Quality Considerations for Demonstrating Bio-similarity to Reference Product – What Does FDA Draft Guidance Say?

  • By: Staff Editor
  • Date: March 23, 2012
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On February 9, 2012, the FDA released draft guidelines about quality considerations in bio-similar product development. These guidelines provide insight into the procedures which are required to show high similarity with an FDA-licensed biological product and are based on key scientific and regulatory factors which should be considered for submission of applications for bio-similar products to the FDA.

In these guidelines, the Agency addresses the factors relevant in determining analytical similarity for a therapeutic protein biological product andprovides recommendations to applicants on the scientific and technical information of the chemistry, manufacturing and controls (CMC) section of a marketing application.
Sponsor Responsibilities
The draft guidelines recommend that a Sponsor of a biological product should
  • Conduct extensive data collection prior to filing of a 351(k) application, as data collection is the foundation in establishing the bio-similarity of the biological product
  • Follow a step-by-step approach to data collection in developing the biologic.
  • Closely follow the guidelines during the data collection process.
  • Consider analytical factors like elucidation of the expression system, physicochemical properties, functional activities, receptor and immunochemical properties, and stability etc, while submitting the 351(k) application to the Agency.
The draft guidelines are useful for the Sponsor to position their biological product for approval and for demonstrating that a proposed therapeutic protein product is bio-similar to a reference product.
Quality Considerations in demonstrating Bio-similarity to a Reference Protein Product:
  • All 351(k) applications should contain a comprehensive and detailed chemistry, manufacturing and controls (CMC) section which provides all relevant information for the product to be sufficiently reviewed.
  • Specific CMC issues, if any, should be discussed with the FDA.
  • A meaningful assessment of a proposed product's bio-similarity with a reference product should be based on the data collected from analytical, animal and clinical studies.
General Principles
  • The main objective behind analytical similarity assessment should be clearly described with consideration for the known quality attributes and performance characteristics of the specific reference product.
  • Comprehensive and extensive comparative physicochemical and functional studies should be carried out to evaluate whether the proposed bio-similar product and the reference product are similar.
  • Sponsors should describe the capability of the methods used in the analytical assessment and specify limitations, if any.
  • Studies which are carried out (physicochemical and functional characterization studies) to evaluate the bio-similarity of the proposed product should be adequate to establish relevant quality attributes and other product characteristics like quantity, purity, potency, and consistency.
  • The product-related impurities, substances, and process-related impurities should be identified, characterized as appropriate, quantified, and then be compared with those of the reference product, to the extent possible.
  • If the reference product cannot be properly characterized with advanced technology, Sponsors should consult the FDA for guidance on whether an application for such a therapeutic protein product is suitable for 351 (k) submissions.
  • Sponsors should provide information to demonstrate bio-similarity based on data directly comparing the proposed protein product with the reference product.
  • Analytical studies designed to support a demonstration of bio-similarity for purposes of 351(k) application must, as a scientific matter, include an adequate comparison to the licensed reference product.
  • Sponsors should discuss with FDA, the development program used for providing adequate scientific justification for demonstrating bio-similarity of the proposed product to the U.S.-licensed reference product.
Factors for consideration in assessing whether the two products are highly similar:
  • An extensive understanding of all steps involved in the manufacturing process for the proposed bio-similar product should be established during product development.
  • Information gained during process development must be specific for the proposed product and manufacturing process.
  • The license holder should have knowledge and control over the manufacturing process of the proposed product.
  • The applicant should address the concept of the desired product when designing and conducting the characterization studies.
  • Complementary analytical techniques which are used should provide meaningful and sensitive methods for comparing products.
  • Tests used to characterize the product should be scientifically sound, suitable for their intended use, and provide reliable and precise results.
  • Data regarding the ability of a method to recognize prominent differences between the proposed and reference product should be submitted to the Agency.
  • Tests which are used for detecting and characterizing post-translational protein modifications should be demonstrated to be of required sensitivity and specificity in order to provide meaningful information as to whether the proposed bio-similar product and the reference product are highly similar.
Functional activities
  • If a reference product exhibits multiple functional activities, manufacturers should perform a group of suitable assays designed to evaluate the range of activities.
  • The manufacturer should recognize the potential limitations of specific functional assays which can identify small but significant differences between the two products.
  • Relevant analytical tests should be performed to characterize the therapeutic protein product in terms of specific properties like receptor binding, immunochemical properties etc.
  • The process-related impurities and other factors should be evaluated and the potential impact of significant differences in the impurity profile upon safety should be addressed and supported by relevant data.
  • The selected analytical procedures should be adequate to detect, identify, and accurately quantify biologically significant levels of impurities in the products.
  • The safety of the proposed product should be ensured by screening raw materials and confirmation of virus removal and inactivation.
Reference Product and Reference Standards
  • A thorough physicochemical and biological assessment of the reference product should provide required information so as to develop the proposed product. The safety of the proposed product should be ensured by screening raw materials and
  • Assessment should be done during early product development and discussed with the concerned staff of the Agency.
  • The 351(k) application should include a detailed and extensive analytical comparison between the proposed and reference products.
  • When a number of approved comparators are available in the market, Sponsors should demonstrate that the proposed therapeutic product is bio-similar to a licensed reference product.
  • In case, the new drug has been extracted from the reference product, Sponsors should detail about the extraction procedure and provide scientific justification that the quality of the product is not compromised.
  • Analytical studies carried out to justify the bio-similarity of the new product should not focus solely on the characterization procedures and should be part of a broad comparison.
Finished Drug Product
  • If the finished drug product is best suited for a specific type of analysis, the characterization should compare the proposed finished bio-similar product and the finished reference product.
  • The acceptability of the type, nature, and extent of any discrepancies between the proposed finished bio-similar product and the finished reference product should be properly evaluated and scientifically justified by relevant data and rationale.
  • Various excipients in the proposed product should be supported by existing toxicology data or by carrying out additional toxicity studies with the formulation of the proposed bio-similar product.

 Additional Resources

Read the FDA guidance in full

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