Expiration Dating and National Drug Code Rules

Function

National Drug Code

The introduction of the Drug Listing Act requiring that all drugs have a unique 10 or 11 digit NDC has allowed for better regulation of medications by the FDA. In accordance with Section 510 of the U.S. Federal Food, Drug, and Cosmetic Act, every manufactured or compounded drug is required to have this unique 10 or 11 digit identifier, known as an NDC. All products that are prescription drugs, OTC medications, or insulin products are required by law to have an NDC. The FDA inputs all NDCs into Drug Registration and Listing System (DRLS) database.[2]

National Drug Code – Subpart A - General

Subpart A of the National Drug Code law encompasses the definitions and interpretations, bulk drug substance, the purpose of this part, which this part covers, and who is exempt from the registration and listing requirements. Section 207.1 of Subpart A discusses the definitions and interpretations of terms that apply to National Drug Code Law. [Title 21, Chapter I, Subchapter C, Part 207, Subpart A, Section 207.1]

The purpose of the National Drug Code law is to help the FDA establish registration information on companies that are manufacturing, repackaging, relabeling, and salvaging drugs and where these operations are performed. Drug listing information gives the FDA a current list of manufactured, repacked, relabeled, or salvaged drugs for commercial distribution. This information allows the FDA to better implement and enforce the Federal Food, Drug, and Cosmetic Act. [Title 21, Chapter I, Subchapter C, Part 207, Subpart A, Section 207.5]

Organizations covered under this law:

• Domestic manufacturers, domestic repackers, domestic relabelers, and domestic salvagers.
• Foreign manufacturers, repackers, relabelers, and salvagers are also covered under this act if their product is to be imported into the United States.
• Private label distributors, since they must have labeler codes.
• Establishments that engage in the manufacturing, repackaging, relabeling, or salvaging human drugs regulated under the biologic license applications. These requirements apply to them unless they are required to register and list such drugs as human blood or blood product. Human whole blood and blood products do not include the plasma derivatives such as albumin, Immune Globulin, Factor VIII and Factor IX, and recombinant versions of plasma derivatives or animal-derived plasma derivatives, or bulk substance such as fractionation intermediates or pastes.
• Establishments engaged in the manufacturing of human cells, tissues, and cellular and tissue-based products.
• Some organizations may be exempt from registration and drug listing if their registration is not necessary to protect public health. 

[Title 21, Chapter I, Subchapter C, Part 207, Subpart A, Section 207.9]

Organizations exempt from this law:

• Pharmacies:
  • Operate in conformance with all applicable local laws regulating the practice of pharmacy and medicine, including all applicable local laws regulating the dispensing of prescription drugs.
  • Regularly engage in dispensing prescription drugs upon a valid prescription by practitioners licensed by law to administer these drugs to patients under their professional care.
  • Do not manufacture, repack, relabel, or salvage drugs other than in the regular course of their business of dispensing or selling drugs at retail.

• Hospitals, clinics, or other health care entities, and public health agencies located in any state.
• Individuals or establishments under contract, agreement, or other arrangements with a registered establishment and engaged solely in recovering cells or tissues and sending the recovered cells or tissues to the registered establishment to become components of biological product
• Practitioners who are licensed by law to prescribe or administer drugs and who manufacture repack, relabel, or salvage drugs solely for use in their professional practice
• Manufacturers, repackers, relabelers, or salvagers who manufacture, repack, relabel, or salvage drugs solely for use in research teaching or chemical analysis and not for sale
• Manufacturers, repackers, and relabelers of harmless, inactive ingredients such as excipients, colorings, flavorings, emulsifiers, lubricants, preservatives, or solvents that become components of drugs.
• Carriers, in their receipt, carriage, holding, or delivery of drugs in the usual course of business as carriers.
• Foreign establishments whose drugs enter a foreign trade zone and are re-exported without having entered U.S. commerce.
• Entities that are registered with FDA as outsourcing facilities
  • These facilities are required to be registered as 503B outsourcing facilities meaning that they do not have to be a licensed pharmacy[3] 

 [Title 21, Chapter I, Subchapter C, Part 207, Subpart A, Section 207.13]

National Drug  Code – Subpart B

In accordance with section 510 of the Federal Food, Drug, and Cosmetic Act, all manufacturers, repackers, relabelers, and salvagers must register each domestic establishment. Foreign Establishments that also manufacture, repack, relabel, or salvage a drug that is intended to be imported into the United States must also register with the FDA. If organizations operate at more than one establishment and common ownership and control among all the establishments exist, the parent, subsidiary, or affiliate company may submit registration information for all establishments. [Title 21, Chapter I, Subchapter C, Part 207, Subpart B, Section 207.17] 

Initial registration for establishments must be registered within 5 calendar days after the beginning of manufacturing, repackaging, relabeling, or salvaging of a drug. Registrants must also register all foreign establishments before a drug can be manufactured, repacked, relabeled, or salvaged at the establishment is imported or offered for import into the United States. [Title 21, Chapter I, Subchapter C, Part 207, Subpart B, Section 207.21] 

Information that is required for registration:

1. Name of the owner or operator of each establishment; if a partnership, the name of each partner; if a corporation, the name of each corporate officer and director, and the place of incorporation\
2. Each establishment’s name, physical address, and telephone number
3. All name(s) of the establishment, including names under which the establishment conducts business or names by which the establishment is known.
4. Registration number of each establishment, previously assigned by the FDA
5. A Unique Facility Identifier
6. All types of operations performed at each establishment
7. Name, mailing address, telephone number, and email address of the official contact for the establishment

[Title 21, Chapter I, Subchapter C, Part 207, Subpart B, Section 207.25]

If an establishment is closed or sold, has a change in the name or physical address, or there is a change in the name, mailing address, telephone number, or email address of the official in contact or the United States agent, the establishment is required to update their registration within 30 calendar days. [Title 21, Chapter I, Subchapter C, Part 207, Subpart B, Section 207.29]

Every year each registrant is required to review and update all registration information between October 1 and December 31. Updates must reflect all changes that have occurred since registration or the last annual review and update. If there have been no changes since the last registration, registrants must certify that no changes have occurred. [Title 21, Chapter I, Subchapter C, Part 207, Subpart B, Section 207.29] 

National Drug Code - Subpart C

The NDC of each drug is broken down into three segments identifying the labeler/vendor, product, and package size and type. The first segment of the NDC is known as the labeler code and consists of 4, 5, or 6 digits. The labeler code is an identifier for any firm that distributes, repacks, or manufactures a drug. The FDA assigns each labeler code to individual establishments. The second segment of the NDC is the product code, consisting of 3 or 4 digits, and is used to identify the dosage, strength, and formulation of the drug. The third and final segment of the NDC represents the packaging code. This segment is 1 or 2 digits and represents the size and form of the package. Both the product code and packaging code are assigned by the distributor and submitted to the FDA for approval. [Title 21, Chapter I, Subchapter C, Part 207, Subpart C, Section 207.33]

Combinations of labeler code, product code, and package code that are permissible:

If a labeler code is either 5 or 6 digits in length, it may be combined with:

A product code consisting of 4 digits and a package code consisting of 1 digit for a total NDC length of 10 or 11 digits (5-4-1 or 6-4-1).

Or

A product code consisting of 3 digits and a packaging code consisting of 2 digits for a total NDC length of 10 or 11 digits (5-3-2 or 6-3-2).

If a labeler code is 4 digits in length, it may be combined only with a product code consisting of 4 digits and a package code consisting of 2 digits for a total NDC length of 10 digits (4-4-2).

[Title 21, Chapter I, Subchapter C, Part 207, Subpart C, Section 207.33]

Example: Atorvastatin Calcium Trihydrate 10mg quantity of 90 tablets have the NDC 0093-5056-98.

• 0093 represents the labeler; 
• 5056 is the product code; 10mg Atorvastatin Calcium Trihydrate.
• 98 is the packaging code and stands for 90 tablets, film-coated in one bottle.

Drug manufactures are required by law to propose a new NDC to the FDA when a drug has been changed after it has been marketed. Changes to a drug that requires a new NDC to be created include;

• The drug's established name or proprietary name, if any;
• Any active pharmaceutical ingredient or the strength of any active pharmaceutical ingredient;
• The dosage form;
• A change in the drug's status, between prescription and nonprescription, or for animal drugs, between prescription, nonprescription, or veterinary feed directive (VFD) status;
• A change in the drug's intended use between human and animal; or
• The drug's distinguishing characteristics include size, shape, color, code imprint, flavor, and scoring (if any).
• If there is only a change to the package size or type, the newly proposed NDC only requires there to be a change in the package code (segment three) unless all possible package codes have already been used with the existing product code.

 [Title 21, Chapter I, Subchapter C, Part 207, Subpart C, Section 207.35]

Subpart D – Listing

Every institution registered with a labeler code is required by law to “list each drug that it manufactures, repacks, relabels, or salvages for commercial distribution.” Initial registration information for domestic labelers must be provided to the FDA within 5 calendar days of the beginning of manufacturing, repacking, relabeling, or salvage of a drug. Any drug that an establishment wishes to import must already be registered within the DRLS database before it can be imported or offered for import into the United States. All registered establishments must update drug listing data every June and December to prevent missed listing. [Title 21, Chapter I, Subchapter C, Part 207, Subpart C, Section 207.57]

For each drug that is manufactured, repacked, relabeled, or salvaged for commercial distribution an establishment at the time of initial registrations, drug listing information must be submitted no later than 3 calendar days after the initial registration of the establishment. [Title 21, Chapter I, Subchapter C, Part 207, Subpart C, Section 207.45]

Information that is required for the registration of a drug that is manufactured:

1. Appropriate NDC that includes all package code variations
2. Package type and volume information corresponding to package code segment of the NDC
3. The listed drug’s established name and proprietary name
4. The name and quantity of each active pharmaceutical ingredient in the listed drug
5. The name of each inactive ingredient in the listed drug, along with any assertions of confidentiality associated with individual inactive ingredients
6. The dosage form
7. The drug’s approved U.S. application number
8. The drug type
9. In the case of an unfinished drug, the number assigned to the Drug Master File or Veterinary Master File that describes the manufacture of the drug
10. The route or routes of administration of the drug
11. The schedule of the drug under section 202 of the Controlled Substance Act

More information regarding what must be included in the registration of a drug with the FDA can be found in the Code of Federal Regulations Title 21, Chapter I, Subchapter C, Part 207, Section 207.49.

Expiration Dating

Since 1979 all manufactured prescription drugs, OTC medications, and insulin products must have an expiration date. Expiration dates are required by law to ensure that all drug products meet specific “standards of identity, strength, quality, and purity at the time of use.”  Any medication that has been found to not have an expiration date in accordance with FDA regulations “is cause for regulatory action against the product and/or responsible firm." [4][Title 21, Chapter I, Subchapter C, Part 211, Section 211.137] 

Every expiration date is determined by stability testing performed by the drug manufacturers in accordance with the Code of Federal Regulations Title 21, Chapter I, Subchapter C, Part 211.166. The stability testing is designed to determine the appropriate storage conditions and expiration dates. This testing includes

• Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;
• Storage conditions for samples retained for testing;
• Reliable, meaningful, and specific test methods;
• Testing of the drug product in the same container closure system as that in which the drug product is marketed;
• Testing drug products for reconstitution at the time of dispensing (as directed in the labeling) and after they are reconstituted.

New drugs used for investigational purposes are exempt from the expiration dating requirements if they meet appropriate standards or specifications demonstrated with stability studies performed during their clinical investigations. When these drugs are reconstituted at the time of dispensing, their labels are required to have an expiration date for the reconstituted drug product. Other expiration dating exemptions include homeopathic drugs and allergenic extracts that are labeled “No U.S. Standard of Potency.” [Title 21, Chapter I, Subchapter C, Part 211, Subpart C, Section 211.137] 

It is important to note that drug expiration dates do not always mean that a drug has been found to be unstable after the date of expiration. The expiration date is the date that the manufacture has determined a medication to be stable in the original sealed container based on stability testing and accelerated degradation studies. Once the seal on the medication’s original container has been broken, the expiration date may not apply because all expiration dates are related to the storage conditions stated on the labeling.[5]

Issues of Concern

In preparation for national health emergencies, the United States government has created medical countermeasures (MCMs). MCMs include FDA-regulated products that consist of biologics, drugs, and devices stockpiled by the government and some private sector partners. Some types of drugs that may be included in MCM stockpiles are antimicrobials and antiviral drugs.[6]

Since all drugs are required by law to have an expiration date and are not approved for use past their expiration date, the U.S. Department of Defense (DoD) began administrating the Shelf-Life Extension Program (SLEP) in 1986. The purpose of SLEP is to prevent the need to replace stockpiles of medications every few years. The SLEP is a fee-for-service program where MCM medications can be selected to undergo stability testing performed by the FDA to increase their shelf lives. The FDA’s Office of Regulatory Affairs Field Science Laboratories is in charge of performing these stability studies on selected medications. Currently, testing medications for expiration dating extensions focuses on military-significant products or drugs purchased in large quantities. Two drugs that are stockpiled in large quantities are ciprofloxacin and doxycycline. The SLEP program extended the expiration dates of eighty-eight percent of 122 medications stored in ideal conditions by 66 months.[7][8][9]

Another way drugs can be authorized for use past their expiration date is through an Emergency Use Authorization (EUA). Before a drug can be authorized for use, the HHS Secretary must issue a declaration justifying the use of a drug past the expiration date. For a drug to be authorized for emergency usage, it must first go through five steps. The steps include determining an emergency, declaration of an emergency, reviewing the request for EUA by FDA, issuance of the EUA or denial of the request, and termination of the EUA. The Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) also gives the FDA full authority to use a drug past the stated expiration date. Both EUA and PAHPRA are intended to be used in chemical, biological, radiological, and/or nuclear emergencies.[10][11]

Clinical Significance

It is important for all healthcare providers, including physicians, pharmacists, and nurses, to be aware of expiration dating and how it could affect their patients' medications. Some medications, when expired, can have a decrease in efficacy, change in chemical composition, or harbor bacterial growth. Liquid antibiotics and medicated eye drops have been linked to bacterial growth due to nonsterile compounding procedures. Medications such as Nitroglycerin are sensitive to heat and light.

Patients who take nitroglycerin should be educated that after the medication has been opened, it may no longer be effective. There have also been cases of Fanconi Syndrome reported due to patients taking old tetracyclines. As tetracycline degrades, byproducts such as epi-anhydrotetracycline or anhydrotetracycline can lead to serious illness. Although medications may not look different after they have expired, it is important to educate patients on the proper disposal of medications after they have expired. One study estimated that between 2004 and 2013 there were over 640,000 children are taken to the emergency room after getting into their parent’s medicine cabinets and accidentally taking medication.[12][13]

Enhancing Healthcare Team Outcomes

Patient education by all healthcare team members about the proper disposal of expired medications can reduce costs to the healthcare system and save lives. Members of the healthcare team should be aware of projects such as National Drug Take-Back Day, which is coordinated by the DEA. This program allows patients to turn in expired and unused medications for safe disposal. If there are currently no programs available, healthcare members can educate patients on proper disposal techniques located on the FDA’s website. Infographics are provided by the FDA and can be displayed in clinics and pharmacies to increase patient awareness. It is easy to educate patients on the importance of taking the medications they are being prescribed, but members of the healthcare team sometimes neglect the importance of educating patients on how to dispose of left-over medications.[13]