Identifying marks

Identifying marks: advances in marking, coding, and inspection technology have led to new anticounterfeiting tools for drug makers trying to protect products that are in pill formSolid dosage form manufacturers have long relied on shape and color as well as on-pill imprints of

Get Your Wonder Drugs!

Get Your Wonder Drugs!: But do you know what it takes to produce them? - high costs of drug research and developmentHarry Howard almost made the biggest blunder of his life when he tossed the building blocks of a wonder drug

Generic makers are

Generic makers are seeing promise in field of biotech engineering - Generic drugs: special reportGeneric drug makers are knocking on a door that never has been opened. With a strong undercurrent

Drug Bust: Killing the

Drug Bust: Killing the golden goose - pharmaceutical price controls - Industry OverviewIn an unprecedented series of 60-second radio spots in Michigan last fall, the head of Pfizer's Ann

FDA eyes manufacturing innovation to boost drug development: new technologies, along with changes in agency oversight, may provide a critical path to make more new drugs available more quickly to patients

FDA eyes manufacturing innovation to boost drug development: new technologies, along with changes in agency oversight, may provide a critical path to make more new drugs available more quickly to patientsFDA unveiled a report in March that maps out strategies for converting new biomedical discoveries into safe and effective therapies more quickly and efficiently. Although most of the specific proposals are not new to those familiar with drug manufacturing practices, the report shines a spotlight on the agency's desire to eliminate roadblocks to the development and approval of new drugs. This initiative to map "critical pathways" to drug development lends support to efforts by the Center for Drug Evaluation and Research (CDER) to streamline regulatory policies and better manage the review process.

Removing R&D obstacles

A main objective for FDA is to reverse the recent decline in new drug applications (NDAs) filed with the agency, especially for new molecular entities. Former FDA Commissioner Mark McClellan frequently commented on the lag between gains in genomic and other cutting-edge biomedical research, and the development of new therapies able to improve public health. One of McClellan's last acts at FDA was to issue a report entitled "Innovation or Stagnation?--Challenge and Opportunity on the Critical Path to New Medical Products" which identifies obstacles and possible solutions for moving potential new medical products from laboratory concept to useful medicine (

The report notes growing interest in "translational research" that can help speed basic biomedical research into clinical testing. For the next step, FDA wants to provide new tools related more to downstream product development: preclinical safety testing, clinical efficacy studies, and efforts to refine manufacturing processes.

It is noteworthy that FDA identifies product industrialization as the third dimension of this critical path in drug development. Although researchers and industry professionals often discuss the need to better assess drug safety and efficacy to accelerate the R&D process, this report also focuses on the difficulties in drug formulation, delivery, and manufacturing that block many potential medical products from reaching the market. FDA recognizes that outdated manufacturing systems and tools can stymie efforts to achieve high quality mass production of cutting-edge therapies--a problem that FDA believes is "highly underrated in the scientific community." In FDA's opinion, the failure to solve difficulties in product design, characterization, manufacturing scale-up, and quality control may "routinely derail or delay development programs and keep needed treatments from patients"--particularly therapies using new technologies, which frequently are more complex than traditional products and lack standard assessment tools.

At a recent Drug Information Association conference on chemistry, manufacturing, and controls (CMC) strategies, Liam Feeley, director of pharmaceutical R&D at Abbott Laboratories, estimated that up to 50% of the factors causing attrition of drug candidates during development could be related to CMC issues. He emphasized the importance of investing more resources in product formulation, characterization, and scale-up requirements to avoid wasted clinical studies and later manufacturing problems.

Janet Woodcock, currently serving as FDA acting deputy commissioner and author of the new critical pathways report, wants to work with the industry to gain more information about the root causes of product development failures. If a drug does not show efficacy in Phase III studies, she wonders how it got that far. Is the failure due to poor bioavailability, or too much variability in formulation? Gaining more insight into these issues is an FDA priority.

Making a list

FDA's next step is to create a critical-path opportunities list. Agency staffers are beginning to look for opportunities to develop standards or policies able to remove or overcome specific obstacles to drug development. FDA leaders plan to seek additional suggestions from manufacturers, academics, and National Institutes of Health officials who are involved in its "roadmap" initiative to improve clinical trials. One proposal, says Woodcock, is to develop a better FDA database of how manufacturing changes affect product performance, and to identify changes that are most critical to success. These initiatives were discussed at the April meeting of FDA's Science Board, along with proposals to devote a portion of the agency's $135-million research bud get to critical path projects.

In addition to calling for new efforts to improve drug development, the report acknowledges the need to build on initiatives to improve manufacturing processes and operations already underway.

Updating GMPs. FDA is continuing to implement this initiative to modernize current good manufacturing practices (GMP) standards, and plans to roll out additional policies in upcoming months. Under this program, the agency has established a pharmaceutical inspectorate and is training field inspectors to conduct more-targeted GMP inspections. A new high-level FDA panel has been formed to resolve disputes involving manufacturing science issues, and FDA is encouraging international harmonization of GMP quality issues. FDA also has launched several collaborative efforts with manufacturers and researchers to articulate new approaches for understanding manufacturing science and risk management techniques.

Promoting PAT. A high-profile component of the GMP initiative is to encourage broader industry adoption of process analytical technologies (PAT) to reduce costs and increase the efficiency of drug manufacturing processes. FDA issued a draft guidance in September 2003 outlining a framework for agency review and oversight of PAT manufacturing applications. Agency staffers are preparing a final guidance, and also are developing scientific principles and tools to support analytical and manufacturing control innovations. CDER's Office of Pharmaceutical Science (OPS) is establishing a PAT team to review applications and inspect facilities with PAT components; OPS has received six applications with PAT innovations and has begun to conduct PAT field inspections.

New guidance. In addition to several guidances issued as part of the GMP initiative (on PAT, 21 CFR Part 11, aseptic processing, and comparability protocols, among others), FDA is developing new policies related to process validation and CMC review. In March, CDER published a revised process validation policy to reduce requirements that delayed the launch of innovative new drugs in the past (see Sidebar, "New validation policy aims to overcome roadblocks"). CDER also is working with the industry to evaluate the best way to set product specifications that reflect product risk and consistency of manufacturing processes.

According to OPS Director Helen Winkle, these policy proposals reflect a move by CDER to devise a risk-based approach for submitting and reviewing CMC data. FDA has been discussing this issue for some time and now is stepping back to look at postapproval change requirements and comparability protocols to formulate a more workable approach. In the meantime, the agency may issue more targeted, informal guidances that address specific CMC issues raised in plant inspections.

More collaboration. A main objective of the critical pathway initiative is to launch more joint efforts by FDA and manufacturers to address product development issues. FDA believes that its staff can help identify problems common to similar products because they have access to information about failed drug development programs that is not publicly available. "FDA holds the only broad, cross-cutting knowledge about how certain investigational products fail, why certain therapeutic areas remain under-developed, and when certain development hurdles persist despite advances in technology that could mitigate them," the report explains. The agency seeks more public-private collaborative work on genomics, proteomics, bioinformatics systems, and new imaging technologies to help detect safety problems early, identify patients likely to respond to therapy, and address product design, characterization, and manufacturing issues.