USP Reference Standard Development: From Cradle to Catalog

1. Identifying the Need for a New Reference Standard

Establishing a USP Reference Standard begins with the need for bulk material stemming from the development of a new monograph or a new application of an existing monograph or standard.

2. Procurement of Candidate Materials

USP partners with sponsors of the USP documentary standards and, when necessary, with other manufacturers of the articles of commerce to obtain candidate materials. Essential information such as stability data, packaging, storage, and handling conditions are also requested from the suppliers. USP seeks input from the manufacturers, as they are experts for the pharmaceutical, excipient, dietary supplement, food chemical, and biological materials. Download the USP Guideline for Suppliers of Reference Standard Materials.

Prior to obtaining material for reference standard candidates, Procurement Specifications are identified based on the compendial uses. We request that the candidate materials

• Are supported by structural confirmation
• Are the highest purity available
• Meet applicable USP–NF monograph requirements

3. The Collaborative Study

The goals of the collaborative study are to determine the suitability of the candidate material in the compendial applications, provide the user with all necessary information and directions for use, and to acquire time-zero information for stability studies. Collaborative studies are typically designed to

• Confirm identity
  • Spectroscopic analysis (FTIR, NMR, MS, UV/VIS)
  • Chromatographic analysis (TLC, HPLC, GC)
• Assess purity
  • Direct purity tests
    • Chromatographic purity
    • Inorganic impurities
    • Volatiles (water, residual solvents)
  • Indirect purity tests (some examples)
    • Specific rotation
    • Elemental analysis
    • Titration of functional groups
• Provide supplementary information to support a mass balance assignment and assess lot-to-lot continuity (i.e., assaying against another well-characterized standard)
• Assess other attributes
  • Hygroscopicity using vapor sorption analysis (supports use on the as is, dried, or anhydrous basis)
  • Counter ion or salt verification (NMR, ICP–OES, ion chromatography, etc.)

Test Protocol

To ensure consistency of testing methodology, the same key tests are requested from all collaborators. Once the protocol is established, the candidate samples and any additional Reference Standards needed for testing are sent to the collaborators.

Collaborative Study Participants

• USP Laboratories (USA, India, China, Brazil)
• Supplier of the material
• FDA Office of Regulatory Affairs labs
• Industry Laboratories
• Health Canada (Montreal, Toronto)
• Contract Laboratories
• Therapeutic Goods Administration (TGA) in Australia
• Shanghai Institute for Food and Drug Control (SIFDC)
• National Institute for Biological Standardization and Control (NIBSC)

The USP laboratories are accredited to ISO 17025:2005. USP strives to use accredited laboratories in all collaborative studies.

4. Data Review

The collaborator reports and raw data packages are analyzed and evaluated by the Reference Standards Scientists. All results, along with the proposed RS label text, are collated into a Reference Standards Candidate Evaluation Package for review. For quantitative standards, a purity value is calculated by a mass balance approach using the collaborator data.

Calculation Value
mg of chemical substance per mg of material = [(100.0% - I) ÷ 100] x [(100.0% - Water - inorganic residue - RS - X) ÷ 100], where I = Average Total Detected Area (%) displayed by the impurity peaks in HPLC or GC method, RS = Residual solvents (% w/w), and X = Other contributions, on a case-by-case basis (% w/w).

5. The USP RS Label Text

The label text is approved by the volunteer Expert Committee Members as part of the RS Candidate Evaluation Package. The text contains:

• Directions for use
• Content or potency value for standards used quantitatively
• Safety warnings
• Required regulatory information for controlled substances
• Additional technical information or reference to data sheets as needed

6. Approval of a Candidate Material as Suitable for Use in a Compendial Method

The volunteer Expert Committees are responsible for the review and approval of the Reference Standards Candidate Evaluation Package.

• Each Reference Standard goes through a 3-phase internal review and approval process.
• Only after unanimous approval by an internal scientific review panel in the third phase is the Reference Standard referred to a monograph or General Chapter Expert Committee for balloting.
• A single "NO" vote by a member of the Scientific Review Panel sends the material back for additional testing and/or clarification.
• The volunteer Expert Committees can also require additional testing and/or clarification and make the final decision on the suitability of the Reference Standard.

7. Packaging

USP utilizes many different packaging configurations. The container-closure system of each RS is selected to best maintain the integrity of the material and for ease of use. Vial closure systems and protective foil bags have undergone extensive validation to assure quality performance. In cases of limited material availability, USP can also prepare lyophilized products in single-use vials.

• Amber vials with teflon coated stoppers—typical packaging for USP RS and CRMs
• Clear conical vials—for standards with small package size (10-15 mg)
• Ampuls—for liquids
• Hermetically sealed foil bags—provide additional protection from oxygen and moisture

8. Post-packaging Quality Control (QC) and Quality Assurance (QA) Review

USP adheres to an ISO 9001:2000 quality management system as well as cGMP quality principles. Reference Standards are packaged and labeled with line clearance between lots. Post packaging QC testing, label reconciliation, and final QA batch record audit are performed on every lot before release to inventory.

9. Entry into USP Store and Catalog

After packaging, the Reference Standard is entered into the USP store and catalog where it is offered for sale. Access reference standard listings and catalog here.

10. Continued Suitability for Use Program

USP Reference Standards are periodically reevaluated throughout their lifecycles. Retest intervals are determined using historical data and results of prior Continued Suitability for Use testing. The goal is to re-confirm the ongoing suitability for use of a USP Reference Standard in its compendial applications.