# Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs that are Regulated Under a Biologics License Application, and Animal Drugs > Briefs, arguments, decisions, and more. URL: https://www.frixlaw.com/law-library/documents/fr%3A06-7172 ## Record - **Collection:** Federal Register - **Document type:** Proposed Rule - **Published:** August 29, 2006 - **Citation:** 71 FR 51276 ## Text DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Parts 20, 201, 207, 314, 330, 514, 515, 601, 607, 610, and 1271 [Docket No. 2005N-0403] RIN 0910-AA49 Requirements for Foreign and Domestic Establishment Registration and Listing for Human Drugs, Including Drugs that are Regulated Under a Biologics License Application, and Animal Drugs AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule. SUMMARY: The Food and Drug Administration (FDA) is proposing to amend its regulations governing drug establishment registration and drug listing. The proposed revisions would reorganize, consolidate, clarify, and modify current regulations concerning who must register establishments and list human drugs, human drugs that are also biological products (including vaccines and allergenic products), and/or human cells, tissues, and cellular and tissue-based products (HCT/Ps), and animal drugs. The proposal describes when and how to register and list and what information must be submitted for registration and listing. In addition, the proposal would make certain changes to the National Drug Code (NDC) system and would require the appropriate NDC number to appear on the labels for drugs subject to the listing requirements. The proposed regulations generally would require the electronic submission of all registration and most listing information. We (FDA) rely on establishment registration and drug listing information for administering many of our programs, such as postmarketing surveillance (including FDA inspections), bioterrorism, drug shortages and availability, and user fee assessments. We are taking this action to use the latest technology to improve our registration and listing system, which would further our goal of protecting the public health. We also believe that the conversion to an electronic system would make the registration and listing processes more efficient and effective for industry and us. We are also taking this action to support the implementation of, for example, the electronic prescribing provisions of the Medicare Prescription Drug, Improvement, and Modernization Act, our rulemaking requiring a bar code on certain drug products, and the DailyMed initiative. DATES: Submit written or electronic comments by November 27, 2006. Submit written comments on the information collection requirements by September 28, 2006 to OMB (see ADDRESSES ). See section IX of this document for the proposed effective date and section X for the proposed compliance dates of a final rule based on this document. ADDRESSES: You may submit comments, identified by Docket No. 2005N-0403 and/RIN 0910-AA49, by any of the following methods: Electronic Submissions Submit electronic comments in the following ways: • Federal eRulemaking Portal: http://www.regulations.gov . Follow the instructions for submitting comments. • Agency Web site: http://www.fda.gov/dockets/ecomments . Follow the instructions for submitting comments on the agency Web site. Written Submissions Submit written submissions in the following ways: • FAX: 301-827-6870. • Mail/Hand delivery/Courier [For paper, disk, or CD-ROM submissions]: Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. To ensure more timely processing of comments, FDA is no longer accepting comments submitted to the agency by e-mail. FDA encourages you to continue to submit electronic comments by using the Federal eRulemaking Portal or the agency Web site, as described in the Electronic Submissions portion of this paragraph. Instructions : All submissions received must include the agency name and Docket No(s). and Regulatory Information Number (RIN) (if a RIN number has been assigned) for this rulemaking. All comments received may be posted without change to http://www.fda.gov/ohrms/dockets/default.htm , including any personal information provided. For additional information on submitting comments, see the “Comments” heading of the SUPPLEMENTARY INFORMATION section of this document. Docket : For access to the docket to read background documents or comments received, go to http://www.fda.gov/ohrms/dockets/default.htm and insert the docket number(s), found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Information Collection Provisions : Submit written comments on the information collection provisions to the Office of Information and Regulatory Affairs, Office of Management and Budget (OMB).To ensure that comments on the information collection are received, OMB recommends that written comments be faxed to the Office of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-6974. FOR FURTHER INFORMATION CONTACT: For information concerning drugs regulated by the Center for Drug Evaluation and Research (CDER) : Herbert Gerstenzang or John W. Gardner, Center for Drug Evaluation and Research (HFD-330), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-8920, herbert.gerstenzang@fda.hhs.gov or john.gardner@fda.hhs.gov . For information concerning products regulated by the Center for Biologics Evaluation and Research (CBER) : Valerie A. Butler, Center for Biologics Evaluation and Research (HFM-17), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-6210, valerie.butler@fda.hhs.gov . For information concerning animal drugs : Lowell Fried (HFV-212) or Isabel W. Pocurull (HFV-226), Center for Veterinary Medicine (CVM), Food and Drug Administration, 7519 Standish Pl., Rockville, MD 20855, 301-827-7820 or 240-453-6853, lowell.fried@fda.hhs.gov or isabel.pocurull@fda.hhs.gov . SUPPLEMENTARY INFORMATION: Table of Contents I. Background II. Summary of Current Registration and Listing Requirements A. Summary of Section 510 of the Act B. Summary of Current Registration and Listing Regulations 1. Who Must Register and List Under Current Regulations? 2. What Are the Current Registration Requirements? 3. What Are the Current Listing Requirements? 4. What Are the Current Requirements Associated With the Use of the NDC Number? 5. Who Is Exempt from Registration and Listing Under Current Regulations and Who Is Not Covered by the Current Registration and Listing Requirements in 21 CFR part 207? 6. Do Current Regulations Permit the Disclosure of Registration and Listing Information? III. Highlights of the Proposed Rule A. Proposed Changes to the Current Registration and Listing Requirements B. Promotion of Department of Health and Human Services Federal Health Information Technology Initiatives IV. Description of the Proposed Rule A. General 1. What Is the Purpose of Proposed Part 207? 2. Who Would Part 207 Cover? 3. Who Would Not Be Subject to Part 207? 4. Who Would Be Exempt from Registration and Listing? 5. What Definitions and Interpretations of Terms Would Apply to Part 207? B. Registration 1. Who Would Be Required to Register? 2. When Would Initial Registration Information Be Provided? 3. What Information Would Be Required for Registration? 4. What Are the Proposed Requirements for Reviewing and Updating Registration Information? C. The National Drug Code (NDC) Number: What is It? How is It Used? What Changes Are We Proposing? 1. What Is the NDC Number? 2. How Did NDC Numbers Originate? How Are They Used? 3. What Changes Are We Proposing? 4. How Do We Intend to Implement the NDC Number Changes? D. Listing 1. Who Would Be Required to List Drugs? 2. When Would Initial Listing Information Be Provided? 3. What Listing Information Would Be Required? 4. What Listing Information Would Be Required for Manufacturers? 5. What Listing Information Would Be Required for Repackers and Relabelers? 6. What Listing Information Would Be Required for Drug Product Salvagers Who are Not Repackers or Relabelers? 7. What Additional Drug Listing Information May Be Required? 8. What Are the Proposed Requirements for Reviewing and Updating Listing Information? E. Electronic Format 1. How Would Registration and Listing Information Be Provided to FDA? 2. What Was the Electronic Submission Pilot Project? 3. How Would the Electronic Registration and Listing System Work? 4. What Are the Proposed Requirements for the Submission of Content of Labeling in Electronic Format? 5. Would the Proposal Require Electronic Submission of Advertisements and Other Labeling? 6. What Guidance Documents Do We Intend To Issue on Providing Registration and Listing Information Electronically? 7. How Would 21 CFR Part 11 Apply to the Electronic Submission of Registration and Listing Information? 8. What Language Would Be Used to Provide Registration and Listing Information? 9. Could the Electronic Format Requirements Be Waived? F. Miscellaneous 1. What Are the Proposed Requirements for an Official Contact and a United States Agent? 2. What Legal Status Is Conferred by Registration and Listing? 3. What Registration and Listing Information Would Be Made Available for Public Disclosure? G. Conforming Actions 1. Withdrawal from Sale of Drugs with Approved Marketing Applications 2. Proposed Revisions to Other Regulations 3. Compliance Verification Reports V. Legal Authority VI. Analysis of Economic Impacts VII. Paperwork Reduction Act of 1995 VIII. Environmental Impact IX. Proposed Effective Date X. Proposed Compliance Dates XI. Federalism XII. Request for Comments XIII. References I. Background We originally published establishment registration regulations for human drugs, certain biological products, and animal drugs in the Federal Register of February 14, 1963 (28 FR 1457) (proposed rule) and April 3, 1963 (28 FR 3195) (final rule), and listing regulations for these drugs in the Federal Register of December 12, 1972 (37 FR 26431) (proposed rule) and March 7, 1973 (38 FR 6258) (final rule). We currently maintain a database containing the establishment registration and drug listing information submitted on paper to us. We rely on complete and accurate registration and listing information to accomplish a number of our statutory and regulatory objectives. For example, we use registration and listing information to: • Identify the manufacturers, repackers, relabelers, and drug product salvagers of marketed drugs; 1 1 “Drug” or “drugs” refers to human drugs, including drugs that are regulated under a biologics license application, and animal drugs (including Type A medicated articles), unless otherwise specifically stated. “Drugs” is defined in proposed § 207.1 and discussed in section IV.A.5 of this document. Biological products subject to proposed part 207 are described in proposed § 207.9(c). • Identify the manufacturers, repackers, or relabelers of a specific drug or ingredient when that drug or ingredient is in short supply or is needed for a national emergency. This information helps us facilitate prompt drug shipment to the place where it is needed. For example, during a bioterrorism incident, we could use drug listing information to identify manufacturers, repackers, and relabelers of drugs that would be helpful in preventing or counteracting the deadly effects of biological weapons. With this information, we could facilitate prompt shipment of the drugs as needed; • Facilitate the recall of drugs marketed by manufacturers, repackers, and relabelers; • Identify and catalogue marketed drugs; • Administer our postmarketing surveillance programs for drugs, including the drug surveillance sampling program that monitors the quality of the national drug supply; • Identify drugs marketed in violation of the law; • Schedule and plan inspections of registered establishments pursuant to section 704 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 374); and • Determine which marketed drugs are identical, related, or similar to drugs reviewed for effectiveness under the Drug Efficacy Study Implementation (DESI) program. We also rely on registration and listing information to help us comply with several other statutory provisions. We use the information to: • Determine which entities are subject to establishment and product user fees under the prescription drug user fee program and the animal drug user fee program (21 U.S.C.379h and 379). • Generate accurate estimates of the number of manufacturers, repackers, relabelers, and drug product salvagers and drugs that are affected by our rulemaking. These estimates help us assess the impact of our regulations on the regulated industry, which we are required to do under the Regulatory Flexibility Act (5 U.S.C. 601-612), as amended by the Small Business Regulatory Enforcement Fairness Act (Public Law 104-121), the Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq. ), the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520), Executive Order 12866 (September 30, 1993), and the Congressional Review Act (section 251 of Public Law 104-121). Registration and listing information will continue to be used for all of the important public health purposes outlined above. Moreover, recent technological advances would allow us to enhance the usefulness of registration and listing information. Specifically, we are proposing that registration and listing information be submitted to us by using the electronic drug registration and listing system that we intend to develop. In addition to making the registration and listing process more efficient for industry, the electronic submission of registration and listing information would allow us to review and use such information more quickly and effectively in carrying out all of the activities described above. Electronic submission of this information would also allow us to fully support the implementation of the provisions of the Medicare Prescription Drug, Improvement, and Modernization Act (Public Law 108-173) (Medicare Modernization Act), specifically the electronic prescribing provisions. In addition, electronic submission of registration and listing information would further the purpose of several statutes: • The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (Public Law 107-188) (Bioterrorism Act) amended section 510(i) of the act (21 U.S.C. 360(i)) to require that foreign establishments submit, among other things, registration information electronically. • The Medical Device User Fee and Modernization Act of 2002 (Public Law 107-250) also amended section 510 of the act (at section 510(p)) to explicitly give the Secretary of Health and Human Services (the Secretary) discretion to require the electronic submission of registration information, upon a finding that electronic receipt of such registration information is feasible, unless the Secretary grants a request for a waiver. • The Government Paperwork Elimination Act of 1998 (Public Law 105-277, Title XVII) (GPEA) requires Federal agencies to give persons who are required to maintain, submit, or disclose information the option of doing so electronically when practicable as a substitute for paper, and to use electronic authentication (electronic signature) methods to verify the identity of the sender and the integrity of the electronic content. We believe that conversion to the electronic submission of registration and listing information will further the purpose of these laws and make the registration and listing processes more efficient and effective for industry and us. II. Summary of Current Registration and Listing Requirements A. Summary of Section 510 of the Act Section 510(c) of the act requires every person upon first engaging in the “manufacture, preparation, propagation, compounding, or processing” of a drug in any establishment that he owns or operates in any State to immediately register his name and place of business and such establishment. Under section 510(a)(1) of the act, the term “manufacture, preparation, propagation, compounding, or processing” must include “repackaging or otherwise changing the container, wrapper, or labeling of any drug package * * * in furtherance of the distribution of the drug * * * from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user.” Section 510(a)(2) of the act mandates that the term “name” include, among other things, the name of each partner of a partnership, and the name of each corporate officer and director of a corporation. An owner or operator of a registered establishment must also immediately register any additional establishment that he owns or operates in any State and in which he begins the “manufacture, preparation, propagation, compounding, or processing” of a drug (section 510(d) of the act). An owner or operator of any establishment that engages in these activities must register its establishment on or before December 31 of each year (section 510(b) of the act). Section 510(i) of the act contains certain registration requirements pertaining to foreign establishments (e.g., submission of the name of each importer of a drug in the United States that is known to the establishment, submission of the name of each person who imports or offers for import a drug into the United States for purposes of importation). Section 510(g) of the act provides for certain exemptions from the registration requirements. In addition, section 510(p) of the act gives the Secretary discretion to require the electronic submission of registration information, upon a finding that electronic receipt of such registration information is feasible, unless the Secretary grants a request for a waiver. Section 510(j)(1) of the act requires that every person, at the time of registration, submit a list of all drugs that are being manufactured, prepared, propagated, compounded, or processed by him for commercial distribution and that have not been previously listed by him. This information must be submitted in the form and manner prescribed by the Secretary (section 510(j)(1) of the act). This listing information must be accompanied by, among other things, a copy of certain labeling and, in some cases, advertising for certain categories of drugs. Section 510(j)(2) of the act requires certain changes in listing information to be reported every June and December, including any material changes in information previously submitted under the listing provisions. Section 510(e) of the act permits the Secretary to assign a registration number to any person or any establishments registered under section 510 and a listing number to each drug or class of drugs listed under section 510(j) as long as the listing number is the same as that assigned pursuant to the National Drug Code. The disclosure provision in section 510(f) of the act requires the Secretary to make available for inspection any registration filed under section 510. Section 510(f) also provides that certain listing information must be exempt from disclosure unless the Secretary finds that such exemption would be inconsistent with protection of the public health. B. Summary of Current Registration and Listing Regulations 1. Who Must Register and List Under Current Regulations? Under current part 207 (21 CFR part 207), with certain exceptions, owners or operators of establishments that engage in the manufacturing or processing of a drug or drugs must, in addition to other requirements, register their establishments and submit listing information for each of their drugs in commercial distribution. 2 Notwithstanding certain exceptions, foreign drug establishments that manufacture, repack, or relabel a drug that is imported or offered for import into the United States must also comply with the registration and listing requirements. As explained in section IV.E of this document, all registration and listing information must currently be submitted to us using paper forms specified by us. 2 “Drug or drugs” includes drugs regulated under a BLA. For a description of biological products covered under proposed part 207, see proposed § 207.9(c). 2. What Are the Current Registration Requirements? Current requirements for registration include, among other things, the following provisions: • Owners or operators of establishments entering into the manufacturing or processing of a drug or drugs must register their establishments within 5 days after beginning the manufacturing or processing of drugs at the establishments (§ 207.21(a)). • If owners or operators of the establishments have not previously entered into such operations, then those owners or operators must register within 5 days after the submission of a new drug application (NDA), abbreviated new drug application (ANDA), new animal drug application (NADA), abbreviated new animal drug application (ANADA), medicated feed mill license application, or biologics license application (BLA) (§ 207.21(a)). • Owners or operators of establishments that are required to register must renew their registration annually in accordance with the specified schedule (§ 207.21(a)). Changes in individual ownership, corporate or partnership structure, location, or drug-handling activity must be submitted as amendments to registration within 5 days of such changes (§ 207.26). • We assign a permanent registration number to each registered establishment (§ 207.35). • Private label distributors that do not otherwise manufacture or process drugs are not required to register; however, they must submit specified information to us to obtain a labeler code (§ 207.20(b)). Private label distributors are owners or operators of establishments not otherwise required to register under section 510 of the act that distribute under their own label or trade name a drug manufactured or processed by a registered establishment. 3. What Are the Current Listing Requirements? Current requirements for listing include, among other things, the following provisions: • Owners or operators of establishments must, at the time of registration, submit a list of every drug being manufactured or processed in commercial distribution at that time (§ 207.21(a)). • Private label distributors that do not otherwise manufacture or process drugs are not required to list, but may elect to submit listing information directly to us (§ 207.20(b)). Currently, private label distributors that elect to submit listing information directly to us assume full responsibility for compliance with the requirements of part 207 (§ 207.20(b)). Owners or operators of establishments that are required to register and list must submit listing information to us on behalf of private label distributors that do not elect to submit listing information directly to us (§ 207.20(b)). • Drugs that may be subject to current listing requirements include bulk drug substances; finished dosage forms, whether prescription or over-the-counter (OTC) drugs; and Type A medicated articles (§ 207.25(b)). • The required listing information submitted to us includes, but is not limited to: —The application number, if applicable, —Copies of current labeling as specified in current § 207.25(b) and, in some cases, a representative sampling of advertisements, —A quantitative listing of the active ingredient(s) (in some cases), —The NDC number, and —Any imprinting information (§ 207.25(b)). • Owners or operators of establishments that are required to register must update their listing information every June and December or, at the discretion of the owner or operator, when the change occurs. Updated information must include, but is not limited to: —A list of each drug introduced by the registrant for commercial distribution that has not been included in any previously submitted list, —A list of all previously listed drugs for which commercial distribution has been discontinued, —A list of all drugs for which a notice of discontinuance was submitted and for which commercial distribution has resumed, and —Any material change, as defined under current § 207.3(a)(3), in any information previously submitted (§ 207.30(a)). 4. What Are the Current Requirements Associated With the Use of the NDC Number? The NDC system is used, among other things, to assign a drug listing number to each drug or class of drugs. • The NDC number currently consists of the labeler code, product code, and package code. We assign the labeler code, and, as stated in current regulations, “establishments” assign the product code and package code within certain parameters specified by us (§ 207.35). • Currently, we request, but not require, that the NDC number appear on all drug labels and labeling (§ 201.2 (21 CFR 201.2), § 207.35(b)(3)). However, drug products described in current § 201.25(b) (21 CFR 201.25(b)) must have on the label a bar code that contains, at a minimum, the appropriate NDC number in a linear bar code that meets specified standards (§ 201.25). • The current regulations specify both format and placement of the NDC number if the NDC number is included on drug labels and labeling (§ 207.35(b)(3)). 5. Who Is Exempt From Registration and Listing Under Current Regulations and Who Is Not Covered by the Current Registration and Listing Requirements in 21 CFR Part 207? Under current regulations, certain establishments are exempt from the registration and listing requirements. For example, practitioners who are licensed by law to prescribe or administer drugs and who manufacture or process drugs solely for use in their professional practice, and persons who manufacture or process drugs not for sale but solely for use in research, teaching, or chemical analysis are exempt from registration and listing requirements. Many of the exemptions in current § 207.10 are also listed in section 510(g) of the act. The current regulations also describe those establishments that are not covered under part 207. Owners and operators of human blood and blood product establishments must register and list their products in accordance with part 607 (21 CFR part 607). However, such owners and operators who also manufacture or process other drug products at the same establishment must also register and list those drugs in accordance with part 207 (§ 207.7). Owners and operators of establishments that solely engage in the manufacture or processing of medical devices are not covered under part 207. However, such owners and operators must register and list their products in accordance with part 807. 6. Do Current Regulations Permit the Disclosure of Registration and Listing Information? The current regulations specify the registration and listing information submitted to us that is available for public disclosure (§ 207.37). III. Highlights of the Proposed Rule This proposal would reorganize, consolidate, and modify the current registration and listing requirements. It would also assist us in promoting other important electronic health initiatives. A. Proposed Changes to the Current Registration and Listing Requirements We are proposing many changes to the current registration and listing requirements. In section IV of this document, we discuss in detail these changes and the reasons for the changes. The most significant proposed changes to the current requirements are as follows: • All registration information and most listing information would be provided to us electronically using the electronic drug registration and listing system that we intend to develop. (Currently, the information is submitted to us on paper forms.) • The appropriate NDC number would be required, with certain exceptions, to appear on drug labels. The appropriate NDC number is the NDC number belonging to the manufacturer, repacker, or relabeler, that corresponds to the particular drug; a repacker or relabeler would not be permitted to place an NDC number that corresponds to an original manufacturer on a repackaged or relabeled drug. Although the NDC number would not be required to appear on other drug labeling (that is, the prescription drug labeling or the package insert), the NDC number would need to accompany the submission of the other drug labeling. (Currently, we only request that the NDC number appear on drug labels and labeling. However, certain drug products must have on the label a bar code that contains, at a minimum, the appropriate NDC number (see § 201.25).) • All three sections of the NDC number—that is, the labeler code, product code, and package code—would be assigned prospectively by us to drugs that have not previously been assigned NDC numbers by a manufacturer, repacker, or relabeler. (Currently, we assign the labeler code, and the registered establishment or private label distributor assigns the product code and package code within certain parameters specified by us.) The labeler code assigned prospectively by us would be the same as the labeler code (or one of the labeler codes) used by the manufacturer, repacker, or relabeler on its currently marketed drugs. • The NDC numbers currently assigned to drugs prior to the effective date of the rule would remain unchanged, provided those NDC numbers comply with the new regulations as finalized. FDA intends to validate that current NDC numbers comply with the new regulations as finalized. Manufacturers, repackers, and relabelers should review the information that they submitted to our registration and listing database to obtain an NDC number and update the information if necessary. They should complete their reviews and updates within 9 months after a final rule's effective date. If, after the effective date of the final rule, there is a change in a drug (in accordance with proposed § 207.33(f)), we would assign a new product code and package code to the newly changed drug, but the drug would keep the labeler code. If, after the effective date of the final rule, there is a change in a drug's packaging, we would assign a new package code to the drug, but the drug would keep the labeler code and the product code. (Currently, the registered establishment or private label distributor may assign the product and package codes within certain parameters specified by us.) • Private label distributors would not be permitted to register or list under the proposed rule. (Currently, private label distributors submit certain information to request a labeler code and may list drugs. If the private label distributor elects not to submit drug listing information directly to us and to obtain a labeler code, the registered establishment must submit the drug listing information.) Manufacturers, repackers, relabelers, or drug product salvagers must submit drug listing information for those drugs they manufacture, repack, relabel, or salvage for a private label distributor. • Drug product salvagers would, in addition to registering, be required to list the drugs they salvage, even if they do not repack or relabel the drugs. (Currently, drug product salvagers are required to register but not list.) • The “content of labeling” as defined in proposed § 207.1 would be electronically submitted at the time of listing in a format that we can process, review, and archive. (Currently, all labeling required for listing is submitted in paper form.) B. Promotion of the Department of Health and Human Services (DHHS) Federal Health Information Technology Initiatives The proposal would allow us to provide important support for the full implementation of the electronic prescription provisions of the Medicare Modernization Act. The proposal would also support other initiatives, described in section IV.C.2 of this document, including DHHS Federal Health Information Technology initiatives. The proposal would result in an up-to-date NDC number system, in which we assign the NDC number, providing for accurate, unique, and unambiguous NDC numbers for each drug. This would allow electronic systems to reliably and consistently link the NDC number to the appropriate drug labeling through another DHHS health information technology initiative, Structured Product Labeling (SPL). The drug labeling would supply the drug ingredient and other information necessary to support the development of the standards for medication terminology necessary for electronic prescribing. Other initiatives supported by this proposal, including bar coding for drugs, are discussed in section IV.C.2 of this document. IV. Description of the Proposed Rule We are proposing to reorganize, consolidate, clarify, and modify the regulations in part 207. As a result, we have revised and recodified some provisions, added new provisions, and eliminated others. The following description of the proposed rule describes both new provisions and changes to existing regulations. A. General 1. What Is the Purpose of Proposed Part 207? We are proposing to add new § 207.5 to explicitly state the purpose of part 207, as set forth in the legislative history of the Drug Amendments of 1962 and the Drug Listing Act of 1972. • Establishment registration information helps us to identify who is manufacturing, repacking, relabeling, or salvaging drugs and where those operations are being performed. As explained in Senate Report No. 1744, “drugs should not be on the market unless [FDA] knows who is making them, and where they are being made. This will help stop illicit and substandard manufacturers who do not follow the methods or establish the controls called for by good manufacturing practice” (1962 U.S.C.C.A.N. 2884, 2889). Knowing where drugs are being made is even more important today because it would increase the Nation's ability to prepare for and respond effectively to bioterrorism and other public health emergencies. • Drug listing information gives us a current inventory of marketed drugs. As stated in Senate Report No. 92-924, “[t]he effective enforcement of the drug provisions of the [a]ct requires the ready availability of a current inventory of all marketed drugs” (1972 U.S.C.C.A.N. 2963, 2964). Moreover, the intent of drug listing is to provide us “with an effective means of surveillance” (Id. at 2965). Both establishment registration and drug listing information facilitate our implementation and enforcement of the act and are used for many important public health purposes. In addition, this information will help us better respond to emergencies (for example, we will be in a better position to effectively facilitate recalls should there be such a need). 2. Who Would Part 207 Cover? We are proposing to add new § 207.9 to explain that part 207 would apply to the following. • Domestic manufacturers, domestic repackers, domestic relabelers, and domestic drug product salvagers, unless they are exempt under section 510(g) of the act or proposed § 207.13. The terms “domestic manufacturers,” “domestic repackers,” “domestic relabelers,” and “domestic drug product salvagers” are defined in proposed § 207.1 and are explained in section IV.A.5 of this document. Proposed § 207.9 does not change the scope of current part 207. Domestic manufacturers, domestic repackers, domestic relabelers, and domestic drug product salvagers would be covered under proposed part 207 whether or not the drugs they manufacture, repack, relabel, or salvage enter interstate commerce. Section 510(b) and (c) of the act refer to an establishment “in any State.” Congress's intention for section 510 of the act to apply to drugs both in interstate and intrastate commerce is stated in section 301 of Public Law 82-781, in part, as follows: “[T]he products of all [establishments in which drugs are manufactured, prepared, propagated, compounded, or processed] are likely to enter the channels of interstate commerce and directly affect such commerce; and * * * the regulation of interstate commerce in drugs without provision for registration and inspection of establishments that may be engaged only in intrastate commerce in such drugs would discriminate against and depress interstate commerce in such drugs, and adversely burden, obstruct, and affect such interstate commerce.” 3 Accordingly, we are proposing to add to proposed § 207.9 the clause “regardless of whether their drugs enter interstate commerce” to reflect this congressional finding. The phrase “Drug products * * * must be listed whether or not the output of such establishments or any particular drug so listed enters interstate commerce” is already included in current § 207.20(a). 3 See footnote 1 of section 510 of the act. • Foreign manufacturers, foreign repackers, foreign relabelers, and foreign drug product salvagers, unless they are exempt under proposed § 207.13(c) through (h). Foreign manufacturers, foreign repackers, foreign relabelers, and foreign drug product salvagers are currently required to register, and foreign manufacturers, foreign repackers, and foreign relabelers are currently required to submit listing information in accordance with section 510 of the act and § 207.40. The terms “foreign manufacturers,” “foreign repackers,” “foreign relabelers,” and “foreign drug product salvagers” are defined in proposed § 207.1 and explained in section IV.A.5 of this document. An increased number of foreign manufacturers, foreign repackers, foreign relabelers, and foreign drug product salvagers may be required to comply with registration and/or listing requirements because we are proposing, as explained in section IV.A.4 of this document, to revoke certain provisions of current § 207.40(a) and (b). We are proposing to revoke the exemption in current § 207.40(a) relating to foreign establishments whose drugs enter a foreign trade zone and are re-exported from the foreign trade zone without having entered U.S. commerce. We are also proposing to revoke, in part, current § 207.40(b), which allows for a component of a drug imported under section 801(d)(3) of the act (21 U.S.C. 381(d)(3)) to be imported or offered for import into the United States even if the component is not listed and manufactured, prepared, propagated, compounded, or processed at a registered foreign establishment. We are proposing to eliminate these two exemptions in current § 207.40(a) and (b) from the registration and listing requirements in light of certain statutory changes that have occurred since the publication of the final rule on foreign establishment registration and listing. Those changes include enactment of the Bioterrorism Act, which reflects Congress' desire to increase the Nation's ability to prepare for and respond effectively to bioterrorism and other public health emergencies. • Manufacturers of drugs regulated under a BLA, as follows: Manufacturers of drugs regulated under a BLA including, but not limited to: (1) Plasma derivatives such as albumin, Immune Globulin, Factor VIII and Factor IX, and recombinant versions of plasma derivatives or animal derived plasma derivatives; (2) vaccines; (3) allergenic products; (4) bulk product substances such as fractionation intermediates or pastes; and (5) therapeutic biological products. Establishments solely engaged in the manufacture, as defined in § 1271.3(e) (21 CFR 1271.3(e)), of HCT/Ps, as defined in § 1271.3(d), that, under § 1271.20, are also drugs regulated under section 351 of the Public Health Service Act (PHS Act) or section 505 of the act. Proposed § 207.9(c)(2) would direct these establishments to register and list those HCT/Ps with CBER by following the procedures described in subpart B of part 1271 (21 CFR part 1271) instead of the procedures for registration and listing described in part 207. Proposed § 207.9(c)(2) is similar to current § 207.20(f), which we propose to revoke and replace with proposed § 207.9(c)(2). We are also explaining the relationship between the requirements for HCT/Ps in part 207 and part 1271 of this chapter. We have implemented, in part 1271, a comprehensive, risk-based regulatory approach for HCT/Ps. Under this approach, some HCT/Ps are regulated solely under section 361 of the PHS Act (42 U.S.C. 264) and the regulations in part 1271; other HCT/Ps are also subject to regulation as drugs or devices under the act and to premarket application or notification requirements (submissions may include BLAs, NDAs, or device PMAs, product development protocols, or 510(k) applications). Current § 207.20(f) also states that the additional listing information requirements in current § 207.31 are applicable to HCT/Ps registered in accordance with the procedures in part 1271, subpart B if they are also drugs regulated under a BLA and/or the act. We are proposing to revoke current § 207.31 and move several of its requirements to other sections of the proposed rule (see discussion in sections IV.C and IV.D of this document). Consistent with the provisions in current § 207.20(f), the requirements will continue to apply to HCT/Ps that, under § 1271.20, are also drugs regulated under a BLA or section 505 of the act. In addition, proposed § 207.9(c)(2) would require the submission of information not currently required for HCT/Ps under part 207, although the submission of such information has been required for drug products that are not HCT/Ps. For example, proposed § 207.9(c)(2) would require establishments to submit the NDC number, as described in proposed §§ 207.49(a), 207.53(a), and 207.54(b)(1), and the route of administration, as described in proposed § 207.49(b). Under these provisions, such HCT/P establishments would not be required to register and list with both CBER and CDER. Rather, we envision that establishments will register with CBER, and then will be asked to provide additional information as required under part 207. We will manage our databases so that both CBER and CDER have use of the registration and listing information provided. The concept is that there will be a link in place when the establishment electronically accesses the electronic registration and listing system at http://www.fda.gov/cber/tissue/tisreg.htm for tissue registration. This will allow access to the drug database fields to fill in the additional information such as the NDC number. If the establishment enters that it manufactures a licensed biologic, this will trigger the link. At the current time, there is only one such product. 3. Who Would Not Be Subject to Part 207? Proposed § 207.9 also describes two categories of establishments that would not be subject to part 207: • Owners and operators of human blood and blood product establishments. This proposed rule does not apply to owners and operators of human blood and blood product establishments unless they manufacture any of the products listed in proposed § 207.9(c)(1)(i) and (c)(1)(iv). If the owners and operators of human blood and blood product establishments manufacture any of those products, then they must register and list under part 207. Establishments that collect or process whole blood and blood products as well as establishments involved in the testing of whole blood and blood products would register and list under part 607. For purposes of this proposal, blood and blood products consist of human whole blood, plasma, or serum or any product derived from human whole blood, plasma, or serum, and the term includes biological products regulated as licensed devices. Manufacturers of licensed devices and manufacturers of licensed biological components used in a licensed device would register and list under part 607. This exclusion is consistent with current § 207.7(a) and would not apply to owners and operators of human blood and blood product establishments who also manufacture other drugs. • Establishments that solely manufacture, prepare, propagate, compound, assemble, or process medical devices. Establishment registration and device listing regulations for such establishments and initial importers of devices, including in vitro diagnostic products, are codified in part 807. Establishments that manufacture, prepare, propagate, compound, assemble, or process medical devices, and also manufacture, prepare, propagate, compound, or process drugs, are subject to part 207 for drugs and part 807 for devices. As a result of these proposed revisions clarifying the scope of part 207, proposed § 207.9 includes the provisions in current § 207.7 that explain the applicability of part 207 to human blood and blood products and medical devices. We are also proposing to revoke related provisions that set forth addresses in the Center for Devices and Radiological Health (CDRH) and CBER for submitting registration and listing information, and provisions that specify the appropriate forms for submitting such information. 4. Who Would Be Exempt From Registration and Listing? Section 510(g) of the act and current § 207.10 provide for exemptions from registration and drug listing requirements. Proposed § 207.13 contains certain changes to some of the exemptions in current § 207.10, as discussed in the first part of this section. Proposed § 207.13 also incorporates without change some exemptions from current § 207.10, as discussed at the end of this section. The introductory paragraph of proposed § 207.13, largely consistent with current § 207.10, states that, except as provided in proposed § 207.13(i), the classes of persons listed in proposed § 207.13 are exempt from registration and drug listing under section 510(g) of the act, or because we have found, under section 510(g)(5) of the act, that their registration is not necessary for the protection of the public health. We are proposing to add the phrase “except as provided in proposed § 207.13(i)” to indicate that even though the classes of persons identified in paragraphs (a) through (h) are exempt from registration and drug listing, if such persons engage in activities as set forth in paragraph (i), the exemption does not apply and they are required nonetheless to register and list. We are also proposing to include in the introductory paragraph a sentence clarifying that the exemption under proposed § 207.13 would not provide exemptions from other provisions of the act or regulations. For example, persons that do not have to register establishments and list drugs are still subject to the adulteration and misbranding provisions under sections 501 and 502 of the act (21 U.S.C. 351 and 352) and also may be subject to the new drug approval requirements under section 505 of the act (21 U.S.C. 355) or new animal drug approval requirements under section 512 of the act (21 U.S.C. 360b). We may inspect their establishments in accordance with section 704 of the act and the current good manufacturing practice requirements. We are proposing to add the clarifying sentence because in the past some manufacturers, repackers, relabelers, and drug product salvagers that were exempt from registration and listing requirements incorrectly believed these provisions provided exemptions from other provisions of the act and regulations. Accordingly, we are proposing to add this sentence to remedy any confusion on this point. a. Pharmacies —The current exemption for pharmacies is codified at § 207.10(a). The proposed rule would revise and clarify the exemption, and would move it to § 207.13(a). Except as noted in the discussion below, proposed § 207.13(a) is generally consistent with current § 207.10(a). Under proposed § 207.13(a), pharmacies would be exempt from the registration and listing requirements if they: Operate in conformance with all applicable local laws regulating the practice of pharmacy, including all applicable local laws regulating the dispensing of prescription drugs; regularly engage in dispensing prescription drugs upon prescription of practitioners licensed by law to administer these drugs to patients under their professional care; and do not manufacture (as defined in proposed § 207.1), repack, or relabel drugs for sale other than in the regular course of the practice of pharmacy, including dispensing and selling drugs at retail. Additional language has been added to proposed § 207.13(a)(1)(i) and (a)(1)(ii) to more closely track the language in section 510(g)(1) of the act. In addition, proposed § 207.13(a) does not include language that is in current § 207.10(a) that provides that the supplying of prescription drugs to a practitioner licensed to administer the drugs for use in the course of the practitioner's professional practice or to other pharmacies to meet temporary inventory shortages are not acts that require pharmacies to register. We are deleting this language because it is not necessary. Pharmacies that engage in such activities would be exempt from registration if they fulfill the following requirements: Operate in conformance with all applicable local laws regulating the practice of pharmacy, including all applicable local laws regulating dispensing of prescription drugs (proposed § 207.13(a)(1)(i)); regularly engage in dispensing prescription drugs upon prescription of practitioners licensed by law to administer these drugs to patients under their professional care (proposed § 207.13(a)(1)(ii)); and do not manufacture (as defined in § 207.1), repack, or relabel drugs for sale other than in the regular course of the practice of pharmacy, including dispensing and selling drugs at retail (proposed § 207.13(a)(1)(iii)). Proposed § 207.13(a)(2) clarifies that pharmacies may potentially qualify for the exemption in proposed § 207.13(a) only if they are located in any State as defined in section 201(a)(l) of the act (21 U.S.C. 321) (that is, any State or Territory of the United States, the District of Columbia, and the Commonwealth of Puerto Rico). This proposed provision is currently located in the introductory paragraph in current § 207.10. We believe it would be more clear to place this provision in proposed § 207.13(a)(2). This aspect of the proposed provision is consistent with current §§ 207.10 and 207.40. b. Hospitals, clinics, other health care entities, and public health agencies —The current exemption for hospitals, clinics, and public health agencies is codified at § 207.10(b). The proposed exemption is generally consistent with current § 207.10(b), except for the addition of “other health care entities” and other mostly minor revisions and clarifications, as described below. The proposed exemption would move to § 207.13(b). Hospitals, clinics, other health care entities, and public health agencies are exempt, under proposed § 207.13(b), from the registration and listing requirements if they: Operate establishments in conformance with all applicable local laws regulating the practice of pharmacy and medicine, including all applicable local laws regulating the dispensing of prescription drugs; regularly engage in dispensing prescription drugs, other than human blood or blood products, upon prescription of practitioners licensed by law to administer these drugs to patients under their professional care; and do not manufacture (as defined in proposed § 207.1), repack, or relabel drugs other than in the regular course of the practice of pharmacy, including dispensing. The exemption in proposed § 207.13(b) would be limited to hospitals, clinics, other health care entities, and public health agencies located in any State as defined in section 201(a)(1) of the act. The proposed provision requiring that such facilities be located in any State is currently located in the introductory paragraph in current § 207.10. We believe it would be more clear to place this provision in proposed § 207.13(b)(2). This proposed provision (except with respect to BLA holders and the clarification with respect to positron emission tomography (PET) drugs) is generally consistent with current §§ 207.10 and 207.40. We are proposing to add “other health care entities” to this exemption because we are aware that other health care entities besides hospitals, clinics, and public health agencies (such as skilled nursing facilities) lawfully provide medical care and dispense drugs and logically are similarly situated to hospitals, clinics, and public health agencies for purposes of exempting them from registration and listing, if they meet the statutory and regulatory requirements. We are also proposing to add language to proposed § 207.13(b) to make the exemption more consistent with the pharmacy exemption in proposed § 207.13(a). For example, we are proposing to add language to proposed § 207.13(b)(1)(i) so that this exemption also specifically requires compliance with all applicable laws regulating dispensing of prescription drugs, as is required by proposed § 207.13(a)(1)(i). We are similarly proposing to add § 207.13(b)(1)(iii) to be consistent with proposed § 207.13(a)(1)(iii), although in proposed § 207.13(b)(1)(iii) we have not included the terms “for sale” or “selling drugs at retail” since this language is appropriate for retail pharmacies relying on the exemption provided by proposed § 207.13(a), but not for hospitals, clinics, other health care entities, and public health agencies relying on the exemption provided by proposed § 207.13(b). We believe that the exemption for hospitals, clinics, other health care entities, and public health agencies provided in proposed § 207.13(b)(2) should be relied upon by pharmacies within these health care entities that dispense drugs to patients receiving care in the health care entities and that meet the requirements of the exemption, but should not be relied upon by retail pharmacies located within these health care entities. Retail pharmacies should rely upon the exemption in proposed § 207.13(a) if they meet the requirements of that proposed provision. c. Persons who manufacture, repack, relabel, or salvage certain medicated feeds —Although we are proposing to reorganize and clarify the exemption for persons who manufacture, repack, relabel, or salvage certain medicated feeds, we are not proposing to change the substance of the exemption. Under proposed § 207.13(f), persons who manufacture, repack, relabel, or salvage Type B or Type C medicated feeds, except for manufacturers, repackers, relabelers, or drug product salvagers of Type B or Type C medicated feeds made from Category II, Type A medicated articles, are exempt from registration. This exemption would not apply to persons who would otherwise be required to register (such as manufacturers, repackers, relabelers, or drug product salvagers of certain free-choice feeds, as defined in 21 CFR 510.455, or certain liquid feeds, as defined in 21 CFR 558.5, where the specifications and/or formulas are not published and a feed mill license is required). Proposed § 207.13(f) also clarifies that all manufacturers, repackers, relabelers, or drug product salvagers of Type B or Type C medicated feeds would be exempt from listing. d. The current exemptions for foreign trade zones and drugs imported under section 801(d)(3) of the act would be revoked —In 2001, we issued a final rule on foreign establishment registration and listing (66 FR 59138, November 27, 2001). The regulation created two exemptions in § 207.40: • Under current § 207.40(a), a foreign establishment is not required to comply with the registration and listing requirements if its drug enters a foreign trade zone and is re-exported from that foreign trade zone without having entered U.S. commerce. We created this exemption as part of the final rule on foreign establishment registration and listing because registering such foreign establishments or listing drugs that were confined to a foreign trade zone—and were therefore not introduced into domestic commerce—was not considered necessary for the protection of the public health (see 66 FR 59138 at 59139 and 59140). • Current § 207.40(b), which states that no drug may be imported or offered for import into the United States unless the drug is listed and manufactured, prepared, propagated, compounded, or processed at a registered foreign establishment, also states that this prohibition does not apply to components of drugs imported under section 801(d)(3) of the act. Section 801(d)(3) of the act, as it existed before June 2002, allowed persons to import unapproved or otherwise noncompliant articles (such as drug components) provided that the imported articles were further processed or incorporated into products and exported or, if not used, the imported articles were destroyed or exported. The provision in § 207.40(b) reflected the fact that, at the time, section 801(d)(3) of the act imposed very few restrictions on the admission of drug components that are imported into the United States for further processing or incorporation into a product that will be exported from the United States (66 FR 59138 at 59148). Given the additional level of import restrictions imposed by the Bioterrorism Act, and the underlying security concerns that led to the Bioterrorism Act's adoption, we are proposing to eliminate these two exemptions in current § 207.40(a) and (b) from the registration and listing requirements. In particular, sections 321 and 322 of the Bioterrorism Act, which affected foreign establishment registration by amending sections 510 and 801 (among other provisions) of the act, suggest that Congress intended the information requirements for foreign establishments and imported products to be comprehensive, and that Congress regarded the information it was requiring to be important to its goal in increasing the Nation's ability to prepare for and respond effectively to bioterrorism and other public health emergencies. This, in turn, suggests to FDA that the exceptions from the registration and listing requirements are therefore no longer appropriate. The Bioterrorism Act affected foreign establishment registration, in relevant part, by amending sections 510(i) and 801 of the act: • To require, as part of an establishment's registration, the name of each importer of the drug that is known to the establishment and the name of each person who imports or offers to import the drug into the United States; and • To provide that we may refuse admission of a product and, if the product is refused admission, that the product shall be held at the port of entry until a statement regarding the foreign establishment's registration is submitted to us. The amendment to section 510(i) of the act reflects a determination on the part of Congress that a foreign establishment shipping drugs to the United States should provide additional information in its registration (that is, information about importers and persons who import or offer for import). FDA is concerned that if a foreign establishment is not subject to this establishment registration requirement—either by virtue of importing into a foreign trade zone or by importing components under section 801(d)(3) of the act—it would allow some importers and persons who import or offer for import to go undetected, thereby creating an unnecessary vulnerability in Congress' system of requiring this information. The amendment to section 801(o) of the act reflects a determination that establishment registration and drug listing information is important enough that, if it is lacking at the time the article is offered for import, the article may be refused admission (and, if refused, shall be held at the port of entry). FDA is concerned that if a foreign establishment is exempt from the registration and listing requirements—either by virtue of importing into a foreign trade zone or by importing components under section 801(d)(3) of the act—FDA would be unable to rely on amended sections 510(i) and 801 of the act to require that imported products be held at the port of entry to the United States or to prevent such product's delivery to the importer or consignee. This situation would stand in the way of implementing Congress' apparent intent that this information be a prerequisite for entry of the imported product into the United States. We believe that removing the exception to the registration and listing requirements for products entering foreign trade zones and for products imported under section 801(d)(3) of the act is consistent with Congress' desire to increase the Nation's ability to prepare for and respond effectively to bioterrorism and other public health emergencies by requiring foreign establishments to provide more, rather than less, information for imported products. The Bioterrorism Act also revised section 801(d)(3) of the act, in part, by: • Requiring importers to identify the manufacturers of the imported drug component, and each processor, packer, distributor, or other entity that had possession of the article from the manufacturer to the importer; • Requiring certificates of analysis to accompany most imported articles; and • Giving us the ability to refuse admission to the United States if we determine there is credible evidence or information indicating that the article is not intended to be further processed by the initial owner or consignee, or incorporated by the initial owner or consignee into a drug, biological product, or other product specified in section 801(d)(3) of the act that will be exported from the United States. These statutory changes also indicate a congressional desire to know more, rather than less, about the articles entering the United States under section 801(d)(3) of the act and to prevent potentially dangerous articles from entering the United States. The legislative history supports this belief, as the conference report for the Bioterrorism Act explained: “Refusal of entry should not involve shipments between known shippers and known recipients unless the Secretary has received credible evidence or information that suggests such shipments may not be legitimate. The Managers intend to permit the Secretary to refuse admission of articles if the Secretary determines there is credible evidence or information that the articles may be used as instruments of terror. Such evidence might include highly toxic or otherwise exceptionally dangerous products going to recipients unknown to the Secretary or to recipients believed to lack the capability to further process such dangerous articles * * *.” (See H. Rept. 107-481, l07th Cong. (2002), “Joint Explanatory Statement of the Committee of Conference,” “Subtitle B—Protection of Drug Supply” (discussing section 322).) The legislative history's references to “known” shippers, “known” recipients, and recipients who may lack the ability to further process an article, combined with the new statutory provision on refusing admission even if the article is imported under section 801(d)(3) of the act, strongly support our proposal to require that all drugs imported or offered for import into the United States be listed and manufactured at a registered foreign establishment. Failure to register such foreign establishments could compromise our ability to refuse admission of a dangerous article. Therefore, the proposed rule would eliminate the exemption from the establishment registration and drug listing requirements for foreign establishments whose drugs enter a foreign trade zone and are re-exported from that foreign trade zone without having entered U.S. commerce. In addition, the proposal would require that all drugs imported or offered for import into the United States be listed and manufactured at a registered foreign drug establishment, even if the drug is imported under section 801(d)(3) of the act. e. Other exemptions —As described in current § 207.10, the following remain exempt from registration and drug listing (proposed § 207.13): • Practitioners who are licensed by law to prescribe or administer drugs and who manufacture, repack, relabel, or salvage drugs solely for use in their professional practice (current § 207.10(c); proposed § 207.13(c)). • Manufacturers, repackers, relabelers, or drug product salvagers of drugs solely for use in research, teaching, or chemical analysis and not for sale (current § 207.10(d); proposed § 207.13(d)). Under proposed § 207.13(d), manufacturers, repackers, relabelers, or drug product salvagers who manufacture, repack, relabel, or salvage drugs solely for use in research, teaching, or chemical analysis and not for sale are exempt from registration requirements. Proposed § 207.13(d) would be consistent with the exemption in section 510(g)(3) of the act, except the language would be modified to take into account the proposed rule's uses of the terms “manufacturer,” “repacker,” “relabeler,” “drug product salvager,” “manufacture,” “repack,” “relabel,” and “salvage.” We want to take the opportunity to remind interested persons that while the exemption from registration would apply to a sponsor that manufactures its own drug for use in its clinical trial of the drug, the exemption would not apply, for example, to a firm that manufactures a drug with the purpose of selling the drug to a sponsor for use in a clinical trial. In the latter situation, the manufacturer of the drug would be required to register. • Manufacturers, repackers, relabelers, and drug product salvagers of harmless inactive ingredients (current § 207.10(e); proposed § 207.13(e)). We considered proposing to revoke this exemption because of concerns related to potential contamination of those inactive ingredients. However, we concluded that submitting and maintaining in the database all excipients, colorings, flavorings, emulsifiers, lubricants, preservatives, or solvents that become components of drugs could be burdensome for industry. In proposing to maintain this exemption, we note that current regulations governing the manufacture of finished drug products require all manufacturers to perform quality control testing to ensure that components meet established specifications (see generally, part 211 (21 CFR part 211)). • Manufacturers, repackers, relabelers, and drug product salvagers of animal viruses, serums, toxins, or analogous products (current § 207.10(g); proposed § 207.13(g)). • Carriers (current § 207.10(h); proposed § 207.13(h)). f. Limits on exemptions —Proposed § 207.13(i) would clarify that any of the persons who otherwise would qualify for an exemption under § 207.13(a) through (h) are not exempt from registration or listing if they: (1) Manufacture (as defined in proposed § 207.1), 4 repack, relabel, or salvage compounded positron emission tomography (PET) drugs as defined in section 201(ii) of the act; (2) manufacture (as defined in § 600.3(u)) a biological product subject to licensing under section 351 of the Public Health Service (PHS) Act; (3) manufacture (as defined in § 1271.3(e)) an HCT/P that, under § 1271.20, are also drugs regulated under section 351 of the PHS Act or section 505 of the act; or (4) engage in activities that would otherwise require them to register under this part. 4 The term “manufacture” is defined in proposed § 207.1 and is used here for brevity to refer to the activities that trigger registration requirements (that is, “manufacture, preparation, propagation, compounding, or processing” of drugs). Although many PET facilities do not consider themselves to be “manufacturing” drugs, but rather preparing or compounding drugs, we are nonetheless using the term “manufacture” for brevity. Thus, any person identified in proposed § 207.13(a) through (h), such as pharmacies, hospitals, clinics, other health care entities, public health agencies, or practitioners, if they manufacture, repack, relabel, or salvage compounded PET drugs, as defined in section 201(ii) of the act (21 U.S.C. 321(ii)), would fall outside the scope of the exemptions provided in proposed § 207.13(a) through (h). Manufacturers, repackers, relabelers, or drug product salvagers of compounded PET drugs are not included among the persons that are exempt from registration under proposed § 207.13 because exempting manufacturers of compounded PET drugs from registration would be inconsistent with section 121 of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act) (Public Law 105-115), which addresses the regulation of PET drug products. Section 121 of the Modernization Act directs us to develop appropriate procedures for the approval of PET drugs under section 505 of the act and appropriate CGMP requirements for such drugs. It also requires the submission of NDAs or ANDAs for PET drugs either 4 years after the date of enactment or 2 years after the date on which we establish approval procedures and CGMPs, whichever is longer. We published proposed CGMPs for PET drugs on September 20, 2005 (70 FR 55038). If Congress had intended to exempt manufacturers, repackers, relabelers, or drug product salvagers of PET drugs from registration requirements, it would have done so. Given that PET manufacturers will be expected to comply with CGMP requirements and FDA will need to inspect them to determine compliance, it is reasonable to require PET manufacturers, repackers, relabelers, or drug product salvagers to register so we can identify PET manufacturers, repackers, relabelers, or drug product salvagers and the drugs they manufacture, repack, relabel, or salvage for inspection purposes. Therefore, the proposed rule would require compounded PET drug manufacturers, repackers, relabelers, or drug product salvagers to register with us and list their drugs in accordance with section 510(j) of the act and proposed part 207. Likewise, any person identified in § 207.13(a) through (h) who would otherwise qualify for an exemption would not qualify for an exemption if it manufactures (as defined in § 600.3(u)) a biological product subject to licensing under section 351 of the PHS Act. We note that to the extent a person manufactures, repacks, relabels, or salvages PET drugs as set forth in proposed § 207.13(i)(1) or manufactures a biological product subject to licensing as set forth in proposed § 207.13(i)(2), the obligation to register and list would only apply to the extent that that person engages in the activities identified in proposed § 207.13(i)(1) or (i)(2). For example, a hospital dispensing and administering drugs and that also manufactures compounded PET drugs would list only the PET drugs it manufactures, assuming none of its other activities would subject it to registration or listing requirements. Likewise, a public health agency dispensing and administering drugs that holds a biologics license application would list only the biological drugs it manufactures, assuming none of its other activities would subject it to registration or listing requirements. Proposed paragraph (i) also states that the exemptions provided in proposed § 207.13(a) through (h) do not apply to such persons if they engage in activities that would otherwise require them to register. This concept appeared in current § 207.10(e). We are proposing to apply this concept to all the exemptions in proposed § 207.13 to reiterate that if a person qualifies for an exemption from the activities stated in proposed § 207.13(a) through (h), that person may still need to register if that person engaged in activities that would otherwise require registration. 5. What Definitions and Interpretations of Terms Would Apply to Part 207? In proposed § 207.1, we set forth new definitions and interpretations of terms for part 207 and revise or revoke certain definitions in current § 207.3(a). Current § 207.3(b) states that the definitions and interpretations of terms in sections 201, 502(e), and 510 of the act apply to the terms used in part 207. We are proposing to revoke this sentence because it is unnecessary and has caused confusion in the past. For purposes of proposed part 207, the following definitions and interpretations of terms would apply to proposed part 207: Act . This term, as used in proposed § 207.1, remains the same as current § 207.3(a)(1). “Act” means the Federal Food, Drug, and Cosmetic Act (52 Stat. 1040 et seq. , as amended (21 U.S.C. 301 et seq. )), except as otherwise provided. Active pharmaceutical ingredient . We are proposing to replace the term “bulk drug substance,” as defined in current § 207.3(a)(4), with the term “active pharmaceutical ingredient.” We believe that the term “bulk drug substance” may be confused with the term “bulk drug.” The term “bulk drug,” as commonly used in the pharmaceutical industry, means an active ingredient, inactive ingredient, or finished dosage form, packaged in a large container (for example, a drum). To prevent confusion, we are proposing to replace the term “bulk drug substance” with the more descriptive term “active pharmaceutical ingredient.” We are also proposing to revise the definition of the current term “bulk drug substance” (changed to “active pharmaceutical ingredient” in the proposal) to make it consistent with the definition of “drug substance” in current § 314.3 (21 CFR 314.3). Current § 207.3(a)(4) states, in part, that a “bulk drug substance * * * becomes an active ingredient,” but does not explain what it means for an ingredient to be “active.” We believe that the definition of “drug substance” in current § 314.3 is more descriptive; that definition explains, in part, that “drug substance means an active ingredient that is intended 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 * * * body.” Consistent with the language of current § 314.3, we are proposing to define “active pharmaceutical ingredient” in proposed § 207.1 as any substance that is intended 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 body. Consistent with both current § 314.3 and current § 207.3(a)(4), the term would not include intermediates used in the synthesis of the substance. As proposed, the term would include both an active pharmaceutical ingredient marketed alone and as part of a finished dosage form. Advertising and labeling . We are proposing to delete current § 207.3(a)(2), which explains that the terms “advertising” and “labeling,” as used in current part 207, include the promotional material described in current § 202.1(l)(1) and (l)(2) (21 CFR 202.1(l)(1) and (l)(2)), respectively. We believe that this information is more appropriately included in the definitions of “representative sampling of advertisements” and “representative sampling of any other labeling.” As a result, we are proposing to revise the definitions of those terms accordingly and delete current § 207.3(a)(2). Commercial distribution . We are not proposing to substantively change the definition of “commercial distribution” from that set forth in current § 207.3(a)(5). The term would still mean any distribution of a human drug, except for investigational use under 21 CFR part 312, and any distribution of an animal drug or an animal feed bearing or containing an animal drug for non-investigational uses. The term would not include internal or interplant transfer of an active pharmaceutical ingredient between registered establishments within the same parent, subsidiary, and/or affiliate company. For foreign manufacturers, foreign repackers, foreign relabelers, foreign drug product salvagers, foreign private label distributors, and foreign establishments, the term “commercial distribution” would have the same meaning except that it does not include distribution of any drug that is neither imported nor offered for import by it into the United States. We are proposing to change the term “bulk drug substance” in the current definition to “active pharmaceutical ingredient” because the proposal replaces the definition of “bulk drug substance” with the definition of “active pharmaceutical ingredient.” Defining “commercial distribution” is important because, under proposed part 207, listing information must be provided to us for any drug that is being manufactured, repacked, relabeled, or salvaged for commercial distribution. Content of labeling . We are proposing to add a new term, “content of labeling,” to part 207. The proposed definition of the term describes the labeling material that would be required to be electronically submitted at the time of listing under proposed §§ 207.49(g) and 207.61(a)(2). The proposed requirement to electronically submit the “content of labeling” would be in addition to the current listing requirement that formatted copies of certain labeling be submitted. We are proposing to define “content of labeling” because, as explained in section IV.E.4 of this document, the electronic submission of the “content of labeling” would be required for drug listing to permit us to electronically review, compare, and extract data from the labeling. • For human prescription drugs that the manufacturer regards as subject to section 505 of the act or section 351 of the PHS Act, we are proposing to define “content of labeling” as the content of the prescription drug labeling, as specified in §§ 201.56, 201.57, and 201.80 (21 CFR 201.56, 201.57, and 201.80), including all text, tables, and figures. 5 5 The use of the language “that the manufacturer regards as subject to section 505 of the act or section 351 of the PHS Act,” is explained in detail in section IV.D.7 of this document. This proposed definition is consistent with how the term “content of labeling” is used in the final rule entitled “Requirements for Submission of Labeling for Human Prescription Drugs and Biologics in Electronic Format,” (electronic labeling final rule), which published in the Federal Register of December 11, 2003 (68 FR 69009). Under the electronic labeling final rule, applicants are required to electronically submit, in a format that we can process, review, and archive, the “content of labeling” for human prescription drugs in NDAs, certain BLAs, ANDAs, supplements, and annual reports. 6 The electronic labeling final rule, including the use of the term “content of labeling,” only applies to this subset of drugs. Under the proposal, however, as set forth in proposed § 207.49(g), the “content of labeling” would be provided for drugs subject to the listing requirements of proposed part 207. 6 For additional information, also see the guidance “Providing Regulatory Submissions in Electronic Format—Content of Labeling” (April 2005) (available at http://www.fda.gov/cder/guidance/index.htm ), which discusses issues related to the submission of the content of labeling in electronic format in marketing applications for human drug and biological products. This guidance reflects our current thinking on providing in electronic format the content of labeling required in 21 CFR parts 314 and 601. Proposed part 207 would also differ in one other respect from the way “content of labeling” is used in the electronic labeling final rule. The electronic labeling final rule states that the “content of labeling” that must be submitted electronically is commonly referred to as the content of the package insert or professional labeling. We are proposing to use the term “prescription drug labeling” instead of the term package insert or professional labeling. “Prescription drug labeling” is used in the final rule entitled “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products,” published in the Federal Register of January 24, 2006 (71 FR 3922). In that final rule, “prescription drug labeling” is used to mean labeling for approved prescription drug products described in §§ 201.56, 201.57, and 201.80, which is commonly described using a variety of terms including “professional labeling,” “package insert,” “direction circular,” or “package circular.” We are proposing that the term “content of labeling” for human prescription drugs, as defined in proposed § 207.1 and required under proposed § 207.49(g), would be the content of the “prescription drug labeling.” • For human prescription drugs that the manufacturer regards as not subject to section 505 of the act or section 351 of the PHS Act, we are proposing to define “content of labeling” as the labeling equivalent to the content of the prescription drug labeling, as specified in §§ 201.56, 201.57, and 201.80, including all text, tables, and figures. • For human OTC drugs, we are proposing to define “content of labeling” as the content of the drug facts labeling required by § 201.66 (21 CFR 201.66) (format and content requirements for OTC drug product labeling), including all text, tables, and figures. Under § 201.66(b)(10), drug facts labeling means the title, headings, subheadings, and information required under or described in § 201.66(c) (content requirements). • For animal drugs (including, but not limited to, drugs that the manufacturer regards as subject to section 512 of the act), we are proposing to define “content of labeling” as the content of the labeling that accompanies the drug that is necessary to enable safe and proper administration of the drug (for example, the labeling specified in §§ 201.1 and 201.5 (21 CFR 201.1 and 201.5)), including all text, tables, and figures. Domestic . For the purposes of registration and listing under this proposal, and when used to modify the term “manufacturer,” “repacker,” “relabeler,” “drug product salvager,” “private label distributor,” or “establishment,” we are proposing to use the term “domestic” to refer to a manufacturer, repacker, relabeler, drug product salvager, private label distributor, or establishment within any State or Territory of the United States, the District of Columbia, or the Commonwealth of Puerto Rico. The terms “manufacturer,” “repacker,” “relabeler,” “drug product salvager,” “private label distributor,” and “establishment” are defined in proposed § 207.1, and these definitions are discussed elsewhere in this section of the preamble. We are proposing to define the term “domestic” separately rather than repeat the meaning of the term under separate definitions for domestic manufacturer, domestic repacker, domestic relabeler, domestic drug product salvager, domestic private label distributor, and domestic establishment. The definition of “foreign,” as it would modify manufacturer, repacker, relabeler, drug product salvager, private label distributor, and establishment, is discussed elsewhere in this section of the preamble. Drug(s) . We are proposing to use the term “drug(s),” for purposes of proposed part 207, to mean the same as the definition of “drug” in section 201(g)(1) of the act. Section 201(g)(1) of the act defines “drug” to include, among other things, articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, and articles (other than food) intended to affect the structure or any function of the body of man or other animals. “Drug(s)” under proposed § 207.1 would include drugs intended for use in humans, including the biologics described in proposed § 207.9(c), and animal drugs, including Type A medicated articles, and also includes articles “intended for use as a component” of any drug. The proposed term includes active pharmaceutical ingredients and finished dosage forms (prescription and OTC). Drug product salvager, drug product salvaging . We are proposing to use the term “drug product salvaging” to mean applying manufacturing controls such as those required by current good manufacturing practice in parts 210 (21 CFR part 210) and part 211 to drug products and segregating out those drug products that may have been subjected to improper storage conditions (such as extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation) for the purpose of returning the products to the marketplace. We note, however, that drug product salvaging, like all manufacturing, must be conducted in accordance with current good manufacturing practice. We are proposing to use the term “drug product salvager” to mean a person who owns or operates an establishment that engages in drug product salvaging. When not modified by “domestic” or “foreign,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, the term would include both domestic drug product salvagers and foreign drug product salvagers. Under current § 207.3(a)(6), drug product salvaging means the act of segregating drug products that may have been subjected to improper storage conditions, such as extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation, for the purpose of returning some or all of the products to the marketplace. We are proposing to revise the current definition of drug product salvaging to include “applying manufacturing controls such as those required by current good manufacturing practice in part 210 and part 211 to drug products.” We are not proposing to change the meaning of drug product salvaging but to clarify the current definition by explaining that the term also includes applying manufacturing controls to drug products. Drug product salvagers apply manufacturing controls to drug products so that they can determine whether the drug products may have been subjected to improper storage conditions. As discussed further in sections IV.B.1 and IV.D.1 of this document, “applying manufacturing controls to drug products and segregating drug products” would be covered under the scope of manufacturing, preparing, propagating, compounding, or processing, and repackaging or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the distribution of the drug from the original place of manufacture to the person who makes the final delivery or sale to the ultimate consumer or user (section 510(a)(1) of the act). This activity would trigger the requirement to register under the act. In addition, under the proposal, drug product salvagers would also be subject to the drug listing requirements in section 510(j)(1) of the act because their activities involve conducting one of the aforementioned activities with respect to a given drug for the purpose of commercial distribution. As discussed in section IV.D.1 of this document, we are requesting comments specifically on whether drug product salvagers should be subject to the drug listing requirements because the drug products are being salvaged for commercial distribution. Establishment . We are proposing to revise the definition of “establishment” at current § 207.3(a)(7) to mean, for purposes of registration and drug listing, a place of business under one management at one geographic location. Under the proposed definition, one geographic location may include separate buildings within the same city if their activities are closely related to the same business enterprise and are under the supervision of the same local management. When not modified by “domestic” or “foreign,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, the term would include both domestic establishments and foreign establishments. We are proposing to define the term “establishment” because, under proposed part 207, manufacturers, repackers, relabelers, and drug product salvagers must register each establishment, providing to us such information as the name and address of the establishment and type of operation performed at the establishment. The proposed definition of “establishment” would clarify the phrase “at one general physical location” in the current definition by revising the phrase to read “one geographic location” and stating that this may include separate buildings within the same city if their activities are closely related to the same business enterprise and are under the supervision of the same local management. The proposed definition of “establishment” is intended to simplify the current definition. The current definition defines establishment as a place of business under one management at one general physical location, and includes, among others, independent laboratories that engage in control activities for a registered drug establishment (for example, consulting laboratories), manufacturers of medicated feeds and vitamin products that are drugs in accordance with section 201(g) of the act, human blood donor centers, animal facilities used for the production or control testing of licensed biologics, and establishments engaged in drug product salvaging. For brevity, the proposed definition of establishment does not restate the examples of establishments stated in the current definition. Some of these establishments would be covered under other definitions set forth in proposed § 207.1 and explained in section IV.A.5 of this document. For example, “independent laboratories that engage in control activities for a registered drug establishment” would be covered under the proposed definition of “manufacturer.” “Establishments engaged in drug product salvaging” would be covered under the proposed definition of “drug product salvager.” Establishment registration number . We are proposing to define “establishment registration number” as the number assigned by FDA to the establishment during the establishment registration process required in this part. The establishment registration number is assigned to each establishment of each manufacturer, repacker, relabeler, or drug product salvager inspected by our district office. The establishment registration number is assigned when the manufacturer, repacker, relabeler, or drug product salvager begins manufacturing, repacking, relabeling, or salvaging drugs subject to part 207. The establishment registration number would identify, among other things, where the drug is manufactured, repacked, relabeled, or salvaged. Currently, the FDA Establishment Identifier (FEI) will be the number we assign as the establishment registration number. In the future, however, we may use a different number as the establishment registration number. Foreign . For the purposes of registration and listing under this proposal, and when used to modify the term “manufacturer,” “repacker,” “relabeler,” “drug product salvager,” or “private label distributor,” we are proposing to use the term “foreign” to refer to a manufacturer, repacker, relabeler, drug product salvager, or private label distributor who is located in a foreign country and who manufactures, repacks, relabels, salvages, or distributes a drug that is imported or offered for import into the United States. When used to modify the term “establishment,” we are proposing to use the term “foreign” to refer to an establishment that is located in a foreign country and is the site where a drug that is imported or offered for import into the United States was manufactured, repacked, relabeled, salvaged or distributed. The terms “manufacturer,” “repacker,” “relabeler,” “drug product salvager,” “private label distributor,” and “establishment” are defined in proposed § 207.1, and these definitions are discussed elsewhere in this section of the preamble. We are proposing to define the term “foreign” separately rather than repeat the meaning of the term under separate definitions for foreign manufacturer, foreign repacker, foreign relabeler, foreign drug product salvager, foreign private label distributor, and foreign establishment. The definition of “domestic,” as it would modify manufacturer, repacker, relabeler, drug product salvager, private label distributor, and establishment, is discussed elsewhere in this section of the preamble. Importer . We are proposing to define “importer” to mean a company or individual in the United States that is an owner, consignee, or recipient of the foreign establishment's drug that is imported into the United States. We recognize that a foreign establishment may have more than one “importer” and we are proposing to include in this term any owner, consignee, or recipient, even if not the initial owner, consignee, or recipient, of the foreign establishment's drug that is imported into the United States. Under this proposal, the recipient of the drug would not include the consumer or patient who ultimately purchases, receives, or is administered the drug, unless the foreign establishment ships the drug directly to the consumer or patient. As described in section IV.B.3 of this document, this proposal would require foreign establishments to provide, for drugs manufactured, repacked, relabeled, or salvaged at the establishment, the name of each importer known to the establishment of such drug into the United States. Therefore, the establishment would need to provide the name of each owner, consignee, or recipient of the foreign establishment's drug imported into the United States that was known to the establishment. We describe more fully what we mean by “known to the establishment” in section IV.B.3 of this document. We invite comments on our definition of importer, including the scope of the entities included in the definition. Manufacture, manufacturer . We are proposing to use the term “manufacture” for purposes of this part to mean each step in the manufacture, preparation, propagation, compounding, or processing of a drug. Manufacture includes the making by chemical, physical, biological, or other procedures or manipulations of a drug, including control procedures applied to the final product or to any part of the process. Manufacture includes manipulation, sampling, testing, or control procedures applied to the final product or to any part of the process, including, for example, analytical testing of drugs, for another registered establishment's drug. We are proposing to use the term “manufacturer” for purposes of this part to mean a person who owns or operates an establishment that manufactures a drug. When not modified by “domestic” or “foreign,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, “manufacturer” would include both domestic manufacturers and foreign manufacturers. Under section 510(a)(1) of the act, the term “manufacture, preparation, propagation, compounding, or processing” includes repackaging or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the distribution of the drug from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user. Accordingly, section 510(a)(1) of the act sets up a shorthand way of referring to all the activities that trigger registration requirements by using the specified phrase “manufacture, preparation, propagation, compounding, or processing” throughout section 510 of the act. However, for purposes of proposed part 207, the term “manufacture” would refer to the manufacture, preparation, propagation, compounding, or processing of a drug, as set forth in the proposed definition. The term “manufacturer” would include, among others, control laboratories, contract laboratories, contract manufacturers, contract packers, contract labelers, and other entities that manufacture a drug, as defined in proposed § 207.1 and discussed in section IV.A.5 of this document. A “control laboratory” and a “contract laboratory” include independent establishments that manipulate, sample, test, or perform other quality control functions for another registered establishment's drug, including, for example, analytical testing of drugs. A “contract manufacturer” is sometimes employed by other manufacturers to manufacture the drug. Similarly, a manufacturer may sometimes subcontract part of the manufacturing process such as packing or labeling to a “contract packer” or a “contract labeler.” The term “manufacturer” would include control laboratories, contract laboratories, contract manufacturers, and other entities that manufacture a drug because their activities include the making of drugs by chemical, physical, biological, or other procedures, including the manipulation, sampling, testing, or control procedures applied to the final drug product or to a part of the process. Such activities would fall under the scope of activities (that is, manufacture, prepare, propagate, compound, or process) in section 510(a)(1) of the act that trigger registration requirements. The proposed definition of “manufacture” also explains that, for purposes of proposed part 207, the term manufacture is defined and used separately from the terms relabel, repack, and drug product salvage. Although we explain that repacking, relabeling, and drug product salvaging are activities that trigger registration (because the term “manufacture, preparation, propagation, compounding, or processing,” under section 510 of the act includes repackaging or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the distribution of the drug from the original place of manufacture to the person who makes the final delivery or sale to the ultimate consumer or user), we believe that it is clearer to use four separate terms for the different activities for purposes of proposed part 207. We use separate terms so that we can clarify and differentiate the responsibilities of the four types of parties engaged in the separate activities of: ((1) Manufacturing that does not include repacking, relabeling, or drug product salvaging; (2) repacking; (3) relabeling; and (4) drug product salvaging). Similarly, the proposed definition of “manufacturer” explains that the term manufacturer is defined and used separately from the terms relabeler, repacker, and drug product salvager. We explain that repackers, relabelers, and drug product salvagers are “manufacturers” (as that entity is contemplated in section 510 of the act), but we believe that, for purposes of proposed part 207, it is clearer to use four separate terms for the different entities: (1) Manufacturers (that are not also repackers, relabelers, or drug product salvagers); (2) repackers; (3) relabelers; and (4) drug product salvagers. Repackers, relabelers, and drug product salvagers would be subject to the provisions of part 207 that are applicable to repackers, relabelers, and drug product salvagers, respectively, but would not be subject to the provisions of part 207 that are applicable to “manufacturers,” as that term is defined in this proposal. For example, if a repacker, relabeler, or a drug product salvager supplies us with the manufacturer's NDC number, we would not require the repacker, relabeler, or drug product salvager to provide all of the information that the manufacturer provides to list a drug or, for the repacker or relabeler, to obtain an NDC number. We would already have much of the information in the database linked to the manufacturer's NDC number, and it would be an unnecessary burden to require that the information be provided again. We are proposing to delete the definition of “manufacturing or processing” at current § 207.3(a)(8) and incorporate parts of the definition elsewhere in the proposed definitions. For example, the phrase “control procedures applied to the final product or to any part of the process” in the proposed definition of “manufacture” is part of the current definition of “manufacturing or processing.” Material change . We are proposing to revise the definition of “any material change” in current § 207.3(a)(3). The current definition includes, but is not limited to: (1) Any change in the name of the drug; (2) any change in the identity or quantity of the active ingredient(s); (3) any change in the identity or quantity of the inactive ingredient(s) where quantitative listing of all ingredients is required by current § 207.31(a)(2); (4) any significant change in the labeling of a prescription drug; and (5) any significant change in the label or package insert of an OTC drug. Changes that are not significant currently include changes in arrangement or printing or changes of an editorial nature. The proposed definition would continue to exclude labeling changes in arrangement or printing or labeling changes of an editorial nature. The inclusion of a bar code or NDC number on the label would not be considered a material change because it would be too burdensome to require the resubmission of labeling if the only change was to include a bar code or an NDC number. We are, however, proposing to rename the term “material change” and to more precisely identify all of the changes that would be considered “material” in the current definition. With respect to manufacturers, repackers, and relabelers, and drug product salvagers, a change in any information provided under proposed §§ 207.49, 207.53, 207.54, 207.55, or 207.57 would be considered a material change. All listing information required under the proposal is needed to identify the drug. Under the broader definition of material change, as proposed, we would be better informed of changes to marketed drugs. This would result in more accurate and up-to-date drug listing information. Under proposed § 207.57 and section 510(j)(2)(D) of the act, the June and December updates of listing information must include reports of “material changes” in listing information previously submitted. The proposed definition of “material change” has been revised to more precisely identify which changes must be reported under proposed § 207.57. Person who imports or offers for import . We are proposing to define a “person who imports or offers for import” as an agent, broker, or other entity that the foreign establishment uses to facilitate the import of its drug into the United States. As described in section IV.B.3 of this document, this proposal would require foreign establishments to provide, for drugs manufactured, repacked, relabeled, or salvaged at the establishment, the name of each person known to the establishment who imports or offers for import such drug into the United States. Therefore, the establishment would need to provide the name of each agent, broker, or other entity that the foreign registrant uses to facilitate the import of its drug into the United States. We describe more fully what we mean by “known to the establishment” in section IV.B.3 of this document. The term “person who imports or offers to import” would not include carriers, consistent with the legislative history of the Bioterrorism Act. The legislative history shows that although the House provision originally would have required registration information for importers and carriers, the conference substitute changed the language. The conference substitute deleted the term “carriers,” replacing it with “persons who import or offer for import,” clarifying that foreign manufacturers are not required to include information on carriers with annual registration. (See H. Rept. 107-481, 107th Cong., 2d sess., p. 140, 2002, Conf. Rept. to accompany H.R. 3448) We invite comments on our proposed definition of “persons who import or offer for import.” We also invite comment on our use of the word “facilitate” in the proposed definition. We recognize that the term could be interpreted to include middlemen or other entities that may be viewed as assisting with or promoting the importation of a drug into the United States. For example, we are aware that “buyer's clubs” could be captured in the definition if “facilitate” were to be interpreted broadly. Buyer's clubs are groups that consolidate orders for drugs purchased from foreign establishments and then, once those drugs are imported into the United States, send them to the individuals or other entities who ordered the drugs through the clubs. It is also possible that “facilitate” could be interpreted to include organizations that may promote the awareness and sale of products through advertisements on the internet, for example. We recognize that, under this proposal, foreign establishments would only be required to give us information for persons who import or offer for import that are known to the establishments. Although the knowledge requirement in this proposed rule would include information that the foreign establishment, and persons in the foreign establishment, has reason to know of, we believe it is likely that foreign establishments generally would not know about most of the “middlemen” described previously. Therefore, even though the term “facilitate” in the proposed definition would be interpreted broadly to include middlemen, if the foreign establishment did not know of, or have reason to know of, the middlemen, the foreign establishment would not be required to report information about the middlemen under this proposal. We also note that the terms “broker” or “agent” include “customhouse brokers” who facilitate importation by filing documents with the U.S. Customs Service, as well as FDA and other Federal agencies responsible for the regulation of imported products. We specifically invite comment on our use of the term “facilitate” in this proposal. We invite comment on whether we should interpret the term “facilitate” broadly to include middlemen as described previously. We also invite comment on whether foreign establishments would know about such middlemen and, if so, what effect a requirement to report information about those middlemen would have on foreign establishments. We also invite comment on whether there are benefits associated with such a reporting requirement, and, if so, what they are. Private label distributor . We are proposing to define “private label distributor” to mean a person who owns or operates an establishment that commercially distributes, under its own label or trade name, any drug manufactured, repacked, relabeled, or salvaged by a registered establishment. When not modified by “domestic” or “foreign,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, the term would include both domestic private label distributors and foreign private label distributors. Private label distributors are not considered to be manufacturers, repackers, relabelers, or drug product salvagers because they do not conduct any of the activities covered in section 510(a)(1) of the act with respect to the products they commercially distribute. Private label distributors only distribute drugs under their own label or trade name. The proposed definition is consistent with current § 207.20(b) and the description of private label distributors set forth in the 1973 final rule on drug listing requirements (38 FR 6258 at 6259). We are proposing to define this term to clarify its meaning and to distinguish private label distributors from manufacturers, repackers, relabelers, and drug product salvagers. Under the proposed definition, a private label distributor does not engage in any activities performed by a manufacturer, repacker, relabeler, or drug product salvager for the drug it distributes. As discussed in section IV.D.1 of this document, private label distributors currently may elect to submit listing information to us for the drugs they distribute. Under the proposal, private label distributors would not be permitted to list, and manufacturers, repackers, relabelers, and drug product salvagers would be required to provide listing information to us for drugs being manufactured, repacked, relabeled, or salvaged for private label distributors. However, if a private label distributor is a manufacturer with respect to a particular drug or drugs, for example, the private label distributor is subject to the registration and listing requirements for manufacturers in proposed part 207 with respect to that drug or drugs. Relabel, relabeler . We are proposing to use the term “relabel” to mean changing the label or labels on a drug or drug package, or adding to the labeling for a drug or drug package, without repacking the drug or drug package. We remind interested persons that those activities must be conducted in accordance with the act and FDA regulations. We are proposing to use the term “relabeler” to mean a person who owns or operates an establishment that relabels a drug. When not modified by “domestic” or “foreign,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, the term would include both domestic relabelers and foreign relabelers. Under the proposal, relabelers must provide registration and listing information. Under section 510(a)(1) of the act, the term “manufacture, preparation, propagation, compounding, or processing” includes repackaging or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the distribution of the drug from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user. As discussed previously, we use the term “relabeler” separately from the term “manufacturer” because, although the relabeler's registration and listing responsibilities in general are the same as those for manufacturers under the act, the proposal would modify some of these requirements. For example, as described under the definition of “manufacturer” in section IV.A.5 of this document, if a relabeler supplies us with the manufacturer's NDC number, we would not require the relabeler to provide all of the information that the manufacturer provides to obtain an NDC number and to list a drug. We would already have much of the information in the database linked to the manufacturer's NDC number, and it would be an unnecessary burden to require that the information be provided again. Under the proposed definition, a relabeler does not engage in any other activity performed by a manufacturer for the drugs they relabel. Repack, repacker . We are proposing to use the term “repack” to mean repack or repackage or otherwise change the container or wrapper of a drug or drug package. We are proposing to use both the terms “repack” and “repackage” in the definition because these terms are often used interchangeably with respect to drugs and, whether such activities are characterized as repacking or repackaging, they are subject to the requirements of this part. Although the term “repackaging” is used in section 510(a)(1) of the act, the terms “repacking,” “repack,” and “repacker” are more commonly used by industry when referring to this activity, and, therefore, we are using these terms throughout the proposal. We are proposing to use the term “repacker” to mean a person who owns or operates an establishment that repacks a drug or drug package. When not modified by “domestic” or “foreign,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, the term would include both domestic repackers and foreign repackers. Under the proposal, repackers must provide registration and listing information. Under section 510(a)(1) of the act, the term “manufacture, preparation, propagation, compounding, or processing” includes repackaging or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the distribution of the drug from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user. We use the term “repacker” separately from the term “manufacturer” because, although the repacker's registration and listing responsibilities in general are the same as those for manufacturers under the act, the proposal would modify some of these requirements. For example, as described under the definition of “manufacturer” in section IV.A.5 of this document, if a repacker supplies us with the manufacturer's NDC number, we would not require the repacker to provide all of the information that the manufacturer provides to obtain an NDC number and to list a drug. We would already have much of the information in the database linked to the manufacturer's NDC number, and it would be an unnecessary burden to require that the information be provided again. Under the proposed definition, a repacker does not engage in any other activity performed by a manufacturer for the drugs they repack. Representative sampling of advertisements . We are proposing to revise the definition of “representative sampling of advertisements.” Currently, § 207.3(a)(2) explains that the term “advertising” as used in part 207 includes the promotional material described in § 202.1(l). However, current § 207.3(a)(9) expressly excludes such material from the definition of “representative sampling of advertisements.” We believe that the inconsistency between the two provisions was an unintended result of certain editorial amendments made to part 207. We are proposing to revise the definition of “representative sampling of advertisements” to resolve the inconsistency. Specifically, we believe that the content of current § 207.3(a)(2) should be incorporated into the definition of “representative sampling of advertisements” to clarify that the term includes the promotional material described in § 202.1(l)(1). We are proposing to define “representative sampling of advertisements” as typical advertising material (including the promotional material described in § 202.1(l)(1), but excluding labeling as determined in § 202.1(l)(2)), that gives a balanced picture of the promotional claims used for the drug. In addition to resolving the inconsistency described previously, the proposed definition would delete the example currently provided in § 207.3(a)(9) (that is, if more than one medical journal advertisement is used but the promotional content is essentially identical, only one needs to be submitted). We believe that this example is unnecessary and are proposing to simplify the definition by deleting it. Representative sampling of any other labeling . We are proposing to revise the definition of “representative sampling of any other labeling.” We are proposing to delete current § 207.3(a)(2), which explains that the term “labeling” as used in part 207 includes the promotional material described in § 202.1(l)(2). We believe that this information would be more appropriately included in the definition of “representative sampling of any other labeling.” We are proposing to define “representative sampling of any other labeling” as typical labeling material (including the promotional material described in § 202.1(l)(2), but excluding labels and package inserts) that gives a balanced picture of the promotional claims used for the drug. In addition to incorporating the relevant content of current § 207.3(a)(2), the proposed definition would delete the example currently provided in current § 207.3(a)(10) (that is, if more than one brochure is used but the promotional content is essentially identical, only one needs to be submitted). We believe that this example is unnecessary and are proposing to simplify the definition by deleting it. United States agent . We are proposing to remove the definition of “United States agent” in current § 207.3(a)(11). Proposed § 207.69 would incorporate many of the provisions of the current definition of United States agent and current § 207.40 (registration and listing requirements for foreign establishments). The same requirements in the current definition appear at proposed § 207.69(b)(1), (b)(2), and (b)(3). B. Registration 1. Who Would Be Required to Register? Proposed § 207.17(a) would require manufacturers, repackers, relabelers, and drug product salvagers to register each establishment. This provision would replace the requirement at current § 207.20(a) that owners or operators of all drug establishments that engage in the manufacture, preparation, propagation, compounding, or processing of a drug must register. The terms “manufacturer,” “repacker,” “relabeler,” and “drug product salvager,” as defined in proposed § 207.1 and discussed in section IV.A.5 of this document, more clearly indicate who must register. Manufacturers, repackers, relabelers, and drug product salvagers would be required to register because the activities they perform fall within the scope of activities that trigger registration requirements in section 510(a)(1) of the act. Section 510(a)(1) states that the phrase “manufacture, preparation, propagation, compounding, or processing” includes repacking or otherwise changing the container, wrapper, or labeling of any drug package in furtherance of the distribution of the drug from the original place of manufacture to the person who makes final delivery or sale to the ultimate consumer or user. We are proposing to use the terms “repacker,” “relabeler,” and “drug product salvager” separately from the term “manufacturer” in the proposal because, although the repacker, relabeler, and drug product salvager's listing responsibilities in general are similar to those for manufacturers under the act, the proposal would modify some of these requirements. In particular, if a repacker, relabeler, or drug product salvager supplies us with the manufacturer's NDC number, we would not require the repacker, relabeler, or drug product salvager to provide all of the information that the manufacturer provides to list a drug. Similarly, we would not require repackers and relabelers to submit all of the information that the manufacturer submits to obtain an NDC number. Proposed § 207.17(a) would enable us to identify who is making drugs and where they are being made. Being able to accurately identify who makes drugs and where they are made is very important. Certain marketed drugs may need to be quickly identified and used to help counteract the effects of a bioterrorism attack. Registration information also assists us in scheduling and planning inspections of registered establishments pursuant to section 704 of the act. Proposed § 207.17(a) also provides that registration information may be submitted by the parent, subsidiary, and/or affiliate company for all establishments when operations are conducted at more than one establishment and there exists joint ownership and control among all the establishments. This provision would also apply when operations are conducted at both domestic and foreign establishments and there exists joint ownership and control among all the establishments. This provision is consistent with current § 207.20(a). We are proposing to revoke the requirement in current § 207.20(a) that no owner or operator may register an establishment if any part of that establishment is registered by another owner or operator. The requirement has caused uncertainty about who must register and which establishment must be registered. Under proposed § 207.17(a), manufacturers, repackers, relabelers, and drug product salvagers must register each establishment unless they are otherwise exempt under section 510(g) of the act or proposed § 207.13. Under proposed § 207.17(b), private label distributors would not register with us unless they also manufacture, repack, relabel, or salvage drugs and are required to register under the act or proposed § 207.17(a). Private label distributors are not considered to be manufacturers, repackers, relabelers, or drug product salvagers because they do not conduct any of the activities covered under section 510(a)(1) of the act with respect to the drugs they commercially distribute. Private label distributors only distribute drugs under their own label or trade name. Proposed § 207.17(b) would revise the provision in current § 207.20(b) that owners or operators of establishments that distribute under their own label or trade name a drug manufactured or processed (as defined in current § 207.3(a)(8)) by a registered establishment may elect to obtain a labeler code from us and submit listing information directly to us. Under current regulations, if a private label distributor does not elect to submit drug listing information to us, the registered establishment must submit the drug listing inf [Text truncated at 120,000 characters. The full text is on the page linked above.] --- Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A06-7172. Public record. Not legal advice.