FDA Seeks Input on Establishment Registration & Listing

Warning: This is going to be a really long posting! But, it's important.

On August 23rd, the FDA issued a proposed rule to make managing drug information more efficient and effective by automating the process by which drug firms register themselves and list their products with FDA.

With this issuance, the FDA is seeking input by those potentially affected by the proposed rule.

In my estimation, if enacted as described in the Federal Register, the rule will place a significant operating and financial burden on each and every company that manufactures and distributes drugs and biologics.

In addition, the proposed rule has significant implications on existing and future IT systems and applications.

So, now is your chance to affect this piece of legislation or be forced to swallow it whole. You have until November 20th to submit your comments.

The proposed rule is described in a (PDF Format) 319 page document posted in the Federal Register.

It is identified as: FDA 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."

The key elements of the proposed ruling are that manufacturers, repackers, relablers and salvagers must:

• Submit registration and listing information electronically (instead of paper);
• Provide some information not required in the past;
• Give up the right to assign NDC numbers themselves (i.e. the FDA will do this);
• Accept that more of the submitted information will be available to the public.

Despite these changes, we need to assume that the FDA has not only their own interest at heart. For example, the document points out how manufacturers would be able to leverage the electronic data and even realize some productivity gains.

However, the document makes some assertions about the potential benefits from the proposed changes that I would consider to be a stretch. Of course, each person will interpret the proposed rules from his/her own perspective so it's not that important for you to know my opinions. You need to do your own homework, decide how the changes would potentially affect your company and then make constructive comments to the FDA on modifications you'd like them to consider.

To ease the homework part, I have extracted the most important parts of the document. This is not necessarily meant to be a substitute for reading the whole thing. After all, the very act of extraction on my part is biased. So, caveat emptor!

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Extracts from the Proposed Ruling:

(Note: P stands for Page Number in the FDA document)

P1: 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.

P2: 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.

P2: Submit written or electronic comments by [insert date 90 days after date of publication in the Federal Register]. Submit written comments on the information collection requirements by [insert date 30 days after date of publication in the Federal Register] to OMB.

P9: ...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.

P12: [Currently,] 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.

P16: 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).

P16: 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).

P18: [In the future] 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).)

P18: 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.)

P19: 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.

P20: 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.)

P20: 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).

P35: 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.

P44: 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.

P45: We are proposing to use the term ‘‘prescription drug labeling’’ instead of the term package insert or professional labeling.

P49: 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.

P51: 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.

P59: 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.

P60: What Information Would Be Required for Registration? (following are excerpted)

• Name of the owner or operator of each establishment;
• Name, trade name(s), and address of each establishment;
• Registration number of each establishment;
• Type of operations(s) performed at each establishment;
• Name, address, telephone and fax numbers, and e-mail address of the official contact
• [Additional] Information for foreign establishments only

P86: In brief, we believe that to ensure that the numbers are unique and unambiguous, we need to take on the responsibility of assigning the NDC numbers prospectively to drugs that have not previously been assigned NDC numbers by a manufacturer, repacker, or relabeler.

P87: The proposal would revise § 201.2 to explain:

• What drugs must have an NDC number, in human-readable form, on the label;
• What an appropriate NDC number is;
• Whether any other NDC number may appear on a label;
• What prefix must be used to identify the NDC number on the label;
• Where the NDC number goes on the label.

P93: Proposed § 201.2(d) would require the human-readable NDC number to be immediately preceded by the letters ‘‘NDC.’’

P100: Proposed § 207.33(c) and (d) describes the information that a manufacturer, repacker, or relabeler would be required to submit before we assign an NDC number to a drug.

P103: Information to be submitted to receive an NDC number: (following are excerpted)

• Name, address, telephone and fax numbers, e-mail address, and labeler code;
• The drug’s or active pharmaceutical ingredient’s established name and proprietary name (if any);
• The Drug Master File (DMF) number or Veterinary Master File (VMF) number;
• Name and quantity of each active pharmaceutical ingredient in a drug;
• Name of the inactive ingredient(s);
• Dosage form;
• Package size and type;
• Marketing status;
• Drug or drug product type;
• Imprinting information;
• NDC number assigned to the drug immediately before the repacker or relabeler received that drug;
• Type of operation;Information regarding private label distributors.

P117: We are proposing that our electronic drug registration and listing system be used to enter and update all NDC number information, as well as all registration and listing information, no later than 9 months after the effective date of a final rule.

P119: We intend to phase-in the requirements for NDC number placement and appearance on human and animal prescription drug labels over a 3-year period, starting from the effective date of a final rule.

P126: What Listing Information Would Be Required?

The following summary table was created by George Laszlo from the prose in the proposed ruling:

(Click on the table for a larger view) 

P155: As mentioned previously, our electronic drug registration and listing system is expected to be a Web-enabled, integrated system that provides controlled database access for you to register establishments and list drugs. A separate capability—an extranet—could be used that authenticates external users and controls their access to the our online registration and listing database. This system would allow you to create user accounts and manage additional users.

P157: Our electronic drug registration and listing system would be made available using an Internet-based data collection system accessed through our FDA Internet site.

P160: We are proposing that manufacturers provide the NDC number electronically with the content of labeling during listing so that we can more easily link the content of labeling to the listed drug and, thus, expedite the listing process.

P162: We are prepared at this time to receive the content of labeling as a portable document format (PDF) file that is searchable.

P162: ...we may recommend in the future that new file formats such as extensible markup language and software applications be used to submit labeling electronically.

P163: Under proposed § 207.61(a)(3), advertisements and labeling, other than the content of labeling, required under proposed §§ 207.49(g) and (h) and 207.53(d) and (e) would be provided to us in paper or electronic format. Information on how and where to send labeling and advertisements that are not provided electronically will be described in the guidance document we intend to develop, as discussed in section IV.E.6 of this document.

P164: We plan to publish draft guidance and technical specifications on the electronic submission of registration and listing information through our electronic drug registration and listing system (the draft guidance).

P168: We are proposing to exempt the submission of electronic content of labeling from certain part 11 requirements because we believe these part 11 requirements are not critical to ensure the quality of the content of labeling that would be submitted under this proposed rule and we do not think it is necessary for industry to expend resources on controls that are not necessary to further the goals of part 11.

P177: ...we intend to make most information that is available for public disclosure accessible via the Internet.

P212: The major potential cost of the proposed rule is the assignment of NDC numbers by FDA.

P235: ...the improved processes in the proposed regulation would generate up-to-date, complete medication information, including NDC numbers, to support a growing number of medical and health information technology initiatives.

P236: We have estimated that if the lack of reliable NDC numbers would delay the rate of technological acceptance by 1 year, the potential benefits of the bar code regulation would be reduced by about $600 million per year and an average of 25,000 additional adverse drug events would occur.

P236: A key element for encouraging the use of technology to ensure public health will be the assurance that NDC numbers are unique and accurately identify drugs. The proposed rule would accomplish this by making assignment of NDC numbers our responsibility, rather than a responsibility diffused throughout the industry.

P236: ...by ensuring that these NDC numbers are available in human readable format, patients and others would be able to access important patient safety information from the DailyMed system, the NDC Directory, or other drug information electronic systems without the use of bar code scanners.

P236: ...the human-readable NDC number would enable us to trace the origin of each product (a particularly important issue when dealing with recalls or drug quality issues) and more easily identify drug products and their sources

P237: ...electronic database of drugs would allow for timely notification of any recalls of unsafe drugs and identification of affected manufacturers, repackers, relabelers, or drug product salvagers.

P237: After we have introduced increased oversight for new product codes and package codes, the likelihood of unsafe counterfeit drug products entering the supply chain would decline because would-be counterfeiters would be unsure of numerical sequences used for NDC numbers.

P245: We have analyzed the expected impacts of the proposed rule. This proposal is expected to have average annualized costs of $5.6 million (using a 3 percent annual discount rate) or $5.8 million (using a 7 percent annual discount rate). The benefits include assurance of correct NDC numbers, which would also mean correct bar-coded information, and electronic access to important product information for patients that will improve public health.

P256: Based on the current receipts of Forms FDA 2657 and 2658 for new listings, we estimate that approximately 1,812 manufacturers, repackers, relabelers, and drug product salvagers will provide electronically approximately 13,821 new listings annually.

P256: Based on the number of drugs in our listing database and the current receipts of Forms FDA 2657 and 2658 for changes to listing information (and, until recently, the number of receipts of compliance verification reports), we estimate that approximately 2,278 manufacturers, repackers, relabelers, and drug product salvagers will provide approximately 22,568 June and 22,568 December reviews and updates of listing information (a total of 45,136 submissions annually), and that approximately 5,594 manufacturers, repackers, relabelers, and drug product salvagers will provide approximately 81,980 June and 81,980 December reviews and certifications that no changes have occurred (a total of 163,960 submissions annually).

P257: ...we estimate that it will take manufacturers, repackers, relabelers, and drug product salvagers approximately 1 hour and 30 minutes to provide electronically information for each drug they list for the first time (for both foreign and domestic listings).

P263: Under proposed § 207.61, establishment registration and drug listing information must be submitted to us in electronic format. In addition, the content of labeling must be submitted in electronic format. Other labeling and advertisements may be provided in paper or electronic format. Electronic format submissions must be in a form that we can process, review, and archive.

P263: We estimate that approximately 8,343 manufacturers, repackers, relabelers, and drug product salvagers will provide this information (approximately 8,343 submissions) and that it will take approximately 15 minutes to provide the requested information.

P268: We are proposing that our electronic drug registration and listing system be used to enter and update all registration, listing, and NDC number information no later than 9 months after the effective date of a final rule.

P289: The NDC number is a unique 10 digit number with 3 segments. The three segments are the labeler code, the product code, and the package code. We will assign the complete NDC number (that will include the existing labeler code, if any) to each drug that is subject to the listing requirements in this part.

Comments

[Joe Alan]

Maybe I am misinterpreting this, but it doesn't seem to me that any kind of investment in new IT software or systems would be required within the Regulatory Submissions environment, as the NDC information would be submitted / gathered via an FDA run web-application.

However it seems this could have a great impact on any current systems that are used within industry to assign and track NDC numbers.

Does anyone else have a different take on how this could affect IT systems?