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Planning For Regulatory Variation In NDA To BLA Transitions

Thought Leadership In Association With Lachman Consultants

To date, much of the discussion around this transition has centered on issues such as which approval pathways are most viable for biological products developed as NDAs under the Section 505 provisions, loss of marketing exclusivities applied to NDA-approved biologics, and biosimilarity and interchangeability requirements for follow-on insulin products under the BPCIA. Nonetheless, there are further regulatory considerations for transitioning biologics that may lack the urgency of these debates, yet should be of significant concern to NDA-holders planning for the long term as new BLA licensees.

by Keith Webber, Ph.D. Vice President, Biotechnology Lachman Consultant Services, Inc.

While regulatory requirements for NDA and BLA products in the US are, to a large extent, harmonized, marked differences remain in areas such as post-approval reporting, validation of post-approval CMC (chemistry, manufacturing, and control) changes, and product labeling. Of particular interest to transitioning biologics are the following regulations affecting biologics under Title 21 of the Code of Federal Regulations (CFR): 600.14 (biologic-product deviation reports); 600.81 (distribution reports); 601.5 (revocation of license); 601.6 (suspension of license); 601.9 (reissuance of license); 601.22 (products in short supply); 610.13 (purity); 610.12 (sterility); 610.15 (constituent materials); and 610.30 (testing for mycoplasma).

Of the regulations cited, those pertaining to the revocation, suspension or reissuance of a biologics license are likely to have the least impact on transitioning products. The regulatory differences that sponsors of transitioned biological products will need to be most aware of are described in more detail below.

Reporting Requirements

Product Distributions Reports

The information that has to be submitted in Product Distribution Reports for biological products regulated as BLAs under 21 CFR 600.81 is more detailed than the requirements for NDA products under 21 CFR 314.81. The product-distribution report for an NDA product includes the National Drug Code number, the total number of dosage units for each strength distributed, and the quantities distributed both domestically and for foreign use. The product-distribution report for a BLA product must also include the lot numbers of the bulk lots and products distributed, their expiry dates, the dates of lot release, and information on any lots returned from distribution.

In addition, the product-distribution report for an NDA product is included in the product’s Annual Report, while the product-distribution report for a BLA product has to be submitted every six months (although a waiver may be requested to allow submission annually).

Biological Product Deviation Reports

Sponsors with approved NDAs are generally familiar with the requirements for submitting Field Alert Reports (FARs) to their local FDA District Office, if they discover that a product in distribution may be misbranded or adulterated. For biological products regulated under the PHSA, the events that would require FDA notification are essentially the same.  But the what, when, how, and where of submitting these alerts are different for BLA products.

For these products, the requisite document is a Biological Product Deviation Report (BPDR). BPDRs must be submitted as soon as possible, and no later than 45 days, after receiving information about a reportable event as defined in 21 CFR 600.14(b).  Rather than submitting the report to the local FDA District Office, the license holder must file it with the Center for Drug Evaluation and Research’s Division of Compliance Risk Management and Surveillance, using Form FDA 3486.

Impact On Chemistry, Manufacturing, And Controls Submissions

Post-Approval CMC Supplements

Although the types of manufacturing changes that must be reported to the FDA for NDA and BLA products are similar (cf. 21 CFR 314.70 vs. 21 CFR 601.12), the types of information that need to be submitted in support of these changes can differ significantly.  For example, a supplement for a substantial manufacturing change to a BLA product generally requires analytical-comparability data from multiple lots of the product manufactured by the pre-change process, and from multiple lots of the product manufactured by the revised process at commercial scale. The comparability assessment should include stability studies under labeled storage conditions as well as accelerated/stressed storage conditions. In addition, BLA license holders will need to include relevant process-validation data (at commercial scale) in the supplement to support the revised process.    

General Testing Requirements

New requirements for specific testing procedures will come into play when regulatory oversight for transitioning products shifts from NDA to BLA status.  Sterility testing procedures for BLA products are specified in 21 CFR 610.12, and in considerable detail. If license holders want to use alternative methods to demonstrate sterility, these must be shown to give equivalent assurance that the product will be sterile (refer to 21 CFR 610.9).

In addition, under 21 CFR 610.13, each lot of a biological product intended to be administered by injection must be tested for pyrogenic substances, using the rabbit pyrogenicity test specified in the regulation.  As is the case with sterility testing, if a company wants to use an alternative method to test for pyrogens or endotoxins, it must demonstrate that the alternative method provides equivalent assurance of safety to the stipulated animal procedure.

Another safety-related procedure that may be new to sponsors of NDA products transitioning to BLAs is the mycoplasma test.  The regulation describing the method for testing products for mycoplasma contamination (21 CFR 610.30) refers to its use for live viral vaccine products. However, this test is generally required for all protein products manufactured by cell culture processes, since they are also susceptible to mycoplasma contamination.

Product Labelling

There are distinct differences in the labelling requirements for products regulated as biologics under the PHSA relative to those regulated under the FFDCA. In accordance with the regulations for biologic products (21 CFR 610.60, 610.61, 610.62, 610.63, 610.64), the BLA product container label and the package label must include specific items of information that may or may not have been included in the product’s labeling when it fell under the NDA regulations. 

These include, but are not limited to, items such as: the address of the manufacturer; the license number; the year of initial approval of a new biological product; the recommended individual dose for multi-dose containers; and the identity of micro-organisms used in the manufacture of the product. BLA license holders can disregard the regulations under 21 CFR 201.1 that describe the labeling requirements for identifying the manufacturer, packer, or distributor of an NDA product. These do not apply to biological products regulated under the PHSA (refer to 201.1(m)).

Although the FDA does not plan to enforce the new labeling requirements for products transitioning from NDA to BLA status until 23 March 2025, the Agency recommends that all proposed revisions to the labeling of products whose NDA has been ‘deemed to be’ a biologics license should be submitted in a single Prior Approval Supplement before 23 March 2022. 

Making The Transition

The timelines for adjusting to these new regulations are laid out in the FDA’s guidances on its interpretation of the BPCIA’s ‘Deemed to be a License’ provisions[1], [2]. In this respect, the transition from NDA to BLA should be relatively seamless, without any pressing deadlines for license holders. However, once the BLA status of an application is in place after 23 March 2020, the license holder will need to be mindful of timelines for new regulatory obligations, such as submitting distribution reports and biological product deviation reports.

Regulatory variations for biologics transitioning from NDA to BLA status do not pose the kind of fundamental challenges to manufacturers’ financial or operational paradigms that arise from loss of exclusivity or a change in approval pathway. All the same, companies will want to ensure that these more pressing concerns are not aggravated post-transition by a failure to recognize, and act on, the small

[1] FDA Guidance for Industry: Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009, December 2018.
[2] FDA Guidance for Industry: The “Deemed to be a License” Provision of the BPCI Act – Questions and Answers, Draft Guidance, December 2018.




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