FAQs: Reference Standards

Uses and Development

1. Are USP Reference Standards suitable for use as drugs, medical devices, or for diagnostic purposes?

USP Reference Standards are intended for test and assay use only as directed by USP compendia; they are not for use in humans or animals as drugs or medical devices. View USP's policy statement on USP Reference Standard’s Uses and Applications.

2. Are USP Reference Standards suitable for applications not specified in the USP-NF online publication and other USP compendia (e.g. Food Chemicals Codex)?

USP Reference Standards are intended only for use in analytical or laboratory applications as specified in USP compendia. It may be possible to use a USP Reference Standard in other compendial or quality assessment applications; however, it is the responsibility of the user to determine the suitability of the USP Reference Standard for these non-USP compendial purposes. View USP’s policy statement on USP Reference Standard’s Uses and Applications.

3. Are USP Reference Standards considered primary standards?

USP Reference Standards are generally considered primary compendial standards, with a few rare exceptions. Some of the biologic RS’s are considered secondary compendial standards because they are calibrated and tested against World Health Organization (WHO) International Standards. Unlike a typical primary and secondary standard, primary and secondary compendial standards undergo rigorous testing in a collaborative study and are subject to statistical analysis. Compendial standards are considered to have the highest level of accuracy and traceability.

4. What guidance does USP provide related to the qualification of in-house standards and the use of non-USP reference materials?

USP does not provide guidance on the qualification or use of non-USP secondary reference standards, including in-house standards. In addition, guidance cannot be provided on the use of a non-USP primary standard in place of a USP Reference Standard. A USP RS, where explicitly mentioned in an official USP compendial procedure, is considered to be part of the official method. In the event of a dispute, it is the USP procedure with its associated USP RS(s) which determines compliance. This is also stated in Section 5.80. USP Reference Standards of the General Notices and Requirements in the USP-NF online publication: “Where USP or NF tests or assays call for the use of a USP Reference Standard, only those results obtained using the specified USP Reference Standard are conclusive.”

Users are advised to consult with the regulatory authority where their products are marketed for guidance on the qualification of in-house standards and the use of a non-USP reference material.

View USP’s policy statement on USP Reference Standard’s Uses and Applications.

5. What is the development process of a USP Reference Standard?

Please see the Cradle to Catalog document.

6. Do USP Reference Standards require any special preparation before use?

All available instructions for use are provided in a USP Reference Standard’s associated USP compendial application(s), the label of the USP RS and in its USP Certificate, if available. Some lots can be used as–is but others may require drying before use or a correction with a concurrent moisture or Loss on Drying determination. Additional information on special preparation requirements for USP RS’s may be found in General Chapter <11> USP Reference Standards in the USP-NF online publication and in the RS’s associated USP compendial application(s).

7. How do I reliably remove powdered material from the vial?

Availability and Validity

8. What happens if a new USP Reference Standard that is specified in a USP compendial monograph is not yet available for purchase?

In accordance with Section 5.80. USP Reference Standards of the General Notices and Requirements in the USP-NF online publication, if any new USP or NF documentary standard requires the use of a new USP Reference Standard that is not yet available for purchase, that portion of the documentary standard containing the USP RS requirement shall not be official until the specified USP RS is available. This rule does not apply to already existing USP RS’s that are on back order; it is only applicable to never-before sold USP RS’s.

To receive a monthly list of new USP RS releases as well as lot changeovers and more, please subscribe to our free monthly newsletter, The Standard.

9. How do I determine the estimated release date of a back-ordered USP Reference Standard and how do I sign up to get notified when it becomes available for shipping? Can I order a back-ordered USP RS?

The availability of USP Reference Standards is generally better than 97 percent. USP strives to plan ahead to ensure the availability of all RS’s. However, despite our best efforts, some USP RS’s may occasionally be temporarily unavailable. Contact Reference Standards Technical Services (rstech@usp.org) to find out when a specific RS is expected to be available for shipping. You are also encouraged to subscribe to our free monthly newsletter, The Standard, which provides the estimated availability of USP RS’s on back order as well as lot changeover details and more.

To be notified as soon as an RS is available again, please go to our online store, search for the RS of interest, and click on the ‘Notify Me When Available’ button next to ‘Available for Shipping: No.’ You will then be able to sign-up to be notified via email as soon as the RS becomes available again.

Another option is the use of the USP Reference Standards Mobile App on a phone or tablet. The App allows you to set notifications for RS’s of interest. By doing so, you will receive a push notification when changes are made to the RS’s selected. This includes the release of new lots.

You can place an order for RS’s that are currently unavailable. RS’s that become available within 30 days of your order date will be shipped to you automatically. If the RS becomes available after 30 days, USP will send a Notice of Availability (NoA) to the email address associated with the order. We require a response to the NoA in order to ship your order.

10. Are the impurities listed in a table of a specific USP compendial monograph and other required chemicals and reagents available from USP?

All USP Reference Standards that are required to carry out the tests within a specific monograph will be provided in a list at the end of a monograph. The RS’s are written as "USP (name) RS." Other chemicals, reagents, impurities, etc. that are listed in a monograph or General Chapter are not available as USP RS’s.

11. What is USP’s policy on Product Withdrawals?

If a USP Reference Standard is determined by USP to no longer be suitable for use in its associated USP compendial applications as labeled, customers who purchased the lot from USP in the previous 12 months will be notified. A letter is sent via email and physical mail to the contact associated with the order. A letter is also posted on the RS’s product page in the online store.

USP highly recommends referring to the store or the USP Reference Standards Catalog prior to using a USP RS to make sure the specific lot is valid for use. These sources are updated on a daily basis.

12. How do I determine if a USP Reference Standard is still valid for use or has expired?

With the exception of USP Prednisone Tablets RS catalog #1559505, current lots of USP Reference Standards do not have valid use dates (expiration dates). As long as a lot is listed as being the “current lot,” it is valid and suitable for use. Once a current lot is depleted, it becomes the “previous lot.” At this time a valid use date is assigned, which is typically 3-12 months from the date of depletion.

It is the responsibility of the user to ascertain that a particular lot of a USP Reference Standard has official status either as a "Current Lot" or as a "Previous Lot" within the valid use date. The USP Reference Standards Catalog and the online USP store are updated daily. USP recommends referring to one of these sources prior to using a USP Reference Standard to make sure the lot is valid for use. View USP's policy statement on Expiration Dating of USP Reference Standards.

Technical Data Sheets (USP Certificates, Safety Data Sheets, etc.)

13. Does USP issue Certificates of Analysis (COAs) for USP Reference Standards?

USP does not provide COAs. USP does provide USP Certificates for most USP Reference Standards (RS). USP Certificates do not completely describe the test results obtained during evaluation. Rather, they are issued to provide customers with information such as a hard copy of the USP RS label text, molecular information, typical chromatograms (limited cases), and additional use/handling information that may not be contained on the RS label. View USP’s policy statement on USP Certificates and Assigned Values.

14. Where can I find the USP Certificate for a USP Reference Standard?

USP Certificates for current & previous lots, when available, can be viewed on our web site by clicking on the Product Description in the online USP store. This product page in the online store can also be accessed by clicking on the catalog number of the product in the USP Reference Standards Catalog. If there is not a link to view the USP Certificate for a specific lot number, then a USP Certificate is not available for that lot. View USP’s policy statement on USP Certificates and Assigned Values.

15. Where can I find the Safety Data Sheet (SDS) for a USP Reference Standard?

SDSs are available online for all USP Reference Standards at www.usp.org/sds. They can also be viewed by clicking on the Product Description in the online USP store. This product page in the online store can also be accessed by clicking on the catalog number of the product in the USP Reference Standards Catalog.

16. Are Safety Data Sheets (SDSs) available in different formats and languages?

SDSs are not available in additional formats and languages. It is the responsibility of the importer to provide SDSs in the required format, if different.

17. Is the Safety Data Sheet (SDS) available on the USP website the most up-to-date version?

The SDS's posted on our web site are the most recently updated versions. The U.S. OSHA Hazard Communication Standard does not specify a specific time frame beyond which SDS information is to be considered unacceptable.

18. Do Safety Data Sheets (SDS’s) for USP Reference Standards meet the U.S. Occupational Safety and Health Administration (OSHA) standard (HazCom2012) requirements that went into effect on May 25, 2012?

USP revised all applicable SDSs to comply with HazCom2012. OSHA published the HazCom2012 requirements to bring U.S. SDSs in line with the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). These requirements are applicable only to hazardous materials as defined by HazCom2012.

19. Is the information on the Safety Data Sheet (SDS) of a USP Reference Standard obtained in USP laboratories?

Testing is not required by the U.S. Occupational Safety and Health Administration (OSHA) as the basis for a safety evaluation or an SDS. USP relies on published and supplier data in conformance with OSHA regulations. SDS’s should not be used as Certificates of Analysis. USP Reference Standards are intended only for use in their associated USP compendial applications. Any use beyond these applications is the responsibility of the user. USP Reference Standards are not for human and animal use.

20. Does USP provide chromatograms and IR spectra for USP Reference Standards?

There are a limited number of USP Reference Standards that have an available Typical Chromatogram. If provided, the Typical Chromatogram is included in the USP Certificate. Details that are not included on the chromatogram are confidential and not available. IR spectra are not available for any USP Reference Standards.

21. Where can I find specific test results for a USP Reference Standard?

All information required for the official use of a USP Reference Standard is provided in the associated USP compendial procedure, the label of the RS, and on its USP Certificate, if available. Test results and data that are not included in these sources cannot be shared as they are considered proprietary to the USP Reference Standard program.

Assigned Value (Purity/Potency)

22. Where can I find the purity/potency value of a USP Reference Standard?

The assigned value of a USP Reference Standard is provided on the label and/or the USP Certificate of a particular lot. Assigned values are not provided for RS’s developed only for qualitative use in USP compendial procedures. A statement such as “Labeled for Qualitative Use” may also be included on the label. A value of 100.0% cannot be assumed for any USP RS without an assigned value included on its label and/or USP Certificate. If an assigned value is not provided, then the particular lot was not developed for quantitative use. View USP’s policy statement on USP Certificates and Assigned Values.

23. How is the assigned value of a USP Reference Standard calculated?

The method of choice in computing the assigned value of a USP Reference Standard is a mass balance analysis using independently determined components such as moisture, solvent residues, inorganic residues, chromatographic impurities and ion content. The values determined for each component included in the mass balance equation cannot be shared as such test results and data are considered proprietary to the USP Reference Standard program. USP uses the mass balance approach as this provides a more precise determination of the assigned value than assaying versus a previous lot. The assaying versus a previous lot approach inherently causes greater variability and less precision due to the variability of the previous lot being incorporated into the overall variability of the lot under evaluation. The mass balance approach results in higher accuracy. The assay against a previous lot or against another validated standard and a functional group analysis is performed during development for confirmatory purposes only.

Exceptions to the mass balance approach include many biological RS’s, especially those which define the Unit of Activity. A value is not assigned to RS’s having only qualitative USP compendial uses.

24. Why has the basis (e.g. dried, anhydrous) of the assigned value changed from one lot to another?

Assigned values, including their basis, are lot-specific and may change from one lot to another. For the convenience of our customer, USP is labeling a USP Reference Standard on the "as is basis" whenever possible. It is the preferred option and is selected whenever valid data indicates that the volatiles content is constant over time. The change to "as is" will not affect the USP compendial use of a USP Reference Standard.

25. How do USP Units convert to International Units?

Refer to the USP compendial monograph of a specific material for available information on the Unit of measurement used by USP for purity, potency, etc. of a specific compound. Conversion factors for USP Units may not be available as USP does not regularly use International Units. If a conversion is not included in the USP compendial monograph, it is not available from USP.

Please click here to read USP’s statement on the Heparin Potency Unit Assignment and Harmonization with the International Standard for Unfractionated Heparin.

Label Format and Content

26. Do USP Reference Standard labels meet the requirements in U.S. Occupational Safety and Health Administration (OSHA) HazCom2012?

USP has revised label formats to meet the labeling requirements in HazCom2012. The required label elements are signal words, hazard statements, precautionary statements & pictograms, product identifier, and supplier identification. All elements except the precautionary statements are visible on the outside label of a USP Reference Standard vial. The precautionary statements can be found under the wrap-label.

27. Why is a USP Reference Standard over-labeled?

Some USP Reference Standards have a wrap-label with all label elements required by HazCom2012 placed over the original labels. The updated wrap-label includes the same information as the label in the old format with the addition of precautionary statements & pictograms, and the updated language for signal words and hazard statements. These products will include a statement on the label indicating that they are intentionally over-labeled. Please refer to FAQ #25 for more details about the new label format.

28. What does “AS” stand for on the label of a USP Reference Standard? What is the intended use of an RS having this designation and other USP Reference Standards without an official USP compendial use?

AS stands for Authentic Substance. These RS’s do not have an associated USP compendial use. The AS designation is being phased out and will no longer be included on the label of new lots of RS’s previously designated as an AS or on the label of new RS’s released without an official USP compendial use.

USP provides RS’s without official USP compendial uses as a service primarily to analytical, clinical, pharmaceutical, and research laboratories. They are developed following the same quality systems used for the characterization and release of RS’s having official USP compendial uses. They are generally intended to address common quality issues and challenges inherent to technologies that cut across different types of products (e.g., system suitability samples, calibrators used to demonstrate performance of an analytical procedure, process, or equipment). Users may choose to use these RS’s for identification, method development, evaluation of method performance, or other applications as found suitable and validated by the user. All available information can be found on the RS label. No additional data is publicly available.

29. Why does the catalog number on my USP Reference Standard not match the catalog number in the online USP store and the USP Reference Standards Catalog, and will that affect its USP compendial use(s)?

USP changed the numbering system for all USP Reference Standard catalog numbers. A “1” was added as the first digit to the existing catalog number and an additional digit was added to the end if the existing number was only 5 digits. If there was a hyphen in the existing catalog number followed by a sixth digit, the hyphen was removed. All catalog numbers are now 7 digits in length. Please see the table below for examples.

Product Description Old Catalog No. New Catalog No.
Hypromellose Phthalate (100 mg) 33530 1335304
Bumetanide Related Compound B (25 mg) 07833 1078336

There are still lots that were labeled prior to this change in distribution, so the catalog number on the label will be the old catalog number. Whether the catalog number printed on the USP RS label is from the old or new numbering system, it has no bearing on the potency, stability, or suitability for use of the USP RS. USP monitors products in our inventory on a regular basis in the Continued Suitability for Use (CSU) Program.

30. Is the package size of a USP Reference Standard an exact amount?

The package size of a USP Reference Standard is not an exact amount unless otherwise labeled (e.g., lyophilized products). USP typically overfills RS containers to ensure that users can retrieve the labeled amount from the container. It is possible to receive a container with more or less material than the stated package size.

In-house standard operating procedures should be in place for recording the quantities consumed from containers of controlled substances. The total amount consumed will not exactly equal the package size since it is an approximate value. A common practice is to record the weight of the container and any packaging components (e.g. the rubber stopper of a vial) prior to removing any material. Then every time material is removed for weighing, the amount weighed should be recorded as well as the weight of the container and packaging components. Process details should be determined and controlled in-house.

USP performs fill verifications of every lot and performs calculations to ensure that the average amount filled into the containers is greater than or equal to the label claim. We are unable to share the tolerance/range allowed when filling RS containers as this is considered proprietary to the USP Reference Standard program.

31. When the label of a USP Reference Standard instructs users to determine the water content titrimetrically, what method should be used?

General Chapter <11> USP Reference Standards in the USP-NF online publication states ”… proceed as directed for Method I under Water Determination <921>.” General Chapter <921> states “Determine the water by Method Ia, unless otherwise specified in the individual monograph.” Based on these standards, first refer to the monograph for the raw material/drug substance. If a monograph does not exist or if the monograph does not provide a specific method, proceed with Method 1a. General Chapter <11> allows for the use of smaller sample sizes of RS material when determining the water content (typical amounts are about 50 mg).

Shipping and Storage

32. Why does the label of my USP Reference Standard have a storage condition in the main body of the label and “Keep cool” in the fine print of the label?

The fine print statement “Keep cool” comes from the hazard information section of the label. This hazard information is a requirement from the U.S. Occupational Safety and Health Administration (OSHA) which have different definitions than USP. Users should refer to the main body of the label (under the RS name) to determine how to properly store a USP RS. When a specific storage condition is not included in the main body of the label, users should use the default condition.

Default: If no specific directions or limitations are provided on the USP RS label, the conditions of storage shall include storage at room temperature and protection from moisture, light, freezing, and excessive heat.

Refer to General Chapter <659> Packaging and Storage Requirements in the USP-NF online publication for definitions of storage and handling terms.

33. What is the storage condition for a USP Reference Standard?

The storage condition for an unopened USP Reference Standard can typically be found on the container label. Storage conditions are not provided in the Safety Data Sheets (SDSs). Instead, the SDS refers users to the USP RS label.

Storage conditions are lot-specific and may change from one lot to another. If no specific directions or limitations are provided on the RS label, the conditions of storage shall include storage at room temperature and protection from moisture, light, freezing, and excessive heat. Refer to General Chapter <659> Packaging and Storage Requirements in the USP-NF online publication for definitions of storage and handling terms.

View USP’s policy statement on Shipping and Storage Conditions of USP Reference Standards.

34. Can USP Reference Standards be stored after opening for future use?

Any unused portions remaining after the container has been opened should be carefully stored in accordance with prudent laboratory procedures. Many variables are outside of the control of USP. Therefore, USP makes no warranties concerning the continued suitability of previously opened RS’s. Decisions concerning the proper use of previously opened RS’s are the responsibility of the user.

View USP’s policy statement on Shipping and Storage Conditions of USP Reference Standards.

35. Why is the storage condition of a USP Reference Standard different from the storage condition provided in a USP compendial monograph?

The storage condition of a USP Reference Standard is determined based on the recommendation from the material’s supplier/manufacturer. Data obtained during the collaborative study of a lot and historic data are also considered. The provided storage condition of a RS is intended to preserve the integrity of the lot for the duration of its use as an RS. The storage condition in a USP compendial monograph is based on the recommendation of the monograph’s sponsor. The storage condition provided in a monograph is for the article of commerce.

36. Can a USP Reference Standard be stored at a different temperature other than what is provided on the label? Is the material still suitable for use if a temperature excursion occurs?

The provided storage condition is also how USP stores the specific RS. USP performs Continued Suitability for Use (CSU) testing on the material stored as per its labeled conditions. For this reason, USP does not have data to support the continued suitability of the material when stored at an alternate temperature. It is the responsibility of the user to determine if an RS remains suitable for use when handled differently than the provided instructions. USP also cannot comment on the potential effect of temperature excursions that occurred on a USP RS. The user should consult their own internal policies and SOP’s and use their best scientific judgment to make the decision on whether or not to use the RS if an excursion occurs.

37. Do USP Reference Standards require special shipping?

The storage and shipping conditions of USP Reference Standards are two different components. USP RS’s are not customarily shipped on ice or under refrigerated conditions, despite their labeled storage condition. If scientific evidence suggests the need to ship a USP RS on ice or dry ice, USP will do so. For these products, a statement that a cold shipment is required will be included in the Product name [e.g. Endotoxin (10,000 USP Endotoxin Units) (COLD SHIPMENT REQUIRED)]. It is the responsibility of the user to store a USP RS as described on its label upon delivery, regardless of the shipping condition.

Shipping on ice or dry ice is available for all USP RS’s on request and for an extra charge. The buyer assumes responsibility for the suitability of a USP RS when shipped differently than USP’s default condition. - Call USP Customer Service at 1-800-227-8772 (U.S. and Canada), +1-301-881-0666, or 00-800-4875-5555 (Select Europe) for details.

View USP’s policy statement on Shipping and Storage Conditions of USP Reference Standards.

38. What are the different shipment methods for USP Reference Standards? What is the temperature of a cold shipment of a USP RS?

USP does not assign temperature ranges to the different methods used to ship USP Reference Standards. There are 4 methods USP may use to ship RS – cold chain, ice packs, dry ice, and normal transit conditions.

Cold chain RS’s are shipped on dry ice. International shipments are re-iced throughout transit by the courier to ensure the material remains frozen at all times. RS’s shipped with this method include “International Cold Chain Shipment Required” in their product name in the USP store and catalog.

RS’s shipped with ice packs or dry ice include “Cold Shipment Required” in their description. These shipments are not re-iced by the courier throughout transit. These RS’s are shipped the same way to customers all over the world.

RS’s without a cold shipment designation included in the product description are shipped under normal transit conditions to customers all over the world.

Shipping conditions are assigned knowing that an order may take up to 2 weeks or more depending on the destination. Material shipped properly should not be compromised during a typical shipment.

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