Manufacturing and Immunogenicity are Key Considerations for Approval of Biological Products: BLA vs NDA


Author: Suzanne Broussard, PhD 

Biological products warrant special regulatory consideration because of their complex nature and susceptibility to variation during manufacturing. Biologics are not only complex in their physical structure, they are produced from living organisms and thus pose a myriad of potential issues in the manufacturing and isolation processes that all have the potential to induce immunogenicity. Regulations for developing a biological product take these potential risks into consideration 

In this second piece evaluating BLA and NDA, we focus on understanding some of the nuances between biologic and drug development. See the first BLA vs NDA blog for a more focused look at regulations.   

Manufacturing of Biological Products is Inherently Riskier than Production of Drugs. 

The manufacturing processes for biological products are different than processes for pharmaceuticals. Traditional drug products are typically manufactured using pure chemical substances that are sterile, and the end products can be relatively easily analyzed. On the other hand, biological products are made from living organisms and are much more complex in nature — making product analysis very difficult. Indeed, most biological products are defined by the manufacturing processes used for production. The manufacturing process and manufacturing facilities are so crucial to biologics that “purity” is part of the agency’s requirements for licensing. 

The FDA strictly controls changes to the manufacturing processes that evolve during the development of the biologic, as well as after licensing. Biologics are much more sensitive to process changes than are drugs – even a small change in the manufacturing process can result in an adverse change in the biological product. This is why biological products are regulated under the PHS Act. Initial manufacturing procedures are detailed in the IND application and then modified as needed throughout the IND phase of clinical evaluation and through the final BLA submission. 

Modification to manufacturing may be needed to scale up from pilot to full-scale production or to improve efficiency; this can include any changes in equipment, facilities, handling, or storage and testing of cell substrates that may be required.  

Changes to the biologic’s manufacturing process, equipment, facilities, or handling have the potential to affect the products identity, safety, purity, and potency. Therefore, any changes to production must be brought to the attention of the regulatory authorities, and the FDA will use its “comparability” ruler to determine if additional studies are required to support the license application 

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Comparability Testing 

FDA issued two guidance documents to help manufacturers understand the concept of comparability and gracefully jump through the hoops to achieve a license to sell their therapeutic biologics.  

The Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products “describes those steps that manufacturers may perform and which FDA may evaluate to allow manufacturers to make manufacturing changes without performing additional clinical studies to demonstrate safety and efficacy.”  

The Q5 Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process is “intended to assist manufacturers in the collection of relevant technical information that serves as evidence that the manufacturing process changes will not have an adverse impact on the quality, safety, and efficacy of the drug product.” 

If changes are needed to an approved license, the Changes to an Approved Application: Biological Products Guidance for Industry is available on the FDA website.  

For any situation, the FDA encourages sponsors to consult with them prior to implementing changes.  

Clinical Development of Biologics Must Include Assessment of Immunogenicity 

There are unique clinical considerations for biologics since they are derived from living organisms. Either the biologic itself or impurities from manufacturing could trigger an immune response with potentially disastrous consequences. Therefore, the clinical development of biologics must include the assessment of immunogenicity. This differs from manufacturing and isolation of drug molecules which do not typically pose an immunogenicity threat.  

In January 2019, FDA announced that the final industry guidance on immunogenicity testing is available: Immunogenicity Testing of Therapeutic Protein Products–Developing and Validating Assays for Anti-Drug Antibody Detection.  

This guidance provides: 

  • Recommendations to facilitate industry’s development and validation of assays for assessment of the immunogenicity of therapeutic protein products during clinical trials 
  • Applies to assays for the detection of anti-drug antibodies (ADAs) and may also apply to some peptides, oligonucleotides, and combination products on a case-by-case basis 
  • Includes recommendations regarding the development and validation of screening assays, confirmatory assays, titration assays, and neutralization assays 
  • Finalizes the revised draft guidance for industry entitled “Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products” issued in April 2016 and includes a revised title 


The biggest differences between the approval of therapeutic biological products or drug compounds center around the complex nature of biologics and the many challenges that occur in their manufacturing. Because biologics come from living organisms, immunogenicity is always a concern. The FDA’s regulatory landscape is complicated and always changing.

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In this blog, we share our insights and experiences to help companies build quality, scalability, and flexibility into their regulatory writing.  We hope you find it insightful. For questions, please contact info@criterionedge.com.

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