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U.S. Department of Health and Human Services

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Guidance for Industry on Biosimilars: Q & As Regarding Implementation of the BPCI Act of 2009: Questions and Answers Part II

 

Table of Contents

 Part II.        PROVISIONS RELATED TO REQUIREMENT TO SUBMIT A BLA FOR A “BIOLOGICAL PRODUCT”

 Q.II.1.How does FDA interpret the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in section 351(i)(1) of the PHS Act? 
 
 Q.II.2. How is “product class” defined for purposes of determining whether an application for a biological product may be submitted under section 505 of the FD&C Act during the transition period?
  
 Q.II.1.How does FDA interpret the category of “protein (except any chemically synthesized polypeptide)” in the amended definition of “biological product” in section 351(i)(1) of the PHS Act?
 A.II.1.

(Proposed Answer): The BPCI Act amends the definition of “biological product” in section 351(i) of the PHS Act to include a “protein (except any chemically synthesized polypeptide)” and provides that an application for a biological product must be submitted under section 351 of the PHS Act, subject to certain exceptions during the 10-year transition period ending on March 23, 2020, described in section 7002(e) of the Affordable Care Act.
 
FDA has developed the following regulatory definitions of “protein” and “chemically synthesized polypeptide” to implement the amended definition of “biological product” and provide clarity to prospective applicants regarding the statutory authority under which products will be regulated.
 
Protein — The term “protein” means any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.
 
Compounds greater than 40 amino acids in size will be scrutinized to determine whether they are related to a natural peptide of shorter length and, if so, whether the additional amino acids raise any concerns about the risk/benefit profile of the product.
 
Chemically synthesized polypeptide — The term “chemically synthesized polypeptide” means any alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.
 
A chemically synthesized polypeptide, as defined, is not a “biological product” and will be regulated as a drug under the FD&C Act unless the polypeptide otherwise meets the statutory definition of a “biological product.”

Chemically synthesized compounds greater than 99 amino acids in size will be scrutinized to determine whether they are related to a natural peptide of shorter length and, if so, whether the additional amino acids raise any concerns about the risk/benefit profile of the product. 

FDA’s interpretation of these statutory terms is informed by several factors, including the following. The scientific literature describes a “protein” as a defined sequence of alpha amino acid polymers linked by peptide bonds, and generally excludes “peptides” from the category of “protein.” A “peptide” generally refers to polymers that are smaller, perform fewer functions, contain less three-dimensional structure, are less likely to be post-translationally modified, and thus are generally characterized more easily than proteins. Consistent with the scientific literature, FDA has decided that the term “protein” in the statutory definition of biological product does not include peptides. To enhance regulatory clarity and minimize administrative complexity, FDA has decided to distinguish proteins from peptides based solely on size (i.e., number of amino acids).
 
Although scientific references do not agree on the criteria that distinguish proteins from peptides, including the exact size at which a chain of amino acids becomes a protein, several references support a threshold of 40 amino acids as defining the upper size boundary of a peptide. Accordingly, FDA considers any polymer composed of 40 or fewer amino acids to be a peptide and not a protein. Therefore, unless a peptide otherwise meets the statutory definition of a “biological product” (e.g., a peptide vaccine), it will be regulated as a drug under the FD&C Act.
 
The statutory category of “protein” parenthetically excludes “any chemically synthesized polypeptide.” There are several definitions of “polypeptide” in the scientific literature. Some are broad (e.g., polypeptide means any amino acid polymer), while others are more narrow (e.g., polypeptide means any amino acid polymer composed of fewer than 100 amino acids). FDA believes that a narrow definition of polypeptide is most appropriate in this context because, among other reasons, this avoids describing an exception to the category of protein using a term that relates to a larger category of molecules. Therefore, FDA interprets the statutory exclusion for “chemically synthesized polypeptide” to mean any molecule that is made entirely by chemical synthesis and that is composed of up to 99 amino acids. Such molecules will be regulated as drugs under the FD&C Act, unless the chemically synthesized polypeptide otherwise meets the statutory definition of a “biological product.”                                          
 
There may be additional considerations for proposed products that are combination products or meet the statutory definition of both a “device” and a “biological product.” We encourage prospective sponsors to contact FDA for further information on a product-specific basis.
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 Q.II.2.How is “product class” defined for purposes of determining whether an application for a biological product may be submitted under section 505 of the FD&C Act during the transition period?
 A.II.2.

(Proposed Answer): For purposes of section 7002(e)(2) of the Affordable Care Act, a proposed biological product will be considered to be in the same “product class” as a protein product previously approved under section 505 of the FD&C Act on or before March 23, 2010, if both products are homologous to the same gene-coded sequence (e.g., the INS gene for insulin and insulin glargine) with allowance for additional novel flanking sequences (including sequences from other genes). Products with discrete changes in gene-coded sequence or discrete changes in post-translational modifications may be in the same product class as the previously approved product even if the result may be a change in product pharmacokinetics.
 
For naturally derived protein products that do not have identified sequences linked to specific genes and that were approved under section 505 of the FD&C Act on or before March 23, 2010, a proposed biological product is in the same product class as the naturally derived protein product if both products share a primary biological activity (e.g., the 4-number Enzyme Commission code for enzyme activity).
 
However, for any protein product (whether naturally derived or otherwise), if the difference between the proposed product and the protein product previously approved under section 505 of the FD&C Act alters a biological target or effect, the products are not in the same product class for purposes of section 7002(e)(2) of the Affordable Care Act.
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