[Federal Register Volume 89, Number 143 (Thursday, July 25, 2024)]
[Notices]
[Pages 60436-60438]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-16356]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2024-N-2980]


Evaluating the Immunogenicity Risk of Host Cell Proteins in 
Follow-On Recombinant Peptide Products; Establishment of a Public 
Docket; Request for Information and Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; establishment of a public docket; request for 
information and comments.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is 
establishing a public docket to collect information and comments on 
evaluating and mitigating the immunogenicity risk of host cell proteins 
(HCPs). For the purpose of this request, FDA is specifically interested 
in comments on suitable methods to detect, identify, and quantify HCPs, 
on achievable residual amounts of HCPs for recombinant peptide 
products, and on the use of in vitro, in silico immunogenicity 
assessment (IVISIA) of HCPs in a recombinant peptide (rPeptide) 
product. For the purpose of this request, a ``follow-on'' peptide 
product refers to the applications currently evaluated through the 
505(b)(2) pathway. Although follow-on recombinant peptide products can 
rely on FDA's findings of safety and effectiveness for a listed drug 
that is a peptide product, differences in recombinant expression 
systems used during the peptide production could result in quality 
attribute differences, including in the HCP profile, which in turn, 
could contribute to differences in immunogenicity risks between a 
follow-on recombinant peptide product and the listed drug. The public 
comments collected will help FDA develop recommendations on how HCP 
control and characterization can support comparative immunogenicity 
risk assessment between a recombinant follow-on peptide and the listed 
product.

[[Page 60437]]


DATES: 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.

ADDRESSES: 

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2024-N-2980 for ``Evaluating the Immunogenicity Risk of Host Cell 
Proteins in Follow-On Recombinant Peptide Products; Establishment of a 
Public Docket; Request for Information and Comments.'' Received 
comments, those filed in a timely manner (see ADDRESSES), will be 
placed in the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at https://www.regulations.gov or at 
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through 
Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Mohsen Rajabiabhari, Office of 
Clinical Pharmacology, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 
20993-0002, 240-402-2794.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA for purposes of this notice uses the term ``peptide'' to refer 
to alpha amino acid polymers composed of 40 or fewer amino acids.\1\ 
Peptides can be isolated from natural sources or produced synthetically 
or through recombinant expression in a host cell. Peptides that are 
isolated from recombinant (i.e., genetically-modified) prokaryotic or 
eukaryotic host cells using cell culture/fermentation techniques are 
called recombinant peptides (rPeptides).
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    \1\ See, e.g., FDA Final Rule ``Definition of the Term 
`Biological Product' '' (85 FR 10057, March 23, 2020).
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    HCPs are process-related impurities derived from the host cell that 
may copurify with the recombinant peptide of interest and be present in 
the final drug product. HCPs are characterized and routinely well 
controlled during manufacturing of the peptide product. The types and 
amounts of HCPs in a product differ depending on many parameters, 
including differences in the expression cell substrate, culture 
conditions, the purification process, and amongst different facilities. 
Therefore, for a proposed follow-on rPeptide product, differences in 
HCP profiles between the follow-on product and the listed drug would be 
expected, and such differences have the potential to impact the safety 
and/or efficacy of the follow-on product by increasing that product's 
immunogenicity risk. Advances in technology may support the use of 
IVISIA methods to assess comparative immunogenicity risk.

II. Request for Information and Comments

    Interested persons are invited to provide detailed information 
(including any supportive data) and comments on suitable methods to 
detect, identify, and quantify HCPs and the minimal residual amounts of 
HCPs achievable in commercial lots of rPeptide products. Specifically, 
to assess the potential impact of HCP differences, FDA is interested in 
responses to the following questions:
    1. What is the lowest and routinely achievable level of total HCPs 
across your well-controlled rPeptide manufacturing process(es), and how 
are they calculated/established?
    2. What are the challenges in reducing HCP levels?
    3. What analytical methods are currently being used to detect, 
identify, and quantify HCPs in a rPeptide product? Do you conduct 
comparative assessments of HCPs, such as ELISA (enzyme-linked 
immunosorbent assay) vs LC/MS/MS (liquid chromatography tandem mass 
spectrometry), during manufacturing development? What is the 
sensitivity of these methods for detecting HCPs and their limits of 
quantification? Are you using a combination of orthogonal analytical 
methods (such as ELISA + LC/MS/MS) for HCP control during process 
development and manufacturing?

[[Page 60438]]

    4. What is the generally achievable percent coverage \2\ of the HCP 
spectrum for your HCP quantification assay? What considerations, (e.g., 
percent coverage of HCPs, other coverage characteristics, etc.), are 
important in choosing methods to evaluate HCPs?
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    \2\ HCP coverage is an estimate of the percentage of HCPs 
specific to a cell substrate detected or covered by the capture 
antibodies of the ELISA. This coverage analysis is often done using 
2D techniques.
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    5. Are there any qualitative or quantitative characteristics of 
HCPs associated with a higher likelihood of adverse clinical sequelae?
    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 upon such data?
    The public comments collected will help FDA develop recommendations 
on how HCP control and characterization can support comparative 
immunogenicity risk assessment between a recombinant follow-on peptide 
and the listed product.

III. Electronic Access

    Persons with access to the internet may obtain relevant guidance at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-pharmacology-considerations-peptide-drug-products.

    Dated: July 18, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-16356 Filed 7-24-24; 8:45 am]
BILLING CODE 4164-01-P