API 非直接出口美国是否要做Drug Establishment Registration

偶尔范范小糊涂

引坛友的帖子https://www.ouryao.com/thread-321333-1-1.html。

1. 即非直接进口至美国的API，关联的制剂（非美国）在在申请美国上市销售。
上述这种情况，是否需要做Drug Establishment Registration？ （除了FDA邮件, 告知，是否有法规明确？有没有大佬给个指示）
（FDA电话告知：不直接出口不需要做）？？？？？？

已知API 企业是需要做Self-Identification的
根据FDA 指南Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing（如附件所示）
1. Who must register, when, and how?
The owner or operator of an establishment entering into the manufacture, preparation, propagation, compounding, or processing (which includes, among other things, repackaging and relabeling) of a drug or drugs14 and not exempt under section 510(g) of the Act or subpart B of 21 CFR part 207, must register the establishment with FDA within 5 days after beginning the operation (21 CFR 207.21(a) and 21 CFR 207.3(a)(8)).
Alternatively, if the establishment has not previously entered into such an operation, the owner or operator must register within 5 days after submitting (among other things) a drug application, biological license application, or medicated feed mill license application. (21 CFR 207.21(a)). Owners or operators must renew their registration information annually (Section 510(b)(1) of the Act; 21 CFR 207.21(a)).

Establishments within any foreign country that engage in the manufacture, preparation, propagation, compounding, or processing (which includes, among other things, repackaging and relabeling) of a drug that is imported or offered for import into the United States (and that are not exempt) must upon first engaging in such activity immediately register and register annually thereafter (Section 510(i) of the Act; 21 CFR 207.40). Amendments to drug establishment registration must be submitted in accordance with 21 CFR 207.26.

§ 207.21 When must initial registration information be provided?（www.ecfr.gov)  

(a) Registrants must register each domestic establishment no later than 5 calendar days after beginning to manufacture, repack, relabel, or salvage a drug or an animal feed bearing or containing a new animal drug at such establishment.

(b) Registrants must register each foreign establishment before a drug or an animal feed bearing or containing a new animal drug manufactured, repacked, relabeled, or salvaged at the establishment is imported or offered for import into the United States.

§ 207.17 Who must register?  

(a) Unless exempt under section 510(g) of the Federal Food, Drug, and Cosmetic Act or this part, all manufacturers, repackers, relabelers, and salvagers must register each domestic establishment that manufactures, repacks, relabels, or salvages a drug, or an animal feed bearing or containing a new animal drug, and each foreign establishment that manufactures, repacks, relabels, or salvages a drug, or an animal feed bearing or containing a new animal drug, that is imported or offered for import into the United States. When operations are conducted at more than one establishment and common ownership and control among all the establishments exists, the parent, subsidiary, or affiliate company may submit registration information for all establishments

§ 207.21 When must initial registration information be provided?  

(a) Registrants must register each domestic establishment no later than 5 calendar days after beginning to manufacture, repack, relabel, or salvage a drug or an animal feed bearing or containing a new animal drug at such establishment.

(b) Registrants must register each foreign establishment before a drug or an animal feed bearing or containing a new animal drug manufactured, repacked, relabeled, or salvaged at the establishment is imported or offered for import into the United States.

同时根据Electronic Drug Registration and Listing Instructions

（https://www.fda.gov/drugs/electronic-drug-registration-and-listing-system-edrls/electronic-drug-registration-and-listing-instructions）

Do I need to register?

Any establishment, with certain exemptions, engaged in manufacturing, repacking, relabeling or salvaging drug products for U.S. distribution is required to register with FDA. Some exemptions include:

• Pharmacies that:
  
  • Operate in conformance with local laws regulating the practice of pharmacy and medicine
  • Regularly engage in dispensing prescription drugs to fill patients’ prescriptions
  • Do not manufacture, repack, relabel or salvage drugs other than in the regular course of their business of dispensing or selling drugs at retail
    
• Hospitals, clinics, other health care entities and public health agencies that:
  
  • Operate establishments in conformance with all applicable local laws regulating the practice of pharmacy and medicine
  • Regularly engage in dispensing prescription drugs upon a valid order or prescription
  • Do not manufacture, repack, relabel or salvage drugs other than in the regular course of their practice of pharmacy, including dispensing
    
• Licensed practitioners who prescribe or administer drugs and who manufacture, repack, relabel or salvage drugs for use only in their professional practice
• Companies or individuals that manufacture, repack, relabel or salvage drugs solely for use in research, teaching or chemical analysis and not for sale
• Manufacturers, repackers and relabelers of certain inactive ingredients such as excipients, colorings, flavorings, emulsifiers, lubricants, preservatives or solvents that become components of drugs
• Carriers in their receipt, carriage, holding or delivery of drugs in their usual course of business
• Storage facilities that do not perform any manufacturing function
  

通过SPL文件，可知有Type 中有APi 制造选项。

偶尔范范小糊涂

21 CFR 207.3(a)(8))
§ 207.3 Bulk drug substance.
Bulk drug substance,   as referenced in sections 503A(b)(1)(A) and 503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, previously defined in in.207.1
此处涉及到APi
最终在503B(a)(2) 找到了答案

偶尔范范小糊涂

最终根据和EDRLS@fda.hhs.gov的联系，得到以上的回复：
The FDA statute requires all establishments in the final marketable drug product’s supply chain to register and list.
That includes the manufacturer of the active pharmaceutical ingredient (API) used in the product awarded ANDA approval.