(ALEX CAO, RAY MASSEY/GETTY IMAGES. ILLUSTRATION: M.MCEVOY)
In 1985, when Hubertus Folttmann, now head of global marketing excipients at BASF (Limbergerhof, Germany) started his career
in the pharmaceutical industry, his company manufactured a drug product in three strengths, including an 80-mg tablet and
a 120-mg tablet. To manufacture the 80-mg tablet, formulators simply replaced 40 mg of active ingredient in the 120 mg tablet
with filler. "At that time, the world of pharma was okay," he says, "Health costs were not a topic, and manufacturing costs
in the pharmaceutical industry were of minor importance."
Today, concerns about manufacturing costs and process times are at the forefront of fiscal budgets, and improving formulations
is on every company's agenda. "Nowadays, smaller tablets are the advantage, and if you need less active ingredient, you are
happy because then you need less excipients to formulate it." Not only do patients want to swallow smaller tablets, but if
the capacity of process equipment determines the batch size, then there are more smaller tablets in a batch, which means less
batch documentation, smaller packaging, less volume for transportation, and so forth. "Nowadays, these issues count," says
Folttmann. "Excipients that perform their functions at lower concentration so that less material needs to be handled have
a good chance of success in the marketplace."
Functionality and QbD
The US Food and Drug Administration's quality-by-design (QbD) initiative has changed the way excipient suppliers develop,
characterize, and manufacture their materials. "We have seen some benefits of implementing QbD into the pharmaceutical manufacturing
process, including a reduction in approval delays, a more streamlined approval process and an easier course for implementing
postapproval changes," says Nandu Deorkar, director of research and development, laboratory and pharmaceutical products at
Mallinckrodt Baker (Phillipsburg, NJ). "However, the concept of QbD can present implementation opportunities and challenges
to both raw-material (excipient) suppliers and pharmaceutical manufacturers. As a part of the QbD system, raw-material characteristics
and their variability on the process and product quality or performance should be studied and documented. As such, raw materials
must be well-characterized and developed using QbD principles to reduce variability"
(IMAGES ARE COURTESY OF BASF.)
QbD principles also can facilitate the evaluation of excipient functionality performance and its correlation with physical
and chemical properties. Better understanding of excipient properties related to intended uses can help design better dosage
forms. "That is where we are getting involved now," says Dave Schoneker, director of global regulatory affairs at Colorcon
(West Point, PA), "to build quality into the design from the beginning in terms of what customers want to achieve to make
it a better product in the marketplace. In the past there has been a limited number of people within some pharmaceutical companies
who could to do that." The company has built a computer-aided design program to help pharmaceutical clients virtually design
their dosage forms, including size, shape, and color and produce physical models before producing placebo-type coated tablets.
The modeling tool allows manufacturers to get a firm grasp of the tablet designs they want to take forward in development.
Engineering and coprocessing are additional sophisticated tools that can help excipient suppliers enhance their materials
to the high-quality level demanded by drug makers. "QbD initiatives require well-characterized and highly functional excipients
to enable their implementation by drug formulators," says Deorkar. "Excipient technology development is centered on particle
engineering and new chemical entities." For example, Mallinckrodt Baker recently developed "PanExcea" performance excipients,
spherical homogeneous particles for immediate-release oral dosage forms and orally disintegrating tablet forms, using a proprietary
particle engineering technology. This technology enables the precise tailoring of physical attributes such as particle size,
distribution, porosity, and density in homogeneous particles containing multiple components, without changing the chemistry.
"This reduces unfavorable attributes, while enhancing the functional characteristics of individual components through synergistic
effects," says Deorkar.