USP Reference Standards
USP Reference Standards Topics
What is a Reference Standard (RS)?
Why are Reference Standards important?
How does USP develop a RS?
How are RSs used?
How should I store and handle my USP RS?
RS FAQs
What is a USP Reference Standard?
Highly characterized specimens of:
drug substances excipients impurities degradation products biologics
food ingredients dietary supplements compendial reagents performance test tablets
Rigorously tested by USP, industry, and government scientists
Intended for use in compendial methods (a few exceptions)
Established and released under the authority of the USP Board of Trustees and Council of Experts
DRAFT FDA Guidance for Industry
“Analytical
Procedures and Methods Validation”
– Chemistry, Manufacturing, and Controls Documentation, August 2000 Reference
Standards
Types of Standards A reference
standard (i.e. primary standard) may be obtained from the USP-NF or other official sources (e.g. CBER, 21 CFR 610.20). When there is no official source, a reference standard should be of the highest possible purity and be fully characterized.”
“A working
standard (i.e. in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard.”
DRAFT FDA Guidance for Industry Characterization of a Reference Standard “Reference
standards from USP-NF and other official sources do not require further characterization.
A reference
standard that is not obtained from an official source should be of the highest purity that can be obtained by reasonable effort, and it should be thoroughly characterized to ensure its identity, strength, quality, purity, and potency.”
DRAFT FDA Guidance for Industry Characterization of a Reference Standard (Cont.) The
qualitative and quantitative analytical procedures used to characterize a reference standard are expected to be different from, and more extensive than, those used to control the identity, strength, quality, purity, and potency of the drug substance or the drug product.
Analytical procedures used to characterize a reference standard should not rely solely on comparison testing to a previously designated reference standard.”
USP Reference Standards–History
RS
History
USP
X–1926: First mention of future availability
USP
XI–1936: First list of USP Reference Standards (6 standards)
USP
has provided Reference Standards since 1936—over 70 years of history and experience
2013:
>3000 standards with over 400 new RS in various stages of development
Reference Standards
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RS Development: Procurement
Procurement Candidate Bulk
bulk material obtained from industry
supplier provides Certificate of Analysis (CoA)
– Data and methodology to support CoA – MSDS, handling, storage and stability data as available For
donated bulks:
– Tax deductible donation – Supplier receives Evaluation Package – House bulk traceable to USP RS
RS Development: Collaborative Study
Collaborative
Study
A minimum
of three to five laboratories— USP, FDA, Health Canada, supplier, and/or other laboratory
Collaborators
thoroughly characterize each RS candidate using compendial and non-compendial tests
Collaborators
may or may not perform the same tests
RS Development: Collaborative Study Test
Methods Typically Employed:
Appearance Identification
Tests (e.g., NMR, IR, UV, etc.)
Indirect
purity tests (e.g. Melting range, Specific rotation, Refractive index, etc)
Direct
purity tests
– Chromatographic purity – Inorganic contaminants determination (ROI, etc.) – Volatiles (water, solvents) Functional Assays
group analysis (titration, UV/Vis, Elemental Analysis, etc.)
against another well-characterized standard
RS Development: Data Evaluation & Review Data
Evaluation and Internal Review
Analyze
Data/Value Assignment
– Mass balance approach 100% - % sum of all impurities (w/w) – Impurities including – Organic impurities by chromatography (e.g., process impurities), Inorganic impurities (e.g., catalyst, salt, etc), Volatile impurities (residual solvents, water) Prepare
RS Candidate Evaluation Package
– Demonstrate suitability for use in monograph tests – Create label text – Package size (sufficient quantity for the monograph uses), Handling directions (hazard level, light sensitive, hygroscopic), Storage conditions (room temperature, refrigerator, freezer), Shipping requirements Review
of RS material by an internal scientific panel and approval by a USP committee of experts
RS Development: Packaging, QC/QA, CSU
Packaging,
QC testing, QA review, External review, and Continuing Suitability for Use Determine
packaging configuration
– Humidity control/actinic light/O2 sensitive QC
testing/QA approval/Release
Approval
of suitability for compendial use by Expert Committee
Continuing
Suitability for Use (CSU) studies
Types of USP Reference Standards
There
are two main types of USP Reference Standards:
Standards
with Quantitative Applications
– Assays (for drug substances and for formulations) – Limit tests (e.g., Impurity Reference Standards) Standards
with only Qualitative Applications
– Identification tests – Elution markers – System Suitability tests
Reference Standard Usage
Proper
Reference Standard Use
RSs
are provided for use as required in pharmacopeial tests and assays
Suitability For
for other non-official application(s) rests with the purchaser
quantitative standards
– Purity of 100.0% unless labeled otherwise Value Use
assigned for assay and limit standards
the current or valid lot
– How do I determine the current lot? Subscribe to the USP Email Notice: http://www.usp.org/support-home/opt-information-service
USP Reference Standard Valid Use Date
From the USP Catalog… Catalog Number
1011007
Description
Current Lot
Purity Value/Conc.
Acitretin (200 mg)
F0E266
0.998 mg/mg (ai)
1049000 Bendroflumethiazide I0M111 0.994 mg/mg (200 mg) (ai)
Current Lot No Valid Use Date assigned
Change Code
2
Previous Lot Valid Use Date
H0C402 (03/14) G-1 (06/05)
CAS Number
Price
[55079-83-9]
$491
[73-48-3]
Lot H0C402, Valid for Use until March 31, 2014
Link to Expiration Dating Policy Statement for USP Reference Standards
$210
Proper Reference Standard Usage
How
to Dry a RS
Use
a clean and dry vessel
Do
not use original container as a drying vessel
Do
not dry a specimen repeatedly at temperatures above 25°
Reference Standard Storage
How Use
to Store a RS original stoppered containers
Keep
container tightly closed
Keep
away from heat
Protect Avoid When
from light
humid storage areas
special conditions are necessary, directions are given on the label
Proper RS Use And Storage—Labels
Label
text
– Provides storage and use information – Assigned value for standards with quantitative applications. – Safety warnings Label
text takes precedence over compendium or catalog
Additional
documentation provided where necessary (technical sheets or typical chromatograms)
MSDS
available at www.usp.org/products/MSDS/
RS Storage vs. Shipping Conditions
My
RS label says store in the freezer, but it shipped ambient. Is this a problem? – No. Label storage conditions are for long term storage. Shipping conditions are based on the individual compound’s stability during typical transit times. If special shipping is required, it is noted at time of order.
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New Reference Standard Release Notification Program The
New Reference Standard Release Notification Program notifies you when a new never-before-released Reference Standard becomes available
This
program does not communicate the release of back-ordered Reference Standards or lot changeovers
Visit
the link below and enter the Reference Standard(s) you are looking for – You will be notified of the status of the item as well as an estimated date of availability if the standard is in development
www.usp.org/referenceStandards/notificationProgram.html
New Reference Standards Under Development
List
of USP Reference Standards Under Development
Posted
on USP website List provides a 9-month preview of anticipated Reference Standard releases. Updated quarterly Downloadable as .xls file Item No.
1000437 1000521
Description
Abacavir Related Compound D Acarbose
Projected Release Date
Compendium
Apr1- Jun 30, 2013
MC
Apr1- Jun 30, 2013
USP
http://www.usp.org/reference-standards/find-referencestandard/reference-standards-under-development
Reference Standard Summary
USP
Reference Standards development reflects voluntary collaboration between USP, industry, and FDA laboratories
Collaborative
studies seek to establish suitability for intended use, purity and identity
Studies
employ compendial and non-compendial analytical tests to establish identity and verify structure
There
is value in the vial
USP Web Resources
Free Resources
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Compendial Tools Compendial Tools are documents, spreadsheets, databases, photographs, and other items that are intended to aid the user in the application of USP standards. These tools are not official, and do not affect the interpretation of the USP, NF, FCC, or any other USP-developed compendium. These tools are not intended to be used to determine that an article does or does not comply with compendial requirements, are not sufficient for that purpose, and should not be used in that manner. These tools are used at the user's own discretion and risk. The following Compendial Tools currently are available: •Calculation Tool for the Performance Verification Test (PVT) of Dissolution Assemblies •Dissolution Toolkit •Uniformity of Dosage Units (General Chapter<905>) Calculator •Column Equivalency •USP Four Parameter Logistic (4PL) Bioasay Simulator
Compendial Tools
USP Interactive Resources USP
Reference Standards Catalog – www.uspcatalog.com
USP Store
24/7
order access
Updated
every 24 hours
Order
tracking and order history
Ability
to personalize your ordering and shipping requirements
Order
confirmation
All
products (except controlled substances)
USP Store
Spirit of Voluntarism
Your Involvement with USP
USP–NF
– Submission of monographs, revision proposals – Comment through PF – Better understanding and use through Pharmacopeial Education – Council of Experts – Opportunity to impact public standards Reference
Standards
– Bulk donation – Participation in collaborative testing Become an USP Expert Volunteer
