Transcript REFERENCE STANDARD - PARAS'S PHARMACY WORLD

Smt.R.D.Gardi B.pharmacy college
M.Pharm (sem-I)
Quality Assurance
Prepared By: paras shah
Guided By: Mr.Ketan Dadhania
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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.
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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.
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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)
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Mainly two types of sources
1.Compendial (primary)
2.Noncompendial (secondary
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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.
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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 R&D
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.
characterization requirement
measurement technique
1. Physical properties
NMR,MS,FTIR,UV-visible,
functional group
analysis, crystallinity
Proof of structure
Physical description
Appearance
melting point, pka, optical
rotation X-ray diffraction
Physical properties
2.purity
Related compound
Chiral purity
Inorganic impurities
Solvents
HPLC purity
HPLC,ZE chiral purity
Residue on ignition, ICP ,AAS
ICP, GS
Water
Karl Fischer titration
Ion chromatography
Counter ions
Verification organic impurities
TLC
3.Assay
Verification
Titration, Assay by difference,
C,H,N analysis
Mass balance calculation
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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.
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
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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
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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);
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c. name and address of the issuing authority;
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d. approximate quantity of material in the container; and
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e. batch or control number
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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.
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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.
Establishment of expiry dates:
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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
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 user’s location. Open
slowly and carefully to avoid dispersion of the material.
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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:
Date of preparation:
Calibrated Against:
Quantity:
Control No:
Use before:
Reference Standard Lot No:
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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
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
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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)
Somatropin (recombinant growth hormone)
Somatropin
(recombinant
growth
hormone)
Growth hormone has undergone the
transition from a biological to a
nonbiological
Assay method
1985
191 amino-acid
22kD
Non- glycosylated
Biosynthetic
Weight gain or tibial width
increase
In hypophysectomised rats
2005
Size exclusion -HPLC
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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.
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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, Nondisintegrating) - 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.
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USP/NF 2007
www.who.int/biologicals
http://bit.ly/QOS-Expl
www.pharmatech.com
http://www.fda.gov/cder/guidance/2396dft.
htm.