USP, EDQM Reference standard

Reference Standard Question, Use, Development of monograph, FAQ about RS, Types of Standard

1. Reference Standard Presented By- Lalit Kumar Jubilant Generic Ltd.

2. Contents Introduction Source Utilization Preparation COA Storage

3. Introduction A  reference standard  is a substance prepared for use as the  standard  in an assay, identification, or purity test and should have a quality appropriate for its use. A reference standard is a prerequisite to measuring potency .  To measure potency, a sample of unknown potency must be compared to a standard of known potency, so that the potency ratio can be calculated.

4. RSs are generally obtained and prepared from United States of Pharmacopeia-National Formulary (USP-NF) USP RSs collection consists of more than 3,000 items ranging from drug substances, related impurities, residual solvents, biologics, excipients, botanicals, polymers and melting point standards. In India, Central Drug Laboratory is responsible for making available IP RSs. NIST (National Institute of Standard & Technology) provide a wide variety of standard reference materials (SRMs) for validating and calibrating analytical methods.

5. Definitions As Per USP :- USP Reference Standards  are highly-characterized physical specimens used to ensure the identity, strength, quality, and purity of medicines (drugs, biologics, and excipients), dietary supplements, and food ingredients. 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.

6. Utilization Reference standards are utilized to support measurements concerned with chemical composition, biological, clinical, physical and miscellaneous areas. Substances characterized for chemical purity and/or trace impurities. Reference objects characterized for functional properties such as taste, odour , octane number, and hardness. Physico -chemical reference materials characterized for properties such as melting point, viscosity

7. Qualitative analysis of materials by comparison of RS & chemical substance in aspects. 1- IR- Functional Group Conformation 2- Melting point & HPLC- Purity identification 3- U.V.- identification. Quantitative analysis 1- HPLC 2- Limit tests Specific Uses 1- Method validation 2- Calibration of Instruments

8. Includes following aspects, 1- Identification 2- Purity analysis 3- Assay of sample. Data of Analysis must be meet with the standards of Reference Standards.

9. Calibration of Instruments

10. Method validation & Uncertainty of Method Generally in a method validation estimation of Bias is most critical aspect . RSs will have limited values of Uncertainty. Uncertainty associated with RS should be NMT 1/3rd of sample measurement.

11. Classification

12. Analytical Reference Standards 1- Reference Material (RM): A material or substance one or more properties of which are sufficiently well established to be used for the calibration of apparatus the assessment of a measurement method or for assigning values to materials. 2- Certified Reference Material (CRM): A reference material one or more of whose property values are certified by a technically valid procedure accompanied by or traceable to a certificate or other documentation which is issued by a certifying body .

13. Working standard Standard  that is used routinely to calibrate or check material measures, measuring instruments or reference materials. A  working standard  is usually calibrated against a reference  standard.

14. Preparation Of RS & Monograph as Per USP

15. Ph. Eur. Reference Standards: Purpose and use The EDQM supplies  chemical reference substances (CRS) ,  herbal reference standards (HRS)  and  biological reference preparations (BRP)  as well as reference spectra for the tests and assays to be carried out in accordance with the official methods prescribed in the  European Pharmacopoeia .

16. WHO International Standards for Antibiotics (ISA) : Purpose & Use On 4 May 2006, as decided during the 56th meeting of the  WHO Expert Committee on Biological Standardisation  (ECBS ), the  EDQM took over responsibility for the establishment, storage and distribution of  WHO International Standards for Antibiotics  (ISA) from the National Institute for Biological Standards and Control (NIBSC). ISA are generally intended for the establishment of regional or national secondary standards subsequently used in routine laboratory tests and assays . ISA Establishment Studies The decision whether or not to start a new ISA establishment study is taken by the WHO ECBS. This committee is composed of scientists from different backgrounds who meet annually and who report directly to the WHO Executive Board. The EDQM is responsible for providing scientific and technical support and for co- ordinating the studies. This entails procurement of suitable bulk material, organisation of the study, production of candidate batches, storage and distribution of the established standards.

17. WHO International Chemical Reference Substances (ICRS) : Purposes & Use On 16 April 2010, the EDQM took over responsibility for the establishment, storage and distribution of WHO ICRS from Apoteket AB, the previous WHO Collaborating Centre for these substances. ICRS are adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. They are intended primarily for use in physical and chemical tests and assays described in the specifications published in ‘ The International Pharmacopoeia ' for the  quality control of pharmaceutical substances and preparations . Secretariat of The International Pharmacopoeia – Intended use of ICRS The International Pharmacopoeia constantly develops new monographs and revises existing ones to stay abreast of advances in analytical science and regulatory affairs. Along with these changes the intended use of already established ICRS often needs to be adjusted, for example, because an ICRS previously used for identification only shall newly also be employed in quantitative tests.

18. The user of The International Pharmacopoeia finds information on the actually established intended uses of an ICRS in the leaflet enclosed with the substance when distributed or accessible via the  ICRS online database . The information found in current leaflets is applicable to all standards of the respective batch number . The   ICRS  Establishment Studies DQM   organises international collaborative studies to establish new standards when required, with the WHO's assistance .

19. Basic Requirements For Qualification Should understand Physico chemical Profile of RS ARS should have good chemical stability on wide range of storage Requirements for characterization should be cross-checked to avoid Analytical errors. The validity (i.e., accuracy, precision, sensitivity, specificity) of the analytical methods used for purity determination should be demonstrated . Highly pure (i.e., ≥99.5%). In total the degradation and by-products should not be more then 0.5% . The levels of all impurities found (including those not chemically identified, isolated, and characterized) should be provided as a summary tabulation. Content of enantiomer in case of chiral compound is not taken into account as by- products and degradation products by normalized area percent

20. Purity 1- Loss On Drying (LOD) 2- Karl Fisher Titration 3-Thermo Gravimetric Analysis (TGA) 4-Differential Scanning Calorimetry (DSC) 5-Residue On Ignition (ROI) 6-Thin Layer Chromatography (TLC) 7-High Performance Liquid Chromatography (HPLC) 8-Gas Chromatography (GC) Assay 1- Titration 2- Phase - Solubility Analysis

21. Stability, Expiry & Retest Expiration and Retest Date:- 1-For any new chemical entity an initial expiry or retest date decided as 6 months if stock material stored at -20⁰C. 2-Availability of stability data for 3 months at 40⁰C/75%RH demonstrates the retest period of 24 months if stored at -20⁰C. 3-Expiry date is periodically extended on the basis of retest performed and stability proved. 4-Reference standard may have a maximum 5 years expiry period.

22. USP–NF 's Continuous Revision Process and Superseded Text The United States Pharmacopeia–National Formulary ( USP–NF ) is continuously Revisions include Revision Bulletins, Interim Revision Announcements (IRAs), and Errata- 1-A Revision Bulletin posted on the USP website indicates its official date and the date that it will be incorporated into an official publication . 2- IRAs  are proposed in PF for a 90-day public comment period. Once comments (if any) are reviewed and the IRA is approved by the appropriate Expert Committee, final IRAs are posted on the USP website .

23. 3- Errata are posted on the Web site and are official the first day of the following month. Errata are incorporated into the next available official publication . Once published in the print and online publications, Revision Bulletins and IRAs are official as of the date indicated on the website and are not subject to the general six-month delayed official date for the particular publication.