Common SPL Errors Experienced by FDA DRLS Paul Loebach FDA, Center for Drug Evaluation and Research September 2016

Overview Topics we’ll cover in this presentation include: Basic background of the Drug Registration and Listing System (DRLS) “Top ten” SPL errors encountered by DRLS Staff Summary

Background Section 510(b) of Food Drug and Cosmetic Act (FD&C) During the period beginning October 1st and ending on December 31 of each year every person who owns or operates any establishment in any State engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs ... shall register with the Secretary his name, places of business and all such establishments. Section 510(i) of FD&C During the period beginning October 1st and ending on December 31 of each year, any establishments within any foreign country engaged in the manufacture, preparation, ... of a drug that is imported or offered for import into the United States shall ... register with the Secretary the name and place of the establishment, the name of the United States agent for the establishment, the name of each importer of such drug that is known to the establishment Section 510(j) of the FD&C Every person who registers with the Secretary shall file a list of all drugs which are being manufactured, prepared, ... 21 CFR 207 Code of Federal Regulations Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Establishment Registration and Drug Listing Establishes Structured Product Labeling (SPL) as standard

Background (cont’d) 2009 – accepting only SPL – did not migrate data from legacy paper system-maintained two systems - 2012 - Switched NDC Directory to just electronic data Published the last of what is now called the “OLD NDC Directory” Paper listings still technically active 2016 – 21 CFR 207 publishes Mostly catches us up to current SPL practice, requires electronic submission All mention of Paper forms gone Requires UFI, should include FEI if known Requires annual listing certification. Effective date is November 2016

Top Ten Errors (Notes and Caveats) Not really the top ten most prevalent Some are just reoccurring errors and questions we encounter on a regular basis Some are head scratching or amusing Some are prevented by automated validations But we get calls on a daily basis asking why the submission is being rejected No particular order Examples not intended to shame or embarrass any particular firm. Our goal is accurate data! Highlight errors to the experts so errors can be prevented.

Incorrect DEA Schedule Assignment Top Ten Errors (10) Incorrect DEA Schedule Assignment Though these are internal listings by CMs, there were other finished listings that have since been corrected. Validations have been improved.

Top Ten Errors (9) Product Listings Referencing Unapproved or Non-existent Application Numbers Some occurrences received before validations were put in place Some are claiming an approval inappropriately Kits containing a component that has a separate approval Some unauthorized repacked and relabeled products Non-compliant monograph citations Some are products where the application has since been withdrawn Efforts underway to address this

Top Ten Errors (8) Product Listings Using Incorrect Strength Representation Firms don’t understand or know how to express a percentage strength as an appropriate ratio (incorrect calculations, incorrect units, or both) Continued education of drug companies and SPL consultants/providers is needed If expressed strength is actually wrong, possible regulatory actions such as flagging in or removal from NDC Directory, and potentially DailyMed. SPL-drug information says 0.7mL/1mL which turns out to be 70% volume solution (vol/vol%). The label however says 62%.

Top Ten Errors (8 cont’d) Product Listings Using Incorrect Strength Representation Example 2

Top Ten Errors (7) Failure to use the Same SetID to Submit an Update One of the common errors for SPL rejection (that people call us about) is that a DUNS or NDC is linked to another SetID Occurs on both the registration and listing side. The following doc types should use same setID as original registration/labeler code request/listing file: Submission of deregistrations, no change notifications name changes and updates to contact info for labeler codes Updates to listing, labeling, and delisting of products should all use the same setID as previous/original listing Company personnel turnover. New person in charge of SPL submissions has no idea where old submissions were saved, or if they were saved. Can happen if company split packages of same product out into separate SPL Save all successful submissions! Create new versions from previous submissions to prevent errors.

Top Ten Errors (6) DUNS Data do not match Establishment Name and Address Make sure any address changes or name changes are fixed at Dun and Bradstreet (DnB) first May be a small delay between when new changes/data is effective at DnB and when FDA can access it for validation Ensure the DUNS number is associated with the actual establishment address and not the corporate address or another establishment location Translation differences of foreign data between DnB and company submitting to FDA FDA uses a “confidence level 10” validation threshold Minor differences/variations are allowed (e.g. “Inc” vs “Inc.” or “Street” vs “St.”) Interesting loophole in the logic that was recently fixed allowed for a completely different street number

Top Ten Errors (5) Problems with Non-Proprietary Name field Fields are free text, so validation is difficult to impossible Due to this, for searching, recommend using a concatenation of Active Ingredient names based on UNII Sometimes ALL CAPS is used, sometimes Mixed Case. Sometimes it does not identify active ingredients. Sometimes it’s an actual marketing statement!

Problems with Non-Proprietary Name field Top Ten Errors (5) Problems with Non-Proprietary Name field For multiple ingredients, sometimes separated with commas, sometimes the word “and”. Included strength and still had to provide it later with active ingredients

Problems with Non-Proprietary Name field (cont’d) Top Ten Errors (5) Problems with Non-Proprietary Name field (cont’d)

Top Ten Errors (4) Both Private Label Distributors (PLDs) and their Contract Manufacturers (CMs) must list under their own NDCs The 2016 version of 21 CFR 207 continues the longstanding requirement that the ultimate responsibility for a PLD’s product listing lies with the registered manufacturing establishment. However, a PLD may still choose to submit its own product listing, acting as an agent for the registered manufacturer. Regardless of which party submits the PLD’s listing data, the registered manufacturer is still obligated to list the product under its own NDC as well. These manufacturer listings should employ one of the MANUFACTURED EXCLUSIVELY FOR PRIVATE LABEL DISTRIBUTOR marketing categories. Listings under these categories are not published. If a manufacturer makes an identical product for multiple PLDs, it need only list the product once under a single NDC with its own labeler code. However, we expect a unique NDC from each PLD for their version of the product.

Hypothetical Supply Chain Listings Top Ten Errors (4) Hypothetical Supply Chain Listings Mfr A : Makes API Mfr B : Mixes API and presses into tablets Lab L : performs release testing and QC Mfr C : Places imprint on tablet, packs and labels it for PLD PLD : ANDA holder and distributes product Facility Register? Operations List? Marketing Category ------------------------------------------------------------------------------------------------- Mfr A Yes API Manufacture Yes Bulk Ingredient Mfr B Yes Manufacture Yes Drug for Further Processing Lab L Yes Analysis No -- Mfr C Yes Manufacture, Yes Approved Drug Mfr’d Pack, Label Exclusively for PLD PLD No -- Yes Approved Drug ANDA

Top Ten Errors (3) Image Files When including image files with the SPL: Ensure all images are JPG format (not GIF, PNG, BMP, etc) Image files are limited to 1MB each Ensure that all images included in the zip file are referenced somewhere in the Content of Labeling Reference the correct images in the correct sections Package label/Principle display panel Product images for solid oral dosage forms Graphs, charts, figures for content of labeling Ensure all appropriate packaging is represented in the images Do not include labeling proofs: Included with an outer carton labeling image

Top Ten Errors (2) Changes Requiring New NDCs SPLs are often rejected when a company changes certain data elements on a product listing. A new NDC Product code is required for any change or difference in: Active ingredient list (add/delete/change active ingredient UNII Strength of any active ingredient Dosage form Physical characteristics of solid oral dosage forms: Size Shape Color Flavor Scoring Imprint A new NDC Product code is not required for changes to inactive ingredients (unless it affects a change to one of the characteristics above) So double check these data elements prior to initial submission. If they are incorrect a fix requires a new NDC! And the #1 SPL error is…

Top Ten Errors (1) Product Listings Referencing Unregistered Establishments Over 22,000! Validation prevents the submission of unregistered establishments in the establishment section Establishments are registered upon initial submission, but then registration expires and/or the labeler switches manufacturing establishments and does not update the establishment section Required annual updates/certification should take care of some issues Possible regulatory actions such as flagging in or removal from NDC Directory, and potentially DailyMed, should take care of even more.

Top Ten Errors Summary Examples not intended to shame or embarrass any particular firm. Our goal is accurate data! Highlight errors to the experts so errors can be prevented. Regulatory actions (Untitled Letters and Warning Letters) can help but take a lot of resources to fix a single error. They are necessary, however, if errors are serious enough and/or firms are unwilling to comply. Education and outreach is the best remedy. “An ounce of prevention is worth a pound of cure.” You are the experts. Help spread the word to make the data complete and accurate for everyone!

Contact information DRLS Helpdesk edrls@fda.hhs.gov www.fda.gov/edrls SPL Helpdesk spl@fda.hhs.gov http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm CDER Direct Helpdesk cderdirect@fda.hhs.gov https://direct.fda.gov Electronic Systems Gateway Helpdesk ESGHelpDesk@fda.hhs.gov http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm2005551.htm