Note: The revision of this Import Alert (IA) dated 10/10/2024 updates the reason for alert, guidance section including agency contacts, and PAC. Changes to the import alert are bracketed by asterisks (***). *** A large volume of bulk drug substances, also known as active pharmaceutical ingredients (APIs), that are intended for use in the manufacture of drug products subject to a new drug application (NDA), abbreviated NDA (ANDA), biologics license application (BLA), or investigational new drug application (IND), or intended for use in laboratory or non-human research and development, or drug compounding are being offered for import into the United States. Under section 502(f)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act or the Act), a drug is deemed misbranded if its labeling fails to bear adequate directions for use. A drug in a bulk package (except tablets, capsules, or other dosage unit forms) intended for processing, repacking, or use in the manufacture of another drug is exempt from the requirements of 502(f)(1) if certain conditions are met pursuant to 21 CFR 201.122. Specifically, as relevant to human drug use, if the API is intended for a use that causes the finished article to be a new drug, the API will be exempt from section 502(f)(1) if it bears certain required labeling and: (1) an approved application covers the production and delivery of the API to the application holder by persons named in the application; (2) delivery is made for use only in the manufacture of such new drug limited to investigational use as provided in 21 CFR part 312; or (3) a pending application covers the use of the API in the production of a finished drug product, and the finished drug product is not further distributed after it is manufactured until the application is approved. See 21 CFR 201.122. In addition, there are certain uses of API that may be lawful and articles offered for import in accordance with these uses may not necessarily be subject to detention. For example: A. For certain laboratory or non-human research and development, such as for investigational use (see, e.g., 21 CFR 312.160). B. For manufacture of a drug product for use in a bioavailability (BA) or bioequivalence (BE) study in humans that qualifies for exemption from IND requirements. C. Uses of API for compounding in accordance with section 503A or 503B of the FD&C Act. For other uses of API involving compounding, import divisions should consult CDERImports@fda.hhs.gov. Some persons importing APIs have attempted to obtain entry of these articles by simply supplying an application number, that is, an NDA, ANDA, BLA, or IND number at the time of entry. Import Divisions should be alert to the possibility that: 1) the application number provided is not associated with the particular API or 2) the persons importing the API have no authorization to refer to the particular application number. In the past, the persons importing an API have referred to legitimate application numbers to get their APIs released, but the APIs were not destined for use in the applications referenced.***
Active Pharmaceutical Ingredients (APIs)
The article is subject to refusal of admission pursuant to section 801(a)(3) in that it appears to be a drug within the meaning of Section 201(g) and it lacks adequate directions for use. [Misbranding, Section 502(f)(1)] OASIS Charge Code: DIRSEXMPT
*** Divisions may detain without physical examination, shipments of APIs from the manufacturers identified on the Red List of this Alert because it appears that the APIs are misbranded based on their lack of adequate directions for use as required by section 502(f)(1) of the Act and their failure to meet the requirements of the exemption found in 21 CFR 201.122. Recommendations for additions to the Red List of this import alert should be forwarded to the Division of Import Operations (DIO). The Center for Drug Evaluation and Research (CDER) Office of Compliance (OC)/Office of Drug Security, Integrity, and Response (ODSIR)/Division of Global Drug Distribution and Policy (DGDDP)/Imports Compliance Branch will evaluate regulatory packages on a case-by-case basis.*** Release of Articles Subject to Detention Without Physical Examination Under This Import Alert: In order to secure release of an individual shipment subject to detention without physical examination under this Import Alert, the owner, consignee, and/or other responsible party associated with the shipment should provide evidence that the shipment does not contain a misbranded API. Manufacturers importing these APIs may obtain release of the detained articles if they can supply evidence establishing that the article is ***in compliance with relevant requirements. For example: 1. The API is intended for use in the manufacture of a drug product subject to an approved application, pending application, or pending supplement of an approved application in accordance 21 CFR 201.122. Information that may be reviewed includes: *** a. The API foreign manufacturer is registered, and the API and drug product are listed; b. The API foreign manufacturer is identified in the approved application, pending application, or pending supplement; c. The entry consignee is named in the approved application, pending application, or pending supplement; and d. The API labeling complies with the requirements in 21 CFR 201.122. 2. Intended for use in the manufacture of an investigational new drug for use in a clinical investigation subject to an Investigational New Drug Application (IND). ***Relevant information to review may include: a. The IND is active, i.e., in effect, consistent with 21 CFR 312.40, and the declared drug matches what is in the IND; or on earlier FDA authorization to ship the drug, consistent with 21 CFR 312.40 (c)(2); *** b. The importer of record, consignee, or firm listed in the entry documentation matches the sponsor or domestic agent of the foreign sponsor identified in the IND; and c. The API labeling complies with the requirement in 21 CFR 201.122(b). 3. Intended for use in laboratory or non-human research and development. ***Relevant information may include information that shows: a. The intended use of the API is limited to non-human research and development, such as for generation of data (e.g., to collect chemistry, manufacturing, and control information) to support submission of an application or supplement to an application, or submission of an IND. If an intended use statement is not provided with the entry, consider requesting an explanation of the API's intended use, including (1)the specific type of non-human research and development to be conducted; and (2) affirmation that the quantity of the drug offered for import is reasonable for the intended non-human research use.*** 4. Intended for use in the manufacture of a drug product for use in a BA or BE study in humans that qualifies for exemption from IND requirements. Verify: a. The intended use documentation includes information that justifies that the drug product is exempt from submitting an IND per 21 CFR 320.31. If help is needed, contact CDERImports@fda.hhs.gov and attach a copy of the entry documents to the email. 5. ***Intended for use in drug compounding. Relevant information to consider may include: a. The API foreign manufacturer is registered, and the API and drug product are listed; and b. The drug to be compounded has not been removed or withdrawn from the market for reasons of safety or effectiveness per 21 CFR 216.24. c. Other information or resources that may be relevant to FDA�s policies involving the compounding. If help is needed, contact CDERImports@fda.hhs.gov and attach a copy of the entry documents to the email. *** Removal from Detention Without Physical Examination (REMOVE FROM RED LIST): ***In order to remove a firm and its API from the Red List, information should be provided to the Agency to adequately demonstrate that the firm has resolved the conditions that gave rise to the appearance of the violation to give the Agency confidence that future shipments will be in compliance with the FD&C Act. For further guidance on removal from detention without physical examination, refer to FDA's Regulatory Procedures Manual, Chapter 9-8, "Detention without Physical Examination (DWPE). *** If a firm and/or a representative thereof would like to petition for removal from detention without physical examination under this Import Alert, all relevant information supporting the request should be forwarded to the following address: Food and Drug Administration Division of Import Operations 12420 Parklawn Drive, ELEM-3109 Rockville, MD 20857 Or, be sent via email to: Importalerts2@fda.hhs.gov. Questions or issues involving import operations should be addressed to ORA/DIO at (301) 796-0356 or FDAImportsInquiry@fda.hhs.gov. *** *** Questions or issues involving compliance of imported APIs should be addressed to the CDER/OC/ODSIR/DGDDP/Imports Compliance Branch at: cderimports@fda.hhs.gov.
This alert authorizes Detention Without Physical Examination (DWPE) for products matching this alert. Reason: Note: The revision of this Import Alert (IA) dated 10/10/2024 updates the reason for alert, guidance section including agency contacts, and PAC. Changes to the import alert are bracketed by asterisks (***). *** A large volume of bulk drug substances, also known as active pharmaceutical ingredients (APIs), that are intended for use in the manufacture of drug products subject to a new drug application (NDA), abbreviated NDA (ANDA), biologics license application (BLA), or investigational new drug application (IND), or intended for use in laboratory or non-human research and development, or drug compounding are being offered for import into the United States. Under section 502(f)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act or the Act), a drug is deemed misbranded if its labeling fails to bear adequate directions for use. A drug in a bulk package (except tablets, capsules, or other dosage unit forms) intended for processing, repacking, or use in the manufacture of another drug is exempt from the requirements of 502(f)(1) if certain conditions are met pursuant to 21 CFR 201.122. Specifically, as relevant to human drug use, if the API is intended for a use that causes the finished article to be a new drug, the API will be exempt from section 502(f)(1) if it bears certain required labeling and: (1) an approved application covers the production and delivery of the API to the application holder by persons named in the application; (2) delivery is made for use only in the manufacture of such new drug limited to investigational use as provided in 21 CFR part 312; or (3) a pending application covers the use of the API in the production of a finished drug product, and the finished drug product is not further distributed after it is manufactured until the application is approved. See 21 CFR 201.122. In addition, there are certain uses of API that may be lawful and articles offered for import in accordance with these uses may not necessarily be subject to detention. For example: A. For certain laboratory or non-human research and development, such as for investigational use (see, e.g., 21 CFR 312.160). B. For manufacture of a drug product for use in a bioavailability (BA) or bioequivalence (BE) study in humans that qualifies for exemption from IND requirements. C. Uses of API for compounding in accordance with section 503A or 503B of the FD&C Act. For other uses of API involving compounding, import divisions should consult CDERImports@fda.hhs.gov. Some persons importing APIs have attempted to obtain entry of these articles by simply supplying an application number, that is, an NDA, ANDA, BLA, or IND number at the time of entry. Import Divisions should be alert to the possibility that: 1) the application number provided is not associated with the particular API or 2) the persons importing the API have no authorization to refer to the particular application number. In the past, the persons importing an API have referred to legitimate application numbers to get their APIs released, but the APIs were not destined for use in the applications referenced.***
Country-specific information is available in the full alert detail on the FDA website.
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