Key Takeaways
- On Sept. 5, the FDA announced an import alert and green list for glucagon-like peptide-1 (GLP-1) active pharmaceutical ingredient (API) manufacturers.
- The FDA included manufacturers on the green list who, based on the FDA’s evaluation of on-site inspections and remote regulatory assessments, appear to be in compliance with current Good Manufacturing Practices.
- Although the names of the included manufacturers are at this time redacted, once the unredacted list is available, importers and compounders should ensure that they source API from a manufacturer on the GLP-1 Green List.
In response to the Food and Drug Administration’s (FDA) announcement on Sept. 5 establishing an Import Alert Green List for glucagon-like peptide-1 (GLP-1) active pharmaceutical ingredient (API), this article explains the FDA’s authority over imports – and import alerts generally – and specifically examines the meaning and effect of the FDA’s GLP-1 Green List.
FDA Authority Over Imports
The FDA’s authority over imports comes from the Federal Food, Drug, and Cosmetic Act’s (FDCA) Section 801,[1] which gives the FDA authority to refuse entry to the United States of products that appear to be in violation of the FDCA or FDA regulations. The violations may be based on, for example, the appearance that the article was manufactured, processed or packed under insanitary conditions[2] or not in compliance with current Good Manufacturing Practices (cGMP),[3] or that the article is adulterated[4] or misbranded[5] or is a new drug not in compliance with Section 505[6] of the FDCA regarding the approval of new drugs.
Types of FDA Actions
With regard to API for use in pharmacy compounding, a common Notice of FDA Action for a specific shipment is a detention[7] alleging the API is misbranded under FDCA Section 502(f)(1),[8] which requires drugs to have adequate directions for use. This allegation is typically based on a comparison of the paperwork accompanying the API against the tracking of the import in the FDA’s and Customs and Border Patrol’s electronic tracking systems. This allegation can be overcome by providing an end use letter citing that the imported article is intended for use in pharmacy compounding because Section 503A[9] and Section 503B[10] of the FDCA exempt drug products for compounding from compliance with the “adequate directions for use” provision of the FDCA when certain conditions are met. As another example, the FDA may detain an investigational drug if it is coded in the electronic system as investigational and the supporting paperwork does not confirm the sponsor holds an Investigational New Drug Application. Additionally, rather than conducting a mere paperwork or appearance review, the FDA may sample an article intended for import.[11] Whenever the FDA intends to sample an article intended for import, it issues a Notice of Sampling to the importer of record, consignee and filer, notifying them of its intent to sample the article.[12] The FDA’s next steps depend on whether the assay performed on the sample shows the product to be in compliance or not.
Aside from detention or sampling of specific shipments, the FDA has authority to detain future shipments of a specific product, a product from a specific firm or products from a specific country, typically based on a history of violations or because the product or firm has been placed on an import alert.[13] The FDA refers to this type of detention as Detention Without Physical Examination (DWPE).[14] DWPE was first used by the FDA in 1974.[15] DWPE serves to remind importers of their responsibility for ensuring compliance generally rather than attempting an import and being issued a Notice of FDA Action – Detention.[16]
Import Alerts
According to the FDA, import alerts are used to improve uniformity of enforcement with regard to the firm or product at issue in the alert.[17] Import alerts follow a specific format, including having an Import Alert Name, a Reason for the Alert and Guidance regarding the actions the FDA may take.[18] Import alerts may[19] have Red, Yellow and Green lists, with the colors loosely corresponding to the meaning of a traffic signal. A Red List is for firms or products that have met the criteria for DWPE.[20] A firm or product on an Import Alert Red List will be detained.[21] A Yellow List is for firms, products and/or countries subject to intensified surveillance or firms that may have satisfied prior cGMP issues but the nature of whose violations may warrant further field examinations of individual entries and/or additional analyses.[22] A firm or product on an Import Alert Yellow List will face increased scrutiny at the border.[23] A Green List is for firms, products and/or countries that have met criteria for exemption from DWPE under an import alert.[24] A firm or product on an Import Alert Green List is not automatically detained and is not expected to face increased scrutiny; however, as part of the FDA’s routine surveillance, it is possible for detention to occur as a result of conditions unrelated to the Green List.[25]
FDA’s Import Alert 66-80, ‘Detention Without Physical Examination of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Bulk Drug Substances’
As mentioned at the beginning of this alert, on Sept. 5, the FDA published an import alert titled “Detention Without Physical Examination of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Bulk Drug Substances.” As you now know from the above information, the DWPE designation is a result of a history of noncompliance associated with the product class. The Guidance given to FDA officials in the import alert is:
Divisions may detain without physical examination (DWPE) shipments of GLP-1 APIs offered for entry, except for the products and firms identified on the Green List of this Alert. The Green List, as of the date of initial issuance of this import alert, lists GLP-1 APIs of registered foreign manufacturers whose facilities and associated products, based on FDA’s evaluation of recent evidence, appear to be in compliance with CGMP requirements.[26] (Emphasis added.)
Accordingly, establishments on the FDA’s GLP-1 Green List are not subject to DWPE. GLP-1 products from Green List firms will not automatically be detained and are not expected to face increased scrutiny. The GLP-1 Green List was developed as a result of both FDA on-site inspections and remote regulatory assessments.[27] Thirty-seven manufacturers were placed on the FDA’s GLP-1 Green List as of Sept. 5.[28] Import Alert 66-80 also contains instructions for firms seeking to be added to the Green List so as to not be subject to DWPE.
Although at the time of this writing the manufacturer names on the Green List have been redacted, the manufacturers have received letters notifying them of their inclusion on the list that contain instructions to authorize the FDA to publicize the unredacted information. Because inclusion on the Green List indicates the FDA’s conclusion that the manufacturer appears to be in compliance with cGMP requirements, we anticipate most firms will agree to FDA publication of their names. Once the unredacted list is available, importers and compounders should ensure that they source API from a manufacturer on the GLP-1 Green List.
It must also be noted that despite ongoing attempts by pharmaceutical manufacturers to spread misinformation about the legitimacy of pharmacy compounding, including attempts to commandeer the enforcement and rulemaking authority of state regulatory entities,[29] the FDA’s publication of a Green List specific to GLP-1 API manufacturers amounts to acknowledgment from the FDA of a legitimate need for pharmacy compounding of GLP-1 products as long as the applicable regulatory requirements are met.
[1] 21 USC 381.
[2] 21 USC 381(a)(1).
[3] 21 USC 381(a)(3), “Adulterated” includes not conforming with cGMP at 21 USC 351(a)(2)(b).
[4] 21 USC 381(a)(3), “Adulterated” defined at 21 USC 351.
[5] 21 USC 381(a)(3), “Misbranded” defined at 21 USC 352.
[6] 21 USC 355.
[7] FDA, Regulatory Procedures Manual, Chapter 9: Import Operations and Actions, Section 9-9, Notice of FDA Action – Detained for Non-Mail Shipments. https://www.fda.gov/media/71776/download.
[8] 21 USC 352(f)(1), (“A drug or device shall be deemed to be misbranded – unless its labeling bears (1) adequate directions for use”).
[9] 21 USC 353a.
[10] 21 USC 353b.
[11] FDA, Regulatory Procedures Manual, Chapter 9: Import Operations and Actions, Section 9-1-4, Sampling. https://www.fda.gov/media/71776/download.
[12] Id.
[13] Id. at Section 9-8, Detention Without Physical Examination, and Section 9-15-4, Import Alerts.
[14] Id. at Section 9-8, Detention Without Physical Examination.
[15] Id.
[16] Id.
[17] Id.
[18] FDA, How to Read an Import Alert. https://www.fda.gov/industry/import-alerts/how-read-import-alert.
[19] FDA, Import Alerts. https://www.fda.gov/industry/actions-enforcement/import-alerts.
[20] FDA, Industry FAQs for Import Alerts, What is a red, green and yellow list? https://www.fda.gov/industry/import-alerts/industry-faqs-import-alerts
[21] Id.
[22] Id.
[23] Id.
[24] Id.
[25] Id.
[26] FDA, Import Alert 66-80, “Detention Without Physical Examination of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Bulk Drug Substances.” https://www.accessdata.fda.gov/CMS_IA/importalert_1186.html?utm_medium=email&utm_source=govdelivery.
[27] Id.
[28] Id.
[29] See, for example, Iowa Legislature, Committees & Schedules, Meetings, Committee Meetings, Administrative Rules Review Committee, Aug. 11 at approximately 10:48:15. https://www.legis.iowa.gov/committees/meetings/meetingsListComm?groupID=705&ga=91.
