Regulatory Beat: FDA: Manufacturing Innovation Can Boost R&D

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BioPharm International, BioPharm International-06-01-2004, Volume 17, Issue 6

New technologies and changes in agency oversight may help make new therapies available more quickly.

In March, FDA unveiled a report identifying obstacles and possible solutions for converting new biomedical discoveries into safe and effective therapies. One of FDA’s main objectives is reversing the recent decline in new drug and biologics applications, especially for new molecular entities (NMEs). Although most of the specific proposals are not new, "Innovation or Stagnation? — Challenge and Opportunity on the Critical Path to New Medical Products" (available online at highlights the agency's desire to eliminate roadblocks to drug development and approval. This initiative to map "critical pathways" to drug development supports CDER's efforts to better manage the review process for drugs and biotech therapies (see "Updating Review Teams").

The critical pathway initiative also seeks to promote joint efforts by FDA and manufacturers to address product development issues. FDA believes its staff can help identify common problems with similar products because they have privileged information on failures in drug development. "FDA holds the only broad, cross-cutting knowledge about how certain investigational products fail, why certain therapeutic areas remain underdeveloped, and when certain development hurdles persist despite advances in technology that could mitigate them," the report explains. The agency seeks more public-private collaboration on genomics, proteomics, bioinformatics systems, as well as new imaging technologies to help detect safety problems early, to identify patients likely to respond to therapy, and also to address product design, characterization, and manufacturing issues.


In the report, FDA identifies the need for new product development tools to improve preclinical safety testing, clinical efficacy studies, and manufacturing process improvements. It is noteworthy that FDA identifies difficulties in drug formulation, delivery, and manufacturing as obstacles capable of preventing many potential medical products from reaching the market. The agency recognizes that outdated manufacturing systems and tools can impede high-quality mass production of cutting-edge therapies — a problem FDA believes is "highly underrated in the scientific community." According to the report, problems in physical design, characterization, manufacturing scale-up, and quality control may "routinely derail or delay development programs and keep needed treatments from patients" — particularly therapies utilizing new and frequently complex technologies that lack standard assessment tools. Industry and FDA leaders estimate that chemistry, manufacturing, and controls (CMC) problems account for up to 50% of drug-candidate attrition.



FDA is developing a "critical path opportunities list" of proposals for overcoming specific obstacles to drug development. One proposal, says acting deputy commissioner Janet Woodcock, is to improve FDA's data on how manufacturing changes affect product performance in order to identify those changes that are most critical to success. These proposals were discussed at the FDA Science Board's April meeting, where CBER Director Jesse Goodman identified possible critical path investment opportunities, including:

  • new vaccine delivery systems, including DNA vaccines and rapid-use vectors, vaccine platforms, and transgenic plant vaccines
  • well-characterized biomarkers that can predict product toxicity and efficacy
  • increased access to screened, well-characterized cell banks for biotech manufacturers (these would be tested for relevant transmissible infectious agents, and they could help reduce the use of animal products in the biologics manufacturing process)
  • methods for detection and inactivation of new pathogens in blood, cellular, and vaccine products
  • systems for improving cryopreservation and thawing of blood, cellular, and tissue products.


In addition to new efforts to spur drug development, the report supports existing initiatives to improve manufacturing processes and operations:

Updating GMPs. FDA is continuing its GMP modernization initiative and plans to roll out additional policies in coming months. A new, high-level FDA panel will resolve disputes involving manufacturing science issues, and FDA is encouraging international harmonization of GMP quality standards.

Promoting PAT. Encouraging broader industry adoption of process analytical technology (PAT) to reduce costs and increase efficiency is a high-profile component of the GMP initiative. While agency staffers prepare a final guidance on PAT manufacturing applications, they 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 is now conducting PAT field inspections.

New guidance. In addition to several guidances issued as part of the GMP initiative (on PAT, 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 reducing those requirements that could delay marketing of innovative new drugs. CDER also is working with industry to evaluate how best to set product specifications that reflect product risk and manufacturing consistency.


To better handle these new challenges, FDA officials are reorganizing staff and procedures. John Jenkins, director of CDER's Office of New Drugs (OND), plans to reorganize OND's six product review divisions, which currently are based on outdated clinical indications and product categories in many cases. Some offices, such as the division of neuropharmacological drug products, are overloaded with applications while others receive only a handful. The oncology office receives half of CDER's investigational new drug applications but few new drug applications (NDAs). Jenkins expects to "improve the logical groupings of the office" to better balance the workload while retaining an indication-based structure.

In the process, biotech therapy applications will be integrated into this indication-based review structure. Staffers transferred last year from CBER to CDER currently remain in a separate new-drug evaluation office. The agency plans to add CBER's oncology reviewers to the larger CDER oncology division and to disperse the rest among other CDER review groups.

Similarly, Office of Pharmaceutical Science Director Helen Winkle is considering a major change to how OPS' Office of New Drug Chemistry (ONDC) reviews manufacturing data in applications. Instead of assigning review chemists to work directly with OND clinical review groups, Winkle plans to establish more flexible review teams better able to adjust to changing work demands.

However, Winkle expects to maintain the Office of Biotechnology Products, which houses former CBER staffers who conduct research and review the manufacturing portions of biotech therapy applications. While the clinical portion of drug and biotech applications is fairly similar, the manufacturing sections are quite different.

These organizational changes likely will occur after much of CDER's staff moves to the new FDA office complex in White Oak, MD next year, a major change bringing most clinical and chemistry reviewers under one roof for the first time in decades. Driving all these changes at CDER is pressure to maintain timely reviews despite increasingly tight resources. Even though the volume of NDAs has not increased, OPS still must process thousands of manufacturing supplements each year and follow tight review timelines.