Handling of Reference Standards_GMP_Dr. A. Amsavel

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Handling of Reference Standards

• Dr. A. Amsavel

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Content

• Definition
• Requirements
• Guidelines
• Pharmacopiea
• Types of Reference Standards
• SOP for handling of Reference Standards
• Qualification of Secondary Standards
• Assigning Potency, Storage and Use
• Documents Records

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Definition (ISO-Guides 30-35)

• Reference Material (RM)Material, sufficiently
  homogeneous and stable with respect to one or
  more specified properties, which has been
  established to be fit for its intended use in a
  measurement process
• Certified Reference Material (CRM)Reference
  material characterised by a metrologically valid
  procedure for one or more specified properties,
  accompanied by a certificate that provides the
  value of the specified property, its associated
  uncertainty, and a statement of metrological
  traceability.

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Definition (ISO- Guides 30-35)

• Primary StandardStandard that is designated or
  widely acknowledged as having the highest
  metrological qualities and whose value is
  accepted without reference to other standards of
  the same quantity, within a specified context.
• Secondary StandardStandard whose value is
  assigned by comparison with a primary standard of
  the same quantity.

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Definition (ICH Q7)

• Reference Standard, PrimaryA substance that has
  been shown by an extensive set of analytical
  tests to be authentic material that should be of
  high purity. This standard can be
• obtained from an officially recognised source, or
  
• prepared by independent synthesis, or
• obtained from existing production material of
  high purity, or
• prepared by further purification of existing
  production material.
• Reference Standard, SecondaryA substance of
  established quality and purity, as shown by
  comparison to a primary reference standard, used
  as a reference standard for routine laboratory
  analysis.

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ICH Q7 PRS Requirement

• 11.17. Primary reference standards (PRS) should
  be obtained as appropriate for the manufacture of
  APIs.
• The source of each primary reference standard
  should be documented and Records should be
  maintained.
• Storage and use as per suppliers
  recommendations.
• PRS obtained from an officially recognised source
  are used without testing if stored as per
  recommended conditions .
• 11.18 Where a PRS is not available from an
  officially recognized source, an in-house
  primary standard should be established.

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ICH Q7PRS Requirement

• Appropriate testing should be performed to
  establish fully the identity and purity.
  Documentation of this testing should be
  maintained.
• 11.19. Secondary reference standards should be
  appropriately prepared, identified, tested,
  approved, and stored.
• The suitability of secondary reference standard
  should be determined prior to first use by
  comparing against a primary reference standard.
• Each batch of secondary reference standard should
  be periodically re-qualified in accordance with a
  written protocol.

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EU GMP Requirement

• EUGMP EudraLex Volume-2, Part-1 Chapter-6 QC-
  6.20
• Reference standards should be established as
  suitable for their intended use. Their
  qualification and certification as such shouldbe
  clearly stated and documented.
• Whenever compendial reference standards from
  anofficial source exist, these should preferably
  be used asprimary reference standards unless
  fully justified (the use ofsecondary standards
  is permitted once their traceability toprimary
  standards has been demonstrated and is documented.

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European Pharmacopoeia

• 5.12. REFERENCE STANDARDS (General Chapter)
• A Primary standard is characterised by a variety
  of analytical techniques chosen to demonstrate
  its suitability for use .
• A Reference standard corresponding to an impurity
  is characterised for identity and purity with
  minimum content of 95.0 , The content being
  considered as 100.0 since there will be no
  appreciable effect on the determination of
  impurities.
• EP Reference standards are mostly stored in
  temperature at 5 3 C, otherwise specified in
  leaflet.
• If the standard is presented in multi-use
  containers then re-testing may be more frequent
  for hygroscopic or oxygen-sensitive substances.
  Eg water/LOD content

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European Pharmacopoeia

• Secondary standard. A standard whose property
  value is assigned by comparison with a primary
  standard of the same property or quantity.
• A secondary standard should exhibit the same
  properties as the primary standard, relevant
  test(s) shall be performed. The extent of testing
  may be scientifically justified. Quantitative
  purpose required comprehensive test to establish
  potency.
• The secondary standard is established by
  comparison with the primary standard to which it
  is traceable.

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Type of EP CRS

• Type of Reference Standards available in EDQM
• Identification
• Assay
• Impurities Quantitative
• Impurities Qualitative
• Mixtures for System Suitability/ Peak
  Identification.
• Purpose/Usage
• Batch testing release
• System suitability test
• Evaluation of a measurement system

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Type of EP CRS

• Availability of EP CRS other than API
  Impurities
• Reference spectrum
• Elemental impurity eg,Lead solution CRS (1.00
  mg/g)
• Instrument calibration / qualification
• Caffeine CRS for Calibration standard for MR,
  WL accuracy for LC
• Sodium Aminosalicylate dihydrate CRS for
  equipment qualification / Calibration. Loss on
  drying(2.2.32 ) Value 169.6 ( 2.4) mg/g
  Uncertainty 0.4 mg/g
• Refer Leaflet Contains Scientific information,
  purpose, use, potency, uncertainty of assigned
  value, Instruction for use, validity, Storage

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USP RS General Chapter lt11gt

• Official applications of USP RS are specified in
  the monographs and general chapters.
• Pharmacopeial Reference Standards are highly
  characterized specimens
• Where USP states in the monograph that use
  USPRS, in the Assays and/or the Identification
  tests. It is legal requirement.
• Secondary standard can be used, but it should be
  qualified using the USPRS.
• Potency or content of USP RS is assumed as100.0
  pure, unless otherwise directed or stated in the
  label

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USP RS General Chapter lt11gt

• In case of dispute in the test results, value
  obtained using the specified USP RS is
  conclusive.
• If any USP RS is not yet available, that portion
  of the standard containing the requirement shall
  not be official until USP RS is available
• USP Reference Standards for Assay and
  Identification for Qualitative or Quantitative
  purpose.
• Refer for more details
• Technical Data Sheets or Typical Chromatograms.
• Weights and Balances lt41gt Volumetric Apparatus
  lt31gt
• 6.50.20.1 Adjustments to Solutions in the General
  Notices

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Types of Reference Standards

• USP Reference Standards for Impurities
• Organic impurities Starting materials,
  intermediates, by-products, reagents, catalysts,
  and/or degradation products.
• Inorganic impurities Reagents, catalysts, heavy
  metals, or inorganic salts
• Residual solvents that may be either inorganic or
  organic liquids.
• Authentic Visual References (AVR) are used for
  visual images to compare certain test that they
  meet compendial requirements.
• Performance Verification Test Standards-
  Instruments qualification and calibration.
  Method-specific uses, (e.g., performance
  verification standards, AVR, melting point
  standards, and the particle count set)

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Information USP RS

• USP RS are provided with Technical Data Sheets or
  Typical Chromatograms.
• USP RS do not carry an expiration date on the
  label. It may be used as long as it is listed as
  "Current Lot" in the Catalog or has not reached
  its Valid Use Date.
• Catalogs published USP website (check quarterly
  for validity)
• Upon depletion, the lot is designated in the
  catalog as "Previous Lot" and a "Valid Use Date"
  is assigned.
• Refer for more details_at_ https//www.usp.org/refere
  nce-standards

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How to Use USP RS

• Use USPRS as per Technical data sheet or as per
  label
• As Is Use without any prior treatment or
  correction for volatiles. (confirm from valid
  data that the volatiles are constant over time)
• Dry Before Use Use immediately after drying
  under stated conditions. Drying should not be
  performed in the original container. A portion of
  the material should be transferred to a separate
  drying vessel.
• Determine Water Content Titrimetrically At Time
  of Use Use with a correction for the water
  content or the loss on drying, determined on a
  separate portion of material.
• Test Water Determination as per Method I (921).
• Instrumental or microanalytical methods are
  acceptable
• When about 50 mg of RS is used for water test,
  use dilute reagent with 2 to 5 fold

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How to Use USP RS

• Some of the USP RS provided in single-use
  containers. Labeled as reconstituted in its
  entirety without any additional weighing, where
  given in the monographs.
• Intended use and that value assignment and
  uncertainty information are considered.
• USP RS should be stored in the packaging
  configuration provided by USP (e.g., vials
  packaged in hermetically sealed).
• When special storage conditions are specified,
  label directions should be followed.

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SOP for Handling of RS/CRS

• Establish the procedure for handling of Reference
  standards to address the following, but not
  limited to .
• Purpose Scope
• Responsibility Assign co-ordinator for handling
  reference standards/ working standards
• obtained from an officially recognized source
  like Pharmacopoeia reference substances /
  certified RS
• Ordering and receipt of RS/CRS
• Label with details

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SOP for Handling of RS/CRS

• Maintain the records such as PO, date of receipt,
  COA or leaf let,
• Storage store as per storage condition in
  secured area
• Use appropriate RS for testing, calibration,
  qualification of equipment, instruments or other
  devices
• Usage log with purpose and reconciliation
• Periodic verification of validity or availability
  of new standard
• Include the qualification of secondary reference
  standard or Prepare separate SOP.

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Qualification of Secondary Standard

• Qualification of Secondary /Working standard
• Standard for Quantitative Use
• Extensive physico-chemical testing is required
  for the standards used for quantitative purpose.
• The level of characterization depends on the
  intended use
• Choose the tests method to confirm the mass
  balance.
• The secondary /working standard can be procured
  external source or synthesis or select from
  commercial batch.
• Assay Select one of the batches which have
  minimum 99.0 of assay /purity and confirm the
  homogeneity
• Purify the material further if purity is less.

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Qualification of Secondary Standard

• Qualify against official Reference Standard
  (USPRS / EPCRS)
• Test the assay / chromatographic purity at least
  in triplicate
• Test other parameters, which are related to
  potency like Loss on drying and / or water by
  TGA or Karl Fischer, Residual solvents, Residue
  on Ignition etc.
• Perform Inter-laboratory study to assign a
  content (if required)
• Calculate the uncertainty of measurement
• Recommended to assign the content on an as is
  basis.
• Assign the potency / content based on mass
  balance considering LOD / water content, Residual
  solvent or ash content etc
• Potency (100 LOD/water/solvents/inorganics)
  x chromatographic purity()/100.

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Qualification of Secondary Standard

• Assigned value has to be checked by Orthogonal
  techniques like non-aqueous titration or other
  suitable techniques, such as CHN-analysis.
• Perform characterization against official
  reference standard Mass, FTIR, NMR, UV
  spectroscopy DSC, XRD polymorph as required.
• In case of impurity standard select the
  assay/purity of min 95
• Record all the details like source batch, tests,
  primary reference used, and potency and keep the
  COA
• Maintain the test record with raw data, ref
  standard used.
• Pack and Label the vials with potency, use,
  validity and storage .

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Qualification of Secondary Standard

• Standard for Quantitative Use (RT
  Identification or system suitability)
• Procure or synthesis or select from in-house,
  ensure that content is at least 95 If t is less
  justify scientifically for its suitability.
• Test against reference standard (if available)
  otherwise perform complete test for
  characterization.
• Test the following physico-chemical properties to
  elucidate the structure.
• Chromatographic purity, FTIR- UV spectrum, mass,
  NMR and CHN-analysis and prepare the COA with
  traceability
• Maintain the test record with raw data, spectrum,
  chromatograms.
• Pack and Label the vials with potency, validity,
  storage and pre-defined date for use and
  numbering the vials
• Retest and confirm to extend the validity / usage
  period.

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Instruction for Usage

• Take a reference standard vial from storage area
  and allow to controlled room temperature prior to
  weighing
• Open the reference standard vial carefully and
  keep the inner cap and outer cap in the inverted
  position on a clean butter paper.
• Use a clean stainless steel spatula or paper for
  one time use for transfer of RS.
• Dont return unused standard to the vial.
• After the weighing / transfer close the vial
  immediately
• Dont expose the reference standard for too long
  to avoid pick up of moisture.
• Return the closed vial to their respective
  places, securely.

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Label Reference Standards

• Reference standards labelled with information
  including
• In-house ref. No
• Name
• Batch, lot No
• Date of opening
• Shelf-life (if applicable)
• Potency
• Storage conditions
• Usage condition
• Vial No.

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Records for Reference standards

• Record for reference standard
• Ref No /identification No. of the material
• Description of the material
• Source date of receipt
• batch designation or other identification code
• Potency , LOD any other details as appropriate
• Intended use of the material (e.g. as an infrared
  reference material, as an impurity reference
  material for thin-layer chromatography, etc.)
• Location of storage in the laboratory, and any
  special storage conditions

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Packing and Use

• Pack the working standard in 2ml/5ml/10ml vials
  or as appropriate.
• Pack required number of vials based on the
  requirement and frequency of use, eg. one vial
  for each month / three months
• Assign the validity / expiry based on the
  shelf-life
• Pack required number of vials and assign validity
  of each vial. Record the details in the working
  standard usage login register
• If molecule is stable assign 2 years and the
  extent validity period after retest. Specify
  clearly in the SOP extend the validity period for
  6 months.
• Label the vials and store at recommended storage
  condition.
• Record the opening date use until the valid date
  of vial
• Dispose the excess sample as per validity/ expiry
  date.

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• Contact Dr. A. Amsavel
• aamsavel_at_gmail.com

Thank You