USP Reference Standards

� 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 andhandle my USP RS?

� RS FAQs

USP Reference Standards Topics

� 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

What is a USP Reference Standard?

� “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.”

DRAFT FDA Guidance for Industry

� 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 since1936—over 70 years of history and experience

� 2013: >3000 standards with over 400 new RS in various stages of development

USP Reference Standards–History

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Reference Standards

�Procurement

�Candidate bulk material obtained from industry

�Bulk 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: Procurement

�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 group analysis (titration, UV/Vis, Elemental Analysis, etc.)

� Assays against another well-characterized standard

RS Development: Collaborative Study

� 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: Data Evaluation & Review

� 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

RS Development: Packaging, QC/QA, CSU

� 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

Types of USP Reference Standards

� Proper Reference Standard Use

� RSs are provided for use as required in pharmacopeial tests and assays

� Suitability for other non-official application(s) rests with the purchaser

� For quantitative standards

– Purity of 100.0% unless labeled otherwise

� Value assigned for assay and limit standards

� Use 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

Reference Standard Usage

USP Reference Standard Valid Use Date

Current LotNo Valid Use Date assigned

Lot H0C402, Valid for Use until March 31, 2014

From the USP Catalog…

CatalogNumber

Description CurrentLot

PurityValue/Conc.

ChangeCode

Previous LotValid Use Date

CAS Number Price

1011007 Acitretin (200 mg) F0E266 0.998 mg/mg (ai)

[55079-83-9] $491

1049000 Bendroflumethiazide(200 mg)

I0M111 0.994 mg/mg (ai)

2 H0C402 (03/14)G-1 (06/05)

[73-48-3]

$210

Link to Expiration Dating Policy Statement for USP Reference Standards

� 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°

Proper Reference Standard Usage

�How to Store a RS

� Use original stoppered containers

� Keep container tightly closed

� Keep away from heat

� Protect from light

� Avoid humid storage areas

� When special conditions are necessary, directions are given on the label

Reference Standard Storage

�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/

Proper RS Use And Storage—Labels

� 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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RS Storage vs. Shipping Conditions

� 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 Standard Release Notification Program

� 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

http://www.usp.org/reference-standards/find-reference-standard/reference-standards-under-development

New Reference Standards Under Development

Item No.

DescriptionProjected Release

DateCompendium

1000437 Abacavir Related Compound D

Apr1- Jun 30, 2013 MC

1000521 Acarbose Apr1- Jun 30, 2013 USP

� 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

Reference Standard Summary

USP Web Resources

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Free Resources

Compendial Tools

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

� USP Reference Standards Catalog

– www.uspcatalog.com

USP Interactive Resources

� 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

USP Store

Spirit of Voluntarism

�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

Your Involvement with USP