As more complex drug products and delivery systems move through the development pipeline, FDA is revising its application
review system to better assess drug quality and manufacturing issues. Nasr's office now includes a manufacturing science branch
staffed by pharmaceutical scientists and engineers with expertise in manufacturing and new dosage forms. Under a new process
for assessing chemistry, Manufacturing, and controls (CMC) data in new drug applications (NDAs), an ONDQA reviewer completes
an initial quality assessment of a new application to identify challenging quality or CMC issues. Such products, including
those with innovative delivery systems, are eligible for review by an interdisciplinary team, an approach that Nasr says is
now being used for approximately 25% of NDAs. The application for the new inhaled insulin product, for example, involved a
team review with expertise in manufacturing, biotech products, and inhaled delivery systems.
For his staff to conduct a more informed application review, Nasr points out that manufacturers must provide more extensive
information about drug development and product design than in the past. "We are looking for more information on design and
manufacturing," he explains. Documentation about how manufacturing controls can ensure product quality may lead to regulatory
One advantage of some new drug formulations is that they are more temperature stable and do not need to meet rigorous cold
chain storage and distribution requirements. Abbott, for example, recently won FDA approval for a new heat-resistant formulation
of its HIV drug "Kaletra," which offers major advantages to health agencies and patients around the world. Even though it
took the company years of research to develop the more stable product, Abbott now faces challenges in distributing the drug
on a low-cost basis to third-world nations in which AIDS is rampant and temperature stability is a major plus (see sidebar
"Product improvement wins little praise").
Nearly 10% of drugs and biologics are temperature sensitive, and the development of more biologicals and vaccines is increasing
the volume of products requiring controlled temperature-storage conditions. This trend is prompting a reexamination of the
diverse regulatory policies that govern cold-chain distribution around the world. Manufacturers find that FDA and other GMP
inspectors are issuing citations for inadequate storage and transportation management practices, despite generally vague requirements.
Health Canada took the lead this past October by posting new guidelines to ensure proper handling and transport of temperature-sensitive
products. The US Pharmacopeia updated its General Chapter ‹1079› about good storage and shipping practices to address the
need to prevent temperature excursions. And, the PDA Pharmaceutical Cold Chain Discussion Group prepared a technical report
(No. 39) about "Maintaining the Quality of Temperature-Sensitive Medicinal Products Through the Transportation Environment."
It proposes standards and validating processes to ensure the quality of products requiring thermally controlled storage and
FDA relies primarily on GMPs and stability guidances to cover distribution and storage practices and monitoring, but the literature
lacks specific requirements for ensuring temperature control. The need to ensure appropriate storage practices and broader
government concerns about protecting the nation against bioterrorism and drug diversion have generated a high level of awareness
about these issues at CDER's Division of Manufacturing and Product Quality. The office is assessing the need for additional
guidance about cold-chain management issues, commented DMPQ Acting Director Nicholas Buhay at a PDA conference about cold
chain management in March. Buhay says this topic has become a formal project to review current requirements and weigh the
need for additional guidance. FDA does not want to establish new rules for storage and transportation, says Buhay, "unless
there is clear value in doing so." One concern is that new policies for documenting distribution or revising product labeling
on appropriate storage conditions could generate a wave of manufacturing supplements. The agency currently prefers to set
overall requirements for ensuring drug quality, without compelling manufacturers to generate massive amounts of new data for
FDA to review.
"The aim of all these initiatives is to prevent drug manufacturing from creating a bottleneck in getting medicines to patients,"
commented Gottlieb in a recent speech about good manufacturing practices. Gottlieb noted that with more novel drug delivery
systems and more complex drugs, it is even more important to address key quality issues and to establish meaningful product
specifications. This strategy means moving away from conventional batch processing systems and adopting modern process development
and control technologies, as encouraged by FDA's initiative to modernize GMPs for the 21st Century. To continue its progress
in this area, FDA plans to issue a final guidance about quality systems this summer and a final report summarizing its risk
model for prioritizing sites for manufacturing inspections.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org