A reference standard material is commonly defined as a highly purified compound. It is well characterized, and the quality and purity of reference standards are essential in determining scientifically reasonable results for analytical methods in the pharmaceutical industry. In addition, it is well-designated by a company, a laboratory, or FDA (U.S. Food and Drug Administration).
Reference standards are highly characterized specimens of drug substances, excipients, reported impurities, degradation products, compendial reagents, and performance calibrators by USP (United States Pharmacopeia).
Reference standards are used to determine quantitative data (such as assay and impurity), qualitative data (such as identification test), and calibration (such as melting point standard). Therefore, the quality and purity of the reference standards are critical in achieving scientifically valid results.
A drug reference standard or the pharmaceutical reference standard is the most characterized material suitable to test the strength, identification, quality, and purity of substances for pharmaceutical uses and medicinal products. A drug reference standard or the pharmaceutical reference standard is the most characterized material suitable to test the strength, identify, quality, and purity of substances for pharmaceutical uses and medicinal products.
USFDA: The U.S. Food and Drug Administration defines the reference standard material as a highly purified compound that is well characterized, specifically prepared drug substance batch and an authentic material of high purity used for structural elucidation and working standards.
ICH (Q6A): ICH (Q6A) defines a reference standard, or reference material, as a substance prepared for the use as the standard in identification, assay, or purity test. For new drug substances, reference standards intended for use in assays, and impurities should be adequately identified and controlled, and a quantitative procedure should measure purity.
USP: The U.S. Pharmacopeiainternational organization defines reference standard materials as “highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators.”
USP reference standards are the integral and essential components of monographs and documentary standards set by the USP to help ensure the quality, strength, identity, and purity of medicines and foods. They are essentially provided for quality control in conducting the tests and assays in these documentary standards.
Further United States Pharmacopeia (USP) – N.F. (National Formulary) includes over 5000 quality standards for medicines, both biological and chemical, active pharmaceutical ingredients, and excipients (inactive ingredients), and is considered the most comprehensive source in the world for medicine quality standards.
USP-NF combines the United States Pharmacopeia (USP) and National Formulary (N.F.). N.F.include monographs for the dosage forms, drug substance, and compounded preparations as featured in USP.
The pharmacopeial reference standards are established for the uses described in pharmacopeial monographs and general chapters, and they are accessible in various pharmacopeias like United States Pharmacopeia and European pharmacopeia.
The EDQM (European Directorate for the quality of Medicines & Healthcare) also supplies the chemical reference substance (CRS), biological reference preparations (BRP) and herbal reference standards (HRS) and also the reference spectra for the assays and tests to be carried out in accordance with the official methods as specified in the European pharmacopeia.
Types of reference standards
- Laboratory-made Reference Standards
- Company Reference Standards
- Official Reference Standards
- Primary Reference Standards
- Secondary Reference Standards
- Supplementary Reference Standards
The reference standards are used as the basis for quantitative and qualitative testing. Impurity Reference standards: Not much guidance from authorities here as per ICH Q3A. “The reference standards used in the analytical procedures to control impurities should be evaluated and characterized according to their intended uses.”
Different types of reference standard materials and their uses
| Type of Reference STD | Uses |
| Essay | To determine the potency of active pharmaceutical ingredients (APIs) and salts |
| Degradation Products | To identify and possibly quantitate degradation products |
| Process Impurities | To identify and possibly quantitate process-related compounds |
| Resolution Standard | To determine assay performance or impurity method |
| Metabolites Standard | To identify and possibly quantitate substances generated through a metabolic process. |
Reference Standards are primarily used for the following types of analytical studies:
- Essay
- Identification tests
- Limit tests for related substances
- Analytical method validation
- System suitability for analysis techniques and in particular spectroscopic and chromatographic analysis
When a pharmacopeia reference standard is not available then it is prepared by synthesis. The first reference material is selected from a particular batch. After assigning its batch number, its characteristic properties are documented for reference purposes and comparison with future production lots. The material selected as a primary standard should be highly stable, free from the water of hydration, and bear traceability to a national or international standards body. Besides the qualification results, the batch-specific certificate of analysis also includes details on the recommended storage conditions, sample spectra, and chromatograms.
The reference standard materials were prepared as per the below procedure:
- Highest purity grade material with completely characterized materials
- Reliable chromatographic methods for purity determination.
- Residual solvent impurities include organic, inorganic, and an aqueous solvent.
- Validated methods used to confirm the consistent and precise results
- Qualified instruments are used for the qualification of the reference standard.
Reference Standard identity and purity standards:
As a part of the qualification of identity and purity standards minimal required tests for initial characterization were typically performed by using the following tests:
- Purity & structure confirmation by 1H-NMR and 13C-NMR spectroscopy,
- Recording of coupled spectra as required Mass spectroscopy
- Metals impurity by inductively coupled plasma mass spectrometry (ICP-MS)
- Identification & structure confirmation by UV and/or IR spectroscopy
- Chromatographic purity by using HPLC
- Residual solvents by Headspace gas chromatography (HSGC-FID)
- Water content by Karl Fischer titration or Thermogravimetric analysis.
- Non-combustible impurities by residue on ignition/sulfated ash test
Scientists and Experts at Veeprho continuously develop and manufacture the highest purity grade reference standard with complete characterization using various analytical techniques like HPLC, ICP-MS, GC-FID, NMR, LC-MS, TGA, and FTIR.
FAQs
The quality and purity of reference standards are crucial in determining scientifically reasonable results for the analytical methods in the pharmaceutical industry, and they are also very well designated by the FDA (U.S. Food and Drug Administration). According to the USP, reference standards are highly characterized specimens of drug substances, excipients, reported impurities, degradation products, compendial reagents, and performance calibrators (U.S. Pharmacopeia).
The USP reference standards are essential components of monographs and documentary standards established by the USP to help ensure the quality, strength, identity, and purity of medicines and foods. They are primarily used for quality control in the tests and assays described in these documentary standards.
The USP reference standard certificates for previous and current lots are available on the R.S. website under the product description, on the online USP store and can also be accessed via the R.S. catalog number in the catalog of USP reference standards
The United States Pharmacopeia (USP) – N.F. (National Formulary) contains over 5000 quality standards for medicines, both biological and chemical, active pharmaceutical ingredients, and excipients (inactive ingredients), and is regarded as the most comprehensive source of medicine quality standards in the world. USP-NF is a mash-up of two compendia, the United States Pharmacopeia (USP) and the National Formulary (N.F.). USP-NF includes monographs for dosage forms, drug substances, and compounded preparations, as do the USP compendia.
References:
- http://www.usp.org/reference-standards
- http://www.fda.gov/downloads/Drugs/Guidances/ucm122858.pdf
- Hand Book Of Isolation And Characterization Of Impurities In Pharmaceuticals, By Satinder Ahuja, Elsevier Publications, Volume 5, Pg No: 15, 119-143.
- www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM122858.pdf
- ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- ICH Q6B Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biological Products.
- https://database.ich.org/sites/default/files/Q6A%20Guideline.pdf
- ICH Q7 Good Manufacturing Practice
- https://www.usp.org › how-read-listings
- Culbert, Paul A.; Johnson, Bruce D. (2004). “Reference standards”. Handbook of Isolation and Characterization of Impurities in Pharmaceuticals. Separation Science and Technology. Vol. 5. pp. 119–143.
- https://www.edqm.eu/en/ph-eur-reference-standards-purpose-and-use https://www.usp.org/about/public-policy/overview-of-monographs
- https://www.usp.org/frequently-asked-questions/excipents
