Regulatory Applications for Biologics

Published on: 
BioPharm International, BioPharm International, August 2022 Issue, Volume 35, Issue 8
Pages: 49, 50

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, answers some commonly asked questions about biologics license applications.

Q. What is a biologics license application (BLA)?

A. BLA is an application sent to FDA that provides information on introducing biological product into interstate commerce. Similar to a new drug application (NDA), a BLA should include the comprehensive product information generated during a development demonstrating safety, purity, and potency of the product including the proposed labeling information to be included in the packaging.All biological products are approved through the BLA pathway, are licensed under Section 351 of the Public Health Service (PHS) Act, and are regulated by the US Food, Drug, and Cosmetic Act (FD&C Act).

Q. What’s the difference between a BLA and an NDA?

A. BLAs and NDAs differ slightly in terms of their application content and submission requirements. The requirements for an NDA are that the drug is proven to be safe and effective, the labeling contains the necessary information, and the manufacturing process does not alter the identity, strength, quality, and purity of the drug. BLAs should also establish that the biological product is safe and potent, but because biologics are manufactured biological living material, the BLA must also provide information that demonstrates the final product does not contain potential extraneous material or viral contamination due to the nature of biologics and the complexities of manufacturing this type of product.

Q. What types of products are filed as BLAs?

A. In Section 351 of the PHS Act, biological products are defined 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” (1). FDA regulations and policies have established that
biological products include blood-derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells or microorganisms, and most protein products.

Q. What FDA center has oversight of BLAs?

A. While traditional drug products (i.e., small molecules) are regulated by FDA’s Center for Drug Evaluation and Research (CDER), biological products can be regulated by either CDER or the Center for Biologics Evaluation (CBER), depending on the product’s classification.

Q. What is the difference between manufacturing a biological product versus a traditional pharmaceutical product?

A. Traditional drug products are formulated pure chemical substances that are easily analyzed and quantified after manufacturing. Biological products are formulated from living material; therefore, there may be limited ability to identify the active component(s) of a complex biological product.

As a result, these products are often defined by their manufacturing processes. Because changes in the manufacturing process, equipment, or facilities could result in changes in the biological product itself, the production of biologics is monitored by FDA from the early stages to make sure the final product turns out as expected.

Q: How does the failure investigation process differ for biologics?


A. The short answer is there is no process difference when performing deviation investigations for traditional pharmaceutical products versus biological products. The differences lie in the complexity of the manufacturing processes and thus the variables that need to be considered regarding what could have impact on the deviation.

Chemical processes, although sometimes quite complex, often have fewer variables even thoughmany of the categories are the same. For instance, when investigating an unknown impurity in a biological process from a simple oligopeptide fermentation process, the considerations may include fermentation conditions (e.g., time, temperature, oxygen uptake, byproduct production), potential contamination of

reactants including master cell banks and fermentation reagents, equipment integrity, and performance. Further considerations for the downstream purification process variables and the effect of a final configuration (e.g., folding) also need to be considered.

The purpose of performing an investigation into a deviation is to determine why the deviation happened and what its impact was on the product quality. To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product you are investigating is biotech or traditional, should require the investigator to review various systems and determine whether they were the cause of the deviation being investigated.

The systems most often reviewed are equipment and machinery, the manufacturing process, the raw materials used in manufacturing, the specifications, the environment, and finally, the operators. This is not to imply that these systems are the only areas you should look at during the investigation but that these are the most probable areas where you will uncover the root cause of the deviation. Each investigation must address the following elements: root cause, impact to the material or product, the immediate correction taken, the corrective action to prevent re-occurrence for specific product/operation, and the preventive action taken to prevent re-occurrences for all products/operations. Once these elements have been investigated, results from the investigation must be documented.

The written narrative should clearly explain what happened, when it happened, and who was involved or observed what happened. The narrative documents the solution and rationale for the root cause that was determined through the investigation process. If you follow your investigation procedure and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a biotech product.


1. US Public Health Service Act,Section 351, Part F—Licensing—Biological Products And Clinical Laboratories, Subpart 1—Biological Products Regulation Of Biological Products As Amended Through P.L. 117–159, Enacted June 25, 2022.

About the author

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates.

Article details

BioPharm International
Vol. 35, No. 8
August 2022
Pages 50, 49


When referring to this article, please cite it as. S. J. Schniepp, “Regulatory Applications for Biologics,” BioPharm International 35 (8) 2022.