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Federal Register / Vol. 86, No. 171 / Wednesday, September 8, 2021 / Notices
B. Participation The Pilot Program will consist of two stages. The first stage is an initial proposal stage for excipient manufacturers to provide a high-level overview of their novel excipient. CDER
intends to accept approximately four initial proposals two for the first year of the Pilot Program, and two for the second year but will consider accepting more proposals as resources allow.
Excipient manufacturers whose initial proposals are accepted would then enter the second stage, during which they would provide a full data package consisting of toxicology and quality data. Both stages are described in further detail below.
As mentioned above, CDER intends to consider for the Pilot Program novel excipients that 1 have not been previously used in FDA-approved drug products, and 2 do not have an established use in food.
C. Procedures
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1. Initial Proposal Stage At the initial proposal stage, excipient manufacturers will submit brief summaries describing the novel excipient, its proposed use, and the public health or drug development need addressed by the excipient. The initial proposal is anticipated to include a summary of the supportive data generated or collected so far and some indication of the timing of any subsequent data needed for submission of the Full Package. FDA has posted an initial proposal model content outline on the Pilot Program web page https
www.fda.gov/drugs/developmentapproval-process-drugs/novel-excipientreview-pilot-program.
Interested excipient manufacturers should submit initial proposals to FDA
via email at Novel-Excipient-Program@
fda.hhs.gov. FDA will accept proposals for the pilot through December 7, 2021.
FDA will notify all submitters whether their proposal is accepted into the Pilot Program.
FDA will review the initial proposals and select approximately four proposals two for the first year and two for the second year to proceed to stage two of the program. FDA will consider the following factors, among other considerations, in determining which proposals to select:
Potential public health benefit of the novel excipient for example, excipients that may facilitate opioid abuse-deterrent formulations or excipients that may promote development of new therapies for serious and life-threatening diseases.

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Likelihood of the novel excipient manufacturers ability to submit a complete package within the timeframe established in this Notice.
Overall potential of the novel excipient to meaningfully improve pharmacokinetic characteristics that may lead to novel drug development.
2. Procedures for Full Packages For novel excipients selected into the program, the developer should submit a full package consisting of toxicology and quality data as described below. See CDER Guidance for industry entitled Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients Ref. 1.
a. Toxicology data package. The toxicology data package should include adequate, supportive safety information for the novel excipient to verify that the proposed excipient is safe in the amounts and type of products in which it may be administered as well as the proposed use e.g., level, route, duration, patient population.
Depending on the proposed use, the toxicology data package may include the information described below.
Additional safety data may be requested if the proposed use is not fully supported by the available data.
Reference is made to the relevant guidance for the proposed toxicology data package below.
Safety pharmacology: Novel excipients should be evaluated for pharmacological activity using a battery of standard tests see FDA guidance for industry entitled S7A Safety Pharmacology Studies for Human Pharmaceuticals Ref. 2.
Pharmacokinetic testing absorption, distribution, metabolism, and excretion: To determine the extent of exposure. A pharmacokinetic profile for an excipient that is extensively absorbed, undergoes extensive biotransformation, or both will be useful.
General toxicology: Chronic, 6month repeat dose toxicology studies in a relevant species by appropriate route with complete clinical pathology, histopathology, and toxicokinetic analysis are recommended. Because excipients generally have low toxicity, the limit dose is recommended as the highest dose for testing see FDA
guidance for industry entitled M3R2
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals Ref. 3.
Genetic toxicology see FDA
guidance for industry entitled S2B
Genotoxicity: A Standard Battery for
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Genotoxicity Testing of Pharmaceuticals Ref. 4.
Reproductive toxicology: Fertility, embryo-fetal, and preand post-natal development see International Council for Harmonization harmonized guidance for industry entitled Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals S5R3 Ref. 5.
Carcinogenicity: One of the following approaches may be used to evaluate carcinogenic potential see FDA guidance for industry entitled The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals Ref. 6:
Two-year carcinogenicity bioassays in two appropriate species by the relevant route;
A 2-year carcinogenicity study in rat plus a transgenic mouse model; or Submission of documentation providing scientific justification that carcinogenicity data are not necessary based on the weight of evidence approach in an assessment to address the carcinogenic potential.
Special studies e.g., local tolerance, Juvenile Animal Studies.
b. Quality data package. The novel excipient chemistry, manufacturing, and controls data submitted to CDER should be similar to that provided in an investigational new drug application IND.
For evaluation of all novel excipients with a proposed use in formulations for small molecule and biological drug products reviewed by CDER/Office of New Drugs OND, submitters should provide:
Excipient specifications.
A description of the source, synthetic pathway/fermentation or extraction for non-synthetic excipients, raw materials, in-process controls, manufacturing process description, characterization and analytical methods, or a letter of authorization right of reference for the excipient Type IV
drug master file DMF or other master file if a master file has been submitted for the excipient.
If the excipient contains a novel moiety with immunogenic potential, an immunogenicity risk assessment that may include in vitro data. Additional information on immunogenicity risk assessment may be found in FDA
guidance for industry entitled S8
Immunotoxicity Studies for Human Pharmaceuticals for types of supporting in vitro studies Ref. 7.
If the excipient is sourced from cells, clearance of host cell protein absence in final excipient and evidence of absence of adventitious agents such as viruses.

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