Regulatory Focus™ > News Articles > Untitled Letters Say Amniotic Product Manufacturers Fall Afoul of Minimal Manipulation Regulations

Untitled Letters Say Amniotic Product Manufacturers Fall Afoul of Minimal Manipulation Regulations

Posted 05 September 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has released four relatively rare Untitled Letters by way of its Center for Biologics Evaluation and Research (CBER), whose inspectors found a number of violations during recent inspections of amniotic/chorionic-based product manufacturers.

Background: Enforcement Letters

FDA is generally in the practice of releasing three main types of enforcement documents: Untitled Letters, Form 483s and Warning Letters. Other types of letters, such as "It has come to our Attention" letters or Advisory Action letters, are issued less frequently for medical device and veterinary products.

The difference in the letters has less to do with form and more with agency intent. A Warning Letter, for example, is used to denote the failure of a company to comply with the agency's regulatory policy and explain that failure to remedy the deviation will result in further agency action.

An Untitled Letter, by contrast, is usually sent to companies that are alleged to have violated a more minor provision or regulation, and often ambiguously so. The most common use of them by far has been by FDA's advertising regulators within the Office of Prescription Drug Promotion, formerly known as the Division of Drug Marketing, Advertising and Communications (DDMAC).

Untitled Letters: Not Just for OPDP

But as CBER's action illustrates, advertising isn't the only thing for which FDA sends Untitled Letters.

On 5 September 2013, CBER released the text of four Untitled Letters sent to separate manufacturers of amniotic and/or chorionic-based products, explaining that all four had failed to comply with various regulations.

In one letter to Georgia-based Surgical Biologics, a subsidiary of MiMedx Group, FDA alleges that the company is not registered with FDA to either store or distribute its AmnioFix Injectable product. The company markets AmnioFix as a treatment for inflammation, scar tissue formation, and soft tissue wounds.

FDA explained that under its understanding of the regulations, these products would be human cells, tissues or cellular and tissue-based products (HCT/Ps) regulated under 21 CFR 1271.

However, FDA said because the products underwent "minimal manipulation," they are technically regulated under 21 CFR 201-that is to say, as biological products requiring the submission of a biologic licensing application (BLA) under 21 CFR 351 of the Federal Food, Drug and Cosmetic Act (FD&C Act).

The distinction is one made in the other three letters as well, though two of those three are to companies that use Surgical Biologics as a contract manufacturer.

Uncertainty Leads to Untitled (Not Warning) Letter

The legal distinction of "minimal manipulation," however, is one that has been fraught with legal uncertainty (2), which likely explains why FDA opted to use Untitled Letters instead of the more formal Warning Letters: It's possible the companies are on firm legal footing despite FDA's assertions to the contrary.

In a statement, MiMedx President Bill Taylor said his company was "surprised by [the] letter considering the FDA conducted a directed inspection of our facility in July 2012." Taylor said FDA had indicated to it after the inspection "that CBER had completed its review and had no findings or further questions and, therefore, the inspection was classified as No Action Indicated (NAI)."

"The Company believes the FDA's conclusion is based on a misunderstanding of the micronization process and is responding to the Untitled Letter and will reiterate its request for a meeting with the FDA," Taylor added.

CBER Untitled Letter to Surgical Biologics

CBER Untitled Letter to Castle Surgical

CBER Untitled Letter to Tides Medical

CBER Untitled Letter to Accel Spine

MiMedx Statement

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