The Generic Drug User Fee Amendments of 2012 (GDUFA) requires that human generic drug facilities, and certain sites and organizations identified in a generic drug submission, provide identification information annually to FDA. This information will assist in constructing an accurate inventory of facilities, sites and organizations involved in the manufacture of generic drugs, setting annual facility fee amounts, and targeting inspections.
- Who is required to self-identify?
- What identification information is required? “Technical Specifications for Self-Identification"
- What is the process for submitting self-identification information?
- Are all facilities, sites, and organizations that must self-identify also required to pay facility fees?
- What is the penalty for failing to self-identify?
The following types of generic industry facilities, sites, and organizations are required to self-identify with FDA:
- Facilities1 that manufacture, or intend to manufacture, human generic drug APIs or FDFs, or both.2
- Sites and organizations that package the FDF of a human generic drug into the primary container/closure system and label the primary container/closure system.3
- Sites that are identified in a generic drug submission and pursuant to a contract with the applicant remove the drug from a primary container/closure system and subdivide the contents into a different primary container/closure system.
- Bioequivalence (BE)/bioavailability (BA) sites that are identified in a generic drug submission and conduct clinical BE/BA testing, bioanalytical testing of samples collected from clinical BE/BA testing, and/or in vitro BE testing.
- Sites that are identified in a generic drug submission and perform testing of one or more attributes or characteristics of the FDF or the API pursuant to a contract with the applicant to satisfy a current good manufacturing practice (CGMP) testing requirement (excludes sites that are testing for research purposes only).
1GDUFA defines a facility as a business or other entity under one management, either direct or indirect, at one geographic location or address, engaged in manufacturing or processing an API or an FDF. It does not include a business or other entity whose only manufacturing or processing activities are one or more of the following: repackaging, relabeling, or testing. Separate buildings within close proximity are considered to be at one geographic location or address if the activities in them are closely related to the same business enterprise; are under the supervision of the same local management; and are capable of being inspected by FDA during a single inspection.
2 For purposes of self-identification and payment of fees, GDUFA defines API and FDF manufacturers differently from the way these categories of manufacturers have been defined historically. For example, generic drug manufacturers who mix an API when the substance is unstable or cannot be transported on its own are considered API manufacturers and not FDF manufacturers for self-identification and the payment of GDUFA fees only.
GDUFA defines an FDF as:
(A) a drug product in the form in which it will be administered to a patient, such as a
tablet, capsule, solution, or topical application;
(B) a drug product in a form in which reconstitution is necessary prior to administration to a patient, such as oral suspensions or lyophilized powders; or
(C) any combination of an active pharmaceutical ingredient (as defined in the statute) with another component of a drug product for purposes of production of a drug product described in subparagraph (A) or (B).
GDUFA defines an API as:
(A) a substance, or a mixture when the substance is unstable or cannot be transported on its own, intended—
(i) to be used as a component of a drug; and
(ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body; or
(B) a substance intended for final crystallization, purification, or salt formation, or any combination of those activities, to become a substance or mixture described in subparagraph (A).
3 Sites and organizations that package the FDF of a human generic drug into the primary container/closure system and label the primary container/closure system are considered to be manufacturers, whether or not that packaging is done pursuant to a contract or by the applicant itself.
Self-identification files should be formatted in the same electronic messaging standard used for drug registration and listing information and for the content of labeling for abbreviated new drug applications (ANDAs). This standard, known as Health Level Seven (HL7) Structured Product Labeling (SPL), allows information to be exchanged, searched, and combined with other data sources in a manner that supports health information technology initiatives to improve patient care.
Required information may be submitted using any of the following tools to generate a self-identification SPL file:
1. CDER Direct is a web portal for creating, reviewing, editing, storing, and submitting SPL without having to use the ESG. CDER Direct can be accessed via the link below: https://direct.fda.gov/. Step-by-step instructions are available on the web portal homepage.
2. eSubmitter tool, a free stand-alone application available at eSubmitter Download and Installation. Step-by-step instructions for electronically creating, validating, and submitting self-identification information through eSubmitter are available in “eSubmitter Quick Guide – Generic Drug Facility Self-Identification;”
3. Xforms, a free tool for generating SPL files available at: SPL Xforms. Step-by-step instructions for electronically creating, validating, and submitting self-identification information using Xforms are available at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm; or
4. Software tools developed internally by generic manufacturers utilizing the SPL technical specifications. Additional information is available at Structured Product Labeling Resources.
5. Other commercially available applications (e.g., vendor tools).
Once a self-identification SPL file is created and finalized, the file should be transmitted to FDA through the Electronic Submissions Gateway (ESG), FDA’s electronic information portal. Information on the ESG is available at Electronic Submissions Gateway.
IMPORTANT! To submit your self-identification file to the FDA, you must first obtain a WebTrader account with the FDA Electronic Submission Gateway (ESG). See Setting up a WebTrader Account Checklist.
Additional information is available in Guidance for industry Self-Identification of Generic Drug Facilities, Sites and Organizations and Overview and Technical Walk-Through of Self-Identification Process.
Are All Facilities, Sites, and Organizations that Must Self-Identify Also Required to Pay Facility Fees?
No. Only facilities that manufacture, or intend to manufacture, generic drug APIs or FDFs, or both, are required to pay facility fees. Sites and organizations that only perform testing, repackaging, or relabeling are not required to pay a user fee.
Readers of the GDUFA guidance documents have pointed out the need for clarification on the issue of whether facilities that package generic drugs are required to pay annual facility fees. FDA intends to address this issue more fully in future guidance, but wanted to provide as quickly as possible clarification for industry.
Facilities that package the FDF of a human generic drug into the primary container/closure system and/or label the primary container/closure system are considered to be manufacturers and are, therefore, required to pay an annual FDF fee. This is true for packaging done pursuant to a contract or by the applicant itself.
No facility is required to pay more than one annual FDF fee and/or one annual API fee, if applicable.
Under GDUFA, if a facility fails to self-identify, all FDF or API products manufactured at the facility and all FDFs containing APIs manufactured at the facility will be deemed misbranded. It is a violation of federal law to ship misbranded products in interstate commerce or to import them into the United States. Such violations can result in prosecution of those responsible, injunctions, or seizures of the misbranded products. Products that are deemed misbranded because of failure of the facility to self-identify are subject to being denied entry into the United States.