Reference Standards, Types, Uses, Preparation & Qualification:

A reference standard material is defined as highly purified compound that is well characterized by FDA (US Food and Drug Administration) or company or laboratory. Reference standards are highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators by USP (US 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 crucial to achieve scientifically valid results

Definitions:

FDA: Specifically, prepared drug substance batch and an authentic material of the highest purity used for structural elucidation and benchmark for working standards.

ICH (Q6A): A reference standard from new drug substances intended for assays, its impurities should be adequately identified and/or controlled and purity should be measured by a quantitative procedure.

The US Pharmacopeia (USP) defines reference-standard materials as “highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators”

Types of Reference Standards:

The reference standards 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 for control of impurities should be evaluated and characterized according to their intended uses.”

Different types of reference standard materials and its uses:

Reference Standards are primarily used for the following types of analytical studies:

• Assay
• Identification tests
• Limit tests for related substances
• Analytical method validation
• System suitability for analysis techniques and in particular spectroscopic and chromatographic analysis

When pharmacopeial reference standard is not available then it is prepared by synthesizing as per below.

Reference material is selected from a particular batch. After assigning its batch number its characteristic properties are documented for reference purpose and comparison with future production lots.

The material selected as a primary standard should be highly stable, free from 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 as well as sample spectra and chromatograms.

The reference standard materials were prepared as per below procedure:

• Highest purity grade material with complete characterized materials
• Reliable chromatographic methods for purity determination.
• Residual solvents impurities including organic, inorganics and aqueous solvent.
• Validated methods used to confirm the consistent and precise results
• Qualified instruments 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 Head space gas chromatography (HSGC-FID)
• Water content by Karl Fischer titration or Thermogravimetric analysis.
• Non-combustible impurities by residue on ignition/sulphated ash test

Scientists and Experts at Veeprho Laboratories continuously developing and manufacturing the highest purity grade reference standard with complete characterization using various techniques. (HPLC, ICP-MS, GC-FID, NMR, LC–MS, TGA and FTIR).

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
• ICH Q7 Good Manufacturing Practice

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