[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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).
---------------------------------------------------------------------------
\1\ See, e.g., FDA Final Rule ``Definition of the Term
`Biological Product' '' (85 FR 10057, March 23, 2020).
---------------------------------------------------------------------------
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?
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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