23.08.49 BDN 1

การใชการใช REFERENCE STANDARDSREFERENCE STANDARDS

ในการควบคุมคุณภาพยาในการควบคุมคุณภาพยา

นิดาพรรณนิดาพรรณ เรืองฤเรืองฤทธินนททธินนท

สํานักยาและวัตถเุสพติดสํานักยาและวัตถเุสพติด

กรมวิทยาศาสตรการแพทยกรมวิทยาศาสตรการแพทย

23 23 สงิหาคมสงิหาคม 25492549

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Definition

• Pharmaceutical Reference StandardsA substance prepared for use as the standard in an assay, identification or purity test, whose relevant properties have been determined and are considered appropriate for its intended use(s).

Pharmaceutical reference standards are required for comparative analytical methods which are included in a manufacturer’s specification or pharmacopoeia monograph.

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Test Methods in PharmacopoeiaTest Methods in Pharmacopoeia;;Required Reference SubstancesRequired Reference Substances

• Infra red Spectrophotometry

• UV-Spectrophotometry

• Colorimetry

• Chromatographic method: TLCTLC,, GCGC,, HPLCHPLC

• Non-stoichiometric Titration

• Microbiological assay

• Calibration of Instruments

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Classification of Reference StandardsClassification of Reference Standards

• Primary Reference Standard

• Secondary Reference Standard

(Working Standard)

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Classification of Reference StandardsClassification of Reference Standards

•Primary Reference Standard

A designated primary chemical reference substance is

one that is widely acknowledged to have the appropriate qualities within a specified context, and whose value when use as an assay standard is accepted without requiring comparison to another chemical substance.

( WHO working document QAS/05.137)

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Classification of Reference StandardsClassification of Reference Standards

• Secondary Reference Standard (Working Standard)

A secondary chemical reference standard is a substance whose characteristics are assigned

and/or calibrated by comparison with a primary

chemical reference substance.

( WHO working document QAS/05.137)

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Primary Reference StandardPrimary Reference Standard

• USPRS : United States Pharmacopoeia Reference Standard

• BPCRS : British Pharmacopoeia Chemical Reference

Standard

• EPCRS : European Pharmacopoeia Chemical Reference

Standard

• ICRS : International Chemical Reference Standard

• NIBSC : National Institute of Biological Standard and Control

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Secondary Reference StandardSecondary Reference Standard

• ARS : ASEAN Reference Standard

• DMScRS : Department of Medical Sciences

Reference Standard

• Inhouse working standards

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Use of Reference StandardUse of Reference Standard

• Identification

• Test for impurities or degradation products

• Assay

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Use of Reference StandardUse of Reference Standard

• Reference standards must be used

consistently to ensure reliable

measurements.

• Important to the user is the fact that the

proper use of an reference standards

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Use of Reference StandardUse of Reference Standard

• Intended information

– Period of validity

– Conditions for storage

– Instruction for use

– Intended use

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Use of Reference StandardUse of Reference Standard

• Sources of information

– Certificate of Analysis

– Catalog book

– Recommendation document

– Label on the vial

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Use Reference StandardUse Reference Standard

• ICRS, ARS, DMScRS : Certificate of Analysis

• EPCRS, BPCRS : Catalog Book, Booklet

• USPRS : - Recommendation document

- Label on the Vial

• NIBSC : Catalog Book

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Certificate of AnalysisCertificate of Analysis

ICRS, ARS, DMScRS

• Assigned value with test methods employed

• Loss on drying / Water content

• Related substances / Degradation products

• Others : IR, Specific optical rotation

• Direction for use and storage

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Certificate of AnalysisCertificate of AnalysisDEXAMETHASONEDEXAMETHASONE

DMScDMSc Reference StandardReference StandardControl No. 447008Control No. 447008

Description : A white, crystalline powder.Infrared absorption : Concordant with the reference

spectrum of Dexamethasone USPRS.Ultraviolet absorption : A 0.001 % solution in methanol

exhibits a maximum at 239 nm with A (1 %, 1 cm) about 399.

Specific optical rotation : + 76.24o ( 10 mg per ml, in dioxane)Chromatographic purity : Total impurities 0.34% (HPLC method)Loss on drying : 0.10 %

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Certificate of AnalysisCertificate of AnalysisDEXAMETHASONEDEXAMETHASONE

DMScDMSc Reference StandardReference StandardControl No. 447008Control No. 447008

Assay : 100.0 % of C22H29FO5 , calculated on the dried basis, determined by HPLC method,compared with USPRS.

Intended use : For chemical assay and identification. Direction for use : Dry at 105๐

C for 3 hours before use.Storage : Keep container tightly closed and protected

from light, preferably at the temperature about 5๐

C.

Tested Date : 8 July 2547Next Retest Date : 8 July 2550Reference Standard CenterBureau of Drug and Narcotic

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Catalog BookCatalog Book

EPCRS

• List of substances, Purity

• Assigned content (as is)

• Where no drying conditions are stated,

the substances is to be used as received

• Use : Code No 1 to 22

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Code Use

1. Identification by IR

2. Identification by TLC

3. Identification by Melting point

4. Identification by LC

6. Identification by GC

8. Identification by UV or Colorimetry

8A. Test for Related substances by UV or Colorimetry

9. Test for Related substances by TLC

10. Test for Related substances by LC

The EPCRS are used in the following cases:The EPCRS are used in the following cases:

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Code Use

13. Test for related substances by GC14. Assay by UV or Colorimetry

15. Assay by LC

16. Assay by GC

17. Microbiological Assay

20. Assay by Volumetric Titration

20A Assay by Hydrolysis Rate

21. General method

22. Other purpose; Enalapril for systen suitability

The EPCRS are used in the following cases:The EPCRS are used in the following cases:

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BookletBooklet

BPCRS

• List of substances, content

• Declared content is quoted on an ‘as is’ basis

• This figure is to be used in calculating the results of the assay

• Batch number on label corresponds with that given on booklet

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Recommendation documentRecommendation document

USPRS

• They are provided for use in the testes and assays of the official methods of USP / NF

• They are utilized at a value of 100.0% ,

unless so otherwise labeled

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Label on the VialLabel on the Vial

USPRS

Example :

• Dry a portion at 105๐C for 3 hours before using.

Keep container tightly closed.

• Do not dry. Each mg of this material is equivalent

to 857 mcg of minocycline on the as is basis

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Catalog BookCatalog Book

NIBSC

WHO International Reference Materials :

Amikacin

• 1st International Standard 1983

• 50600 International Units per ampoule

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StorageStorage

• In well-closed (tightly closed) containers

protected from light

• Temperature

– Between 2๐C and 10

๐C

– About 5๐C

– Below 0๐C / -10

๐C, -20

๐C

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Expiry DateExpiry Date

• WHO guideline :

– Chemical reference standards do not carry on “expiry date”

– Monitoring stability by regular re-examination of the collection by issuing body

– Any material that has deteriorated is replaced by new batches

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Expiry DateExpiry Date

• BPCRS :

– All BPCRS are supplied with at least 3 months shelf-life, the current Batch No is always listed on the website

• EPCRS :

– Official date in catalog “Batch 1 valid until 30 June 2006”

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Expiry DateExpiry Date

• USPRS :

– Current Lot : O

Previous Lot / valid use date : N (11/06)

• ARS : DMScRS

– WHO guideline

– Tested date, Next re-test date

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Website and EWebsite and E--mail Addressmail Address

• ICRS : who.apl@apoteket.se

• EPCRS : www.pheur.org

CRS@pheur.org

• BPCRS : www.bpclab.co.uk

queries@bpclab.co.uk

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Website and EWebsite and E--mail Addressmail Address

• USPRS : www.usp.org

• NIBSC : standards@nibsc.ac.uk

enquiries@nibsc.ac.uk

• ARS, DMScRS : www.dmsc.moph.go.th

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Thank you

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Definition

• Reference Material : ISO Guide 34

Material or substance one or more of whose properties are sufficiently homogeneous and well established to be used for the calibration of an apparatus, the assessment of a measurement method or for assigning values to materials.

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Definition

• Certified reference material: ISO Guide 34Reference material, accompanied by a certificate, one or more of whose property values are certified by a procedure which establishes its traceability to an accurate realization of the unit in which the property values are expressed, and for which each certified value is accompanied by an uncertaintyat a stated level of confidence.