharmaceutical GMP for
product processes and storage assures microbiological quality. A defi cient deionizer
water - monitoring program and product preservative system facilitate microbial contamination.
Filling uniformity is indispensable for potency uniformity of unit - dose
products and depends on the mixing operation. Calibration of provided measuring
devices and the use of clean containers will allow administering the right amount
of the expected components in the liquid dosage form [6] .
Principal product specifi cations are microbial limits and testing methods, particle
size, viscosity, pH, and dissolution of components. Process validation requires control
of critical parameters observed during compounding and scale - up. Product stability
examination is based on chemical degradation of the active components and interac-