FDA interchangeability guidance released: Is your company ready?

By Nitisha Pyndiah, PhD

Part 1: Introduction to interchangeable products and the analytical data required


In the last decade, there has been an emergence of cutting-edge technologies used to discover or create promising biological products. This ever-evolving field requires rapidly adapting measures to allow new therapies to reach patients while ensuring safety and efficacy.

Biologics are complex bodies and this complexity is at the origin of the cost of biological treatments. To reduce such cost, products qualified as biosimilar to an already approved product can be placed on the market upon expiration of the 12-year exclusivity. The FDA defines a biosimilar as a biological product ‘highly similar’ to an already approved biological product with no demonstrated clinical differences in terms of safety and efficacy from the reference product notwithstanding minor differences in clinically inactive components. The type of data needed to demonstrate the safety and efficacy of a biosimilar differ from an originator product. Whereas a reference product marketing application is evaluated based on a full profile of non-clinical and clinical data, the data for a biosimilar application is comparative and focuses on intensive analytical and functional studies.

Six biosimilars have now been approved in the US.

What is the main implication of an interchangeable product?

Under section 351(k) of the PHS Act, an interchangeable product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. So in January 2017, FDA released the long-awaited draft guidance document about the demonstration of Interchangeability for therapeutic proteins. An interchangeable product is required to meet the biosimilarity criteria but with additional aspects to consider as the implications are greater. The interchangeable product ‘can be expected to produce the same clinical result as the reference product in any given patient’.

In this part 1 of our Blog’s Interchangeability series, we will cover the type of analytical data and information required to demonstrate interchangeability.

Interchangeability FDA on Fingerprint-like Characterization

‘Fingerprint-like characterization’

What factors may affect the analytical data required to demonstrate interchangeability?

 FDA highlighted evaluating the complexity of your product to understand the data required. FDA will evaluate the totality of data on a case by case basis. Hence, demonstrating the flexibility of the agency about interchangeable products. For a product to be an interchangeable product, biosimilarity is one of the criteria that needs to be met.

To demonstrate biosimilarity, sponsors need to use a stepwise approach meaning that at each step, the level of residual uncertainty should be reduced. The agency reiterated the importance of evaluating any uncertainty left between the reference product and the interchangeable product and identify the methods required to resolve the uncertainty.

As the pharmacist is able to substitute for the reference product making sure that the patient will not develop an immune response to the therapeutic product, that can be fatal, is crucial.

Structural differences between the reference product and an interchangeable product may be at the origin of such a negative effect. To mitigate such events, appropriate analytical data from protein primary structure and higher order structure to impurities is required. For instance, post-translational modifications such as glycosylation can vary greatly according to the system of expression used. Glycosylation patterns that are not present endogenously in humans may elicit a reaction in patients and sponsors should provide appropriate data to support that the interchangeable product can be expected to produce the same clinical result as the reference product in any given patient. Several analytical methods will allow pinpointing the differences, for instance in glycosylation patterns (from methods to identify differences at the level of your intact glycoproteins to the monosaccharide composition), between the reference product and the interchangeable product. FDA recommends using a fingerprint-like analysis as they will consider the ‘totality of the data and information submitted’. This fingerprint-like characterization will allow for targeted clinical studies necessary to demonstrate interchangeability if residual uncertainty remains.

A protein with a lower structural complexity or binding a single target may require less characterization to resolve the residual uncertainty regarding interchangeability compared to other proteins part of not well-established pathways or with a pleiotropic activity.

The impact on Immunogenicity

As mentioned earlier, minor changes in the structure or characteristic of the protein may elicit an immune response to the therapeutic protein in the patient. The fact that an interchangeable product may be substituted for the reference product without the intervention of the healthcare provider means that it is necessary to make sure that there is no risk associated with alternating or switching products. The agency also highlighted that when reference products have a documented history of eliciting detrimental immune responses, further intensive analytical data will need to be provided for the interchangeable product.

Because of the complexity of biologics, the amount of data required will vary from one product to the other according to its characteristics. It is therefore highly recommended to meet with FDA early during the drug development process to discuss your product.


Nitisha Pyndiah - Biotech Consulting Services

Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.

Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.