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Drugs

An Overview of FDA’s Regulations for OTC Human Drugs

Over-the-counter (OTC) drugs adorn the shelves of many retail outlets in the U.S., including pharmacies, grocery stores, and convenience stores. OTC drugs do not require a written prescription from a medical professional, making them highly accessible. Though there are similarities in the regulations the U.S Food and Drug Administration (FDA) enforces for both prescription drugs and OTC drugs, there are also significant differences. The most noteworthy difference is the ability for companies to market an OTC Drug using an OTC Drug Monograph. This pathway allows companies to market certain OTC drugs without further FDA approval, so long as the drug complies with an existing monograph.

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Keep reading to learn about FDA’s regulations for OTC drugs, including registration, listing, and marketing requirements.

Drug Establishment Registration

All establishments engaged in the manufacturing, repacking, relabeling, or salvaging of a drug product for commercial distribution are required to register with FDA, unless exempt. (21 CFR 201.17). Drug establishment registration informs FDA which facilities are engaging in manufacturing activities of drug products either in the U.S. or offered for import into the U.S.

For a U.S. based establishment, registration includes the facility’s DUNS number, manufacturing facility address, business operation details, and establishment contact information. Non-U.S. based establishments must also include information for their U.S. Contact and U.S. Importer(s).

Drug companies must register with FDA within five days of introducing their drug product into commercial distribution. After registering, FDA will assign the establishment an FDA Establishment Identification (FEI) number and the site becomes subject to inspection.

Establishments must update their registration annually between October 1st and December 31st. The update should include changes to the contact information, the company name, and/or the establishment address. If there are no updates to the registration information, the establishment must submit a No Change Notification. Establishments must also update their registration before shipping to the U.S. when importer information has changed or when a new importer has been added.

Product Listing

Most registered drug establishments must list all of their drug products to let FDA know what drug products are in commercial distribution, who manufacturers each drug product, and what drug products a label distributor distributes. Product listings must be assigned a National Drug Code (NDC) number and must include labeling in Structured Product Labeling (SPL) format.

Establishments exempt from listing requirements include contract testing laboratories, contract assemblers, and manufacturers, repackers, salvagers, or relabelers of Type B or C medicated feeds.

Listings must be updated if there is a change to the company name, DUNS number, or artwork that does not require a new NDC number assignment. Additionally, listings must be verified every year between October 1st and December 31st. If there are no changes, the company must submit a Blanket No Change Certification to FDA.

Marketing Regulations

OTC drugs must meet established standards for safety and effectiveness, be manufactured according to current good manufacturing practices (cGMPs), and comply with the labeling content and format requirements. These products can be regulated through an OTC Drug Monograph or a New Drug Application (NDA)

OTC Drug Monographs

OTC drugs that conform to an existing OTC Drug Monograph follow acceptable ingredients, doses, formulation, and labeling requirements that are specified for a drug already on the market. In this sense, OTC Drug Monographs serve as a “recipe book” for drug companies, allowing the drug to be marketed without further FDA clearance as long as it adheres to the monograph.

Monographs specify the active ingredients that an OTC drug product can contain. An OTC drug product containing ingredients that comply to the standards established in the corresponding OTC monograph for formulation, labeling, and testing is considered to be “generally recognized as safe and effective” (GRASE) and does not require specific FDA approval before marketing.

Applications

If an OTC drug does not adhere to the standards of an OTC Drug Monograph, the sponsor of the drug must submit a New Drug Application (NDA) or an Abbreviated New Drug Application (ANDA) to FDA for approval. FDA must approve the NDA or ANDA before the drug can be marketed.

An OTC drug can be marketed as either a direct-to-nonprescription (direct-to-OTC) or prescription-to-nonprescription switch (Rx-to-OTC switch) drug. For a direct-to-OTC drug, the sponsor can submit an NDA to market a new drug without first receiving approval as a prescription drug. An Rx-to-OTC switch refers to an approved prescription drug that eventually receives FDA approval to be marketed as nonprescription.

Proposed Rule

FDA is proposing a rule that could increase options for applicants to develop and market safe and effective nonprescription drug products, by providing consumers with an additional condition for nonprescription use (ACNU). If the rule passes, an applicant would be able to submit a drug application proposing an ACNU for a product “when labeling alone is not sufficient to ensure that the consumer can appropriately self-select or appropriately actually use, or both, a drug product correctly in a nonprescription setting”. Consumers would need to successfully fulfill the ACNU to obtain the drug product without a prescription.

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FDA Proposes Rule on Revising the NDC Format and Drug Barcode Label Requirements

On July 22, 2022, the U.S. Food and Drug Administration (FDA) announced a proposed rule to revise the ten-digit format for national drug codes (NDCs) to a uniform 12-digit format. This rule, Revising the National Drug Code Format and Drug Label Barcode Requirements (Docket No. FDA-2021-N-1351), would change FDA’s regulations on foreign and domestic establishment registration and listing for drugs listed under section 510 of the Food, Drug, and Cosmetic Act and 21 CFR part 207, including biological products and animal drugs. 

FDA assigns NDCs to uniquely identify drugs marketed in the United States. NDCs have been configured in a 10-digit format since their inception, and FDA is close to exhausting combinations for the 10-digit NDCs. This proposed rule, if finalized, would help minimize the impact of the demise of the 10-digit codes by establishing a uniform format for NDCs consisting of 12 digits with three consistent segments. FDA is also proposing to revise the drug barcode label requirements.   

FDA proposes a gradual transition from the 10-digit NDC to a 12-digit NDC that includes a delay in the date the final rule becomes effective to give the industry time to adjust. By selecting a date in advance of the transition, FDA is attempting to mitigate any confusion that could arise when the current format is no longer viable.  

The proposed changes will have a significant impact throughout the healthcare system and drug supply chain. Keep reading to learn more about what FDA proposes for NDC codes.  

FDA’s Proposed Changes  

When the finalized rule goes into effect, 10-digit NDCs will be required to convert to 12-digit NDCs, according to FDA’s formatting regulations.  

The general current format would remain the same: labeler code – product code – package code. However, FDA is proposing a more consistent approach to the numbers included in the NDC. The labeler code, which is now 4 or 5 digits would be changed to 6 digits. The product code, which is now 3 or 4 digits, would be 4 digits. The package code, now 1 or 2 digits, would be 2 digits.  

The drug barcode label requirements would also change if the rule is finalized. Currently barcodes must be displayed in a linear format, in accordance with 21 CFR 201.25(c). FDA is proposing the allowance for either linear or nonlinear barcodes on labels, as long as they are otherwise compliant.  

What will Companies Need to do?  

Because drug listing files would need to use the 12-digit NDC on or after the final rule’s effective date, some companies that use NDCs would need to ensure that their systems can process the new NDC format by that date.  

Companies would also need to update product labels to display the 12-digit NDC format.  

FDA is proposing a delayed effective date to give the industry ample time to transition to the new format. If finalized, FDA proposes making the final rule effective five years after publication. On that date, FDA will start to assign 6-digit labeler codes. New or updated submissions will need to use the 6-4-2 configuration. 

NDCs for existing drug listing files will need to be converted to the new format by adding leading zeros to the labeler code, product code, and/or package code segments. The table below is an example of how NDCs are currently formatted.

In this example, the NDC, in a 5-4-1 format, is 12345-6789-0: 

 Labeler Code   Product Code  Package Code 
 12345 6789 0

The table below is an example of how this NDC would be converted to the proposed format by adding leading zeros to segments that are currently too short, resulting in the 6-4-2 configuration.

The new NDC is 012345-6789-00: 

 Labeler Code   Product Code  Package Code 
 012345 6789 00

Manufacturers and distributors would have 3 years to transition labels to the 12-digit NDC. Although FDA “does not intend to object to the continued use of 10-digit NDCs on the labeling of products that were assigned a 10-digit NDC prior to the effective date”, FDA encourages those responsible for drug labeling to update their labels to the 12-digit format as soon as possible following the effective date.

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FDA Issues Warning Letters to Companies Selling Honey-Based Food Products That Contain Illegal Ingredients

On July 12, 2022, the U.S. Food and Drug Administration (FDA) issued warning letters to four companies selling honey-based products that were tainted with hidden active drug ingredients. These products were marketed as food, but laboratory testing conducted on samples detected the presence of ingredients that meet FDA’s drug definition. These ingredients include the active drug ingredients found in Cialis (tadalafil) and Viagra (sildenafil), which are drugs that FDA has approved for use in the treatment of erectile dysfunction.

Based on FDA’s review of the companies’ marketing materials as well as results from laboratory analysis, the products cited in the warning letters are in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act).

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Read on to learn about the affected products’ claims, the dangers of hidden ingredients, and FDA’s response to companies.

Undeclared Drug Ingredients

Companies that received the warning letters have been distributing food products, such as honey, that contain undeclared drug ingredients. FDA states: “Subject to a limited exception, it is a prohibited act under section 301(ll) of the FD&C Act [21 U.S.C. 331(II)] to introduce or deliver for introduction into interstate commerce any food to which has been added a drug approved under section 505 of the FD&C Act [21 U.S.C. 355]”.

FDA issued warning letters to the following companies:

  • Thirstyrun LLC (also known as US Royal Honey LLC)
  • MKS Enterprise LLC
  • com
  • 1am USA Incorporated dba Pleasure Products USA

Some of the products cited in the warning letters are also unapproved new drugs because they are intended for use in the cure, mitigation, treatment, or prevention of disease, but do not have FDA approval. If a company markets a product as one that is intended to diagnose, cure, mitigate, treat or prevent a disease, FDA regulates it as a drug, even if the product is marketed as a food.

Some of the cited products reference diseases that require a professional medical diagnosis or treatment. Additionally, some products containing tadalafil and sildenafil are being marketed as dietary supplements, but FDA solely regulates products containing these ingredients as drugs.

Potential Dangers of Hidden Active Drug Ingredients

Sildenafil and tadalafil can only be used under the supervision of a licensed health care professional. If a consumer is taking prescription drugs containing nitrates, consuming sildenafil or tadalafil may cause a dangerous drop in blood pressure, as these ingredients may interact with nitrates. People with diabetes, high blood pressure, high cholesterol, or heart disease often consume nitrates.

FDA has requested that the companies that received the warning letters respond within 15 working days “stating how they will address these issues or providing their reasoning and supporting information as to why they think the products are not in violation of the law.” If companies do not rectify the cited violations, their products may be subject to seizure or injunction.

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5 Potential Violations for FDA Food Contact Substances

The Food and Drug Administration (FDA) defines a food contact substance (FCS) as “any substance that is intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use is not intended to have any technical effect in such food.” Packaging or equipment that come into contact with food may be subject to FDA regulation if FDA deems their chemical components to be food contact substances or “indirect food additives”.

FDA determines the regulatory status of a particular FCS based on the substance’s chemical composition and intended uses. Firms that use food contact substances that are illegal or used in a manner that violates FDA regulations may be subject to enforcement action.

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Read on to learn about potential violations when using food contact substances.

No Notification for the Substance

If your food product includes a substance that FDA has not authorized for food contact use for the purpose you intend to use it, you may be required to submit premarket notification for a food contact substance (FCN) to FDA. The FCN must provide information that demonstrates the FCS is safe to use.

You must submit an FCN for an unauthorized substance even if FDA has approved the substance for a different manufacturer. The FCN is proprietary and only effective for the manufacturer that submitted the approved FCN and the notifiers purchasing the substance from that manufacturer.

An FCN may not be necessary if the FCS:

  • Is covered by a regulation in Title 21 of the Code of Federal Regulations and is being used in the manner described in the FDA approval
  • Is listed as generally recognized as safe (GRAS)
  • Is covered by a prior sanction letter, referring to an FCS or intended uses of an FCS that FDA or USDA documented as having no objection to before 1958
  • Falls under the Threshold of Regulation Exemption because its presence in food exists at levels below the threshold of regulation (0.5 ppb)
  • The substance already has an FCN and you are purchasing from the corresponding manufacturer

Using a Substance with an Ineffective FCN

FDA is authorized to revoke an FCN when the agency has determined that there is no longer reasonable certainty of no harm from the authorized use of the FCS. When FDA revokes authorization of a substance from a manufacturer, that substance can no longer be used according to the intended use previously covered by the FCN. If the manufacturer continues to include the substance in products, FDA may deem these products adulterated and may take enforcement action against firms continuing use the noncompliant FCS.

In January 2022, FDA published a proposal to amend its FCN premarket notification regulations. If finalized, the rule would, among other things, allow manufacturers to provide input before FDA renders an FCN ineffective and would allow FDA more flexibility in determining why an FCN should be revoked.

Using a Substance Outside of Its Approved Application

In some cases, FDA has approved certain FCSs for some purposes, but not for others. An example of such a case is the use of Bisphenol A (BPA).

Previously, FDA’s regulations allowed BPA to be used in certain baby products. In 2012, FDA revoked authorization for the use of BPA-based polycarbonate resins in baby bottles and sippy cups. In 2013, FDA revoked authorization for the use of BPA-based epoxy resins as coatings in packaging for infant formula. FDA amended regulations to no longer provide for the use of BPA in these products, because manufacturers had abandoned the practice of using BPA in the affected products.

However, manufacturers can still use BPA in a variety of other products. FDA has determined that BPA is safe for the currently approved uses in food containers and packaging.

Because regulation of an FCS could vary depending on the product, as it does for BPA, firms should confirm that FDA has approved each FCS for use in the product in which the substance appears.

Exceeding Limit of an Allowed Substance 

FDA places limits on FCSs that could migrate into food when the substance could be harmful if consumed in a certain amount. For example, though there are no FDA-authorized uses of lead as an FCS, FDA does allow lead to appear in products at limited amounts. Those amounts vary according to product.

For example, sets allowable levels of lead in ceramicware based on the average contact time and properties of the foods routinely stored in each item. In this category, cups, mugs, and pitchers are regulated the most strictly, with FDA allowing 0.5 mcg/mL , because these items are typically used more frequently and/or hold food for longer periods of time than other ceramicware. Some dishes that may appear to be used for food may contain lead levels that exceed the allowed amount for a dish that’s intended to be used for food consumption. FDA addresses the potential confusion by requiring high-lead-leaching decorative ceramicware to contain a permanent label stating the item is not for food use and may poison food.

Cross Contamination Due to Unsanitary Conditions

You must frequently monitor your facility’s conditions and practices during processing to ensure that food-contact surfaces are adequately maintained to protect food from contamination from all sources, including unlawful FCSs. If you do not have processes that prevent cross-contamination from unsanitary objects to food, FDA may deem the food unsafe to consume.

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Do I Need to Label My Products with Expiration Dates?

U.S. consumers often look for expiration dates when deciding if a product is safe to consume or use. Dates appear on many products, but the U.S. Food and Drug Administration (FDA) does not regulate most of these dates, so their meaning is based on the manufacturer’s interpretation. Products that do not require dates could include dates that indicate when the manufacturer thinks the quality will diminish, and do not necessarily indicate that a product is unsafe past that date.

However, FDA does regulate expiration dates on certain products more stringently. Even within the same industry, date requirements may vary according to product. Those requirements may include adherence to a particular format.

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Does your product need an expiration date? Read on to learn about expiration date label requirements for certain FDA-regulated products.

Food

FDA does not generally require manufacturers to include an expiration date on a food product’s label. Firms can choose to include an expiration date on a label voluntarily if they wish to inform consumers of the time frame a product can be expected to maintain quality and flavor.

If a manufacturer chooses to apply a date label, the label can not include false or misleading information. The date does not need to be approved since it is an estimation of quality, and firms do not need to provide justification for how they chose the date.

Federal law does not require expiration dates on most food, though regulations at the state level may require dates on certain foods.

However, FDA does require infant formula labels to contain an expiration date. Manufacturers must include a “Use By” date on infant formula and must confirm the date to be an accurate indication of how long the product will be of an acceptable quality, retaining no less than a minimum amount of all listed nutrients.

Supplements

FDA does not require dietary supplement labels to include an expiration date, but manufacturers may include one provided the information is not misleading.

Cosmetics

Currently, federal law does not require cosmetic manufacturers to print expiration dates on the labels of cosmetic products. Manufacturers will often include a “period after opening” (PAO) symbol on the packaging to indicate how long a consumer should use the product, but this is voluntary.

Drugs

FDA requires drugs to bear a label that includes an expiration date on both the inner and outer package. The date must indicate the “time period during which the product is known to remain stable, which means it retains its strength, quality, and purity when it is stored according to its labeled storage conditions”. Certain drugs are exempt; homeopathic drugs and those with no dosage limitations that are stable for at least three years are not required to bear an expiration date.

Drug manufacturers must determine a drug product’s expiration date through stability testing data that demonstrates the product meets applicable standards of strength, quality, and purity during the proposed time period and according to the proposed storage conditions.

Medical Devices

Generally, FDA does not require most medical devices to bear a label indicating an expiration date. If a certain component of a device is not useful past a certain date, FDA may require the label to indicate that date.

Both sterile and nonsterile in vitro diagnostic devices are required to include an expiration date or some other indication of the device’s quality at the time of use.

If a device’s label includes an expiration date, the manufacturer should conduct stability testing to determine the time period the device is fit for its intended use when stored according to the label’s instructions. The expiration date, date of manufacture, or any other date to get the user’s attention, must include the year, date, and month in the following format: yyyy-mm-dd.  For example, February 6, 2019, must appear on the label as 2019-02-06. A device may be exempt from this formatting regulation if it is a combination product that properly bears a National Drug Code (NDC) number or an electronic product for Radiological Health (which is subject to date of manufacture formatting regulations for electronic medical devices).

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FDA Publishes Guidance on New Regulations for Certain Ophthalmic Dispenser Products, Effective Immediately

The U.S. Food and Drug Administration (FDA) recently issued a guidance outlining a regulation change affecting certain ophthalmic dispenser products. The new regulation will require certain products previously regulated as drugs to adhere to requirements applicable for drug-device combination products. The regulation change will apply to companies with pending applications, marketed products, and OTC monograph drugs.

The guidance follows the U.S. Court of Appeals’ ruling in the 2021 case of Genus versus FDA. FDA determined that, based on the case’s outcome, wording previously used to regulate certain ophthalmic products as drugs is now obsolete. The guidance is effective immediately.

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Keep reading to learn which ophthalmic products are subject to new regulations and when FDA expects companies to become compliant.

Genus Versus FDA

On April 16, 2021, the U.S. Court of Appeals for the District of Columbia Circuit issued its decision in the case of Genus Medical Technologies LLC v. U.S. Food and Drug Administration. The court ruled that drugs should be regulated as drugs and devices as devices unless a product is considered a combination product. In keeping with the ruling, FDA determined that it can no longer regulate eye cups, eye droppers, and other dispensers intended for ophthalmic use (ophthalmic dispensers) as drugs, but must regulate them as combination drug-device products.

FDA had previously regulated packages that contain both an ophthalmic device and the drug that is intended to be dispensed by the device as drugs. This was specific to ophthalmic products, as FDA regulated other such packages as combination products.

The guidance that corresponds to the new regulations indicates that, if an ophthalmic dispenser meets the definition of “device”, it is regulated as a device constituent part and subject to all applicable requirements: “Therefore, FDA intends to regulate these products as drug-led combination products composed of a drug constituent part that provides the primary mode of action and a device constituent part (an ophthalmic dispenser). Because the drug constituent part provides the primary mode of action, generally the Center for Drug Evaluation and Research (CDER) will have primary jurisdiction over these products.”

FDA’s Intent to Enforce the Regulations

Firms producing ophthalmic dispenser products with pending applications will need to submit certain information to FDA to meet the new regulations. Information FDA will require varies based on the product’s risk profile, submitted application information, and application type.

Some firms that were only implementing Current Good Manufacturing Practices (CGMPs) for certain ophthalmic products will need to demonstrate compliance with Quality System (QS) requirements during the application process. In this case, FDA may request documentation prior to the product’s approval. FDA may also request documentation during the facility inspection after the product’s approval. The guidance noted that FDA may request documentation during a pre-approval inspection, but this scenario is less likely.

FDA does not intend to take action against ophthalmic product companies subject to the new drug-device combination regulations within 12 months of the guidance’s release. In that time period, applicants and manufacturers need to develop and implement the policies and procedures necessary to comply with all applicable requirements. FDA may take enforcement action against firms not in compliance with the requirements after the 12-month period.

Although the guidance was effective immediately, it is open to public comments, which FDA will consider when deciding if revisions are needed.

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