在梳理这个问题前，我们可以先看看FDA相关法规关于生产商和持有人定义，具体如下： 

在美国21 CFR 207.1中对生产商的定义（如下）：

Manufacturer means a person who owns or operates an establishment that manufactures a drug or an animal feed bearing or containing a new animal drug. This term includes, but is not limited to, control laboratories, contract laboratories, contract manufacturers, contract packers, contract labelers, and other entities that manufacture a drug, or an animal feed bearing or containing a new animal drug, as defined in this paragraph. For purposes of this part, and in order to clarify the responsibilities of the entities engaged in different operations, the term manufacturer is defined and used separately from the terms relabeler, repacker, and salvager, although the term “manufacture, preparation, propagation, compounding, or processing,” as used in section 510 of the Federal Food, Drug, and Cosmetic Act, includes the activities of relabelers, repackers, and salvagers. Repackers, relabelers, and salvagers are subject to the provisions of this part that are applicable to repackers, relabelers, and salvagers, but are not subject to the provisions of this part that are applicable to manufacturers. When not modified by “domestic” or “foreign,” the term includes both domestic manufacturers and foreign manufacturers.

对于生产商，简言之的核心意思是：拥有或经营一家生产药物或动物饲料企业的人。

在美国21 CFR 314.3中对持有人的相关定义（如下）：

ANDA holder is the applicant that owns an approved ANDA.

Applicant is any person who submits an NDA (including a 505(b)(2) application) or ANDA or an amendment or supplement to an NDA or ANDA under this part to obtain FDA approval of a new drug and any person who owns an approved NDA (including a 505(b)(2) application) or ANDA.

可见ANDA 持有人系指拥有已获批准的ANDA的申请人。而对于申请人，简言之的核心意思是：提交 NDA（包括 505(b)(2) 申请）或 ANDA，包括增补等的任何人。 

同样地根据美国21 CFR 314.420, Drug Master Files和FDA发布的DMF工业指南（Drug Master Files for Industry，draft）描述，DMF持有人（holder）系指向FDA提交DMF资料的权属人。

根据美国的联邦管理法规定，药品进入美国须向美国食品药品监督管理局（FDA）申请注册并递交有关文件，诸如ANDA，其中药品使用的活性物质需要提供相关的生产和质量控制信息，可以通过DMF提交。

DMF是用来提供有关一种或多种人用药品的制造、加工、包装和贮藏中使用的设施、工艺和物料的详细机密信息的一份文件，也称药物主文件。DMF的提交并无法律和FDA的规章的必需要求，提交与否完全由持有人自行决定。DMF没有批准与否，只有当经过备案的原料药被其他厂商使用时，FDA才会启动审核。 另一方面，制剂厂家需要引用DMF，需要持有人签署授权信给制剂申请人后，对方才可以引用。

查阅FDA目前发布的关于ANDA和DMF的指南，可以发现对于一个药品或原料药的DMF相关活动包括它们的提交与申请、授权与引用、沟通与联系（如变更通知）、费用缴纳、GMP符合性、药物安全性等等，其责任主体均为持有人或申请人，并不直接和生产商关联。

【思考和建议】

1、生产商把持有人给第三方，从药政监管角度，主体的决策和权力基本已经失去了。

2、对于市场销售的自由决策权这类个人理解是纯商业行为，并不在FDA法规明文范围内，建议生产商可以考虑通过合同和第三方持有人协商、约定。

【法规依据与参考指南】 

21 CFR 207.1

21 CFR 314.3

21 CFR 314.420

Drug Master Files for Industry

以上，希望对你有所帮助。

美国市场，对于原料药DMF，只有持有人签署授权书（LOA）给制剂客户参引，FDA才会对DMF进行正常的审评批准，否则制剂客户无法参引相关的文件