FDA’s Generic Drug User Fee Act (GDUFA) – Drug Master Files (DMFs)

By Charles “Chris” Celeste, Director of Regulatory Information and Submissions

Two years have passed since passage of the Generic Drug User Fee Act (GDUFA).

GDUFA is a significant law that introduced new requirements for active pharmaceutical ingredient (API) manufacturers, including fees associated with their Type II drug master files (DMFs), as well as for establishment registrations and for conversion of type II DMFs into Electronic Common Technical Document (eCTD) format.

The FDA does not require that a DMF be filed. The information may be submitted directly in a new drug application (NDA) or in an abbreviated new drug application (ANDA). So why submit a DMF? One reason is to maintain confidentiality of the proprietary information of the active pharmaceutical ingredient. Another is that a single DMF may support multiple applications.

Currently, FDA does not require that the DMF be submitted in eCTD format, but the agency has said the electronic format can aid in the review of the application.

Upon receipt of an initial submission, FDA’s DMF staff will check that the file is complete. If the file is found acceptable, the agency will send a letter to the DMF holder (for foreign DMF holders, the U.S. Agent will receive a copy of the letter) acknowledging receipt of the DMF. If the file is found to be incomplete, a letter will be sent detailing the missing information. Once that information has been provided, FDA will issue the acknowledgement letter. DMF holders are obligated to submit all changes as amendments, to notify authorized parties of changes, to properly maintain the DMF (with annual reports), and to issue Letters of Authorization to each customer to the DMF.

Reporting a change to a DMF can be done at any time through the submission of an amendment. But the DMF holder needs to notify customers of any changes.

It is important for DMF holders to remember that DMFs are not approved or disapproved by the agency. A DMF is reviewed to determine whether it is adequate to support a specific application. If the file is acceptable, FDA will consider it available for reference and will issue a letter to the DMF holder indicating that it has “No Further Comments.”

The Drug Master Files require a one-time only fee. If a holder has paid a DMF fee for a Type II active pharmaceutical ingredient, the holder is not required to pay a subsequent drug master file fee when that Type II active pharmaceutical ingredient drug master file is subsequently referenced in drug application submissions. According to the Act, the DMF fee will be due no later than the date on which the first generic drug submission is submitted that references the associated Type II API DMF. FDA is recommending that the DMF fee be paid at least 6 months prior to the submission of an ANDA. This will ensure that the Completeness Assessments can be performed and the DMF will be available to reference. This will require the ANDA applicant and DMF holder to communicate regarding the timing of the submission of the application. FDA has issued a draft “Guidance for Industry: Initial Completeness Assessments for Type II API DMFs Under GDUFA” listing the information the agency will check for in the DMF.

In addition, FDA will be accepting written requests from the DMF holder within 10 working days from the issuance of a deficiency letter to discuss any questions regarding the letter. The holder will need to provide an outline of the questions to be addressed and will be limited to the content of the deficiency letter. FDA will allow for a 30 minute conference call per DMF holder per month.

FDA will be performing risk-adjusted biennial cGMP surveillance inspections of the API and finished dosage form (FDF) manufacturers. The agency will be prioritizing inspections related to ANDAs that are approvable or eligible for tentative approval and establishments that have not previously been inspected. FDA will post the inspection classification results and the date of the last inspection on its website. Also, the agency will be making use of foreign inspection classifications.

In addition to the user fees on the type II DMFs, FDA will impose an annual fee for each facility registration of an API manufacturer. Here is the fee schedule for FY 2015, which began October 1, 2014.


Fee Category Fee rates for FY 2015
Original ANDA $58,730 (per application)
PAS* ANDA $29,370 (per PAS)
DMF $26,720
Domestic Facility FDF $247,717 (per facility)
Foreign Facility FDF $262,717(per facility)
Domestic Facility API $41,926 (per facility)
Foreign Facility API $56,926 (per facility)
  • Prior Approval Supplement

FDA Learns from ‘Listening Sessions’ on the Re-proposed FSMA Rules


Senior Food and Drug Administration officials, including Mike Taylor, FDA Deputy Commissioner for Foods and Veterinary Medicine, traveled to Georgia, North Carolina, Florida, California and Vermont in recent weeks for “listening sessions” with stakeholders to discuss the agency’s re-proposed Food Safety Modernization Act rules. The agency also hosted a public meeting November 13 in College Park, Md. on the supplemental rules.

In a recent FDA Voice blog, Taylor says the emphasis in these sessions has shifted from concerns about the cost of certain measures to “mostly clarifying questions about the content of the rules,” and what has to be done once the rules take effect. “We’re getting down to the nitty gritty of implementation,” he says. However, there appears to be ongoing confusion about the water quality and testing requirement for produce growers. The agency is “committed to providing clear guidance so that expectations are understood,” Taylor says.

In the listening sessions and in their discussions with state representatives, the FDA officials were asked how the agency plans to pay for its FSMA-related activities.

“It is urgent that FDA receive adequate funding for the training, technical assistance, state partnerships and import oversight that is essential for sound implementation of the FSMA rules beginning in late 2016 and 2017,” Taylor says.

The agency will be relying heavily on its state counterparts to provide training, technical assistance and compliance oversight, he said.

He reported separately on the New England listening session in another blog post, noting that many stakeholders are “finding the complexity of the proposed rules daunting, such as the technical underpinnings of the E.coli benchmark for water quality and the various boundary lines and exemptions that determine who is covered.” The agency has opted not to take a “one size fits all” approach, which has contributed to making the rules more complicated.

“This only underscores our responsibility to explain the rules clearly and to provide education, technical assistance and guidance,” Taylor says.

Indeed, these activities are likely to be among the agency’s biggest challenges in achieving a successful implementation of FSMA both for domestic and imported foods.

FDA has declined requests for extensions of the December 15 deadline for public comment on its re-proposed rules, citing its urgent need to move forward because of its court-imposed deadlines for implementing the final rules.

The Importance of Food Recall Readiness

By EAS Senior Consultant Dan Okenu, Ph.D.

Product recalls are a fact of life in the food industry. Recalls occurred an average of 12 times per week. Allergens remain the largest cause of recalls, due to mislabeling, cross-contamination or being undeclared. Large recalls of peanut products, eggs, ground beef and cantaloupe in recent years remind us of the potentially devastating impact of food recalls on the food industry. The good news is that there are measures the food industry can implement to significantly reduce or prevent situations which require product recalls. According to Dan Sowards, senior consultant at EAS Consulting Group, due diligence is critical in protecting against recalls.

On the issue of food safety, Willie Bryant, senior EAS consultant, points out that having the authority to order a food recall gives the FDA leverage over firms hesitant to initiate a recall voluntarily. This is a new authority of FSMA that did not exist during Willie’s 33 years of working in recall operations at the FDA.

It is highly unlikely that an FDA-regulated food firm would fail to protect the public, the company and its brand by refusing to take a recall action after receiving notification from FDA that a recall action is necessary. If the firm takes the action based on the notification by FDA and an FDA order to recall is not required, the recall is still considered “voluntary”, as are all other class I, II, or III recalls.

FDA’s enforcement power for FSMA’s provision for a foreign supplier verification program mandates an approved food safety plan, requires extensive documentation, and audits to satisfy the new proactive science-based preventive control measures. These regulatory provisions will have far reaching implications for recall, shipment tracking and traceability requirements for imported food products including private-label foods manufactured outside the United States. Compliance with FSMA requirements will require smart innovations by the food industry to keep costs down.

Effective product tracking and traceability are vital for speedy trace-back or trace-forward to identify affected products and to remove them from suppliers’ warehouses, retailers’ shelves and consumers’ refrigerators and pantries. A centralized, electronic system that can quickly trace UPC/SKU product codes linking all material ingredients, rework, process conditions and the customers is desirable in any traceability system.

Effective product tracing is an important piece of the puzzle during recalls or foodborne illness outbreaks. In addition to helping to quickly remove adulterated products from the food supply, it assists in pinpointing the problem area within the food production system so corrective action can be taken. A traceability system also provides good record keeping compliance for food defense in case of bioterrorism or economic-motivated adulteration. The effectiveness of the system should be validated annually through mock recalls and traceability testing to ascertain the preparedness of the recall protocol and the recall implementation team.

Staff training is critical at every level of the operational process. Companies should invest in a quality program that evaluates and updates its recall implementation capabilities. From there, your organization can plug in the gaps and protect your business against recalls, reduce recall operational costs, and protect your business brand.

It makes a lot of business sense to invest in proper training of staff and preparedness for a multi-disciplinary recall team that is ready to roll at a moment’s notice. To put the cost of recall readiness or the cost of recall reduction strategies in perspective, managers should consider the colossal cost of implementing a recall and the added cost of recovering from such a huge exercise, including brand image laundering to regain the eroded customer confidence.

EAS can provide specialized training that deals with the nuts and bolts of effective recall and traceability system, emphasizing FDA roles and requirements, best practices for trace-back and trace-forward, legal and regulatory challenges, the recall decision making process, risk assessment/testing, and time management before and after recalls. Other training modules include effective risk communication and media management, creation and preparedness of a multi-disciplinary recall team, and recall reduction strategies. The training highlights specific steps that companies can take to avoid situations that may lead to recalls or to minimize the extent of a recall and its impact on the business.

Revised FSMA Proposed Rules Address Stakeholder Concerns


The Food and Drug Administration’s supplemental texts for four proposed rules that would implement provisions of the Food Safety Modernization Act (FSMA), published September 29 in the Federal Register, address numerous concerns raised by stakeholders. The agency, for example, changed its thinking on significant issues in response to comments on the proposed rule for Current Good Manufacturing Practice (CGMP) and Hazard Analysis and Risk-Based Preventive Controls for Human Food.

Under the new proposal, for example, a farm would not be required to register as a food facility just because it packs or holds raw agricultural commodities grown on another farm under a different ownership. In addition, on-farm packing and holding of produce would be subject to the proposed produce safety rule, not the human food preventive controls rule. However, farms that conduct additional processing or manufacturing may be subject to preventive controls rules for those activities, the agency says.

In another policy shift, FDA proposes to exempt distribution centers from the requirement to conduct hazard analyses and supplier verifications.

FDA now proposes to define a “very small business” as one having less than $1 million in total annual sales of human food. Previously, the agency had proposed three options: annual sales of $250,000, $500,000, and $1 million. The new proposed definition would exempt less than 1 percent of the dollar value of food produced in the United States, the agency says.

Under the new proposal, very small businesses would have three years after publication of the final rule to comply. Very small business would be categorized as “qualified facilities,” and would be subject to modified preventive control requirements. Small businesses, defined as those with fewer than 500 persons would have two years after publication of the final rule to comply, unless they qualify for an exemption. All other businesses would have to comply with the final rule one year after its publication.

FDA is seeking comment on whether the preventive controls for human food rule should require a facility, in certain circumstances, to conduct product testing and environmental monitoring to verify preventive controls – if contamination of a ready-to-eat food with an environmental pathogen is a significant hazard, for example.

Supplier controls are proposed when a receiving facility’s hazard analysis identifies a significant hazard for a raw material or ingredient, and that hazard is controlled before the facility receives the raw material or ingredient from a supplier, the agency says. In such situations, the facility would have the flexibility to determine the appropriate verification activity (such as onsite audit, sampling and testing) unless there is a reasonable probability that exposure to the hazard will result in serious adverse health consequences or death to humans, FDA says.

In that instance, an annual onsite audit of the supplier would be required unless the facility can show that other verification activities and/or less frequent onsite auditing of the supplier provide adequate assurance that the hazards are controlled.

In addition, the agency is inviting comment on whether a facility should be required to address, as part of its hazard analysis, hazards that may be intentionally introduced for purposes of economic gain as part of its hazard analysis.

The agency is inviting comment through Dec. 15, 2014 on just the newly proposed changes in the supplemental text and is planning to hold a public meeting on the revised proposals on Thursday, November, 13, 2014 in College Park, Md.

Expediting FDA Approval of Sunscreen Ingredients

By EAS Senior Consultant, Norma Skolnik

Eight new sunscreen active ingredients have been awaiting approval—or any sort of decision—from the FDA for at least 12 years, with the last over-the-counter sunscreen ingredient approved by the agency in the 1990s. Meanwhile, some of these sunscreen ingredients have been available in Europe, Asia, or Latin America for more than 15 years.

However, the 12-year backlog may soon be ending. On July 28, the House of Representatives passed a bill, HR 4250, known as the Sunscreen Innovation Act, to expedite the FDA’s approval process for sunscreen ingredients. The Sunscreen Innovation Act passed by a voice vote just before Congress left for their August recess. The bill is expected to be taken up by the Senate in the near future.

The legislation aims to improve on FDA’s latest attempt to make new OTC active ingredients more available—a 2002 procedural change from the FDA that the agency hoped would speed up its approval process. In 2002 the agency created a new process, called the Time and Extent Application (TEA), to give an alternate pathway for over the counter drug ingredients to be approved. Since then, eight sunscreen ingredients have been submitted for review under that process; none has yet been approved.

Without a single ingredient being approved since then, Rep. Ed Whitfield (R-KY) and John Dingell (D-MI) introduced HR 4250, the Sunscreen Innovation Act. HR 4250 sets up a system under which sunscreen active ingredients that have been marketed continuously for at least 5 years in another country and that meet certain other conditions, would be eligible for review by an FDA advisory committee. After the advisory committee issues a recommendation, FDA would have 45 days to affirm or deny the recommendation. If FDA didn’t deny an approval recommendation within 45 days, the sunscreen would automatically be approved as generally recognized as safe and effective. The bill also provides an appeals process for situations in which the sponsoring company disagrees with the FDA determination.

The Sunscreen Innovation Act not only would institute a timeline for review, it would no longer require the FDA to issue a regulation every time it wants to approve an active ingredient. The bill requires final decisions on pending applications within 300 days for new requests and a shorter timeframe for requests that were pending before enactment of the law. Under current law, if an ingredient is on the market in another country for five years, it may go through a process to be determined eligible by the FDA. FDA’s advisory committee of experts weighs in on the safety and effectiveness of the product, and the agency then makes the final determination as to whether the ingredient is approved. However, there’s currently no timeline for review or decision making.

The Sunscreen Innovation Act also directs the Comptroller General of the Governmental Accountability Office (GAO) to report on the progress of the Secretary of HHS in establishing this new process and the role of the FDA Commissioner in issuing determinations on pending sunscreen active ingredient requests. It requires the HHS Secretary to report on decisions made about the safety and efficacy of sunscreen active ingredients, the amount of time between submission and decision for each request, the cost of the review process, and recommended improvements to the review process.

Prior to passage of the bill, an FDA spokesperson said that the agency has “prioritized reviewing the safety and effectiveness of additional sunscreen ingredients as quickly as possible given the agency’s resources.”

FDA recently issued feedback letters about two sunscreen ingredients. Both asked for more data to prove the ingredients are generally recognized as safe and effective. Andrea Fischer, a spokeswoman for the FDA, said that “the FDA will issue responses to the safety and efficacy data submitted for each ingredient in the near future. We are committed to completing the TEA process for the sunscreen active ingredients currently under review as quickly as possible, consistent with available agency resources and competing public health priorities.”

It remains to be seen if the Senate will pass this act and if passage of the act could set a precedent for expediting the approval process for other categories of OTC active ingredients.

FDA Officials Discuss Phase Two of FSMA Implementation


Although still in the phase 1 rulemaking stage of implementing the Food Safety Modernization Act (FSMA), the Food and Drug Administration is planning for moving forward with “phase 2” which will involve training and compliance activities.

FDA Deputy Director for Regulatory Affairs, Roberta Wagner, discussed the agency’s current thinking about how it will tackle the next implementation phase, in an August 26 webinar sponsored by the Food Safety Preventive Controls Alliance (FSPCA). FSPCA is a collaborative program of the Illinois Institute of Technology, industry, academic and government stakeholders which is developing a core curriculum, training and outreach programs for companies producing human and animal food in compliance with FSMA’s preventive control provisions.

A similar presentation, sponsored by the Produce Safety Alliance (PSA), was made in early July by Kathy Gombas, who has the lead role for FSMA change management in FDA’s Center for Food Safety and Applied Nutrition (CFSAN). PSA is a collaborative project between Cornell University, USDA and FDA that will provide training and education on current best practices and guidance, and on the regulatory requirements for produce.

In Phase 2, FDA will be investing in regulatory training to promote consistent inspections. Because not every inspector will be an expert in the products being inspected in every establishment, inspectors will have access to subject matter experts in FDA headquarters who can answer questions that arise. The inspectors will be assessing a company’s “food safety culture” which will determine what approach the agency will take with that facility, using a risk-based approach, the FDA officials explained

FDA plans to facilitate industry implementation of preventive practices by expanding its oversight toolkit to encourage voluntary compliance. This expanded toolkit will include:

  • Commodity and sector-specific guidance;
  • Education, outreach and technical assistance;
  • Regulatory incentives for compliance.

So, a company’s food safety culture will guide FDA’s regulatory approach, using targeted, risk-based inspection models. In addition, the agency will be conducting more sampling, although the sampling will focus on fewer commodities, the agency says.

FDA expects to “educate before regulating,” providing technical assistance and considering work performed by public-private partners. For produce, for example, it plans to conduct targeted on-farm surveys and inspections and to “deploy a cadre of specialized produce safety experts for on-farm activities, to encourage voluntary compliance.”

For Phase 2, the agency has created a steering committee that oversees three workgroups: on Preventive Controls in Food and Feed Facilities, Produce Safety Standards, and Import Oversight. In addition, it plans to set up a Regulator Technical Assistance Call Center, to allow for inquiries and responses while inspectors are at the inspection sites.

The agency also plans to continue stakeholder engagement and to work with multiple partners to foster industry understanding of final rules/guidance and to facilitate high rates of voluntary compliance.

The FSPCA is developing a training curriculum consistent with FSMA. This curriculum will be publicly available when the final preventive controls rule is published. The Produce Safety Alliance is also developing a training curriculum and expects to be in the train-the-trainer phase in the fall or early winter.

Training and education are key to the success of FSMA, not only for the regulated industry but for the FDA regulators who are charged with inspections and enforcement of the sweeping new rules. There is concern within the food industry that the FDA will not be prepared when the final rules take effect leading to inconsistent interpretation and enforcement of the law. Just as the industry is required to employ “qualified individuals” to oversee food safety plans, it has been suggested that the FDA require inspectors to be “qualified” through formal training before performing compliance activities under FSMA.

FDA to Enforce New Infant Formula Rules Immediately

By EAS Senior Consultant Allen Sayler

An estimated one million infants (roughly one-third) in the United States are fed infant formula from birth, and by the time they are three months old, about 2.7 million (roughly two-thirds) rely on formula for at least part of their nutrition. US-produced and packaged infant formula is in high demand internationally because of its excellent safety and nutrition record and because of the concerns raised by the melamine scandal in China and the tainted milk powder incident in New Zealand.

Based on a number of unfinished infant formula regulations and the need to update existing regulations, FDA published an interim final rule on February 10, 2014 and announced on June 9, 2014 that it was finalizing this rule, intended to set standards for the manufacture of infant formula either processed in the US or intended to be marketed in the US. The final rule is similar to the interim rule with a few modifications based on comments received by the agency after the February 2014 publication.

While infant formula processors have been applying many of the newly required Good Manufacturing Practices (GMPs) as part of their own internal product safety and quality programs, these finalized GMPs and other parts of the new rule now become federally enforceable. As a result, the industry requested that FDA delay enforcement to allow the industry to become familiar with and implement these new requirements. FDA rejected industry requests, setting a date of September 8, 2014 for manufacturer compliance. It is hoped that for the rest of 2014, FDA will instruct its field inspection/auditing staff to be reserved in their enforcement to allow the industry time to adapt to the vast new regulation, but there is no certainty of this.

Below is a reference table with links to additional information as well as the complete and final GMPs for infant formula processing.

The final rule applies only to infant formulas intended for use by healthy infants without unusual medical or dietary problems. Under the final rule, some points addressed include:

  • Current good manufacturing practices specifically designed for infant formula, including required testing for the harmful pathogens (disease-causing bacteria) Salmonella and Cronobacter.
  • A requirement that manufacturers demonstrate that the infant formulas they produce support normal physical growth (of infants).
  • A requirement that infant formulas be tested for nutrient content in the final product stage, before entering the market, and at the end of the products’ shelf life.
  • A few other existing requirements:
  • “Use by” date. This is the date after which a package or container of infant formula should not be fed to infants. It indicates that the manufacturer guarantees the nutrient content and the general acceptability of the quality of the formula up to that date. FDA regulations require this date to be specified on each container of infant formula.
  • Storage. Manufacturers must include instructions on infant formula packaging for its handling before and after the container is opened. They must also include information on the storage and disposal of prepared formula.

FDA does not approve infant formulas before they can be marketed. However, all formulas marketed in the United States must meet federal nutrient requirements, which are not changed by the new rule. Infant formula manufacturers are required to register with FDA and provide the agency with a notification prior to marketing a new formula. Proof of compliance with existing and new requirements will be required when FDA investigators conduct their annual inspections/audits of all infant formula processors selling product in the US market. In addition, FDA also collects and analyzes product samples. Based on the inspections/audits and sampling, if FDA believes that an infant formula presents a risk to human health, the manufacturer of the formula must conduct a recall.

Additional references regarding the FDA requirements for processing infant formula for the US market include:

  • 21 CFR 106 Infant Formula Quality Control Procedures
  • 21 CFR 106.100 Records and Reports Regulations
  • 21 CFR 107.3 – 107.30 Infant Formula Labeling Requirements
  • 21 CFR 107.50 Exempt Infant Formulas
  • 21 CFR 107.100 Nutrient Requirements for Infant Formulas
  • 21 CFR 107.200 – 107.280 Infant Formula Recall Requirement

If you have additional questions regarding this new extension of the existing US FDA infant formula regulation or experiences with FDA enforcement of this new rule, please feel free to contact Mr. Sayler at asayler@easconsultinggroup.com.

FDA Announces FSMA Fees for Fiscal Year 2015


FDA announced the Food Safety Modernization Act (FSMA) domestic and foreign facility reinspection, recall and importer reinspection fee rates for Fiscal Year (FY) 2015, in an August 1, 2014 Federal Register notice. Section 107 of FSMA added section 743 to the FD&C Act giving FDA the authority to assess and collect fees from the responsible parties of domestic and U.S. Agents of foreign facilities requiring reinspections; domestic facilities and an importer who do not comply with a recall order and importers subject to reinspections. The FSMA Fee Schedule for FY 2015:

  • Hourly rate if domestic travel is required $217 and
  • Hourly rate if foreign travel is required $305

These fees are effective on October 1, 2014, and will remain in effect through September 30, 2015.

These fees will be assessed for the reinspection to evaluate if a firm has taken the appropriate corrective actions from the prior inspection in where “Official Action Indicated” (OAI) was indicated. The responsible party for each domestic facility and the U.S. agent for the foreign facility will be required to pay the reinspection fees. The fees will be based on the number of hours spent on the reinspection. This will include time to conduct the physical inspection preparation for the reinspection, travel time, report writing, collecting and analyzing samples, etc. to ensure the facility is compliant.

In addition FDA will be assessing fees for non-compliance with a recall order to cover food recalls. Non-compliance may include: not initiating a recall as ordered by FDA and/or not performing the recall in a manner specified by FDA recall order and/or not providing FDA with requested information regarding the recall order. The responsible parties for a domestic facility and an importer who does not comply with the recall will be responsible for paying the assessed fees. These fees will be assessed on the direct number of hours spent on the FDA taking action in response to the firm’s failure to comply with the recall order.

FDA will be invoicing the responsible parties for paying the fees after the Agency has completed the work for which the invoice is based and payment will be required within 90 days in U.S currency by check, bank draft or U.S. postal money order.

Also, FDA is developing guidance documents to outline the new processes for requesting a reduction of fees for the reinspection and recalls and the agency’s process for assessment and collection of fees from importers.

FDA’s reinspection fees for 2015


FDA Sends Revised FSVP Rule to OMB


The Food and Drug Administration recently sent a revised rule to the White House Office of Management and Budget (OMB) that will be an important tool in FDA’s future oversight of foods and ingredients imported into the United States.

Under FSMA, FDA has increased regulatory authority over imported foods. For example, it can block a food from entry if the facility has refused inspection by U.S. officials. Of course, resource-related constraints prevent FDA inspection of more than a handful of foreign producers annually. Lawmakers recognized these limitations and included other provisions in section 301 to increase oversight of imports.

On July 26, 2013, FDA released proposed Foreign Supplier Verification Program (FSVP) regulations that would require importers to verify that food imported into the United States is produced in a way that “provides the same level of public health protection as is required for domestic food producers.” The revised rule will not be publicly available until OMB completes its review.

However, many proposed elements will certainly be included in the final document. Under the proposed FSVP, importers must have a foreign supplier verification program; they must review the compliance status of the food, and of the potential foreign supplier, before importing the food. These reviews would take into account any FDA warning letters, import alerts, and certification requirements issued by FDA.

Importers would also be required to identify the hazards associated with each food they import. Among other tasks, they would be required to review any complaints they receive about the foods they import, take corrective actions and revise their FSVPs as needed.

As originally proposed, FDA set out two risk-based options for supplier verification activities. Either foreign suppliers will control the hazards, or will verify that the hazards are being controlled by its raw material or ingredient supplier.

Under Option 1, if the foreign supplier controls the hazard at its establishment and there is a reasonable probability that exposure to the hazard will result in serious adverse health consequences or death to humans or animals (SAHCODHA), the importer would be required to show documentation of onsite auditing of the foreign supplier. For non-SAHCODHA hazards that the foreign supplier controls, the importer would be required to conduct one of more of the verification activities (onsite auditing, sampling and testing, review of the supplier’s food safety records, or some other appropriate procedure) before using or distributing the food.

Under Option 2, for all hazards that the foreign supplier will either control or verify that its supplier is controlling, importers would need to choose a verification procedure from among onsite auditing, sampling and testing, review of supplier food safety records, or some other appropriate procedure.

If the importer’s customer will be controlling a hazard identified by the importer, the importer would need to obtain written assurance, at least annually, that its customer is following procedures (identified in the written assurance) that adequately control the hazard.

The proposed rule also states FDA’s intent is to align the supplier verification provisions in the FSVP regulations with any other supplier verification provisions that may be included in the final rules on preventive controls for human and animal food. This would avoid duplicative requirements for an entity that is both a food importer and a registered food facility.

Under the proposed rule, modified FSVP requirements would apply in certain circumstances, including the following:

  • Importation of a dietary supplement or dietary supplement component;
  • Importation of food by a very small importer or importation of food from a very small foreign supplier; and
  • Importation of food from a foreign supplier in good standing with a food safety system that FDA has officially recognized as comparable or determined to be equivalent to that of the United States.
  • The proposed rule would exempt importation of the following foods from FSVP requirements:
    • Juice and seafood from facilities that are in compliance with the Hazard Analysis & Critical Control Points (HACCP) regulations, which contain their own supplier verification provisions;
    • Food imported for research or evaluation purposes;
    • Food imported for personal consumption;
    • Alcoholic beverages; and
    • Food that is transshipped or imported for further processing and export.

Deciding which food products are high-risk will be an especially difficult part of the implementation of the FSVP. The term “reasonable probability” of exposure to a hazard is imprecise and likely to be contested. Adequate control of hazards will not mean a “high risk” product becomes non-high risk no matter how many safety measures they put in place. The fact that such controls are needed determines the high risk status of a food.

The Impact of Social Media on FDA-Regulated Products

By Susan Crane, EAS Senior Consultant

Historically, it has been straightforward for the FDA to review and monitor labeling and advertising for products under their jurisdiction, particularly drugs and medical devices. However, the widespread use of the internet and social media has added increasing complexity to the issue for the agency as well as for FDA-regulated industries.

As a result, the FDA issued several guidance documents this year and, while applicable only to prescription human and animal drugs and medical devices, they should be used to gauge the agency’s current thinking with regard to social media and its use for promoting the products they regulate. The first guidance, issued in January, clarified FDA’s position on what constitutes interactive promotional media and how manufacturers, packers, distributors and those entities acting on their behalf can fulfill their regulatory obligations with regard to such communications. In June, the agency issued two further guidances; one detailing how firms should go about correcting misinformation that is disseminated through a third party and another addressing how risk and benefit information should be presented for those social media platforms with character space limitations, e.g., Twitter. It is clear that this subject is being given considerable attention at the FDA.

These guidances stress that firms are responsible for promotional communications and other content on internet-based platforms that they own, control, create, influence, or that are operated by, or on behalf of themselves (or any employee or agent working for them.) For content posted on third party platforms, a firm may also be responsible if it has any control over or influence on that platform. The FDA recommends that firms clearly disclose their involvement with any platform for which they own or influence the content.

However, the internet and associated technologies have made it easier for those not affiliated with these firms to disseminate product information. This user-generated content (UGC) created by third party entities may be incorrect or incomplete, thus potentially endangering public health either by understating safety information or inflating the benefits of a particular product.

The FDA’s position is that firms are “generally not responsible” for third party UGC as long as they are truly independent of its source. However, if a firm voluntarily chooses to correct misinformation of which they become aware, the FDA has set forth specific recommendations as to how this should be accomplished and recommended that records be maintained accordingly.

While these guidance documents are applicable only to prescription drugs and medical devices, it is reasonable to expect that the FDA believes these same principles apply to OTC drugs, dietary supplements, foods and cosmetics. For such products, the FDA regulates the content of the labeling and the Federal Trade Commission is responsible for regulations regarding advertising. However, on social media platforms the information may be presented in such a way that it could be considered both labeling and advertising. For example, a website or Facebook page may include product usage details and claims, as well as a link to purchase the product or “Share” or “Like” it to another site.

Indeed, a recent FDA warning letter issued to Zarbee’s Inc., a dietary supplement company, dealt with just this issue. While other companies have received warning letters for making false or misleading claims on their websites, in this instance the agency also cited Zarbee’s for personal testimonials that had been posted and subsequently “Liked” on their Facebook page. These “Likes” were considered equivalent to an endorsement or promotion of Zarbee’s products that were, as formulated and labeled, considered “new drugs” and hence subject to FDA oversight.

In all cases, firms must ensure that any communication for which they have control or oversight is truthful, not misleading and substantiated. Although they may not be held responsible for content generated by third parties, they should be careful not use such information or endorsements in their own advertising and promotions. In addition, firms should consider correcting any misinformation of which they become aware, particularly if it is a safety issue.

Social media is a powerful tool and fast-evolving information platform. There is no doubt that the FDA, FTC and other regulatory bodies worldwide will further define and clarify their approaches to monitoring and regulating advertising and promotion of products this way. It would therefore be wise for industry to become familiar with current agency expectations and stay abreast of future developments. In addition, companies should have their websites and social media sites reviewed for compliance with FDA regulations to ensure that all of the content is truthful, substantiated, permissible and not misleading.

Follow-Up to the July Issue of the Month

By EAS Senior Consultant James Hoadley Ph. D.

Our July Issue of the Month article titled “Why Submit a GRAS Notification for a Dietary Ingredient?” drew a lot of attention from readers. In this follow-up note, Jim Hoadley responds to one significant question.

Is an NDI exempt from the NDI notification requirement when the same substance is the subject of a food ingredient GRAS determination, but the ingredient has not been marketed as a conventional food ingredient?

Good question – I’m glad you brought it up because the newsletter article was not as clear as it could have been on this point. The NDI notification requirement exemption is for “ingredients which have been present in the food supply as an article used for food…” Submitting a GRAS notification does not exempt a dietary ingredient from the NDI notification requirement – the GRAS determination is only the first step and it must be followed by actually getting this ingredient into the food supply through marketing it as a food ingredient. Submitting the GRAS notification to FDA is voluntary; however, when your use of a new ingredient as a GRAS food ingredient serves as an alternative to a NDI notification then it is wise to submit the GRAS notification as documentation of your conclusion that the consumption of the ingredient will be safe. In this sense the FDA’s GRAS Notification Program serves as a substitute to an NDI notification. GRAS self-determination as a food ingredient is not a path to be used to avoid submitting a safety notification for your NDI.

When you have submitted a GRAS notification for a food ingredient use; but, have not yet actually marketed the ingredient for the food use then the ingredient is NOT present in the food supply. The exemption from the NDI notification requirement kicks in only when the ingredient is present in the food supply.

When the marketing of a substance as a GRAS food ingredient is being used as a substitute for submitting an NDI Notification there are a couple points to keep in mind. Firstly, ingredients specified in the GRAS Notification and the NDI must be in the same chemical form without alteration. Secondly, the NDI consumption resulting from its dietary supplement use should be the same as, or lower than, the intake level that has been determined to GRAS.

Why Submit GRAS Notification for a Dietary Ingredient?

By James Hoadley, Ph.D., EAS Senior Consultant

A new dietary ingredient (NDI) is a dietary ingredient that was not sold in the United States as a dietary supplement ingredient before October 15, 1994. Manufacturers of NDI-containing dietary supplements must notify FDA of their intent to market a NDI-containing supplement at least 75 days before the supplement is marketed in the U.S. The NDI Notification must thoroughly identify the NDI, how it is used in the NDI-containing supplement, and present the evidence the manufacturer relied upon to determine their use of the NDI in the supplement is reasonably expected to be safe. The NDI Notification requirement applies to every NDI-containing dietary supplement regardless of whether other firms have submitted NDI Notifications on the same substance. There is an exemption to the NDI Notification requirement provided for dietary supplements containing only NDIs that have been used for food in the same chemical form as is being used as a NDI (21 U.S.C. 350b(a)(1)). FDA has codified these requirements at 21 CFR 190.6.

FDA discussed its positions on NDI related issues in a draft guidance. One Q&A in the FDA’s guidance speaks directly to whether a NDI Notification would be required for a NDI that also has a GRAS food ingredient use. FDA noted that a substance legally marketed as a food ingredient in conventional food would be exempt from the NDI notification requirement because it has been present in the food supply as an article used for food in a form in which the food is not chemically altered. Submission of a GRAS Notification will establish a basis for a NDI to be legally marketed as a food ingredient.

The NDI Notification process intended in DSHEA for FDA to have some oversight on dietary supplement manufacturers’ safety assessments of their NDI-containing dietary supplements. However, in some situations it may make more sense to submit a generally recognized as safe (GRAS) Notification for NDIs.

Dietary Ingredients, are defined (21 U.S.C. 321(ff)(1)), include (a) vitamins, (b) minerals, (c) herbs or other botanicals, (d) amino acids, (e) dietary substances for use by man to supplement the diet by increasing the total dietary intake, or (f) concentrates, constituents, extracts, or combinations of the (a) through (e) ingredient categories.

Something such as a new, patented bacteria strain does not qualify as a dietary ingredient because it is not one of the categories named in (a) – (d), nor is it a “dietary substance” (category (e)) because it has never been in the human diet. Thus, FDA is likely to reject a New Dietary Ingredient (NDI) Notification for the new bacteria strain on the basis that the substance is not a dietary ingredient.

Submitting a GRAS Notification for food ingredient applications of the new bacteria strain establishes food ingredient uses for the new bacteria strain. A substance’s GRAS Notification becomes the basis to assert that the substance is a ‘dietary substance for use by man to supplement the diet’ and thus eligible as a dietary ingredient use.

When the substance of interest for dietary ingredient use is NOT clearly in one of the (a) – (e) dietary ingredient categories, then submitting a GRAS Notification will be imperative because there is a great risk that a new dietary ingredient (NDI) Notification would be rejected outright on the basis that the substance does not qualify as a dietary ingredient and thus cannot be a NDI.

Taking the GRAS Notification path allows supplement manufacturers to side-step the need for filing multiple NDI Notifications for each NDI-containing dietary supplement.

Section 413 of the FD&C Act states that a NDI Notification is not required of a dietary supplement containing only dietary ingredients which have been present in the food supply as an article used for food [413(A)(1)].

Submitting a GRAS Notification for food ingredient and dietary ingredient applications of a substance establishes there are recognized uses of the substance “as an article used for food.” Dietary supplements are not subject to the NDI Notification requirement when they contain only dietary ingredients which have been present in the food supply as an article used for food. A substance’s GRAS Notification becomes a basis to assert that the substance is in the food supply as an article used for food and therefore exempt from the NDI Notification requirement.

The NDI Notification requirement applies to each dietary supplement containing a NDI irrespective of how many previous NDI Notifications have been submitted for the same NDI. It would be advantageous for a dietary ingredient supplier to submit a GRAS Notification for a NDI substance (establishing the NDI substance to be in the food supply) and thereby exempting the NDI from the NDI Notification requirement.

Follow up (August 2014)

Proposed Changes in Nutrition Labeling – Time to Make Your Comments

By Elizabeth Campbell, EAS Senior Advisor for Labeling & Claims

In March, FDA published proposals for changes to Nutrition Facts and Supplement Facts. The proposed changes include reformatting of all conventional food labels in the servings per container and calorie declarations. The specifics of the new format may change a little based on information in comments, but it is likely that the basic approach of increasing emphasis on calorie consumption will remain in the final requirements. Most dietary supplement labels would not have to make this change. Other major changes include the addition of Vitamin D and potassium as mandatory nutrients instead of vitamins C and E and the requirement for declaration of added sugars. These changes will impact essentially all labels.

Proposed revisions in Daily Values (DV) may not only require revising the label, but some companies would need to consider reformulating some of their products. Changes in Reference Amounts Customarily Consumed (RACC) would result in serving size changes, but just as important, would result in changes in whether some products qualify for claims. The proposed DVs and RACCs are not likely to be different in the final regulation unless new, persuasive data are provided to FDA in comments.

For more information including the proposals and information on submitting comments see: http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ LabelingNutrition/ucm385663.htm. Companies should be diligently studying the proposals to see how the changes will affect them so that they can submit comments to FDA to ask for different provisions. FDA had originally set June 2 as the deadline for comments, but they have now extended the deadline until August 1. Comments must include data and/or other information to justify requests for different requirements.

Once the comment period has closed, FDA will analyze the issues raised in the comments, prepare responses to all the issues and develop a final regulation. This ordinarily would take about two years, but there appears to be a sense of urgency at the agency that could result in a final regulation by the end of 2015. FDA proposed 60 days after publication of the final rule for the effective date of the regulation and there would be two years after that date for changing labels. The agency didn’t specifically say how we should interpret these dates, but I think it means that any label revised after the effective date must comply with the new requirements and all changes must be completed within the two years. Generally, that would mean any product initially shipped in interstate commerce after the final date (60 days + 2 years after publication) must comply with the new requirements.

The sooner that companies begin to absorb the changes, the smoother will be the changeover. Some industry staff can remember the trauma of creating the Nutrition Facts in the early 1990’s when the NLEA became effective. Numbers of companies found themselves in tight straights with late changes and waiting lines at the printers at the last minute. More recently, there was the addition of trans fat to Nutrition Facts in 2006, which required a relatively small adjustment compared to the changes coming now.

Betty Campbell will be speaking more on this subject in a session called “Anticipating FDA Proposed Changes to Nutritional Facts Labels,” Monday, June 23, 2014 from 8:30am-10:00 a.m., at the Institute of Food Technologists Annual Meeting in New Orleans, LA. For more information, click here.

Food Label Compass

EAS has entered into an alliance with FoodMinds Inc., and Nutrition Impact LLC, called Food Label Compass, to offer a suite of labeling services to assist clients in adapting to the new Nutrition Facts requirements.

Food Label Compass combines the expertise of all three partners and will provide nutrition analysis, regulatory consulting and strategic services to food and beverage companies. If you need assistance with serving sizes, Daily Values (DVs) or nutrition claims Food Label Compass can help.

FDA Extends Comment Deadline on Sanitary Transportation Rule


In 1990, Congress enacted the Sanitary Food Transportation Act that directed the Department of Transportation to promulgate regulations for the transportation of food to ensure its safety. DOT issued a proposed rule in 1993, but later determined that it lacked the expertise to implement the law. Congress amended the law in 2005 giving FDA the authority to implement it, but with no deadline for rule making. Section 111 of the Food Safety Modernization Act directed FDA to promulgate final regulations no later than 18 months after enactment of the act. FDA published a proposed rule on February 5, 2014.

In response to requests from stakeholders, FDA extended the May 31, 2014 comment deadline on its proposal to establish sanitary transportation requirements for vehicles and transportation equipment. The new deadline for public comment is July 30, 2014. In a May 8 letter, 22 industry groups sought a 90-day extension and said they needed more time to consider several sections of the proposed rule that could have “unintended consequences.” FDA granted a 60-day extension. The agency has a court-ordered deadline of March 31, 2016 for issuing the final rule.

The proposed rule on sanitary transportation of human and animal foods is one of seven regulations mandated by the Food Safety Modernization Act.

As I mentioned in the February issue, this rule is a key component of the implementation of FSMA’s provisions. The sanitary transportation rule deals with requirements for refrigeration of food, cleaning of vehicles between shipments, and protection of food during transportation. The proposed rule would establish requirements for vehicles and transportation equipment and operations, as well as for training, records and procedures for waivers.

With some exceptions, the rule would apply to shippers, receivers, and carriers who transport food in the United States by motor or rail vehicle, whether or not the food enters interstate commerce. It would also apply to a person outside of the United States, such as an exporter, who ships food to the United States in an international freight container if it will be consumed or distributed in the United States.

Among the exemptions are the transportation of raw agricultural commodities performed by farms. Also exempt are shippers, receivers, or carriers engaged in food transportation operations that have less than $500,000 in total annual sales. Food that is transshipped and not meant for consumption in the U.S. is also exempt, as well as shelf-stable foods, compressed food gases and live food animals.

According to FDA’s estimates the proposed sanitary transportation rule will impact 83,609 businesses and the average cost is estimated at $1,784 per business in the first year, for a total of $149.1 million. The ongoing annual cost to the regulated companies is estimated at over $30 million.

As you will see elsewhere in this issue, I will be participating in a FSMA panel with CFSAN Director Michael Landa and former CFSAN Director Robert Brackett at the IFT annual meeting in New Orleans in a June 23 1:30 p.m. session. And it’s a safe bet that this proposed transportation rule will feature there among other hot topics.

FDA’s Strategy for Implementing Next Phase of FSMA

FDA offers some insights into its strategy for implementing the next phase of the Food Safety Modernization Act (FSMA) in a guidance document posted on the agency’s website May 2. A key element of the agency’s operational strategy will be to rely heavily on the industry to implement preventive measures.

The agency says the industry needs to work in a continuous improvement mode and to manage operations and supply chains “in a manner that provides documented assurances that appropriate preventive measures are being implemented as a matter of routine practice every day.”

I would especially draw your attention to the appendix to the guidance, which details some of the ways the agency plans to implement FSMA’s provisions. FDA will vary its strategy for different types of food facilities. For food and animal feed facilities, for example, the agency says it will significantly expand its inspection and surveillance tools to include a wider range of inspection, sampling, testing, and other data collection activities conducted through its own field force and through collaboration with partner agencies and the food industry.

For these facilities, inspection and surveillance will include:

  • Efficiently screening firms for food safety performance to guide risk-based inspection priority, frequency, depth, and approach;
  • Providing firms incentives for compliance through enhanced presence in and targeted scrutiny of high-risk firms and products and reduced scrutiny of firms with records of demonstrated good performance;
  • Assessing the compliance of individual firms through a range of inspection and sampling techniques used in a strategic, risk-based way to maximize coverage of priority sectors and firms;
  • Making in-depth assessments of individual firms when needed to increase the incentive for compliance and determine the need for compliance or enforcement actions
  • Collecting data to inform understanding and analysis of sector-wide hazards, practices, and preventive control deficiencies; and
  • Collecting data on compliance rates to evaluate program performance and plan future efforts

The agency says its primary compliance tools will be administrative actions rather than court enforcement cases. The administrative actions will include:

  • Voluntary correction of problems at the facility level, achieved immediately during the course of an inspection through communication with firm management by investigators and, as needed, Center technical staff;
  • Voluntary correction achieved at the District level through deficiency letters, issued within days after an inspection with Center back up, to document significant safety-related deficiencies and request correction within a specified period, with immediate inspection follow up to verify correction;
  • Administrative detention of product if needed to provide immediate public health protection or for other appropriate purposes;
  • Voluntary and mandatory recalls to remove potentially hazardous food from the market; and
  • Administrative suspension of registration when other administrative compliance measures have failed or are inadequate to achieve correction of significant deficiencies that put consumers at risk.

FDA’s judicial enforcement tools will include:

  • Seizure actions that are needed to back up administrative detentions;
  • Injunction actions when suspension of registration or other measures are inadequate to prevent future non-compliance; and
  • Criminal prosecution for falsifying records, lying to FDA, knowingly putting consumers at risk, or in other appropriate cases.

A Different Approach for Produce

Implementation of FSMA’s produce safety standards will require a different approach, the agency says. Because of the scale and diversity of the produced sector, “there is no reasonable expectation FDA will have the resources to make routine on-farm inspection a major source of accountability for compliance with produce safety standards.”

So, the agency explains, “FDA’s implementation of produce safety standards will entail a broad, collaborative effort to foster awareness and compliance through guidance, education, and technical assistance, coupled with accountability for compliance from multiple public and private sources, including FDA and partner agencies, USDA audits, marketing agreements, and private audits required by commercial purchasers.”

A Strategy for Imports

For imported foods, the agency will rely primarily on “importers providing documented assurances that their foreign suppliers have taken proper steps to prevent problems.” The agency plans to build its skills and capacity and to focus on auditing foreign supplier verification programs and on holding importers accountable for managing their supply chains.


According to the Congressional Budget Office, FDA needed $1.4 billion through 2015 to fulfill FSMA requirements. But the agency’s budget for FSMA received only modest increases since the legislation’s enactment.

As examples, the Foreign Supplier Verification Program will require new staff and skills to audit and verify the adequacy of the importer’s verification plan; conduct more foreign inspections; work more on food safety with foreign governments to leverage their efforts; and improve the agency’s data and import systems to facilitate prompt entry of foods that meet U.S. safety standards.

FDA’s strategy relies on partnerships with state departments of agriculture, other state partners, and local, territorial, and tribal authorities to deliver the education, training and technical assistance, as well as compliance oversight, needed to ensure the rules are implemented properly. However, additional resources are required to build the capacity of these partners and provide the needed assistance to growers, especially small and mid-size operators.

This cannot be done unless FDA finds additional resources to build the capacity of its partners and provide the needed assistance to growers, especially small and mid-size operators. The current appropriations are insufficient to take advantage of these opportunities and meet the objectives of FSMA.

FDA Has Higher Expectations for Generic Drug Applications

Generic Drug User Fee Amendment (GDUFA) and You

By Charles “Chris” Celeste, Director of Regulatory Information and Submissions

FDA expects industry to begin submitting higher-quality applications to facilitate expedited reviews and approvals of generic drugs, agency officials explained at the Generic Drug User Fee Amendment (GDUFA) and You Conference in Lake Buena Vista, FL, March 27-28.

The goal of the meeting — which was hosted by the Office of Small Business and Industry Assistance (SBIA) in FDA’s Center for Drug Evaluation and Research (CDER) and presented by FDA’s Office of Generic Drugs (OGD) — was to update participants on FDA’s current activities and future plans for generic drug reviews.

The purpose of GDUFA was to increase the access of U.S. consumers to generic drugs, to ensure that the drugs are manufactured in compliance with FDA regulations, and to improve FDA’s communication with manufacturers of generic drugs and active pharmaceutical ingredients. In short, the goals are to improve access, safety, and transparency. To achieve these goals, FDA will be using a fee-based program to supplement appropriated Congressional funding.

At the Lake Buena Vista meeting, agency officials provided a reviewer’s perspective of an Abbreviated New Drug Application (ANDA), Drug Master Files (DMFs) and the completeness assessment for type II DMFs. The second day featured GDUFA implementation and policy updates; regulatory science; user fees, arrears lists, appeals and waivers; post approval inspections programs and a review of efficiency enhancements.

In GDUFA-related achievements, the agency has made significant progress in reducing the ANDA review backlog. FDA has hired 291 employees, exceeding the hiring target in the Fiscal Year 2013 goal. It has published criteria for Type II DMFs completeness assessments and refuse-to-receive (RTR) standards and it has posted a list of Type II DMFs that have passed the completeness assessment. And it is establishing a public docket to invite comment on ways to improve the quality of the ANDAs, amendments and supplements.

Here are some of my take-home notes from the meeting:

  • The agency will refuse to receive an ANDA if the number of easily remedied deficiencies is equal to or more than 10 or if a response to the fewer than 10 deficiencies is not received within 10 U.S. business days.
  • ANDAs submitted as a single, continuous, non-bookmarked PDF file will be refused.
  • If an applicant is requesting an expedited review, the cover letter must indicate in boldface “Expedited Review Requested” or “eligible for Expedited Review, GDUFA Year 1 or 2 Cohort.”
  • Upon issuing final guidance, FDA will contact a sponsor of an ANDA containing less than 10 easily remedied deficiencies. A response must be provided within 5 U.S. business days. Day 1 of the 5 U.S. business days will commence the day after notification is provided to the applicant. An ANDA will be refused if the number of easily remedied deficiencies is equal to or more than 10 or if a response to the fewer than 10 deficiencies is not received within 5 U.S. business days.
  • Any deficiencies revealed in the Active Pharmaceutical Ingredient (API) review will be communicated to the applicant. If a response is not received within 5 U.S. business days the ANDA will be refused for receipt.
  • Starting in Cohort Year 3 (FY 2015), which begins October 2, 2014, DMFs must be “Available for Reference” at the time of ANDA submission or they will be Refused to Receive (RTR).
  • Starting in Cohort year 3 the DMF fee should be paid a minimum of 6 months ahead of ANDA submissions to ensure the Completeness Assessment (CA) is done and the DMF is available for reference.
  • FDA is encouraging DMF holders to use a 30 minute teleconference for the first cycle of deficiency letters.
  • The agency is encouraging Type II DMF holders to submit the DMFs in eCTD format. This will aid in the review of the applications.

OGD is issuing the ANDA Filing Checklist on a quarterly basis (March, June, September and December). ANDA applicants should use the checklist as a tool to ensure that their application contains all of the appropriate components.

The agency offered other reference tools for applicants to use when preparing their applications, including Final Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Applications and Related Submission Using the [electronic Common Technical Document (eCTD)] Specifications; FDA eCTD Table of Contents Headings and Hierarchy; Portable Document Format Specifications: Guidance for Industry M4: The CTD – Quality Questions and Answers/Locations Issues, etc.

FDA will be holding a public meeting on May 16, 2014 to provide an overview of the current status of regulatory science initiatives for generic drugs. The agency wants input from industry, academia, professionals and other interested parties as it develops an annual list of regulatory science initiatives specific to generic drugs. FDA will take the information from the public meeting into account in developing its FY 2015 Regulatory Science Plan. The meeting will be held from 9:00 am to 5:00 pm at FDA’s White Oak Campus. Additional information can be found in the February 26, 2014 Federal Register.

In summary, FDA is working on keeping industry updated on the agency’s activities and trying to provide them with as much information as possible. The agency’s expectation is that industry will begin to submit applications that can be reviewed more efficiently.

EAS has available upon request copies of all the slide presentations for the GDUFA and You 2014 meeting.

FDA Issues Revised Draft Guidance on Prior Notice of Imported Foods


FDA announced the release of new draft guidance on requirements for prior notice of imported food, in a March 31 Federal Register notice. Some of the draft guidance responds to provisions in section 304 of the Food Safety Modernization Act (FSMA). The new draft includes several new questions and answers that help throw light on how the agency would deal with particular scenarios.

The prior notice requirement for imported food originated in the Bioterrorism Act of 2002. The current guidance, the second edition, was issued in May 2004. So the new draft will become the third edition when finalized. The agency issued a final rule on prior notice of food, including animal feed, on November 7, 2008 (73 FR 66294). In May 30, 2013, implementing a provision in section 304 of FSMA, the agency issued a final rule requiring the name of any country to which an article has been refused entry be reported in prior notices (78 FR 32359).

In the draft guidance, the agency says it received many questions about the definition of the term “ultimate consignee” for an imported food. “A significant number of people have asked this question, and there has been a lot of variation in what people have been submitting as the ultimate consignee,” the draft guidance states. “FDA considers the location where the imported food is to be delivered as the ultimate consignee for the purposes of prior notice,” it says.

If the imported food is delivered to the owner, the name and full address of the owner should be given as the ultimate consignee. If the food is owned by a foreign shipping firm and is being delivered to a public storage warehouse in the U.S., FDA considers the public storage warehouse to be the ultimate consignee and its name and address should be submitted in the prior notice, the agency says.

Another new question in the draft deals with the FSMA-related requirement to report the name of any country that has refused entry of the article of food. Specifically, the agency says it is necessary to report refusals of entry of food, including food for animals, based on food safety reasons given by the government of the country that refused entry. This includes a refusal by another U.S. port.

Another new question in the draft guidance deals with the definition of the word “article” and whether it refers only to the food in the specific shipment, or if it also includes food from the same batch or lot numbers that was shipped to other countries. The agency says the term “article” does not refer to food from the same batch or lot numbers that is not being imported or offered for import into the U.S. and for which prior notice will not be submitted at the time of the specific shipment, or food of a similar type that was previously refused entry by a country.

The new draft also clarifies that prior notice is required for meat intended for food for animals, including pet food and treats. “Meat intended for food for animals, such as that fed to zoo animals or meat products intended to be incorporated into food for animals, is not under the jurisdiction of USDA/FSIS and is subject to the prior notice requirements. These meats include meat derived from cattle, swine, goats, sheep, horses, and mules that are destined for food for animals,” the agency says.

As always with such agency guidance, it represents FDA’s current thinking on the subject, but it is not binding upon the agency or the regulated community, so alternative approaches may be used if they satisfy the requirements. The 60-day comment period began March 31, 2014.


The Top Ten Reasons for FDA Warning Letters to Medical Device Firms

By EAS Director of Regulatory Affairs and Submissions, Chris Celeste

Since December 1978, medical device manufacturers have been subject to FDA regulations and inspections based on the Good Manufacturing Practices (GMP) requirements. On June 1, 1997 FDA amended the 1978 regulations to include quality system regulations (QSR).

An FDA “Warning Letter” is considered by the agency to be the first step in the enforcement process. In the letter, the agency threatens to take regulatory action if a firm does not correct the violative conditions. The agency requests a response, normally within 15 working days. In situations of a danger to health, the agency may request a response in 24 hours.

In fiscal year 2013, FDA’s Center for Devices and Radiological Health (CDRH) issued 217 Warning Letters, seven more than the center issued in FY12. EAS reviewed a total of 105 of the warning letters issued to manufacturers or other establishments that market medical devices in the U.S. The following were the Top 10 observations noted in those letters:

  1. 21 CFR 803.17 – Failure to develop, maintain, and implement written Medical Device Reporting procedures
  2. 21 CFR 820.22 – Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system
  3. 21 CFR 820.30(i) – Failure to establish and maintain procedures for the identification, documentation, validation or, where appropriate, verification, review, and approval of design changes
  4. 21 CFR 820.50 – Failure to establish and maintain procedures to ensure all purchased or otherwise received product and services conform to specified requirements
  5. 21 CFR 820.75(a) – Failure to ensure that when the results of a process cannot be fully verified by subsequent inspection and testing, the process shall be validated with a high degree of assurance and approved according to established procedure
  6. 21 CFR 820.90(a) – Failure to establish and maintain procedures to control product that does not conform to specified requirements
  7. 21 CFR 820.100(a) – Failure to establish and maintain procedures for implementing corrective and preventive action
  8. 21 CFR 820.181 – Failure to maintain adequate device master records (DMRs)
  9. 21 CFR 820.184 – Failure of the device history record to demonstrate the device was manufactured in accordance with the Quality System Regulations
  10. 21 CFR 820.198(a) – Failure to maintain complaint files and establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit

How to Respond

A firm’s response to a warning letter may be its last chance, prior to a legal or administrative action, to adequately address a situation that FDA has concluded constitutes a violation of the Food, Drug and Cosmetic Act (FD&C Act). Therefore, it is particularly important that the communication be responsive to the issues identified by the agency. Frequently, the letter is the result of an investigator’s inspection and the agency has already received the response to the FDA observations noted on the FDA-483. In some cases, the response may be considered inadequate and FDA will state that and will explain why the response is inadequate. In other cases, FDA may be silent as to their evaluation of the submission addressing the FDA-483 observations. If the initial response has been determined by FDA to be inadequate in whole or in part, FDA has not acknowledged its receipt, or if the firm has not yet responded to FDA’s concerns; this may represent the firm’s last opportunity to prevent a more aggressive action. Immediate affirmative action to correct the objectionable conditions and inform the proper office of the action is necessary to satisfy FDA and to prevent further regulatory action.

FDA may conclude that a firm has already satisfactorily corrected the objectionable conditions, or accept a firm’s response that they have been corrected. However, FDA may still send a warning letter, because they have yet to confirm that the conditions have been corrected and they wish to establish a background of “prior warning” so that if the violations are repeated at some future date, the firm is “on notice” that a more serious regulatory action may result. It therefore, remains important that a firm’s response to a warning letter be adequate to address the issues set forth. It is also important to state what systems and controls have been put into place to prevent these deviations from occurring in the future.

When drafting a response to an FDA warning letter, it is important to remember that the agency has already tentatively concluded that a violation of the law has occurred. The response must contain solid facts to refute the allegations or represent the firm’s action and commitment to afford immediate and permanent correction. If the recipient of the warning letter disagrees with the contentions in the letter, there is an appeal process within FDA. However, our experience indicates that when the situation reaches the point where FDA concludes that the issuance of a warning letter is appropriate, such appeals are futile. The next step would be to have the issues resolved in court.

It is important to meet the FDA timeframe for submitting the response. If you can’t, notify the issuing office and request an extension. The firm should commit to immediate and permanent correction of the violative conditions. They should support their view with facts and expert views. A meeting can be requested with the issuing office to discuss the firm’s views and hear FDA’s position. The firm’s views can be provided in writing as well as verbally in a non-argumentative, straightforward manner. If a specific product(s) are involved, provide the agency with the action the firm intends to take on these products and why. If the firm does not agree with FDA’s conclusion, request a meeting with the issuing office to discuss differing views and hear FDA’s position. The firm should present its arguments in a factual, scientific and if appropriate legal manner.

If the response is satisfactory FDA will, conduct a follow up investigation to assure the corrective action taken is effective. If the response is inadequate or if it has not been accomplished as promised, further regulatory action by FDA is likely.

FDA Proposes Revised Nutrition Labels on Foods (and Some Dietary Supplements)

By Elizabeth Campbell, EAS Senior Advisor for Labeling & Claims

FDA announced on February 27, and published in the March 3 Federal Register, proposals to revise the Nutrition Facts label. This is the first time in the 20 years of the Nutrition Facts label that FDA is making major revisions. The proposed revisions incorporate updated information on advice for healthy dietary practices and food consumption patterns as well as technical updates.

FDA has articulated a detailed rationale for each change in two proposals and has posted links to several information pieces on its website.

Major proposed changes include:

  • Require declaration of “added sugars” as a component of total sugars
  • Add vitamin D and potassium to the mandatory nutrients and convert vitamins A and C to voluntary nutrients
  • Update Daily Values (DV) for nutrients like sodium, dietary fiber and Vitamin D. Changes in DVs would affect whether certain foods qualify for nutrient content and health claims.
  • Require that packaged foods, including drinks, that are typically eaten in one sitting (less than 200% RACC) be labeled as a single serving and that calorie and nutrient information be declared for the entire package
  • Require “dual column” labels to indicate both “per serving” and “per package” calories and nutrient information for packages that are 200% – 400% of the RACC. Because of limited space, labels that qualify to use the tabular or linear formats would not have to declare the second column.
  • Update several RACCs and establish new ones to reflect current consumption patterns. As an example, the RACC for carbonated and non-carbonated beverages, water, coffee, tea would be increased from the current 8 fluid ounces (fl oz) to 12 fl oz. Milk, milk substitutes, milk based beverages would retain the 8 fl oz RACC. Changes in RACCs could affect whether certain foods qualify for nutrient content and health claims.
  • Revise the format to make calories and serving sizes more prominent and to shift the % Daily Value to the left of the label

Nutrition Label Changes

While these changes apply to all food labels, not all the changes would affect dietary supplement labels. Dietary supplements that do not contain “food type” dietary ingredients like fat, protein, and carbs would not need to change labels. The added emphasis on calories and added sugars would mean changes for some dietary supplements, particularly flavored liquids. Some of the changes would affect protein supplements, fiber supplements, and supplements containing RDI vitamins and minerals.

FDA has established a 90 day period for interested parties to submit comments on the proposed changes. The agency will take into account information provided in comments when developing the final regulations. We encourage manufacturers to determine how the changes would affect their product labels. You may want to submit information to FDA if proposed changes would have a negative effect for your product. This article cannot include the amount of detail manufacturers need to understand the proposed changes, but EAS can help you to navigate the details to understand your status.

The proposed effective date is 60 days after the final regulation is published and FDA would allow 2 years for labels to be brought into compliance with the final requirements.

EAS has partnered with FoodMinds and Nutrition Impact, LLC to create Food Label Compass, which harnesses the expertise of all three partners to create a suite of nutrition analysis, regulatory consulting and strategic services to guide food and beverage companies in understanding the impact, complying, communicating, and capitalizing on the new FDA guidelines. Food Label Compass will conduct in-depth analyses of the food and nutrient content of clients’ brands relative to the new FDA guidelines. It will identify the potential changes to the serving size rules (Reference Amounts Customarily Consumed (RACCs)), assess the impact of potential changes on Daily Values (DVs) and on nutrition claim criteria.

Food Label Compass will develop regulatory recommendations and guidance to construct labels modified to reflect the new requirements. In addition, it will validate claim opportunities, answer questions on how to comply with the new nutrition information rules and ensure the information is presented in an approved and consumer-friendly manner.

FDA Issues Proposed Rule on Sanitary Transportation of Food


On January 31, 2014, FDA issued a proposed rule on sanitary transportation of human and animal foods — the seventh of seven regulations mandated by the FDA Food Safety Modernization Act. So we now have all the proposed rules that would implement key elements of FSMA.

The other six rules deal with preventive controls for human food, preventive controls for animal food, produce safety, a Foreign Supplier Verification Program, accreditation of third-party auditors, and the prevention of intentional adulteration.

I view this transportation proposal as a valuable and necessary component of the collection of new rules that will introduce a more preventive approach to food safety in the United States. But there is a possible downside to introducing so many regulations at one time – especially for companies that find themselves suddenly required to understand and comply with several new sets of requirements under separate regulations. Animal feed companies, for example, may be unclear about their status relative to all of the FSMA rules. For example, if farmers have their own mills, does the exemption for feeding your own animals also apply to farmers who may feed their own animals that are housed in facilities owned by contract growers?

The sanitary transportation rule deals with requirements for proper refrigeration of food, the cleaning of vehicles between shipments, and the protection of food during transportation. As mandated by the lawmakers who crafted FSMA, the proposed rule would establish requirements for vehicles and transportation equipment and operations, as well as for training, records and procedures for waivers.

With certain exceptions, the proposed rule would apply to shippers, receivers, and carriers who transport food in the United States by motor or rail vehicle, whether or not the food enters interstate commerce. It would also apply to a person outside of the United States, such as an exporter, who ships food to the United States in an international freight container if it will be consumed or distributed in the United States.

I was interested to see what is not covered by the new requirements. For example, transportation of raw agricultural commodities performed by a farm is exempt. Also exempted are shippers, receivers, or carriers engaged in food transportation operations that have less than $500,000 in total annual sales. Food that is transshipped and not meant for consumption in the United States is also exempt. In addition, shelf-stable foods, compressed food gases and live food animals are exempt.

According to FDA’s estimates the proposed sanitary transportation rule will impact 83,609 businesses and the average cost is estimated at $1,784 per business in the first year, for a total of $149.1 million. The ongoing annual cost to the regulated companies is estimated at over $30 million.

The agency has scheduled three public meetings on the proposed rule, Feb. 27 in Chicago, IL, March 13 in Anaheim, Calif., and March 20 in College Park, MD.

The deadline for public comments is May 31, 2014.

USDA Expands Generic Labeling Regulations

By EAS Senior Consultant Susan Glenn

For years USDA has required labels be submitted for approval in order for product to be shipped out of a plant. In July of 1996 the first set of generic regulations went into effect allowing companies to approved some labels “in house” or generically. This rule included net weight changes, changing the signature line and changing the vignette. The rule also changed how many times the label had to be submitted to USDA for approval and took the inspector in charge out of the equation. Previously, labels were required to receive a sketch approval and a final approval of the actual label. In 1996, the generic regulations did away with final label approvals.

A new generic labeling rule went into effect on January 6, 2014, 18 years after the first set of generic regulations. The new rule states only certain types of labeling – i.e., 1) labels for temporary approval, 2) labels for products produced under religious exemption, 3) labels for products for export with labeling deviations, and 4) labels with claims and special statements — will have to actually be submitted to USDA for evaluation and approval. Some of the labels that will be allowed for generic approvals are labels with allergen statements, defined nutrition claims, and geographic claims. Labels for temporary approval, whole grain statements, nutrition front of package statements, natural claims and animal production claims are some of the types of labels that will still need to be submitted to USDA for approval. The Labeling and Program Delivery Division, which is responsible for all USDA label approvals, will accept labels for review that can be approved generically, but they will be given secondary status. Labels with claims, temporaries, religious exemptions and labels for export that bear labeling deviations will take precedence.

Many see this as another step toward an all-generic labeling system. Establishments will have more responsibility for label approvals. And Inspectors in Charge are expected to know the new rule. Standardized training will be implemented, but there may still be a big difference between how individual inspectors view labels at the plant. Some may still want to see the USDA stamp on the label even though it can be generically approved. That’s where USDA’s Labeling Submission Approval System may prove useful. It includes a section with a series of question to determine if a label can be generically approved. LPDD is hoping this will cut the turnaround time for label approvals. The process can take anywhere from 3-8 weeks.

On FDA’s Proposed Rule on Intentional Adulteration

FDA released its proposed rule on intentional adulteration of food in a December 24 Federal Register notice. The proposed rule, Focused Mitigation Strategies To Protect Food Against Intentional AdulterationFocused Mitigation Strategies To Protect Food Against Intentional Adulteration, would apply to both domestic and foreign facilities that are required to register with the agency and would require those companies to develop and implement a food defense plan.

The proposal introduces some terminology that may initially cause confusion among stakeholders. For example, the term ‘‘actionable process step,’’ is the food defense counterpart of the familiar term ‘‘critical control point’’ (CCP) used in Hazard Analysis and Critical Control Point (HACCP) plans. HACCP per se does not appear in the language of FSMA, which instead allows hazard analysis and preventive controls to be achieved by any means that can be shown to be effective. For the purposes of food defense, we will need to become familiar with the term ‘‘actionable process step,’’ which is a step identified during a vulnerability assessment. A vulnerability assessment, meanwhile, is similar to the hazard analysis conducted in developing a HACCP plan.

Yet another key term, “significant vulnerability,” is the food defense version of the term “reasonably likely to occur” which is used in the preventive controls proposed rules.

In many situations it may be difficult to say what constitutes a significant vulnerability. This is also an issue in the preventive controls rules, where what may or may not be “reasonably likely to occur” is a challenge for the regulators to sharply define. The agency defines a “significant vulnerability” as a vulnerability for which “a prudent person knowledgeable about food defense would employ food defense measures because of the potential for serious adverse health consequences or death and the degree of accessibility to that point in the food process.”

The agency has identified four key activity types as being especially vulnerable to intentional adulteration: bulk liquid receiving and loading; liquid storage and handling; secondary ingredient handling; and mixing and similar activities. But the agency is open to ideas about what other types of products and facilities may be vulnerable. Judging by the number of questions asked in the proposal, it is clear that even some fundamental elements of the proposal may be open to change before a final rule takes shape.

As proposed, the rule includes numerous exemptions. For example, it would apply to food in liquid storage tanks, but not to the holding of food in general. It would not apply to the packing, re-packing, labeling, or re-labeling of food where the container that directly contacts the food remains intact, the agency says. It would not apply to activities of a facility that are subject to produce safety standards. With some exceptions, it would not apply to alcoholic beverages at a facility that meets certain conditions. And it would not apply to the manufacturing, processing, packing, or holding of food for animals.

The proposed rule would not apply to a “qualified” facility. Qualified facilities would include very small businesses, with less than $10 million in annual sales of food. But some companies could be deemed “qualified” if during the preceding 3-year period the average annual value of the food manufactured, processed, packed or held at the facility sold directly to qualified end-users exceeded the average annual monetary value of the food sold by such facility to all other purchasers, and if the average annual monetary value of all food sold during the preceding 3-year period was less than $500,000.

The agency is seeking comments by March 31, 2014 on the proposed exclusions – and, of course, on all other elements of the proposed rule.

FDA’s Proposed Rule on Antibacterial Soaps

By EAS Senior Consultant Norma Skolnik

In 2010 the Natural Resources Defense Council (NRDC) sued FDA to force the agency to issue a final rule on antibacterial soaps. As part of a settlement signed last month, the agency issued a proposed rule Dec. 16, 2013 and committed to taking final action by 2016. Well before this lawsuit, however, FDA was investigating this area and considering action on this topic.

FDA’s focus centers on triclosan, an antibacterial agent that’s long been under agency scrutiny. More than 30 years ago, FDA reviewed evidence and concluded that triclosan wasn’t proven either safe or effective (category III), although years later toothpaste containing triclosan was approved. Nonetheless, antibacterial products have been widely marketed for years. Widespread use of these products and related public health and environmental concerns provided a backdrop for the NRDC lawsuit that was the ultimate catalyst for FDA’s regulatory action. As Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, stated: “Due to consumers’ extensive exposure to the ingredients in antibacterial soaps, we believe there should be a clearly demonstrated benefit from using antibacterial soap to balance any potential risk.”

FDA Action and Rationale

On Dec. 16, 2013 the FDA released a proposed regulation to ban certain ingredients in anti-bacterial soaps if manufacturers cannot prove that these products are safe to use and more effective than plain soap and water for preventing the spread of infections. Such a move could potentially force makers of antibacterial products to reformulate all bar soaps, liquid soaps, body washes, and dishwashing liquids labeled as “anti-bacterial” and “antimicrobial” to keep them on store shelves.

According to Colleen Rogers, a lead microbiologist at FDA, “there’s currently no evi­dence that OTC antibacterial soap products are more effective at preventing illness than washing with plain soap and water”. Moreover, antibacterial soap prod­ucts contain ingredients, such as triclosan and triclocarban, which according to FDA, may pose risks associated with long-term, daily use that may outweigh the benefits. Active ingredients in these soaps may contribute to bacte­rial resistance to antibiotics, and may also have unanticipated hormonal effects that are an FDA concern based on animal study data.

Because of these concerns, FDA’s proposed rule requires manufac­turers to provide more substantial data to demonstrate the safety and effectiveness of antibacterial soaps. The proposed rule covers only consumer antibacterial soaps and body washes that are used with water. It doesn’t apply to hand sanitizers, hand wipes or antibacterial soaps that are used in health care settings such as hospitals.

Most soaps labeled “antibacterial” or “antimicrobial” contain at least one of the antibacterial ingredients that FDA has targeted in this proposed rule. Certain household cleaning products and some toothpastes may also contain them.

Laboratory tests that have historically been used to evaluate the effectiveness of anti­bacterial soaps don’t directly test the effect of a product on infection rates. That would change with FDA’s cur­rent proposal, which would require studies that directly test the ability of an antibacterial soap to provide a clinical benefit over washing with non-antibacterial soap and water.

Environmental concerns also brought the Environmental Protection Agency (EPA) into the picture and the two agencies have been collaborating on scientific and regulatory issues regarding triclosan. EPA is updating its assessment of triclosan’s use in pesticides and its overall environmental impact, while FDA has focused on the antimicrobial’s widespread use by consumers in soaps and body washes. In sharing information, the two agencies are assessing exposure risks.

Next Steps

FDA’s proposed rule doesn’t require the antibacterial soap products to be removed from the market at this time. When the proposed rule is finalized, either companies will have provided adequate data to support an antibacterial claim, or if not, they must reformulate to remove the active ingredients or relabel to remove the antibacterial claim from the product’s labeling in order to continue marketing these products. The proposed rule is available for public comment for 180 days, with a concurrent one year period for companies to submit new data and information, followed by a 60 day rebuttal comment period.

Manufacturers of antibacterial soap and body wash products and trade associations are sure to respond with comments. Two industry trade groups, the Personal Care Products Council and the American Cleaning Institute, already cited a review of two dozen studies they say showed washing hands with antimicrobial soaps produces “statistically greater reductions in bacteria on the skin” than plain soap.” They may also offer legal arguments about the absence of serious adverse event data resulting from antibacterial soap use as well as study data and scientific literature support. Results of animal studies will likely be submitted as well as clinical studies using standardized microbe doses to try to satisfy the agency’s data requirements. However, it’s not likely that manufacturers would incur the enormous cost of full scale clinical trials to obtain prospective human data.

Industry groups intend to file comments reaffirming that use of antibacterial soap products does not contribute to antibiotic resistance. However, the question is whether they can provide sufficient efficacy and safety data to convince FDA that the benefits outweigh the risks. The assessment of published scientific literature alone won’t persuade FDA, since they’ve already concluded that existing scientific data aren’t adequate to support safe and effective product use.

If FDA determines an antibacterial claim is not supported, companies must reformulate to remove or replace a category III ingredient or relabel their products. How one would relabel such a marketed antibacterial soap product is a big unknown. Would FDA permit a disclaimer stating an ingredient like triclosan lacks evidence of safety and efficacy and allow such products to remain on the market? Would consumers continue to use these products without an antibacterial claim? We suspect it will be a while before these issues are resolved.