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Manufacturing and formulation innovation spurs drug develop-ment, but raises new safety and quality issues.
Manufacturers, regulators, and public health officials are establishing new policies and expanding research initiatives to improve drug formulations and delivery systems. The US Food and Drug Administration recently approved many new products with novel delivery methods such as inhaled insulin and a depression drug transdermal patch. The agency also bolstered its staff with experts in pharmaceutical engineering and formulation to assess these challenging products.
The Critical Path Opportunities List unveiled by FDA officials in March cites "manufacturing novel dosage forms" as an area in which collaboration with industry and academia could remove roadblocks to new drug development. And, new drug formulations may eliminate complications related to managing temperature-sensitive drugs and vaccines through the distribution chain.
In providing products that are easier for patients to use, new drugs can improve patient compliance and enhance safety and efficacy, observes Moheb Nasr, director of the Office of New Drug Quality Assessment (ONDQA) in the Center for Drug Evaluation and Research (CDER). Some local inhalation products are absorbed better, thus resulting in smaller dosages that lead to a reduction of undesirable side effects.
FDA approved the first inhaled form of insulin earlier this year, a breakthrough with the potential for improving compliance to prescribed treatment for millions of diabetics. Pfizer's "Exubera" (inhaled powder form of recombinant human insulin) offers a fast-acting alternative to injections or pills for adults with types 1 or 2 diabetes.
Although there have been many notable successes in this area, developing new formulations and delivery systems has its perils. Teva recently announced that it was halting clinical trials for an oral version of its injectable multiple sclerosis drug "Copaxone" (glatiramer) because of poor efficacy results. Separately, FDA recently issued a safety alert regarding cracks in prefilled applicators that can cause inadequate delivery of a rectal diazepam gel that prevents acute seizures. Concerns about the safety of some innovative delivery systems are prompting a closer review of how these products work and the need for new methods to ensure their quality and safety. FDA also is examining bioequivalence issues for generic versions of different delivery systems such as nasal sprays and topical treatments.
Push for patches
New patches and other transdermal drug delivery products have received much attention in the news. Patches are popular because they usually require smaller doses to be effective and are convenient for patients to use, thus improving compliance.
More than 30 patch products are now on the market, including those for birth control and pain relief. In February, FDA approved Somerset Pharmaceuticals's "Emsam" (selegiline), the first patch product for treating major depression. A prime advantage of this treatment is that patients using the lowest dose patch may not have to follow the dietary restrictions needed for oral monoamine oxidase inhibitors. FDA also gave final approval of the first patch treatment for attention deficit–hyperactivity disorder (ADHD), Shire's "Daytrana" (methylphenidate).
Liquid reservoir patches release a medicine through a membrane into the skin, while matrix patches permit a drug to pass directly through the skin. Recent evidence that heat or other factors may increase drug absorption rates with patches, however, has prompted FDA to launch a more detailed review of these products. Johnson & Johnson studies indicate a possible increased risk of blood clots for women using the "Ortho Evra" birth control patch, possibly related to higher estrogen levels in the blood. And, FDA is examining reports of deaths related to fentanyl patches to treat chronic pain. Product labeling for "Emsam" warns that direct heat may result in increased drug absorption and patients should avoid exposing the patch to heating pads, electric blankets, heat lamps, saunas, hot tubs, or prolonged sunlight.
Product improvement wins little praise
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.
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.
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:
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 flexibility.
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 transportation.
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, email@example.com