Studying standards
CDER's Office of Testing and Research (OTR) has launched research projects about establishing better ways to ensure the quality
and safety of new dosage forms. One project is examining factors that might reduce patch adhesion to the skin and thus result
in low drug permeation and poor efficacy, according to OTR Acting Director Cindy Buhse. Her staff is developing standardized
tests for evaluating how heat, occlusion, or compromised skin may affect the adhesive qualities of transdermal drug delivery
systems. Another research group is developing novel in vitro testing methods using artificial membranes and cadaver skin to establish in vitro–in vivo correlations. The aim is to provide faster and less expensive alternatives than in vivo testing for evaluating drug release through patches under various conditions.
OTR also seeks to establish standardized methods for ensuring the quality of inhalation drugs to support the development of
new vaccines, migraine medications, and insulin products using this delivery approach. Researchers are evaluating how drug
parameters and formulation characteristics affect spray impaction force, particle size and distribution, spray pattern, and
plume geometry. Raman microscopic imaging is being evaluated as a possible tool for determining the chemical identity and
particle-size distribution for nasal and pulmonary inhalable formulations. FDA wants to understand the limitations and capabilities
of these new techniques, Buhse explains, to develop guidances and to evaluate new applications properly.
Supporting generics
FDA's analysis is likely to facilitate the approval of generic versions of new dosage forms. FDA recently approved the first
generic allergy nasal spray, Roxane Labs's version of GlaxoSmithKline's "Flonase" (fluticasone propionate). The review of
this application by FDA's Office of Generic Drugs (OGD) was scientifically challenging, commented OGD Director Gary Buehler.
As the first generic nasal-spray suspension product, it involved the review of data about spray and absorption patterns plus
bioequivalent studies with clinical endpoints that compared various clinical effects on seasonal rhinitis.
OGD would like to see additional efforts by scientists to develop standards for these products. In a speech to the Generic
Pharmaceutical Association in February, FDA Deputy Commissioner Scott Gottlieb noted that most topical creams are not substantially
absorbed into the body, making it difficult to evaluate efficacy with standard in vitro analysis and bioequivalence testing. And liposomes, which can target a therapy to specific tissues, require new methods for
bioequivalence testing.
Spurring innovation
Gottlieb said that FDA's Critical Path Initiative outlines opportunities for industry to collaborate on developing more modern
scientific tools for generic drug development, including physiological- based pharmacokinetic models, bioequivalence waivers
on the basis of improved in vitro tests, and pharmacodynamic measures of safety. These tools are just some of the items on FDA's long-awaited Critical Path
Opportunities List, which recognizes that problems in the characterization, testing, and quality management of medical products
can delay clinical trials and even completely block drug development.
One particular opportunity is to collaborate on developing new testing instruments for manufacturing patches, liposomes, topicals,
and nasal and pulmonary inhalers that can better target the delivery of difficult-to-formulate drugs. FDA notes a need for
new methods to assess the quality of these products, pointing out that extracting a drug from a patch many alter efficacy
or safety, and that spray density is key to assessing aerosol quality. New analytical techniques also are needed to assess
the quantities or forms of drugs found in some drug–device combinations products.
Additional Critical Path opportunities for improving drug manufacturing involve developing:
- new standards for the use of rapid spectroscopic analytical methods;
- research about the physical and chemical characteristics of different nanomaterials;
- improved methods for identifying safety problems of excipients early in the product-development process;
- cell lines free from adventitious agents to encourage cell-based influenza vaccines and other biological products;
- new biomarkers and other approaches for characterizing and standardizing cell therapies, tissue engineering, and other biologicals;
- advanced microarray technologies than can detect contamination in biological products;
- improved tests for vaccine potency.
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