PHARMACEUTICAL REFERENCE STANDARDS

Transcription

1 PHARMACEUTICAL REFERENCE STANDARDS 11 th 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

2 ISO/REMCO Guides from the ISO Committee on Reference Materials (ISO/REMCO) Hendrik Emons Chair HE / REMCO ISO Committee on Reference Materials 1 ISO Structure Policy development committees: CASCO COPOLCO DEVCO INFCO Council standing committees: Finance Strategies GENERAL ASSEMBLY: Principal officers Delegates of: Member bodies Correspondent members Subscriber members COUNCIL TECHNICAL MANAGEMENT BOARD Ad hoc advisory groups CENTRAL SECRETARIAT 163 National Standards Bodies > documentary standards REMCO Technical advisory groups Technical committees HE / REMCO ISO Committee on Reference Materials 2 1

3 ISO/REMCO 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 HE / REMCO ISO Committee on Reference Materials 3 REMCO RM stakeholders Guidance for and / byclients RMs role in measurement & testing systems Needs for RMs RM design & production Selection of RMs Handling & use of RMs Communication on RMs (terminology) Evaluation of RMs Evaluation of RM use Metrology bodies Regulators Accreditors User labs HE / Standards bodies RM Producers Application sector organisations REMCO ISO Committee on Reference Materials 4 2

4 REMCO stakeholders Stakeholders and & Clients clients 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) HE / REMCO ISO Committee on Reference Materials 5 Reference Materials Non-certified RMs homogeneous subsamples appropriate stability material characteristics Certified RMs homogeneous subsamples appropriate stability HE / statements on homogeneity & stability performance controls (precision, consistency) of methods or labs (internal & external) method developments additional investigations accompanying information main applications metrologically valid establishment of property value(s) property value(s) traceable to adequate reference system stated meas. uncertainty stated homogeneity & stability intended use calibration trueness control full method validation all QA/QC measures REMCO ISO Committee on Reference Materials 6 3

5 The REMCO Family of Guides ISO Guide 34 covering the required competence of RM producers The reference for accreditation ISO Guide 80 on minimum requirements for in-house preparation of in-house used RMs for quality control ISO TR 79 on production of RMs for qualitative analysis (testing of nominal properties ) ISO Guide 35 on characterisation and certification of RMs ISO Guide 33 on uses of RMs (incl. calibration, method validation & verification, control charts, value transfer, PTs ) ISO Guide 31 on accompanying documentation for RMs (content of certificates / RM labels / statements / transport docs, etc.) ISO Guide 30 on definitions & terminology related to RMs (incl. a thesaurus) HE / REMCO ISO Committee on Reference Materials 7 Revision ISO Guide 34 Comparison of Guide 34:2009 with Guide 34:2000 Confirmed 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 HE / REMCO ISO Committee on Reference Materials 8 4

6 Main Activities Published Guides ISO Guide 30:1992 and its Amd1: Terms and definitions used in connection with reference materials (under revision) ISO Guide 31: Contents of certificates and labels (under revision) ISO Guide 33: Uses of certified reference materials (under revision) ISO Guide 34: General requirements for the competence of reference material producers ISO Guide 35: General and statistical principles for certification (under revision) HE / REMCO ISO Committee on Reference Materials 9 Main Activities New Guides ISO/D Guide 80 : under public enquiry Guidance for in-house Production of Reference Materials for Quality Control (QCMs) HE / REMCO ISO Committee on Reference Materials 10 5

7 Main Activities Technical Reports ISO/TR 10989: Guidance on and keywords used for RM categorization ISO/TR Global distribution of reference materials (under final stage for publication) ISO/AWI TR 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) HE / REMCO ISO Committee on Reference Materials 11 REMCO Members & ISO Liaisons 33 Participating members 38 Observer members ISO/TC34 Food products ISO/TC158 Analysis of gases ISO/CASCO Committee on Conformity Assessment HE / REMCO ISO Committee on Reference Materials 12 6

8 REMCO Liaison Members AOAC BIPM CCQM CITAC EURACHEM IAEA IAG IFCC ILAC IRMM IUPAC OIML PDG UNESCO WASPaLM WHO AOAC International (formerly Association of Official Analytical Chemists) International Bureau of Weights and Measures Consultative Committee for Amount of Substance Co-operation on International Traceability in Analytical Chemistry Network of organizations concerned with analytical chemistry in Europe International Atomic Energy Agency International Association of Geoanalysts International Federation of Clinical Chemistry and Laboratory Medicine International Laboratory Accreditation Cooperation Institute for Reference Materials and Measurements, EC-JRC International Union of Pure and Applied Chemistry International Organization of Legal Metrology Pharmacopeia Discussion Group United Nations Educational, Scientific and Cultural Organization World Association of Societies of Pathology & Laboratory Medicine World Health Organization HE / REMCO ISO Committee on Reference Materials 13 More information Website: remco@iso.org HE / REMCO ISO Committee on Reference Materials 14 7

9 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/ EDQM, Council of Europe. All rights reserved. 1 Contents GHS aims, involved parties and approach Regulatory framework and impact EDQM implementation Future consideration Recommendations 04/09/ EDQM, Council of Europe. All rights reserved. 2 1

10 Globally Harmonized System aims 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 04/09/ EDQM, Council of Europe. All rights reserved. 3 GHS: involved parties Recommend Regulate Implement UNECE OECD UNEP WCO Contribute Inspect Inform Manufacturers suppliers importers users GHS implementation in 67 countries 04/09/ EDQM, Council of Europe. All rights reserved. 4 2

11 References 1. UNECE GHS Globally Harmonized System of Classification and Labelling of Chemicals of United Nations Economic Commission 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/ /09/ EDQM, Council of Europe. All rights reserved. 5 GHS focus Intrinsic properties of chemicals Irrespective of risks: Quantities/volumes supplied Intended use User competence Handling conditions Protective equipment... 04/09/ EDQM, Council of Europe. All rights reserved. 6 3

12 Impact on reference material providers Rules apply to RM providers in the EU Scope and classification may vary between countries H-statements P-statements With translations 04/09/ EDQM, Council of Europe. All rights reserved. 7 EU implementation - exclusion Regulation (EC) No 1272/2008 article 1(2)d: Substances and mixtures for scientific research and development 1, which are not placed on the market 2, 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. 04/09/ EDQM, Council of Europe. All rights reserved. 8 4

13 EDQM 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. 04/09/ EDQM, Council of Europe. All rights reserved. 9 EDQM approach to classification 1. 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 04/09/ EDQM, Council of Europe. All rights reserved. 10 5

14 EDQM 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 Noexceptions due to being an approved therapeutic or from well-established use Absence of classification = absence of hazard, but absence of data cannot be excluded 04/09/ EDQM, Council of Europe. All rights reserved. 11 Use 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 04/09/ EDQM, Council of Europe. All rights reserved. 12 6

15 EDQM 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 04/09/ EDQM, Council of Europe. All rights reserved. 13 Future consideration Classifications are not yet stable Approach by WCO and customs? Re-labelling of pharmaceutical reference substances stock? Availability of pharmaceutical reference substances? 04/09/ EDQM, Council of Europe. All rights reserved. 14 7

16 Recommendations 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 04/09/ EDQM, Council of Europe. All rights reserved. 15 Thank you Any questions? 04/09/ EDQM, Council of Europe. All rights reserved. 16 8

17 04/09/2012 Challenges associated with import and export of RS 11th International Symposium of Pharmaceutical Reference Standards 4 September 2012 Dr Steve Wood Head of Regulatory Measurement Services Outline Understanding reference substances Rules & regulations governing import and export of reference substances 1

18 04/09/2012 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 The reference material producer shall control packing and labelling processes to the extent necessary to ensure conformity with safety and transport requirements The stability of the material under transport conditions shall be assessed. ISO Guide Distribution service The distribution process shall be carefully studied to avoid deterioration of the reference material (see ). 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 The reference material producer shall maintain an up-todate record of all reference material sales or distribution. 2

19 04/09/2012 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 Storage Temperature (months) 40 C 20 C 4 C -18 C 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 3

20 04/09/2012 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 (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 REACH 4

21 04/09/2012 Dangerous Chemicals EU 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 Goods Regulation (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 5

22 04/09/2012 Ozone Layer Regulation (EC) No 1005/2009 Special Codes are required for electronic customs declarations 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 Torture Regulation (EC) No 1236/2005 Special Codes are required for electronic customs declarations For substances falling under this regulation a special export license is required, which is obtained from the relevant authorities (e.g. in Germany BAFA) 6

23 04/09/2012 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 Drugs Category 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. 7

24 04/09/2012 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 ( 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. 8

25 04/09/2012 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 9

26 04/09/2012 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) 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 E E E E E

27 04/09/2012 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 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 11

28 04/09/2012 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 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 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 Does not apply to uncertified materials pharmacopoeia standards? 12

29 04/09/2012 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 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 13

30 04/09/2012 Acknowledgements Jane Firth Business Sector Manager LGC Standards, UK Brigitte Deutschmann Export Manager, LGC Standards, GmbH Iris Schimpf Technical Manager, LGC Standards, GmbH ISO REMCO WG 4 Reference material transportation THANK YOU FOR YOUR ATTENTION QUESTIONS? 14

31 04/09/2012 FAQs and Customer Feedback about USP Reference Materials Shawn Dressman, VP, Standards Acquisition Lisa Corbin, Technical Services Specialist Danielle 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. 1

32 04/09/2012 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 2

33 04/09/2012 USP RS User Survey 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. Focus Group at 2010 IRSS 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. 6 3

34 04/09/2012 RS User Survey 1,388 participants in a 41 question survey. Survey conducted by independent market research firm via in March-April 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. Key Findings 1. USP is perceived as a high quality provider of RS, especially in emerging markets % 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. 4

35 04/09/2012 Feedback on USP CRMs Respondents are interested in CRMs, especially outside North America & Europe Interest in Certified Reference Materials (CRMs) Overall Weighted Average* Middle East Africa Asia Pacific Central South America North America Europe China India US Percent Highly Interested (Rank of 8, 9 or 10) 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,

36 FAQ on CRS of the European Pharmacopoeia Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved Ph. Eur. / USP same approach: Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 1

37 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? Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 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. Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 2

38 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 Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved Ph. Eur. / USP different approach: Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 3

39 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. Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 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 Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 4

40 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. Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 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 predefined expiry dates. Monitoring programme in place o Batch validity statement (BVS) for each reference standards ( Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 5

41 How do I find about expiry date of CRS? Valid at printing date Batch no. 3 is official at the date of printing Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved How do I find about expiry date of CRS? Date at which a batch becomes no longer valid Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 6

42 The CRS/BRP I ordered was shipped under ice but arrived thawed. Is it still usable? o Temperature excursions outside the recommended shipping temperature 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. Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved Can I prepare a secondary standard from a CRS of the European Pharmacopoeia? 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 Two answers are possible depending on the use of the CRS (in line with chapter and ISO Guide 34): Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 7

43 Can I prepare a secondary standard from a CRS of the European Pharmacopoeia? 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 Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved Can I prepare a secondary standard from a CRS of the European Pharmacopoeia? 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. Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 8

44 Can I prepare a secondary standard from a CRS of the European Pharmacopoeia? 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 per cent (dried substance)) (ISO Guide 34, chapter 5.17) No you cannot prepare a secondary standard from this type of CRS Vincent Egloff, 04/09/ EDQM, Council of Europe, All rights reserved 9