Over 30 years ago, one of my responsibilities was overseeing the company’s Reference Standard Program for marketed products.  In-house standards were maintained and provided to company locations throughout the world, which also included providing enough fully characterized/qualified drug substances or impurities to the USP to be considered as a potential future USP Reference Standard lot. 

During my tenure as a Reference Standard Coordinator, there was an instance where a large shift was observed in the Assay value for an in-house reference standard when it was requalified against a new USP Reference Standard lot.  The USP was contacted about the accuracy of the concentration reported on the standard’s label and the response was “USP standards should only be used for their intended purpose.”  The label on the USP Reference Standard indicated “For Assay Use,” but when the USP monograph was reviewed, it was discovered that the standard was for chromatographic peak identification purposes only and not for quantitation.  Lesson learned: USP Reference Standards should only be used for their intended purpose. 

So what other valuable lessons are there to be learned with respect to the storage, handling, and use of USP Reference Standards?  USP General Chapter <11> on “USP Reference Standards” provides guidance in this area.  The following are key points from the General Chapter that should be taken into consideration when using a USP Reference Standard. 

  • “Where USP or NF tests or assays call for the use of a USP RS, only those results obtained using the specified USP RS are conclusive.”  This does not mean that you must use a valid USP Reference Standard.  A fully qualified in-house standard that has been assayed and characterized against the USP Reference Standard may also be used. 
  • USP Reference Standards may be used for other analyses other than those where its usage is required in a USP monograph.  However, it is the responsibility of the user to determine the suitability of the reference standard for these other analyses. 
  • Read the USP Reference Standard vial label and its Certificate, as they provide direction on storage, expiry, and conditions of use, including potency for those standards used in quantitative analyses.  Keep in mind that not all information can fit on the vial label, so the USP Reference Standard Certificate should also be checked for additional information. 
  • USP Reference Standard Certificates may include an example chromatogram from the intended monograph analysis.  However, not all Certificates have chromatograms. 
  • USP Reference Standards should be stored as per the vial label and in the packaging configuration provided by the USP.  If no directions are provided on the label, then the standard is to be stored at room temperature protected from moisture, light, freezing and excessive heat. 
  • It is the user’s responsibility to ensure the content of previously opened USP Reference Standard vials continue to be suitable for use. 
  • USP Reference Standards are valid if their status is “Current Lot” or “Previous Lot.”  Only lots identified as “Previous Lot” will have a valid use date, which is typically 3 months to 12 months from the date the lot was depleted at the USP. 
  • The USP Reference Standard label/Certificate may require the water content to be determined at the time of use.  In these cases, the Water Content is determined to follow USP <921> Method Ia, unless otherwise specified in the individual monograph.  The Water Content may be determined on an aliquot of approximately 50 mg.  The determined Water Content is then used to convert the reported “anhydrous basis” potency to an “as is” basis potency. 
  • The USP Reference Standard label/Certificate may require the Loss On Drying (LOD) to be determined at the time of use.  The LOD value for the standard is then used to convert the reported “dried basis” potency to an “as is” basis potency.  The LOD is determined on a smaller sample amount than that required by the individual monograph. 
  • The USP Reference Standard label/Certificate may require the standard to be dried at the time of use.  An aliquot of the standard is dried as per the label/Certificate instructions.  From the dried aliquot an amount is weighed for the standard preparation.  The potency reported on the vial label is for the dried material.  No adjustment to the reported potency is needed.  The entire USP Reference Standard vial should not be dried, as repetitive drying of the material could impact the quality of the standard. 

 

Another important laboratory practice to ensure integrity of the Reference Standard or reagent is to never return unused material back to the original container.  Otherwise, that will compromise the quality of the material in the original container.  The unused material should be disposed of properly. 

In addition to USP <11>, Section 5.80 of the USP General Notices and Requirements states to assume the Reference Standard is 100.0% pure for use in the official application (monograph test) unless the standard label provides a potency. 

It should also be mentioned that the USP also has FAQs on Reference Standards, which covers Uses and Development, Technical Data Sheets, Availability and Validity, Assigned Value, Shipping and Storage, and Label Format, Content, and Instructions. 

 The next time you use a USP Reference Standard, consider the above points to ensure the quality of the associated data generated.  It cannot be stressed enough to read and follow the directions on the USP Reference Standard label. 

 If you have any questions about USP General Chapter <11> on USP Reference Standards, Lachman can help! Please reach out to us at LCS@LachmanConsultants.com for a free consultation.