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PHARMACEUTICAL REFERENCE STANDARDS

11th International Symposium organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe 3-4 September 2012, Strasbourg, France

Session 3 – Presentations (Part 2) Material Management / Technology Changes

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1HE / 04-09-2012 REMCO – ISO Committee on Reference Materials

REMCOISO/REMCO

Guides from the ISO Committee on

Reference Materials (ISO/REMCO)

Hendrik Emons

[email protected]


CENTRAL SECRETARIAT

Policy development committees:

• CASCO• COPOLCO• DEVCO• INFCO

Policy development committees:

• CASCO• COPOLCO• DEVCO• INFCO

GENERAL ASSEMBLY:• Principal officers• Delegates of:

– Member bodies– Correspondent members– Subscriber members

COUNCIL

Council standing committees:

• Finance• Strategies

Council standing committees:

• Finance• Strategies

Ad hoc advisory groups

Ad hoc advisory groups

TECHNICAL MANAGEMENT BOARD

REMCO

Technical advisory groups

Technical committees

ISO Structure

163 National Standards Bodies

> 19000 documentary standards

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ISO Committee on Reference Materials

ToR to …

… carry out and encourage a broad international effort for the harmonization and promotion of certified reference materials, their production and their application

… be the global centre of excellence in relation to issues relating to reference materials

ISO/REMCO


REMCO stakeholders and clientsRM Guidance for / by

User labs

Standards bodies

Metrology bodies Accreditors

RM Producers‘Application sector’

organisations

Regulators

Communication on RMs (terminology)

Handling & use of RMs

RM design& ‘production’

Needs for RMs

RMs’ role in measurement & testing systems

Selection of RMs

Evaluation of RMs

Evaluation of RM use

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Stakeholders

Standardisation bodies

Metrology institutions

International and regional liaison partners

Clients

ISO committees (horizontal advisory function)

Users of reference materials (e.g., analytical laboratories)

Producers of reference materials

Accreditation bodies (in particular for RM producers)

REMCO stakeholders and clientsREMCO Stakeholders & Clients


Reference Materials

Non-certified RMs Certified RMs

metrologically valid establish-ment of property value(s)

additional investigations

− homogeneous subsamples

− appropriate stability

− homogeneous subsamples

− appropriate stabilitymaterial

characteristics

• property value(s) traceable toadequate reference system

• stated meas. uncertainty• stated homogeneity & stability• intended use

• statements onhomogeneity & stability

accompanying information

calibration trueness control full method validation all QA/QC measures

performance controls(precision, consistency)of methods or labs(internal & external)

method developments

main applications

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ISO Guide 80on ‘minimum require-ments for in-house

preparation of in-house used RMs for quality

control

ISO TR 79on production of RMs

for “qualitative analysis” (testing of ‘nominal

properties’)

ISO Guide 33 on uses of RMs(incl. calibration, method validation & verification, control charts, value transfer, PTs…)

ISO Guide 30 on definitions & terminology related to RMs (incl. a thesaurus)

ISO Guide 35 on ‘characterisation and certification of

RMs’

ISO Guide 31 on accompanying documentation for RMs (content of certificates / RM labels / statements / transport docs, etc.)

ISO Guide 34 – covering the required ‘competence of RM producers’

The REMCO Family of Guides

The reference for accreditation

The reference for accreditation


Revision ISO Guide 34

Comparison of Guide 34:2009with Guide 34:2000Confirmed issues

Modifications

General clarifications and changes

Changes alignment with ISO/IEC 17025:2005

General requirements for the competence of testing and calibration laboratories

Changes alignment with ISO/IEC Guide 99:2007

International vocabulary of metrology – Basic and general concepts and associated terms (VIM3)

Changes alignment with ISO/IEC 17043:2010

Conformity assessment - General requirements for proficiency testing

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ISO Guide 30:1992 and its Amd1:2008- Terms and definitions used in connection with reference

materials (under revision)

ISO Guide 31:2000- Contents of certificates and labels (under revision)

ISO Guide 33:2000- Uses of certified reference materials (under revision)

ISO Guide 34:2009- General requirements for the competence of reference

material producers

ISO Guide 35:2006- General and statistical principles for certification

(under revision)

Main Activities – Published Guides…


ISO/D Guide 80 : under public enquiry

– Guidance for in-house Production of Reference Materials for Quality Control (QCMs)

Main Activities – New Guides…

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ISO/TR 10989:2009 - Guidance on and keywords used for RM categorization

ISO/TR 11773 - Global distribution of reference materials (under final stage for publication)

ISO/AWI TR 16476 - Establishing and expressing metrological traceability of quantity values assigned to reference materials (revised text discussed, Brainstorming session held in June 2012)

ISO/AWI TR 79 : Reference Materials for qualitative analysis -Testing of nominal properties (first text discussed)

Main Activities – Technical Reports…


38 ‘Observer’ members33 ‘Participating’ members

REMCO Members & ISO Liaisons

ISO/CASCO Committee on Conformity Assessment

ISO/TC34 Food products

ISO/TC158Analysis of gases

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AOAC AOAC International (formerly Association of Official Analytical Chemists)

BIPM International Bureau of Weights and Measures

CCQM Consultative Committee for Amount of Substance

CITAC Co-operation on International Traceability in Analytical Chemistry

EURACHEM Network of organizations concerned with analytical chemistry in Europe

IAEA International Atomic Energy Agency

IAG International Association of Geoanalysts

IFCC International Federation of Clinical Chemistry and Laboratory Medicine

ILAC International Laboratory Accreditation Cooperation

IRMM Institute for Reference Materials and Measurements, EC-JRC

IUPAC International Union of Pure and Applied Chemistry

OIML International Organization of Legal Metrology

PDG Pharmacopeia Discussion Group

UNESCO United Nations Educational, Scientific and Cultural Organization

WASPaLM World Association of Societies of Pathology & Laboratory Medicine

WHO World Health Organization

REMCO Liaison Members


Website:www.iso.org/remco

email:[email protected]

More information

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GHS Classification and labelling of pharmaceutical

reference substances

GHS Classification and labelling of pharmaceutical

reference substances

Jonna Sunell-Huet

European Directorate for the Quality of Medicines & HealthCare (EDQM),

Council of Europe

04/09/2012 ©2012 EDQM, Council of Europe. All rights reserved.

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ContentsContents

• GHS aims, involved parties and approach

• Regulatory framework and impact

• EDQM implementation

• Future consideration

• Recommendations

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Globally Harmonized System aimsGlobally Harmonized System aims

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Protect people and the environment; Remove international trade barriers; Harmonise Classification criteria for chemicals’ hazards and communication:

• Symbols • Signal words (Danger/Warning)• Hazard statements• Precautionary statements

To be provided on labels and safety data sheets


GHS: involved partiesGHS: involved parties

Recommend

Inspect

Implement

Manufacturers suppliers importers

users

Contribute

Regulate

UNECE OECDUNEP WCO


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Inform

GHS implementation in 67 countries

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ReferencesReferences1. UNECE GHS Globally Harmonized System of Classification

and Labelling of Chemicals of United Nations EconomicCommission for Europe.

2. OECD Guidelines for the Testing of Chemicals

3. UNEP/WHO SAICM Strategic approach to international chemicals management

4. WCO HS International Convention on the Harmonized Commodity Description and Coding System of the World Customs Organization

5. National/regional laws and regulations, such as, Regulations (EC) No 1272/2008, (EC) No 440/2008 and (EC) No 1907/2006


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GHS focusGHS focus

Intrinsic properties of chemicals

Irrespective of risks:• Quantities/volumes supplied

• Intended use

• User competence

• Handling conditions

• Protective equipment . . .


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Impact on reference material providersImpact on reference material providers

Rules apply to RM providers in the EU

Scope and classification may vary between countries


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H-statementsP-statementsWith translations

EU implementation - exclusionEU implementation - exclusionRegulation (EC) No 1272/2008 article 1(2)d:

“Substances and mixtures for scientific research and development1, which are not placed on the market2, provided they are used under controlled conditions in accordance with Community workplace and environmental legislation.”

1 means any scientific experimentation, analysis or chemical research carried out under controlled conditions

2 whether in return for payment or free of charge, to a third party. Includes import.


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EDQM approach in generalEDQM approach in general

The use of substances of very high concern is avoided in the standards and programs.

But in some cases their use is unavoidable.


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EDQM approach to classificationEDQM approach to classification1. Toxicity, physical hazards, ecotoxicity -

assessment is not in the EDQM / Ph. Eur. mandate

2. Classification for regulatory compliance only

3. Data taken from suppliers’ SDS

4. No access to raw data

5. No hazard testing at the EDQM premises

6. Not verified independently by the Ph. Eur. Commission


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EDQM approach to classificationEDQM approach to classification

• Classifications taken from Annex I to the Regulation (EC) No 1272/2008

• If not available, the GHS rules are applied as such

• No exceptions due to being an approved therapeutic or from well-established use

• Absence of classification = absence of hazard, but absence of data cannot be excluded


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Use of EDQM Safety Data SheetsUse of EDQM Safety Data Sheets

• Occupational health/environment protection of the supplied article for intended laboratory use only

• Not for quality attributes/testing/assays

• Not for substances of other suppliers

• Not for other regulatory use MAA, MRL…


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EDQM actions so farEDQM actions so far

• Collaboration with ECHA, UNECE/GHS, CARACAL and ISO REMCO

• 2800 pharmaceutical reference substances 67/548/EEC and GHS classified

• GHS classifications published for consultation

• SDS with GHS classification under translation

• Collaboration with European Association of Chemical Distributors (FECC), Codema


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Future considerationFuture consideration• Classifications are not yet stable

• Approach by WCO and customs?

• Re-labelling of pharmaceutical reference substances stock?

• Availability of pharmaceutical reference substances?


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RecommendationsRecommendations

To protect patients and people/environment:

• Move from substance hazard communication to risk management

• Avoiding exposure throughout the substance life-cycle

• Ensuring staff competence and training


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Thank youThank you

Any questions?


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04/09/2012

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Challenges associated with import and export of RS

11th International Symposium of Pharmaceutical Reference Standards

4 September 2012

Dr Steve WoodHead of Regulatory Measurement Services

Outline

• Understanding reference substances

• Rules & regulations governing import and export of reference substances

04/09/2012

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Reference Materials / Standards

• ISO Guide 30 Definition

– 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

• ISO Guide 34– 5.7.4 The reference material producer shall control packing and

labelling processes to the extent necessary to ensure conformity with safety and transport requirements

– 5.14.3 The stability of the material under transport conditions shall be assessed.

ISO Guide 34

• 5.18 Distribution service– 5.18.1 The distribution process shall be carefully studied to avoid

deterioration of the reference material (see 5.14.3). The producer shall determine the conditions of shipment, the maximal time the shipment may endure under the conditions chosen and what documentation is required to allow customs clearance.

• NOTE For some reference materials, additional documentation related to, for example, origin, conformity of the material to safety requirements, might be required for customs clearance.

– 5.18.2 The reference material producer shall maintain an up-to-date record of all reference material sales or distribution.

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Reference Substance Stability Testing

• Two aims of stability testing:– Long term – to establish behaviour over its lifetime

– Short term – to establish behaviour during transportation

Approaches to short term stability testing

• Use published and readily available information

• Use of data from related materials– materials, packaging and storage

• New stability study– Mimic conditions of distribution

– Isochronous design

Isochronous Stability Testing

Typical Stability Testing Programme

Storage Time

(months)

Storage Temperature

40C 20C 4C -18C

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2

3

• Some units stored at a reference temperature (e.g. -70°C) where no degradation is expected

• Units of material stored at test temperatures for required times

• All units, including reference units, analysed under repeatability conditions at same time - isochronous

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Import & Export of Reference Substances

• The free movement of reference materials is increasingly difficult and costly

• An earlier UK review identified – 12 international regulations which can severely restrict the free movement of

reference materials.

• Pharmaceutical reference substances often very small quantities (~100 mg)– But often treated as bulk amounts of the material

• Treated without consideration for their use

• ISO REMCO Technical Report – Global distribution of reference materials; March 2011; ISO/PDTR 11773

(Some) Regulations impacting import & export of reference substances

• Chemical supply regulation

• Dangerous chemicals

• Chemical weapons

• CITES

• Globally Harmonised System

• Preferential trade

• Black-lists, denied persons

• Re-Export USA

• Ozone depletion substances

• Dual-Use-goods

• Dangerous goods transport - road, air and sea

• Embargos

• Anti-Terror regulations

• Special Import regulations

• Customs regulation 3822.0000

• REACH

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Dangerous ChemicalsEU Regulation 689/2008

• Affects all European Union based companies involved with the export or import of chemicals or articles containing chemicals. It is commonly known as the Prior Informed Consent (PIC) Regulation

• A Reference Identification Number from the European database export import of dangerous chemicals (EDEXIM) Data Base has to be entered in electronic customs declarations

• Under EU Regulation 689/2008, all exporters of chemicals must:– comply with EU packaging and labelling requirements

– label export with expiry date and production date and give expiry date for different climatic zones;

– not export a chemical later than six months before its expiry date;

– include a safety data sheet (SDS) with export and send SDS to each importer; and

– provide label and SDS information in the official or principal languages of the destination country where practicable

Dual Use GoodsRegulation (EC) No 428/2009

• Goods and technologies are considered to be dual-use when they can be used for both civil and military purposes.– controlled items may not leave the EU customs territory without

an export authorisation.

• Special Codes are required for electronic customs declarations

• Export license from the responsible authority in relevant country (e.g. in Germany BAFA, UK BIS) is required

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Ozone LayerRegulation (EC) No 1005/2009


• For substances falling under this regulation, customers in EU have to provide the distributor their ID Number. – The Customer receives this ID No from the authorities at the EU in

Brussels.

• Export licence required for shipment to customer outside the EU – (e.g. in Germany baua = Bundesanstalt für Arbeitsschutz und

Arbeitsmedizin)

Anti TortureRegulation (EC) No 1236/2005


• For substances falling under this regulation a special export license is required, which is obtained from the relevant authorities (e.g. in Germany BAFA)

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Controlled Drugs

• Controlled Drugs (narcotics) and Drug Precursors (category 1 substances) are subject to import and export control restrictions.

• It is the responsibility of the customer to obtain necessary licences and other relevant documentation to comply with the laws of the importing country.

• Schedule 1 to 5 Controlled Drugs (narcotics):– For UK customers, a copy of the customers "Licence to Possess and Supply"

must be provided.

– For overseas (EU and Worldwide) customers, a valid Import Licence must be provided, detailing the name and address of the Exporter, the name and address of the Importer and the quantity of the controlled substance(s) required.

– A competent distributor/exporter will then obtain the relevant export licence(s) prior to shipment.

Controlled DrugsCategory 1 Substances (precursor chemicals)

• For European Union customers– a "Declaration of Specific Use" must be provided by the customer

– detailing the name, address and Authorisation/Licence/Registration number of the End User,

– the name and address of the Supplier,

– the quantity of the controlled substance(s) required and

– what the substance will be used for.

• For customers outside the EU, – a customer "Declaration of Specific Use" as above and

– a valid Import Licence detailing the name and address of the Exporter, the name and address of the Importer and the quantity of the Category 1 substance(s) required must be provided.

• A competent distributor/exporter will then obtain the relevant export licence(s) prior to shipment.

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Re-Export Law - USA

• Some pharmaceutical reference standards which have a USA origin may need re-export license issued by the US Department of Commerce, Bureau of Industry & Security for export to certain countries (http://www.bis.doc.gov/index.htm)

– Example: Sodium Fluoride from USP

Preferential Agreements

• The European Community has preferential agreements with a many countries in the world (e.g. Switzerland, Korea, Morocco, Mexico, Bosnia, Serbia etc.)

• Stating products are of European Preferential Origin reduces or even eliminates import duties

• To give that preferential statement on invoices (or EURO 1 document if the value if higher than 6000 Euro) a suppliers declaration for preferential origin is needed

• A declaration of origin can be a single declaration or a long term declaration for 1 year

• Some suppliers do not give such a declaration

• The rule for Origin Creation of a product is that the part should make a “Jump” in the custom tariff number, and normally this is achieved through substance has get analysis

• But….the WTO says that for pharmaceutical products you are NOT allowed to change the custom tariff number.

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CITES

• Scope– CITES is an international

agreement between Governments

– International trade in specimens of wild animals and plants does not threaten their survival

– Protects more than 30,000 species of animals and plants, whether they are traded as live specimens, fur coats, or dried herbs

• Impact– CITES protects a number of species, sub-species and populations.

– Species are categorised as most endangered

– Those not necessarily threatened with extinct/on now, but that may become so unless trade is closely controlled

REACH

• Registration, Evaluation, Authorisation and Restriction of Chemical Substances

– Registration if annual quantity supplied exceeds 1 Tonne (2018)

– Authorisation for substances of very high concern (SVHCs)• Only if mass fraction over 0.1%

• Reference substance production is unlikely to reach 1 Tonne production

• REACH does cover substances used for the production of pharmaceuticals

• SVHCs can be authorised for use for a specific purpose

• European Chemicals Agency

www.echa.europa.eu

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Dangerous Goods Transportation

• Dangerous goods (often called hazardous materials in the USA) may be pure chemicals, mixtures of substances, manufactured products or articles which can pose a risk to people, animals or the environment if not properly handled in use or in transport:

• Nine different 'Class' designators indicating the type of hazard a dangerous goods presents,

• Three 'Packing Groups‘ assigned to dangerous goods according to the degree of hazard they present.

– Packing Group I = great danger

– Packing Group II = medium danger

– Packing Group III = minor danger

• Staff need special training and retest every 2 years

• Additional cost (freight charges)

http://www.iata.org/training/Pages/trainingpartners.aspx

Dangerous Goods in excepted quantities

• Pharmaceutical reference standards which fall under the EQ classification are easier to ship by air

– But…. some couriers do not serve certain countries

– it is sometimes difficult and expensive to get them into certain countries (e.g. New Zealand)

• Staff are still required to undertake IATA training courses

Code Maximum Net Quantity per inner packaging(solids – g;Liquids & gases – mL)

Maximum Net Quantity per outer packaging(solids – g;Liquids & gases – mL)

E0 Not permitted as excepted quantity

E1 30 1000

E2 30 500

E3 30 300

E4 1 500

E5 1 300

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Dangerous Goods in limited quantities

• Some pharmaceutical Reference Substances are prepared for sale in vials which exceed the Excepted Quantities (EQ) limits

• These require a shipper’s declaration to be issued

• A Dangerous Goods Surcharge is charged by the Courier Companies

• In these cases it would help if producers would consider making smaller quantities into a vial so that goods fall again under the EQ regulation

• European Agreement concerning the International Carriage of Dangerous Goods by Road

– http://www.unece.org/trans/danger/publi/adr/adr2011/11ContentsE.html

Full Dangerous Goods in the Air (IATA) and on the Road (ADR)

• Standards which are over the limit of Limited Quantities (ADR) are full dangerous goods on the road and in the Air

• Courier options– DHL

– Fedex will, but only for certain destinations

• Door to door (DAP) shipments are difficult/expensive without Fedex– Alternative is door to terminal (DAT) shipments with the Airlines

• Prohibited products– Some pharmaceutical standards e.g.

isosorbide are forbidden to be transported by air

– These are difficult or impossible to export overseas

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Cool and Dry Ice Shipments

• Cool shipments– Standards which require cool shipping temperatures can only be shipped on

certain days

– Goods which stay in transit longer than 5 days are always a problem

– Add dry ice into the package that it stays cool longer?

• Dry Ice Shipments– Add as much dry ice into one box that the goods stay cool for up to 8 days

– In cases where the transport takes even longer, special boxes which can hold up to 30 kg dry ice can be used, increasing cooling to 10-14 days

– Dry ice top up services are available from some couriers

– Temperature indicators/recorders

• Dry Ice is also sometimes difficult to ship – Some major couriers only offer Dry Ice shipment to certain destinations

Customs Regulation 3822.0000

• Introduced in Jan 2002 for “certified reference materials”

• European Commission advice is that that this tariff number should be used for:– Pure substance (certified for im/purity)

– Standard solutions (certified for content)

– Matrix materials

– Physical standards for calibration/validation

• But local customs often view pure substances or solutions as excepted from 3822.0000

• Does not apply to uncertified materials– pharmacopoeia standards?

04/09/2012

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The Special Case for Reference Substances

• For– Small quantities

– Specifically for analytical purposes

– Often destroyed in use

– Circulating in a closed community

• Against– Difficulty of defining a reference material

– Little control or monitoring of end users

– Limited control of producers and distributors

Summary

• Many regulations impact the import & export of reference substances

• No recognition of small quantities involved

• Introduction of the general customs tariff number 3822.0000 has supported the global distribution of certified reference materials

– But experience shows that this UN tariff code is not acknowledged by all customs worldwide

• Interpretation of transport and import/export rules varies – customs station to customs station of the same country

– individual to individual

• Administrative requirements including required documentation for RM transport vary from country to country

• All these obstacles are even more difficult for non-certified reference materials

• Solution– Use an experienced distributor

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Acknowledgements

• Jane Firth Business Sector ManagerLGC Standards, UK

• Brigitte DeutschmannExport Manager,LGC Standards, GmbH

• Iris SchimpfTechnical Manager,LGC Standards, GmbH

• ISO REMCO WG 4Reference material transportation

THANK YOU FOR YOUR ATTENTION

QUESTIONS?

04/09/2012

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FAQs and Customer Feedback about USP Reference MaterialsShawn Dressman, VP, Standards AcquisitionLisa Corbin, Technical Services SpecialistDanielle Seiler, Market Research Manager

FAQs on usage of USP RSs

Why do some USP RS’s require a water determination? Many hygroscopic RS’s are labeled with the instructions to determine the water content titrimetrically at the time of use. The value is expected to vary from vial to vial; therefore, the water content determined for one vial cannot be used for another vial. In addition, if a vial is used more than once, a water determination must be performed prior to each use. The water value determined should be used to correct the weight of the standard in calculations.

Can a USP Reference Standard be used in an in-house method? You may be able to use USP Reference Standards for analytical or laboratory applications other than those specified in the USP–NF, but you are responsible for determining the suitability of the standards for the required purposes.

Can USP assist in the peak identification of a chromatogram for an RS or sample material? USP cannot review your data or advise you on the peak identification. This decision should be made by the user of the monograph based on your expertise.

When can one assume that the purity value of an RS is 100.0%? A purity value of 100.0% can be assumed if a USP RS has a quantitative USP compendial application and does not have a purity value provided on the label. If the RS is used only in qualitative USP compendial applications, 100.0% cannot be assumed. USP does not assign purity values to qualitative RS’s.

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FAQs on Shipping/Storage of USP RSs

What is the expiry date of a current lot? Current lots are not assigned valid use dates. As long as the lot is listed in the catalog as being the “current lot,” it is valid and suitable for use. Once the current lot is depleted, it becomes the “previous lot” and is assigned a valid use date.

Why are many USP RS’s not shipped as per the storage condition on the label? The storage conditions on the label are intended to preserve the integrity of the RS during long–term storage. Shipping conditions are determined based on the stability information for individual RS’s and transit times. If scientific evidence suggests the need to ship an RS on ice or dry ice, USP will do so.

Are the MSDS’s provided on the website the most up to date versions? Yes. U.S. law states that "an MSDS must be updated within three months after the manufacturer becomes aware of significant new health hazard information or new ways to protect against the stated hazard. The new MSDS should be passed on to the buyer or user with the next shipment of the chemical.“ OSHA currently requires no less than the 10-section format for MSDS's. USP complies with these requirements. It is the responsibility of the importer to provide MSDSs in the required format if different from the one provided by USP.

New and Upcoming Changes – Reference Standards

Purity Values Changed from “Dried Basis” to “As Is Basis” When Possible For the convenience of our customers, USP is now trying to label a USP RS “As Is" whenever possible. It is the preferred option and is selected whenever valid data indicates that the volatiles content is constant over time. The change to "as is" will not affect the USP compendial use of a Reference Standard.

International Cold Chain Shipment USP has determined that some RS’s must remain frozen during transit. They will be internationally shipped via World Courier who will re-ice shipments to ensure cold chain is maintained throughout the entire transit.

New Reference Standard Label Design New OSHA requirements as per GHS USP will begin to label new lots of RS’s as per the new rules set by GHS May begin to see changes as early as December Space limitations--some info not required by the new rules may be removed from the label and put onto the USP Certificate to make room for the required information

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Two-phased approach:– Focus group at 2010 IRSS (done)– Independent survey of USP customers (done)

Goals– Better meet the needs of USP Reference Standard

users around the world.– Use research results for: guiding regional marketing

strategies, evaluating new packaging and pricing options, and forecasting.

– Determine perceptions of USP - on a global basis.– Gauge interest in potential new USP product offerings

and configurations.

USP RS User Survey

22 individuals participated in 2 focus groups at the 2010 IRSS.

USP sought input on potential changes to label and certificate information, as well as perspective on Certified Reference Materials from USP.

Feedback • Some study participants were interested in – and associated real

benefits with – USP Certified Reference Materials (CRMs).

• Participants on the whole seemed supportive of the new certificate configuration, but some had real concerns over removing the purity value from the vial label.

• Need for more quantitative (survey) research.

Focus Group at 2010 IRSS

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1,388 participants in a 41 question survey.

Survey conducted by independent market research firm via email in March-April 2011.

Survey focused on user perceptions of USP RS quality, value, technical support, and possible new directions for USP RS program.

Survey was translated from English into Arabic, Chinese, Portuguese and Spanish.

Results showed regional differences.

RS User Survey

1. USP is perceived as a high quality provider of RS, especially in emerging markets.

2. 85% of respondents cite use of USP RS in QC setting; 54% cite R&D usage of USP RSs.

3. Limited interest in ‘single use’ packaging configurations from USP.

4. Interest exists in USP continuing to offer CRMs, especially strong from customers in Middle East, Africa, Asia, Central and South America.

Key Findings

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5

9

53

73

77

54

54

68

71

77

59

62

0 33 66

US

India

China

Europe

North America

Central‐South America

Asia‐Pacific

Middle East‐Africa

Weighted Average*

Overall

Percent Highly Interested (Rank of 8, 9 or 10)

Interest in Certified Reference Materials (CRMs)

Feedback on USP CRMs

•Weighted Average based on USP Reference Standard Unit Sales to Each Region.•“How interested would you or your organization/company be in Certified Reference Materials?” N=1,388.

Respondents are interested in CRMs, especially outside North America & Europe

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Can a Ph. Eur. Chemical Reference Standard be used in an in-house method?

Can EDQM assist in the peak identification of a chromatogram for an CRS or sample ?


Why are some Ph. Eur. CRS’s not shipped as per the storage condition on the catalogue?

The storage conditions on the catalogue are intended to preserve the integrity of the CRS during long–term storage. Shipping conditions are determined based on the stability information for individual CRS’s and transit times. CRS are shipped on ice or dry ice if scientific evidence requests these shipping conditions.

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When can one assume that the purity value of a CRS is 100.0%?

For Ph. Eur. assay CRS a value is provided

For any other quantitative CRS, purity is 100% unless otherwise indicated

For qualitative standards same as the USP : no purity value assigned


Ph. Eur. / USP different approach:

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Why Ph. Eur CRS’s do not require water/LOD determination?

o Because the material is established after filling into vials and the assigned value is given on an as is basis.

o Operating conditions during production are carefully selected to allow homogeneity of the water content of the filled vials.

o The homogeneity is controlled via a sampling plan.


How are the EDQM Reference Standards SDS managed?

All SDS provided on EDQM website are the most recent available.

The EDQM is in the process of revising all SDS for all European Pharmacopoeia Reference Standards in accordance with Annex II of the Regulation No (EC) 1907/2006 (format) and GHS requirements (classification and labelling).EDQM will provide them in all European languages as requested by law.Automatic alert with updated SDS will be sent to users having received the standard in the previous 12 months as requested by law.

The new SDS management system shall be implemented in 2013

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New labelling information for Ph. Eur. CRS

EDQM will start providing labelling information according to GHS (starting in 2013 with quantitative RS).

Due to space limitation and the amount of information to put on the label, it won’t be possible to put all on the primary label. Therefore additional information will be put on the accompanying leaflet.


How do I find out about expiry date of CRS?

o The policy of the Ph.Eur. (and the other pharmacopoeias) is to ensure continuous fitness for purpose and not to provide pre-defined expiry dates.

Monitoring programme in place

o Batch validity statement (BVS) for each reference standards (http://crs.edqm.eu/)

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Batch no. 3 is official atthe date of printing

Valid at printing date

How do I find about expiry date of CRS?


Date at which a batch becomes no longer valid

How do I find about expiry date of CRS?

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The CRS/BRP I ordered was shipped under ice but arrived thawed. Is it still usable?

o Temperature excursions outside the recommended shippingtemperature range are not supported by the data available

o In addition any case is different so the sample would need to be retested

On justified request EDQM will replace them and products should be safely disposed .


Can I prepare a secondary standard from a CRS of the European Pharmacopoeia?

Two answers are possible depending on the use of the CRS (in line with chapter 5.12. and ISO Guide 34):

A secondary reference standard is established against a primary standard using an unbroken chain of comparison

The uncertainty associated with the property value of interest of the primary reference standards shall be known

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QUALITATIVE USE:

Identification

— For use in infrared spectrophotometry

— For use in separation techniques (peak identification)

No uncertainty associated with the property « identity »

Yes you can prepare a secondary standard from this type of CRS



QUANTITATIVE USE

— Purity test. For use in separation techniques: a content relative to the signal from the primary standard is to be established.

— Assay. the property for which a value is to be assigned for the secondary standard is similar in magnitude to that of the primary reference standard with which it is compared.


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You need the uncertainty associated to the property value “content”.

The measurement uncertainty associated to the content value of Ph. Eur. CRS is not stated since it is considered to be negligible in relation to the defined limits of the method-specific assays for which they are used. (ex: content: 97.5 per cent to 102.0 per cent (dried substance))

(ISO Guide 34, chapter 5.17)

No you cannot prepare a secondary standard from this type of CRS


pharmaceutical reference standards - edqm · pdf file1 he / 04-09-2012 remco – iso...

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