A reference standard is a highly purified and well-characterized material suitable to test the identity, strength, quality, and purity of substances for Chemical, pharmaceutical, and medicinal products. Using reference standards, working standard can be prepared. Reference Standards can be taken from USP, EP, BP, and IP or In-house.

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REFERENCE STANDARD

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

  • Reference Standards can be taken from USP, EP, BP, and IP or In-house.

  •   Reference standards plays vital role in all phases of drug development process.

  • Reference standards serves as basis for evaluation of both process and product performance and serves as benchmark for drug safety.

  • Reference standards are highly characterised physical specimens used to ensure the identity, strength, quality, and purity of medicines (drugs biologics and excipients), dietary supplements and food ingredients.

  • Reference standards are one of the key factors for consistently good quality of pharmaceutical products. They are used as primary or secondary standards for the quality control of active pharmaceutical ingredients (API), excipients and finished pharmaceutical products.

  • Types of Pharmaceutical Reference Standards:

    • Chemical origin    

    • Biotechnological origin e.g., Special case: Bio similarity, Cell -Gene therapy

    • Herbal

    • Radio Pharmaceuticals

    • Calibration of equipment (GMP)

  • Reference standards are used to support measurements concerned with chemical composition, biological, clinical, physical, and miscellaneous areas.

  • Where an international or national standard is available and appropriate, reference materials should be calibrated against it.

  • For new molecular entities, it is unlikely that an international or national standard will be available.

  • Manufacturer should have established an appropriately characterized in-house certified reference material prepared from lot representative of production and clinical materials. In-house working reference material used in the testing of production lots should be calibrated against this primary reference material.

  • While it is desirable to use the same reference material for both biological assays and physicochemical testing, in some cases, a separate reference material may be necessary. Also, distinct reference materials for product related substances, product-related impurities, and process-related impurities, may need to be established.

  • When appropriate, a description of the manufacture and/or purification of reference materials should be included in the application. Documentation of the characterization, storage conditions and formulation supportive of reference material stability should also be provided.

  • Major reference standard types used in pharmaceutical analysis are

    • Primary reference standards

    • Secondary reference standards

    • pharmacopeial reference standards

    • Impurity reference standards

PRIMARY REFERENCE STANDARDS:

  • Primary reference standards should be obtained as appropriate for the manufacture of APIs.

  • According to the pharmaceutical reference standards supplier's recommendations, the records of the storage and usage of primary reference standard should be maintained. 

  • Primary reference standards obtained from a certified reference standard supplier are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

  • Usually Primary reference standards purity should be >95%.

  • Full characterization and documentation of Primary reference standards

    • Identity (with several qualitative techniques: NMR, MS, IR, UV/VIS, Elemental analysis, where appropriate X-ray structure analysis)

    • Purity (with HPLC => impurity profile) Identify peaks with area percentage >0.1% Maybe check relative response factor of impurity behind peak.

    • Residual solvents by GC-Headspace methods

    • Water content by Karl-Fischer titration Loss on drying (sum of water r and residual solvents).

    • Melting point (rough purity/identity information).

    • Sulphated Ash (inorganic impurities).

    • Assay, for primary RSs from purity calculation (with the results from all relevant examinations) plus at least one additional independent method (e.g. qNMR, titration).

SECONDARY REFERENCE STANDARDS:

  • Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored.

  • The suitability of each batch suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard.

  • Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.

PHARMACOPOEIAL REFERENCE STANDARDS:

  • Pharmacopeial reference standards officially recognised source.

    • Can be used without further testing

    • widely accepted

    • It must be used according to the use mentioned in the monographs

IMPURITY REFERENCE STANDARDS: 

  • Impurity Reference standards used in the analytical procedures for control of impurities should be evaluated and characterised according to their intended uses.

  • Impurity standards are used for purity tests and during method development and validation of those tests. Identity must be ensured, and purity and assay must be defined.


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