FDA Evaluating Input from Industry on Nanotech Guidance

Biotechnology companies have expressed general support for FDA’s draft guidance defining whether products contain nanomaterials or otherwise involve the application of nanotechnology. But the sector also made its case for less red tape and more leeway, raising issue with some specifics and asking for clarity on other topics.

Questions and suggestions were sent to FDA during the 60-day comment period that followed release of the draft guidance “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology.” FDA has ended its comment period, spokeswoman Erica Jefferson told GEN, but she couldn’t offer a timeframe for issuance of the final guidance.

While the agency is evaluating responses on what to consider as nanomaterials, two Senators and the Obama administration, this month, called for new efforts to address safety. Finding money to support increased regulatory activities will be key to the success of these legislative efforts.

Three Obama administration agencies put out their own policy principles for regulating and overseeing nanotechnology and nanomaterials on June 9, the same day FDA issued its draft guidance. At the time the agency stated that it would determine whether products contain nanomaterials or involve the application of nanotech by their properties and size.

FDA will ask whether engineered materials and their end products have at least one dimension ranging from 1 to 100 nm. The agency will also check whether they exhibit physical or chemical properties or biological effects attributable to its dimensions even if they fall outside the nanoscale range but going up to a maximum of one micrometer.

A Matter of Size

During FDA’s comment period, the Biotechnology Industry Organization (BIO) suggested addressing agglomerates or aggregates by maintaining the draft guidance’s 100 nm upper limit but for larger nanomaterials and nanomaterial formations, by specifying properties or phenomena that differ from those of conventionally scaled material.

The International Pharmaceutical Excipients Council of the Americas (IPEC Americas) had similar concerns. They sought clearer guidance on handling particles between 100 nm and 1 micron. It argued that several long-used common pharmaceutical ingredients should not be considered as engineered nanomaterials or as agglomerates of nanomaterials, even though they contain particles whose size falls within this range.

“These materials have been used in drug products safely for decades, and there is no need for additional safety data to support the use of these materials,” David R. Schoneker, vice chair of scientific and regulatory policy for IPEC Americas, pointed out during FDA’s comment period.

3M also had a suggestion for engineered nanoparticles (ENPs) and technologies resulting from their use. The company believes that end products ranging from 100 nm to 1,000 nm in one dimension should be subject to FDA regulations but only if they comprise ENPs that started in the 1 nm to 100 nm range and were formed by processes such as agglomeration, aggregation, coating, functionalization, or assembly of structures.

3M argued that the guidance as written could be interpreted to apply to all thin coatings of 1,000 nm of less, whether or not such coatings contain ENPs and so long as they show physical properties linked to the thin nature of the coating. “In our interpretation, such coatings should not be within the scope of this document if they are not comprised of ENPs,” wrote Todd M. Fruchterman, M.D., Ph.D., svp of R&D, CTO, and CMO.

Celgene praised FDA for its approach to defining nanotech through a first reference point of 1 to 100 nm, followed by the 1 micron upper limit. But for injectable products using nanotech, “FDA should consider the use of 220 nm for the first reference point analysis,” wrote Celgene’s Neil Desai, vp, strategic platforms, and Christopher Griffett, vp, regulatory affairs, Americas.

He pointed to the fact that the most common sterile filtration membrane uses a maximum pore size of 220 nm for nanomaterials designed for in vivo absorption under sterile conditions; nanomaterials larger than 220 nm may not pass readily between endothelial cells common to tumors or inflamed tissues or may pass through the fenestrations between liver or spleen cells within the mononuclear phagocyte system.

Inclusion Criteria

BIO also wants FDA to include biopersistence as a key criterion for defining nanomaterials. Additionally, it asked the agency to exempt from the guidance inert ingredients that meet the requirements for nanotechnology, such as lubricants, binders, fillers, disintegrants, colorants, buffering agents, and coatings. It also asked the agency to clarify the scope of pharmaceutical products involving nanotech that would be subject to the guidance.

“In the pharmaceutical area, a variety of very different pharmaceutical systems or products such as micelles, polymer systems, liposomes, therapeutic monoclonal antibodies, emulsions, suspensions, crystalline particles, etc., contain nanoscale particles, but most are not considered to be ‘nanomaterials,’” noted Andrew J. Emmett, BIO’s managing director, science, and regulatory affairs.

GlaxoSmithKline (GSK) said FDA should urge nanotech companies to address the possibility of nanomaterials, especially insoluble nanoparticles, being absorbed across the GI tract. This could occur both in solution following solubilization from a nanoparticle construct or via intestinal phagocytosis, which would lead to further distribution throughout the body than for conventional micro-sized material.

“An indication that applicants should demonstrate a knowledge of the absorption mechanisms that the nanomaterial will be subjected to within the body and the breakdown or otherwise of the material once within the body, would in our opinion add to the guidance document,” wrote Bekki Komas, GSK’s director for CMC advocacy and global pre-approval, CMC global regulatory affairs.

Consumers Union (CU) said that FDA’s guidance should be mandatory for all manufacturers of nanomaterials. CU cited EPA’s voluntary Nanoscale Materials Stewardship Program, which began in 2008. A year later EPA told Congress 29 companies submitted info to EPA under the basic program and four stated they were willing to consider doing testing under the in-depth program.

“FDA should learn from EPA’s experience that the only way to ensure that the needed information is obtained is to require manufacturers to report to FDA any of their materials that meet the criteria laid out in the two questions and require safety assessments for such products,” advised CU’s senior scientist Michael Hansen, Ph.D., and program leader Carolyn Cairns.

Policy and Funding

While FDA weighs comments on which FDA-regulated products should be considered as involving nanotech, two Senators are seeking final say on a bill to help FDA better regulate the technology. On October 6, Sen. Mark Pryor (D-AR) introduced the Nanotechnology Regulatory Science Act of 2011. The measure (S.1662) would direct FDA to develop safety regulations for companies using nanotech.

S.1662 has drawn support from co-sponsor Benjamin Cardin (D-MD), who like Sen. Pryor is angling to steer the studies required by the bill to FDA labs in his state. FDA would be authorized to spend $48 million over three years: $15 million in the FY 2013, followed by $16 million and $17 million in FY 2014 and FY 2015, respectively.

About two weeks after the bill came out, on October 20, the Obama administration made its own pitch for nanotech safety by issuing a 136-page “national strategy” designed to ensure that environmental, health, and safety research needs are identified and addressed. The 2011 NNI Environmental, Health, and Safety Research Strategy identified six core categories of research: measurement infrastructure; human exposure assessment; human health; risk assessment and management; informatics; and modeling. The strategy also promises to address ethical, legal, and societal implications connected with nanotech.

The Obama administration, however, is struggling to ramp up funding for the National Nanotechnology Initiative (NNI), which coordinates the individual and cooperative nanotechnology-related activities of 25 federal agencies. Calling NNI among its top science and technology priorities, the administration has proposed raising NNI’s budget to $2.1 billion, up from $1.76 billion in FY 2011.

The prospect of Washington shelling out money on a new FDA program or more funds for NNI is unrealistic at a time when most 2012 election campaigners are positioning themselves as budget-cutters. Greater coordination of nanotech goals and policies is indeed needed for the nanobiotech industry to grow. Such coordination must take place between the administration, Congress, FDA, and industry. Whether that can happen in a presidential and Congressional election year, however, remains to be seen.