Smt.R.D.Gardi B.pharmacy college

M.Pharm (sem-I)Quality Assurance

Prepared By: paras shahGuided By: Mr.Ketan Dadhania

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.

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.

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)

Mainly two types of sources

1.Compendial (primary)

2.Noncompendial (secondary

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.

 

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

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

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 analysisMass balance calculation

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 glassHumidity protection: tight closing containers Inacceptable is parafilm One dose Standards (HPLC-vials)O2 protection: N2 Atmosphere, tight closing container  Suitable container materialResidual solvent: glass Suitable placeThermolability: fridge, deep freezer

 

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

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

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.

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

PREDNISONECERTIFIED REFERENCE MATERIAL

LOT #: P500042CATALOG #: PHR-1042 NOMINAL WT: 1 g

CERTIFICATE VALIDITY DATE: 9 September 2009 VERSION: 500042.3Note: Certificates may be updated due to Compendial Lot changes or the availability of new data. Checkour 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.

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: 

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 

More than250 WHOmeasurementStandardsare available;define the IUof biological activity

Support scientificevaluation ofemerging issues

Global measurement standards

Global written standards

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(recombinantgrowth hormone)

191 amino-acid22kDNon- glycosylatedBiosynthetic

Growth hormone has undergone the transition from a biological to a nonbiological

Assay method

1985

Weight gain or tibial width increaseIn hypophysectomised rats

2005

Size exclusion -HPLC

Somatropin (recombinant growth hormone)

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. 

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.

 

USP/NF 2007 www.who.int/biologicals http://bit.ly/QOS-Expl www.pharmatech.com http://www.fda.gov/cder/guidance/

2396dft.htm.