Navigating the Approval Process for Biologics: Understanding BLA and its Requirements

“Biologics” are biological product categories created to prevent, diagnose, or treat severe medical conditions. Section 351 of the Public Health Service (PHS) Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

These products are inherently different from other FDA-approval-requiring products in part because they are often complex mixtures that are not easily identified or characterized. Therefore, many biologics manufacturers need clarity on whether biologics require FDA approval.

Do biologics require FDA approval?

A biologic refers to a category of products that includes large and complex molecules produced through biotechnology. They are derived from living organisms or their derivatives and used to treat, diagnose or prevent disease.

Biotechnology refers to “exploiting biological processes of living systems such as microorganisms or animal and plant cells for industrial purposes including creation of biological products for diagnosing, treating, or preventing medical conditions, especially through genetic manipulation”.

So, do biologics need FDA approval? The simple answer is yes they do. The approval of a biologic product is a multi-step process regulated by the U.S. Food and Drug Administration (FDA) through the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). The process for biologic approval differs since biologics go through the Biologics License Applications (BLA) process (covered in detail below).

Currently, there are around 621 biologics products licensed by the FDA. Moreover, FDA registered about 5,500 facilities in the biologics sector. One of the main reasons for separating biologics products from other pharmaceutical products is because the regulation and approval process differs from non-biologics drugs.


According to the FDA definition, a Biologics License Application (BLA) is a “request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce”. A New Drug Application (NDA) is similar to the BLA but is used for prescription drugs that are not categorized as biologics.

The BLA and NDA are similar procedures for different products; both requests are submitted after the Investigational New Drug (IND) and are the second step in the FDA approval procedure after clinical studies. The IND is presented for all experimental drugs that show promise in pre-clinical research.

Once the clinical trial is complete, the Center for Drug Evaluation and Research (CDER) will review the NDA or BLA, the trial results, manufacturing practices, labeling, and other critical information that gives insights into the drugs. Moreover, the NDA and the BLA must use Form 365h (discussed later).

What is required for a BLA?

The primary information is specified in Form FDA 356h, which details the necessary information required by the applicant to market the new biologic product for human use. The form must be submitted with the supporting documents and data, which the FDA assesses to confirm the product's safety and potency. The BLA includes critical information about the product, including:

  • Information of the applicant
  • Information on the product and the manufacturing process
  • Dosage
  • Preclinical and clinical studies
  • Labeling

How long does a Biologics License Application (BLA) take?

Considering the entire process, it can take years before the license is approved. While the FDA can evaluate an IND during the Phase-I clinical study, these trials require several months or years to complete.

A BLA can be submitted at the end of the Phase III trial, which can take additional time to gain approval. Several pre- and post-BLA submission steps are involved in the FDA approval procedure that you must consider when planning for a Biologics License Application.

BLA submission and BLA approval in 3 steps

Let’s quickly go over the steps involved in submitting a biologics license application and what to expect after submission.

Step 1: Prepare for BLA submission

The first step towards the BLA process is to create a review committee that will meet with the FDA to communicate your intention of applying for a biologics license.

Moreover, the FDA will need a Bioresearch Monitoring (BIMO) report, a comprehensive report on data audits, inspection, and regulatory assessments of the research. You can also choose to submit a validation plan to the FDA for review or meet with an FDA team to discuss the validation plant before applying.

You will also prepare the From FDA 356h. The Form must be submitted to the document center of the Centre for Biologics Evaluation and Research (CBER) division. The same form is submitted to the Centre for Drug Evaluation and Research (CDER) for any non-biologic drugs.

Step 2: FDA Form 365h

The next step is submitting the FDA Form 365h, an application to introduce a new or abbreviated drug or biologic product to the commerce sector for human benefit. The form includes a range of information the FDA requires on the new biologics product to begin the Biologics License Application process.

Some of the primary information asked for in the Form FDA 365h includes:

  • A summary of all information in the application
  • Applicant information
  • Preclinical data
  • Clinical data
  • Labeling of the to-be licensed product
  • Manufacturing principles, chemical structure, biological properties, and product controls
  • Details on the manufacturing facility
  • Case reports
  • Index

In some cases, the applicants must submit relevant information on whether they are ready for an inspection by the FDA committee. According to FDA guidelines in the Electronic Common Technical Document (eCTD), an electronic format should be used for BLA submission.

Download the Form FDA 365h (pdf) → note that these links are a direct PDF download

Download supplementary instructions for filling out Form FDA 365h

Step 3: BLA FDA approval

The FDA approval timeline can vary. After receiving the application, the FDA will check it to ensure that the information is complete.

First, the FDA will conduct an initial review focused on the standard operating procedure and validate the data. Once the validation is complete, they will meet to discuss any missing information. The FDA provides 74 days to provide any missing information.

After reviewing the information, the FDA will issue either a filing or a “Refuse to File (RTF)” letter. The RTF letter means that the application was denied in the initial review process.

On issuance of a filing letter, the advisory committee conducts a complete review of the documents. This includes a detailed scientific review of all submitted information. At this stage, the FDA may also request verification of compliance with regulations through a pre-licensing inspection of the manufacturing site. The inspection includes a detailed visit of the site to ensure safe practice regulations are met.

Different disciplines in the committee will review the information. A discipline review letter is often issued stating that a discipline has completed its review, but the entire review is still in process.

Once the review has finished, the committee will meet with the advisory committee to discuss problems, agreements, and commitments. If the FDA grants approval of the BLA, an approval letter will be issued. This letter authorizes the manufacturer to begin distributing the product.


Due to the inherent characteristics of biologics products, the FDA requires different processes than those involved in other FDA products to ensure that the safety and efficacy of the product are adequately regulated before they are introduced to the general public.