The revisions to US Food and Drug Administration’s (FDA) regulations, announced Tuesday, are designed to remove unnecessary or outdated biologics requirements and allow industry to employ new manufacturing technology and testing capabilities.
Issued directly as a final rule – because FDA says it believes the updates include “only noncontroversial amendments” and FDA anticipates no major objections from industry – the new regulations are part of FDA’s continuing effort to reduce the burden of unnecessary regulations. The regulations were last altered in 1977.
“Notwithstanding the changes in this rule, FDA will continue to require that each biological product meet standards to assure that the product is safe, pure, and potent, and will continue to require that each lot demonstrate conformance with the standards applicable to that product through appropriate testing,” FDA says. “For many years, because of the potential for impeding scientific progress, FDA has not codified additional specific standard preparations and limits of potency for licensed biological products, but instead the standards are established in the BLA [biologics license application].”
Removal of 610.20
The final rule removes the requirements contained in § 610.20 (21 CFR 610.20) as the standard preparations to perform lot release testing or other specific product characterization assays as they “are obsolete, no longer available, or described on a product specific basis in BLAs,” FDA says.
In addition, standard preparations to help ensure biologics’ safety, purity and potency can often be obtained from sources other than FDA’s Center for Biologics Evaluation and Research (CBER), including international sources, or can be developed internally by the applicant, the agency says.
“Specifically, according to current § 610.20 Standard preparations, standard preparations, made available by CBER, are required to be used in the testing of potency or opacity of certain biological products, mostly biological products that were initially licensed several decades ago. Most of these standard preparations requirements are now obsolete, because either CBER no longer provides the listed standard preparations, or the specific biological products are no longer manufactured, or both,” FDA says.
CBER will, however, continue to make and supply standard preparations when appropriate, as well as collaborate with external organizations in the development and assessment of physical standard preparations for biologics.
Removal of 610.21
Also as part of the new final rule, FDA is removing Section 610.21, which specifies minimal potency limits to be met for certain antibodies and antigens. The removal comes as these potency limits are either obsolete or best described on a product-specific basis in a BLA, FDA says.
“The removal of §§ 610.20 and 610.21 will also increase regulatory flexibility by allowing industry and FDA to more readily use and incorporate current scientific technology and other appropriate reference materials in the manufacture and regulation of licensed biological products,” the agency adds. FDA's update also is intended to have the potency limit be specified in the BLA, and it expects that standard preparations and potency limits may be changed only in accordance with regulations for reporting post-approval changes.
Storage Periods and Conditions
Meanwhile, FDA is updating the table at § 610.53(c), which lists dating periods, manufacturers’ storage periods and storage conditions for many biologics.
“We are retaining those products, specifically Whole Blood and blood components, whose dating periods are based upon data relating to the anticoagulant or preservative solution in the product, usage, clinical experience, laboratory testing, or further processing,” FDA says. “The list is updated to include currently licensed Whole Blood and blood component products with their applicable storage temperatures and dating periods. In listing the dating periods for Whole Blood and blood component products, we took into account existing regulations, guidance documents, package inserts for solutions used for manufacture or storage of Whole Blood and blood components, and operator instruction manuals for devices used in the manufacture of Whole Blood and blood component products.”
Here’s the updated table:
“Because we understand from these materials that these dating periods are in current use, and because blood establishments can request an exception under § 640.120 (21 CFR 640.120), we do not anticipate significant objections to codifying this information,” FDA says.
Other Removals and Changes
In addition, the agency is amending section 610.50 to remove references to sections 610.20 and 610.21 and official potency tests to reflect FDA's updated approach to establishing dates of manufacture.
Section 610.53 is also being “amended to remove products no longer manufactured and products for which dating information is identified in the BLA of each individual product, and to reflect updated practices for the remaining products.”
Under the revised regulation, the date of manufacture must be identified in the approved BLA, the agency says.
“FDA recommends that applicants discuss a suitable date of manufacture with FDA during late clinical development and propose a date of manufacture in the BLA,” the agency says. “We consider the underlying science and manufacturing process testing methods in determining the date of manufacture for each specific product. The approved BLA will specify how the date of manufacture is determined.
“In addition, we recognize that future scientific understanding and new technology, such as the implementation of pathogen reduction technology or the approval of extended storage systems, could affect what dating periods would be necessary, as a scientific matter, for Whole Blood and blood components. For this reason, the rule allows for changes to the dating periods specified in § 610.53(b) when the dating period is otherwise specified in the instructions for use by the blood collection, processing, and storage system approved or cleared for such use by FDA.”
A paragraph is also being added to § 610.50(c) to specify how the date of manufacture for Whole Blood and blood components is determined.
Although it’s designated as a final rule, FDA is still providing a comment period of 75 days after the date of publication in the Federal Register.
“If we receive any significant adverse comments, we intend to withdraw this direct final rule before its effective date by publication of a notice in the Federal Register,” FDA says, clarifying that a significant adverse comment is defined “as a comment that explains why the rule would be inappropriate, including challenges to the rule's underlying premise or approach, or would be ineffective or unacceptable without a change.”
Federal Register Notice on Standard Preparations, Limits of Potency, and Dating Period Limitations for Biological Products