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Procedure for Management of Working Standard, Reference Standard, Calibration Standard, Impurity Standard, GC Standard and Primary Standard.

Working Standard / Reference Standard Management

1.0   Objective :

• • To lay down procedure for management of Working Standard, Reference Standard, Calibration
    Standard, Impurity Standard, GC Standard and Primary Standard in Quality Control Department.

2.0   Scope :

• • This SOP is applicable to –

• • • Procurement receipt, verification, labeling and storage of Working Standard, Reference Standard,
      Calibration Standard, Impurity Standard, GC Standard and Primary Standard.

• • • Issuance, Usage and destruction (Reconciliation) of Working Standard, Reference Standard,
      Calibration Standard, Impurity Standard, GC Standard and Primary Standard.

• • • Qualification of working standard (WS) / GC Standard.

• • • Periodic (Monthly) evaluation of standard management system.

3.0   Responsibility – Working / Reference Standard:

• • All Staff, Quality Control Department – To follow and perform the activity as per the
    SOP.

• • Executive/Manager, Quality Assurance Department – To review monthly evaluation checklist for
    Standards as per SOP.

• • Head, Quality Control Department – Approval and Compliance of SOP.

• • Head, QA Department – Approval and Compliance of SOP, Approval of Certificate of Analysis (COA).

4.0   Definition (s) – Working Standard / Reference Standard / Impurity Standard :

• • Pharmacopoeial Reference Standard: These are authentic substances of a very high purity with
    critical characteristics and suitable for the specific purposes and are provided by official
    pharmacopoeial agencies.

• • Non Pharmacopoeial Reference Standard: These are authentic substances of high purity, which is
    characterized in-house in the event of non-availability of official pharmacopoeia reference
    standard. These are reference standards, which are not mentioned in the pharmacopoeia.

• • Calibration Standard: These are authentic substances of a very high purity and suitable for the
    calibration purposes and are provided by authorized sources.

• • Working Standards: Working Standard is an in-house Secondary reference standard of high purity and qualified by comparison with a Reference Standard.

• • Primary Standard: Primary standard is a standard of highest purity and is sufficiently accurate.
    Primary standard are used to calibrate other standards or instruments. It is typically a reagent
    which can be weighed easily and so pure that its true representative of number of moles of
    substance contain.

5.0   Procedure for Management of Working / Reference / Impurity Standard

• • Management of Working Standard, Reference Standard, Calibration Standard, Impurity Standard, GC Standard and Primary Standard:

(This section is applicable for standards which are not standardized on-site)

• • Procurement of Reference standard Calibration Standard, Impurity Standard, GC Standard and Primary Standard : 

  • Standards qualified by other site: Reference standard, Impurity Standards, Primary
    standard, Calibration standard, GC standard and Working standard procurement shall be done from the
    R & D / other site.

• • High purity commercially available Chemicals/Reagents from reputed companies (Fluka,
    Across, Merck, Sigma Aldrich, etc ) can be used as a working /Impurity/GC /Calibration standard and should have NIST traceability/standardized from valid CRS/RS/ACS.

• • All standards shall be procured from manufacturer along with certificate of analysis.

• • In case NIST traceability is not available for subjected standard then same shall be characterized by method but not limited to NMR, MASS and FTIR.

• • High Purity GC solvents/solids shall be procured from sources like Fluka, Sigma Aldrich, Merck etc, whose purity shall be assessed by Gas Chromatography or other chromatographic technique.

• • These received solvents I solids shall be used for qualification purpose, alternatively solvents / solids having reference of pharmacopoeial standard against which it is qualified (traceable lot number) shall be used directly.

• • If the pharmacopoeial GC reference standard (USP/ Ph. Eur.,/BP, etc.) are available in catalogue, preferably same shall be used for GC standard qualification.

• • Reference standard, Impurity Standards, Primary standard, calibration standard, GC standard and working standard are procured in case, but not limited to:

• • • New lot number of pharmacopoeial reference standard/ impurity standard is released by the agencies.

• • • Standard is expired.

• • • Standard is exhausted.

• • • New product is introduced in the facility.

• • Assigning of Expiry and Validity

  • Validity of Pharmacopoeial standards shall be verified with respective pharmacopoeial catalog as per following web addresses:

For USP: www.usp.org

For BP: http://www.pharmacopoeia.com For EP: http://crs.edqm.eu

• • Validity of other sites standard shall be considered as mentioned on the label / certificate of analysis,

• • Expiry of high purity chemicals/Reagents shall be assigned as mentioned on label/certificate of analysis or 5 years from date of manufacturing, whichever is less and validity shall be assign 2 years from date of opening.

• • If validity of high purity chemicals/Regent is not available and also Manufacturing date is not available then expiry date shall be assign 5 years from date of receipt and validity shall be assign 2 years from date of opening.

• • Receipt and verification of Reference Standard:

• • After procurement, standard shall be received by designated personnel of laboratory.

• • At the time of receipt following check points shall be verified as per annexure-XXI
    (Reference/Working/Impurity/Calibration/Primary/GC standard receipt checklist).

• • On receipt of consignment/ shipment shall be verified against procurement.

• • Received consignment/ shipment shall be verified against its storage condition (As per certificate).

• • Check the details of material with source data (Catalogue, Website or Pharmacopoeia) at the time of
    receipt.

• • Received standards shall be verified for intactness of consignment and individual vial of standard.

• • Received standards shall be verified for physical discrepancy (if any).

• • Certificate of analysis for the received standard along with other data like Characterization data,
    MSDS (as applicable) shall be evaluated for compliance.

• • Any other information shall be reviewed and evaluated like Name of standard, B. No. / Lot No.,
    potency, validity, instructions for usage of material and storage condition.

• • In case any discrepancy noted during receipt of Working/ Reference/ Impurity/GC/Primary/Calibration Standard, same shall be communicated to department Head/Designee for further course of action and same shall be communicated to R & D / other site.

• • Inward and Labeling of Standard (Reference / Working / Impurity):

• • After receipt and verification of Working/ Reference/ Impurity / GC/ Primary/ Calibration Standard
    will be considered for inward.

• • After receiving the standard (Working /Reference /impurity /GC /Primary/Calibration) record the details in the “Inward cum vial issuance log of Reference/Impurity/Working/Calibration/Primary/GC standard”

• • Storage of Standard (Reference / Working / Impurity) :

• • Store the Reference, Impurity, Primary, calibration, and Working standard in a closed box / desiccators and keep as per required storage condition of standard, if no information available regarding storage condition then same shall be store at temperature 2-8°C.

• • Stock & In-use standards should be stored separately and stock shall be stored in locked condition.

• • GC standards shall be kept as per required storage condition of standard, if no information available regarding storage condition then same shall be stored at ambient temperature.

• • Issuance of Standard (Reference / Working / Impurity):

• • After inward and labeling of the standard (Reference, Impurity, Primary, calibration, GC and working standard) one vial shall be issued for further usage and details shall be documented in “Inward cum vial issuance log of Reference/Impurity/Working/Calibration/Primary/GC standard”.

• • If standard is expired, same shall be destroyed and details shall be documented in “Inward cum vial issuance log of Reference/Impurity/Working/Calibration/ Primary/GC standard”.

• • Usage and destruction of Standards:

• • Take the standard vial and keep it in the desiccator for about 15 to 20 minutes for 2°C to Doc storage & 40 to 45 minutes for freezer storage to attain room temperature. After attaining room temperature weigh the required quantity of the standard and close the vial immediately and keep it in the designated place again.

• • Before use of pharmacopoeial reference standard, confirm its validity from the “List of Reference standard’ (Refer Annexure-XX).

• • In case, reference standard (In-house / Pharmacopoeial / Impurity) quantities is less, then less quantity of the same can be used for the analysis, keeping the final concentration same as per the Standard test procedure / Pharmacopoeia monograph.

• • Analyst shall document consumption of Reference/Impurity/ Primary/Calibration/Working/GC standard in respective “Consumption record of Reference/ Impurity/ Working/ Calibration/ Primary/ GC standard”.

• • For screw cap, seal by using parafilm and in case of GC / Pharmacopoeial vial, seal by using crimper. the reference standard/impurity standard vial after usage and keep in the designated place.

• • All standards should be handled in its original container and keep away from heat and light, when in use,

• • Utmost care should be taken to avoid cross contamination during handling and weighing of standards. Use capillary while usage of GC standards.

• • In case of water content needs to be determine for standard, preferably it shall be determine before usage of standard for preparation.

• • Handle the standards carefully, Ensure that the integrity is safeguarded and maintained throughout their period of use.

• • Do not insert spatula/butter paper/pipette in the vial/bottle. Transfer required quantity approximately and discard the remaining quantity taken out. Do not transfer the balance quantity to the original vial/bottle.

• • Do not use the standard, if any change in description during storage is observed, same shall be destroyed and details shall be documented in “Inward cum vial issuance log of Reference/ Impurity/Working /Calibration/ Primary/GC standard”.

• • Alternatively replace the standard as soon as a significant change in such property is observed.

• • Ensure that reference standard/ impurity standard quantity is sufficient for next qualification. If not indent for further procurement or intimate to the Head of department or designee.

• • If the reference standard/impurity standard is expired (for non- pharmacopoeial) and/or replaced (for pharmacopoeial) by a new lot of reference standard/impurity standard dispose of the previous lot by solubilizing in a suitable solvent and discarding the solution. and record the same in “Consumption record of Reference/Impurity/Working/Calibration/Primary/GC standard”.

• • Periodic Evaluation (Standards Management System):

• • Based on the checklist, monthly evaluation shall be performed as per “Monthly Evaluation Checklist for Standards”.

• • Pharmacopoeia Reference standard (USP/EP/BP) shall be used in its official application (testing) as long as it is listed as “Current Lot” in current pharmacopoeial Reference standard catalog or has not reached its valid use date.

• • The list of working/ Reference /ln-house Reference/ Impurity/ Primary/ Calibration/ GC standard shall be updated on the monthly basis or whenever required as per “List of working/ Reference /In-house Reference/ Impurity/ Calibration/ Primary/ GC standard” (Annexure-XX).

• • Drying

  • Before use dry the primary standard as per specified on the label or as per respective GTP, pharmacopoeia and vendor COA,

• • Always use NIST grade primary standard. In case of unavailability of NIST grade primary standard, use A.R. grade reagent and keep them separately.

• • Maintain the date of opening on primary standard at the time of opening for use and also mention use before date on the label as per SOP for Handling of reagent and chemical .  All opened primary standard shall be used within 2 years from the date of opening or within expiry date (if mentioned), whichever is earlier.

• • Qualification of Working standard:

• • Material Selection for working standard Qualification: Material selection criteria, but not limited to:

• • • Material shall be taken from pre-approved batch.
    • Shall have highest purity/potency and lowest impurities.
    • Material shall have lowest water content/LOD.

• • • Material shall have maximum shelf life.

• • Number of batch available (as applicable) shall be identified and designated person shall document the details in the “Material Assessment Form”.

• • Based on the above material selection criteria, batch shall be selected for the qualification of working standard.
  • If the material is available and crossed retest period then this material shall be retested for critical analysis as per retest specification like Related substances, Water/LOO, IR/NMR and any other test. If these tests comply with the specification then this material shall be used for standard qualification and retest period shall be extended as per specification.

• • Obtain the required quantity of material from pre-approved batch from warehouse through intimation duly verified by Head QC and approved by Head QA as per “Requisition of Sample for WS qualification”.

• • Working Standard Qualification:

• • Standardization:

• • Working standard shall be qualified against pharmacopoeia Reference standard or In-house reference standard.

• • Certificate of Analysis and relevant analytical data Characterization data like NMR, Mass, XRD etc.) by chromatographic techniques such as HPLC, GC etc. or any other appropriate techniques shall be ensured for In-House reference standard, prior initiation of Qualification activity.

• • If the pharmacopoeial reference standard (USP/Ph. Eur./BP etc.) are available in catalogue, in that case only pharmacopoeial reference standard shall be used for working standard qualification.

• • If pharmacopoeial reference standard not available in catalogue, in that case the in-house reference standard shall be used.

• • Sufficient quantity of Working standard is received from the R&D, same standard can be used for routine analysis, and otherwise working standard shall be qualified against reference standard.

• • Collect approximately 300 g sample from the selected batch. The sample quantity may be changed as per requirement and availability of material.
  • After receiving material, details of the same shall be entered in “Working Standard / GC Standard standardization and distribution log” and W.S.A.R. Number shall be generated.

• • Tests shall be performed for qualification of working standard but not limited to

    • Description
    • Identification
    • Water Content / Loss on drying
    • Assay / Potency
    • Residual solvents by GC analysis (If Potency required on Solvent free basis). Any additional test, if required

• • All the above tests shall be carried out as per the current standard testing procedure.

• • Record the details of analysis in “Working standard record of Analysis” .

• • Identification and Assay test shall be carried out using respective pharmacopoeia.

• • Perform the assay with triplicate sample preparation and report the average value (as is basis).

• • Sample injection shall be done in duplicate (two in numbers) for assay test.

• • The % RSD of 3 assay values shall not be more than 1.0 %.and individual value of six injections should comply to specification criteria.

• • Perform the Water Content / Loss on drying in triplicate and report the average value and all individual results should comply to specification criteria.

• • If any, result fails to comply the specification/ qualification criteria, then, same shall be handled as per SOP – Handling of Laboratory Investigation.