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REFERENCE STANDARD

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Smt.R.D.Gardi B.pharmacy college M.Pharm (sem-I) Quality Assurance Prepared By: paras shah Guided By: Mr.Ketan Dadhania Reference substances are authentic specimens ... – PowerPoint PPT presentation

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Title: REFERENCE STANDARD


1
REFERENCE STANDARD
  • Smt.R.D.Gardi B.pharmacy college
  • M.Pharm (sem-I)
  • Quality Assurance
  • Prepared By paras shah
  • Guided By Mr.Ketan Dadhania

2
DEFINATION
  • Reference substances are authentic specimens that
    have been approved by the designated agency of
    the country as suitable for use as comparison
    standards in the test and assays specified in the
    respective official pharmacopoeia of the country.

3
For your knowledge
  • Some of these reference standards have been
    identified as
  • - Ph. Eur CRS (Chemical Reference Standards)
  • - BP BPCRS (British Pharmacopoeia)
  • - Intern. Pharm. WHO international CRS
  • - USP USP reference Standard
  • At USP, sights are set on the milestone of
    reaching 3000 RS, to meet by the end of 2012.

4
Types
  • Primary Reference Standard of active compound
  • Secondary Standard (Working Standard /In-House
    reference material)
  • Related Compound Standard
  • Compendial Standard
  • Internal standard
  • Other Standards
  • Former USP and NF Reference Standards
  • FCC Reference Standards
  • Authentic Substances (AS)

5
Sources of reference-standard materials
  • Mainly two types of sources
  • 1.Compendial (primary)
  • 2.Noncompendial (secondary

6
Preparation
  • The primary reference standard of the Current lot
    of drug substances procured from the
    corresponding Pharmacopoeial commission. Primary
    standards used for Standardization, calibration,
    system suitability etc. are procured from the
    approved vendors. Their purity is considered as
    per the label claim by the vendors.
  • The working reference standard of drug substances
    are prepared by taking the released commercial
    batch of the drug substance, which is further
    purified in Research and Development Department
    and analyzed by in-house Quality control
    Department against the primary reference standard
    of the drug substance. 
  • The reference standards of non pharmacopoeial
    product are prepared by taking the highly pure
    chemical substances synthesized by in house
    Research and Development department which is
    identified, fully characterized and analyzed
    before making use for routine analysis.
  •  

7
Preparation
  • The impurity standards are procured from the
    concerned pharmacopoeial commission and are used
    for the routine analysis. If official standards
    for impurities are not available, in house RD
    department prepares the impurity standards. They
    re fully identified and characterized before use
    for routine analysis.
  •  
  • Standards for the solvents are prepared by taking
    the previously approved lots of the solvents and
    record thereof is maintained.
  •  

8
Characterization
characterization requirement measurement technique
1. Physical properties
Proof of structure NMR,MS,FTIR,UV-visible, functional group analysis, crystallinity
Physical description Appearance
Physical properties melting point, pka, optical rotation X-ray diffraction
9
Characterization
2.purity
Related compound HPLC purity
Chiral purity HPLC,ZE chiral purity
Inorganic impurities Residue on ignition, ICP ,AAS
Solvents ICP, GS
Water Karl Fischer titration
Counter ions Ion chromatography
Verification organic impurities TLC
3.Assay
Verification Titration, Assay by difference, C,H,N analysis Mass balance calculation
10
Usage of reference standards
  • The following are the areas wherein the reference
    substances are used
  • A. infrared Spectrophotometry.
  • B. ultraviolet absorption spectrophotometry.
  • C. quantitative methods based on the development
    of a color and the measurement of its intensity,
    whether by instrumental or visual comparison.
  • D. chromatographic separation.
  • E. quantitative methods (including automated
    methods) based on other separative techniques
    that depend upon partition of the material to be
    determined between solvent phases, where the
    precise efficiency of the extraction procedure
    might depend upon ambient conditions.
  • F. assay methods based on measurement of optical
    rotations.

11
Handling and Distribution of Reference Substances
12
Packaging and Storage
  • Suitable packaging
  • Light protection brown glass
  • Humidity protection tight closing containers
    Inacceptable is parafilm One dose Standards
    (HPLC-vials)
  • O2 protection N2 Atmosphere, tight closing
    container
  •  
  • Suitable container material
  • Residual solvent glass
  •  
  • Suitable place
  • Thermolability fridge, deep freezer
  •  

13
Handling
  • Adapt to room temperature prior use
  • Planned operations enable the technicians to
    ensure short periods for opening and handling the
    standards
  • Hygroscopic substances
  • Photo lability
  • Some standards have to be dried prior use -
    possible time consuming error source
  • Contaminations during use
  • One standard - one spattle - one weighing glass

14
Documentation
  • Information to be supplied with Reference
    Substances
  • Labels on chemical reference substances should
    give the following information
  • a. name of the substance
  • b. type of reference substance (e.g.
    International Chemical Reference Substance, or
    National Chemical Reference Substances, or
    Authentic Specimen)
  • c. name and address of the issuing authority
  • d. approximate quantity of material in the
    container and
  • e. batch or control number

15
  • The following information should be given, as
    necessary, either on the labels or in associated
    documents
  • i. recommended storage conditions
  • ii. Intended use of the reference
    substances
  • iii. Directions for use
  • iv. Information about the composition of the
    reference substances
  • v. a disclaimer of responsibility when
    reference substances are misused, or stored under
    inappropriate conditions, or used for other
    purpose than those intended by the Issuing
    Authority.
  • Reference Materials Calibrated Against
    International Chemical Reference Substances It
    is advisable to establish the reference
    substances that have been co-related with
    International Reference Substance.

16
  • Establishment of expiry dates
  • Unopened CRS vials are fit for use as single use
    only
  • Expiry dates for in-house standards
  • Based on stability data of the API
  • Taking into account the following
  • Hygroscopic properties
  • Photo lability
  • Thermo lability
  • Based on scientific literature
  • Based on supplier information
  • Based on own experience analytical data,
    stability program

17
Certificate Of Analysis
PREDNISONE CERTIFIED REFERENCE MATERIAL LOT
P500042 CATALOG PHR-1042
NOMINAL WT 1
g CERTIFICATE VALIDITY DATE 9 September 2009
VERSION 500042.3 Note Certificates may be
updated due to Compendial Lot changes or the
availability of new data. Check our website at
www.RTPharma.com for the most current
version. EXPIRATION 12 Months from Receipt
(Proper Storage and Handling Required). STORAGE
Store at Room Temperature, keep container
tightly closed. Attachment of a 20 mm aluminum
crimp seal recommended for unused
portions. CHEMICAL FORMULA C21H26O5
MW 358.4 PHYSICAL
DESCRIPTION White powder in amber vial CAS
53-03-2 HAZARDS Read MSDS before using. Always
handle as if potentially hazardous using prudent
laboratory techniques. INSTRUCTIONS FOR USE Do
not dry. The internal pressure of the container
may be slightly different from the atmospheric
pressure at the users location. Open slowly and
carefully to avoid dispersion of the material.
18
Certificate Of Analysis
  • In general all standards should have a
    certificate of analysis generated either from a
    qualified supplier or through analysis of in
    house data.
  • A typical certificate of analysis of working
  • reference standard should bear the following
    information
  •  
  • Name of product
  • WRS No
    Control No
  • Date of preparation Use
    before
  • Calibrated Against
    Reference Standard Lot No
  • Quantity
  •  

19
Reference Standard Control Strategy
20
Regulations Governing RS Operations  
  • Food and Drug Administration (FDA)
  • CFR Title 21 Food and Drugs GMP, 211.194(c),
    211.160(b) (1) and 299.5(c)
  • ICH Guidelines Q7, Q6B
  • Various FDA Guidance Documents
  • FDA regulatory observations
  • United States Pharmacopeia
  • European Agency for the Evaluation of Medicinal
    Products (EMEA)
  • EU GMP 32, Annex 18 (transcription of ICH Q7)
  • EU Quality Guideline 32 (regulatory submission
    requirements)
  • ICH Guidelines Q7, Q6B
  • European Pharmacopoeia
  • Japan Ministry of Health Labor and Welfare (MHLW)
  • Japan Pharmacopoeia Technical Information
    (JPTI) 1995, section 2
  • ICH Guidelines Q7, Q6B
  • Japan Pharmacopoeia
  •  

21
Reference Standards for Biologics
Support scientific evaluation of emerging issues
Global measurement standards
Global written standards
More than 250 WHO measurement Standards are
available define the IU of biological activity
22
Underlying principle
  • A biological analyte is considered by WHO as
    one
  • of
    biological origin,
  • which cannot be characterized
    adequately by chemical
  • and/or physical
    means alone
  • This is a practical definition, relating the
    structural complexity of the material being
    standardized to the current utility of analytical
    methods.
  • Approaches to the calibration and value
    assignment of global biological reference
    standards
  • Global biological reference materials are
    established via one of two approaches
  • 1 Those which support a measured quantity, and
    are assigned a value in SI units (eg mg, mol)
  • 2 Those which are used to quantify an effect
    (e.g. biological activity) and are assigned a
    value in arbitrary units (e.g. WHO International
    Units)

23
Approaches for value-assignment can change with
time example of growth hormone
Somatropin
(recombinant growth hormone)
Somatropin (recombinant growth hormone)
Growth hormone has undergone the transition from
a biological to a nonbiological
Assay method
1985
2005
191 amino-acid 22kD Non- glycosylated Biosynthetic
Weight gain or tibial width increase In
hypophysectomised rats
Size exclusion -HPLC
24
Reference Standards for Biologics
  • Reference Standard must be representative of
    product including manufacturing pathway.
  • Storage stability is critical.
  • Protocol with more extensive testing to ensure
    quality that is not dependent on quality of a
    previous reference standard.
  • Identity and purity often requires several
    different assays (ELISA, Western Blot, PCR,
    bioassay, etc.).
  • Actual structure may not be confirmed, but may
    need to be inferred from biological activity.
  • Bioassays need to be expressed in units of
    activity relative to a reference standard using
  • e.g. WHO international units where applicable
  • Warning Letters RS Extracts. 

25
Examples of reference standard
  • USP Warfarin RS - This is the acid form of
    Warfarin. Dry portion in vaccum over phosphorus
    pentoxide for 4 hour before using. Keep container
    tightly closed. Protect from light. 
  • USP Urea RS - Do not dry. 
  • USP Salicylic acid tablet RS (Dissolution
    calibrator, Non-disintegrating) - The label
    states the nominal weight of each tablet. Use
    only whole tablet-extra tablets are provided.
    Remove any surface dust with a soft brush before
    using. Keep container tightly closed.
  • USP Ibuprofen RS - Do not dry. Keep container
    tightly closed.
  • USP Anhydrous lactose RS- Dry portion at 80 0C.
    For 2 hour before using. Keep container tightly
    closed.
  •  

26
REFERENCES
  • USP/NF 2007
  • www.who.int/biologicals
  • http//bit.ly/QOS-Expl
  • www.pharmatech.com
  • http//www.fda.gov/cder/guidance/2396dft.htm.

27
Thank you for your attention
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