Host Cell Proteins - FDA seeks Comments on Immunogenicity Assessment

The Food and Drug Administration (FDA or Agency) is establishing a public notice to solicit information and comments on assessing and mitigating the immunogenicity risk of host cell proteins (HCPs). As part of this request, the FDA is particularly interested in comments on appropriate methods for the detection, identification, and quantification of HCPs, achievable residual levels of HCPs for recombinant peptide products, and the use of in vitro, in silico immunogenicity assessment (IVISIA) of HCPs in a recombinant peptide product (rPeptide). For the purposes of this application, a ‘follow-on’ peptide product refers to those applications currently being evaluated through the 505(b)(2) pathway. Although recombinant peptide follow-on products may rely on FDA's safety and efficacy determinations for a listed drug that is a peptide product, differences in the recombinant expression systems used during peptide production could result in differences in quality attributes, including HCP profile, which in turn could contribute to differences in immunogenicity risks between a recombinant peptide follow-on product and the listed drug. The public comments collected will help the FDA to develop recommendations on how the control and characterisation of HCPs can support the comparative immunogenicity risk assessment between a recombinant follow-on peptide and the approved product. Although you can submit comments and information at any time, to ensure that the Agency considers your comment in our development of recommendations, submit either electronic or written information and comments by September 23, 2024.

Comment address

Electronic submissions should be submitted on the Federal eRulemaking Portal. Confidential submissions, i.e., those that should not be made publicly available, are also acceptable. Such comments containing confidential information should be submitted in writing or on paper. A total of two copies should be submitted, one copy containing the information you consider confidential and with a heading or cover page indicating that this document contains confidential information. The Agency will use this copy, including the requested confidential information, when reviewing the comments. The second copy, with the requested confidential information redacted, will be made available for public inspection and posted on the portal. There is also an option, if you do not want your name and contact details to be published, to include this information on the cover page rather than in the body of your comment and mark it as ‘confidential’. Any information marked ‘confidential’ will be disclosed only in accordance with 21 CFR 10.20 and other applicable disclosure laws. More information is available in FDA's disclosure of comments in public dockets, or see 80 FR 56469, 18 September 2015.

Additional substantive information

I. Background
The FDA uses the term ‘peptide’ in this notice to refer to alpha-amino acid polymers consisting of 40 or fewer amino acids. Peptides can be isolated from natural sources or produced synthetically or by recombinant expression in a host cell. Peptides isolated from recombinant sources (i.e., genetically modified) prokaryotic or eukaryotic host cells by cell culture/fermentation processes are referred to as recombinant peptides (rPeptides). The FDA describes at this point:
HCPs are process-derived impurities from the host cell that copurify with the recombinant peptide of interest and may be present in the final drug product. HCPs are characterised and routinely well controlled during the manufacture of the peptide product. The types and amounts of HCPs in a product depend on many parameters, including differences in the substrate of the expression cells, culture conditions, purification procedure and between different facilities. Therefore, for a proposed rPeptide follow-on product, differences in HCP profiles between the follow-on product and the listed drug product are to be expected, and these differences may impact the safety and/or efficacy of the follow-on product by increasing the immunogenicity risk of that product. Advances in technology may support the use of IVISIA methods to assess comparative immunogenicity risk. Comments submitted by 23 September will be considered. This cannot be guaranteed for comments submitted later.

II. Request for comments
Interested parties are invited to submit detailed information (including supporting data) and comments on appropriate methods for the detection, identification and quantification of HCPs and the minimum residual levels of HCPs that can be achieved in commercial batches of rPeptide products. To assess the potential impact of HCP differences, the FDA is particularly interested in answers to the following questions:

1. What is the lowest and routinely achievable total HCP content in your well-controlled rPeptide manufacturing processes, and how is it calculated/determined?
2. What are the challenges in reducing HCP levels?
3. What analytical methods are currently used to detect, identify and quantify HCPs in a rPeptide product? Do you perform comparative assessments of HCPs during production development, e.g. ELISA (enzyme-linked immunosorbent assay) versus LC/MS/MS (liquid chromatography tandem mass spectrometry)? How sensitive are these methods for the detection of HCPs and what are their quantification limits? Do you use a combination of orthogonal analytical methods (e.g. ELISA + LC/MS/MS) for HCP control during process development and manufacturing?
4. What is the generally achievable percentage coverage of the HCP spectrum for your HCP quantification test? What considerations (e.g., percentage coverage of HCPs, other coverage characteristics, etc.) are important when selecting methods for evaluating HCPs?
5. Are there qualitative or quantitative characteristics of HCPs that are associated with a higher likelihood of adverse clinical outcomes?
6. What tools (in silico, in vitro or in vivo studies) do you currently use or plan to use to compare the potential immunogenicity risk of two products with different HCP profiles? What is your approach to risk assessment of HCPs based on such data?

For more information, see the Federal Register at [Docket No. FDA-2024-N-2980]