FDA Revamps Biosimilar Quality Requirements

Published on: 
BioPharm International, BioPharm International-07-01-2019, Volume 32, Issue 7
Pages: 6–7

New guidance documents clarify production standards and processes for developing interchangeable biologic drugs.

As part of its ongoing support for the development and approval of competitive biotech therapies, FDA has updated and clarified standards and procedures for ensuring the quality and similarity of biosimilars. A new draft guidance recommends a process for developing comparative analytical assessment plans to demonstrate biosimilarity, with added details on procedures for conducting such assessments and for documenting quality in a range of production lots to make biosimilar development and production more predictable and efficient (1).

The new advisory replaces an earlier guidance on quality considerations for biosimilars issued in 2015 and updates a 2017 draft guidance on statistical approaches, both withdrawn later by FDA due to industry concerns and objections. This revised document presents strategies for conducting comparative analytical studies to assess biosimilarity to a reference product and for presenting scientific and technical information in the chemistry, manufacturing, and controls (CMC) section of biosimilar applications. There’s more detail on how comparative analytical assessments should cover key processes, including a product’s expression system, manufacturing process, physicochemical properties, functional activities, target binding, impurities, reference product and reference standards, finished drug product, and stability.

To address concerns about lot-to-lot variability, FDA advises biosimilar makers to include data from at least 10 reference product lots acquired over several years to fully assess reference product drift. Similarly, sponsors should assess 6–10 lots of the proposed biosimilar, including both investigational and commercial-scale lots, validation lots, and lots manufactured at difference scales. Additional sections clarify the submission of reference standards and data on functional activity to demonstrate any structural differences with a reference product. And FDA provides the usual caveat that it will consider alternative approaches from sponsors in analyzing and presenting requested data. 

Support for interchangeables

FDA issued the revised quality assurance advisory soon after publication of a final guidance on developing interchangeable biosimilars, a much-anticipated and hotly debated option for manufacturers (2). That document updates a draft guidance from January 2017 that attracted voluminous comment from multiple stakeholders. The new version instructs manufacturers on conducting switching studies, which FDA says it usually will require to approve an interchangeable label. While some firms consider extensive switching studies unnecessary, FDA justifies this approach as important for demonstrating fully that safety and efficacy are not affected by changing treatment from brand to interchangeable, a finding that is considered important to gain the trust of physicians and patients in pharmacy-level switching.

Important for biosimilar makers, the new guidance supports the use of non-US-licensed comparator products to conduct tests and to produce the data needed to demonstrate interchangeability. Even though FDA wants data from bridging studies to foreign-made reference products, manufacturers still may benefit from leeway to obtain samples of biologics that often are less costly outside the United States and can help reduce the cost and time for developing interchangeable therapies. Sponsors developing interchangeable products may be eligible to gain a year of market exclusivity for being the first to develop such a copycat therapy.

The new guidance also appears less didactic by dropping the frequent use of terms such as “residual uncertainty” and “fingerprint-like” similarity between reference and interchangeable products, which were common in the earlier advisories. FDA here aims to set general standards and requirements for these therapies but notes, however, that the specific data and testing needed to document interchangeability may vary with the structural and functional complexity of the product and with clinical experience with the reference product. Sponsors may seek to justify an exemption from switching studies, and FDA says it will take a flexible approach. 


Eye on insulin

In moving forward on standards for interchangeable products, FDA sets the stage for the development and approval of competitive insulin products, which are scheduled to transition to biologic status in March 2020. There is great anticipation that interchangeable insulin therapies will provide important alternatives to current costly diabetes treatments as multiple sponsors move into this field. These issues were discussed at an FDA public meeting in May on the future of biosimilar insulins, just days after the appearance of the interchangeable biologics guidance. As a relatively simple biotech product that has been available as a drug for 100 years (but ineligible for generic competition), manufacturers expect to be able to utilize a rather streamlined and straight-forward process for documenting similarity and interchangeability for these widely used therapies. Firms planning to produce competitive insulin therapies propose that FDA require data from only one, small immunogenicity study, as opposed to multiple switching studies, and that analytic characterization, bridging studies, and reliance on pharmacokinetic and pharmacodynamic data should provide ample support for interchangeable insulins.

FDA says it plans additional guidance on data needed on product container closure systems and delivery device constituent parts to support the presentation of a proposed interchangeable product. Of interest is how a biosimilar or interchangeable determination may be affected by delivery of insulin through a pump or over-the-counter device.

So far FDA has not approved any biosimilars as interchangeable, but this is expected to change with this added clarification of regulatory process and requirements. The rising price of insulin therapies has become one of the most contentious issues in the escalating drug pricing debate, with Congressional hearings generating multiple legislative proposals on this issue, many supporting the development of biosimilar and interchangeable products. 


1. FDA, Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, Guidance for Industry (CDER, CBER, May 2019). 

2. FDA, Considerations in Demonstrating Interchangeability With a Reference Product, Guidance for Industry (CDER, CBER, May 2019). 

Article Details

BioPharm International
Vol. 32, No. 7
July 2019
Pages: 6-7


When referring to this article, please cite it as J. Wechsler, "FDA Revamps Biosimilar Quality Requirements," BioPharm International 32 (7) July 2019.