Regulatory Guide On Reference Standard

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 1 Presentations (Part 2) Regulatory Aspects
04/09/2012
USE OF REFERENCE STANDARDS AND QUALITY CONTROL: EXPERIENCES AND UNMET NEEDS
Strassburg 3.Sep.2012
Reference Standards and Quality Control Substances and Products in Quality Control Reference Standard Team Sources of Reference Substances Definitions Establishment of Secondary Reference Standards Shelf life of Reference Substances Retest of Reference Substances Storage of Reference Substances Labelling of Reference Substances Unmet Needs Helpful links
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Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
Substances and Products in Quality Control 300 active pharmaceutical ingredients 500 other ingredients ca. 1500 receipts - self manufactured products - from 3rd party manufacturers more than 2000 different primary and secondary reference substances
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Reference Standard Team Five experienced chemical technicians Responsibilities: - Sourcing of Standard Substances - Administration, Organisation and Documentation - Bottling and labelling of standard vials - Distribution of standards to the labs - Shipment of standards to authorities and partners worldwide
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Sources of Reference Substances Ph.Eur. (CRS, BRS) BP, USP. International Pharmacopeia (ICRS) WHO International Standards for Antibiotics Deutscher Arzneimittel Codex (DAC) Manufacturers of APIs Reference substance suppliers (e.g. LGC standards) Suppliers of chemical substances (Merck, SigmaAldrich, VWR)
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Definitions according to Ph. Eur. European Pharmacopoeia Chemical Reference Substance (CRS) A substance or mixture of substances intended for use as stated in a monograph or general chapter of the European Pharmacopoeia. European Pharmacopoeia Chemical Reference Substances are primary standards, except for those (notably antibiotics) that are calibrated in International Units. The latter are secondary standards traceable to the international standard. (e.g. Gentamicin CRS)
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Definitions according to Ph. Eur. Primary Reference Standard A standard shown to have suitable properties for the intended use, the demonstration of suitability being made without comparison to an existing standard. Secondary Reference Standard A standard established by comparison with a primary standard.
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Intended Use of Reference Substances Identity Assay Chemical purity System suitability test
Suitable for the intended use!
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Establishment of Secondary Ref. Standards 2 samples of primary reference standard 6 samples of intended secondary reference standard Use of a validated chromatographic assay method Plausibility check - using independent methods e.g. titration x chromatographic purity or - crosscheck against former standard batch
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Shelf life of Reference Substances Pharmacopeial reference standards - Ph.Eur.: batch validity statement (BVS) www.edqm.eu - BP - USP : current batch no. System www.bpclab.co.uk : daily listings of current lots www.usp.org
Secondary reference standards (regularly) - expiry / retest date based on suppliers data (not longer) - expiry / retest date 2 years after receipt
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Shelf life of Reference Substances (continued) Impurity standards: - quantitative use max. 2 year after first receipt - qualitative use max. 5 years after receipt requirement: chem. purity > 80%
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Retest of Reference Substances No retests for pharmacopoeial standards if stored in the original unopened container and appropriate conditions Depending on the chemical and physical properties of the substance - extend of retesting identity, assay, chemical purity, loss on drying etc. - retest date regularly once per year hygroscopic substances: water content every 3 months
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Storage of Reference Substances Primary pharmacopoeial standards - original unopend container - refrigerator (2 -8C, unless otherwise prescribed) Other standards - air tight and light protected container - depending on physical and chemical properties e.g. sensitive to oxygen (storage under inert gas) hygroscopic (desiccator) sensitive to temperature (refrigerated / deep frozen)
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Labelling of Reference Substances Material name Material no. Batch no. Sample no. Retest/expiry date Storage conditions RT room temperature KS refrigerator (2 8 C) TK deep freezer (> - 15C) EX exsiccator Storage place
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Unmet Needs Replacement of assays by titration by chromatographic assay method CRS with assigned content Availability of Pharmacopoeial Reference Standards e.g. Arcabose; Ceftazidime Imp. A (replaced by CRS for peak ID) CRS should be available before a new monograph comes into force to be able to implement the methods in the labs.
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Unmet Needs (continued) Unsufficient quantities of CRS per vial Missing information of the form of APIs and impurities (HCl, Base, Hydrate etc.) Empirical formula of impurities should be given Plausibility check (old versus new CRS) should be introduced during establishment of new CRS batches
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Unmet Needs (continued) Unspecified impurities listed in the transparency list are not available as CRS. Allocation of these impurities in sample chromatograms and/or relative retention times should be published in the knowledge data base. Since the allocation of impurities is often problematic peak-identification mixtures in conjunction with sample chromatograms would be preferable.
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Unmet Needs (continued) Indicate which impurities are degradation - or by products. The latter do not have to be considered in the finished pharmaceutical products. Numbering of impurities: Identical impurities are used in different monographs. However, in one case it is Imp. A in another Imp. B. Harmonisation would be helpful and may reduce costs. e.g. Enalapril Maleate / Enalaprilat Dihydrate: Imp. B < -- > Imp. F
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Helpful links and publications Ph. Eur.: 5.12. Reference Standards BP: www.pharmacopoeia.gov.uk/reference-standard USP: www.usp.org/reference-standards EDQM: www.edqm.eu/en/Ph-Eur-Reference-Standards-627.html PH.Eur. Reference Standards www.edqm.eu/en/quality-management-guidelines-86.html Handling and use of reference standards in the OMCL network
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Helpful links and publications (continued) ISO - Guide 30: Terms and definitions used in connection with reference materials - Guide 31: Reference materials -- Contents of certificates and labels - Guide 34: General Requirements for the Competence of Reference Material Producers - Guide 35: Certification of reference materials. General and statistical principles
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Helpful links and publications (continued) K. Albrecht (2007): Referenzsubstanzen fr DACAlternativverfahren, Pharm. Zeitung online 49 U. Lipke et al. (2008): Internationale Einheiten oder Milligramm, DAZ.online 50
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SYMPOSIUM PHARMACEUTICAL REFERENCE STANDARDS 03-04 September 2012, STRASBOURG, France
Management of Reference Standards within Sanofi: Experiences and Challenges

Joachim Ermer, Sanofi 03 September, 2012
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Sanofi Structure of RS Management

Scope: (chemical) reference standards within Industrial Affairs Dual structure: centralised / decentralised Centralised storage, distribution, management & coordination by Reference Standards Logistics (RSL) groups
Frankfurt (Germany) and Sisteron (France) Storage facilities: 25C, 4-8C, -20C, -80C (~120 m2) ~ 2000 substances (~ 350 kg) ~ 400 retests / characterisations per year ~ 2500 orders (~ 22 000 units) ~ 500 customers (internal & external)
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Sanofi Structure of RS Management
Decentralised testing by expert laboratories (40)

Performing all required analytical tests (characterisation and retests) QC laboratories, where routine testing of the respective API/substance is performed Process Development for special analysis (including structural identification)
Reference Standards Processes

Request internal testing sites Industrial production site, Process development (PD) External source Expert Labs PD (special tests) IQC (routine tests)
Need of RS (replacement, new) Monitoring (stocks retest dates)
Identification of source
Coordination of characterisation
Retest
Generation of certificate valid RS inclusion in data base R&D, PD new products
Processing of orders, invoice, up-date of data base
Online order
IntraNet RSL Homepage
04/09/2012
RSL Responsibilities

Timely supply of reference standards to external and internal customers (QC sites, API customers, compendia) Appropriate storage and distribution of reference standards
In accordance with CLP regulation
Online ordering system via IntraNet

Download possibility of RS certificates
Assurance of availability of sufficient quantities

Monitoring of inventory and retest dates
Organisation and coordination of synthesis and characterization or retest of reference substances by PD and expert laboratories Issuing of certificates (Reference Standard Data Sheet, RSDS) based on data from expert labs
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Types and Traceability of RS

Compendial Standard Structural Elucidation
Official Standard Reference Material Working Standard
Primary Standard
Routine use (release testing, stability, investigations )
Identity, SST
Content & Identity

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Types of RS: Official Standard (OS)

If a Sanofi batch was delivered to a Compendia (direct use) Characterisation: Not required Identification: Confirmation document from Compendia Use: Identity or content, as defined by the Compendia Declared Content: as defined by the Compendia Storage conditions: as defined by the Compendia or stricter Retest date:
Same as (former) internal RS (for label required) No retest, extension at the end of retest period (as long as compendial standard is valid)
Regular verification of validity of the respective compendial standard

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Types of RS: Primary Standard (PS)

Source: Routine production batch: API (purity > 99.5%), intermediate, starting material,
additional purification if required
Identification: structural elucidation (NMR, MS, etc.) Use:

Identity and content determinations (routine use) Characterisation of Working Standards (non-routine use)
Characterisation: thorough purity investigations

Related substances LC Inorganic impurities Residual solvents, water, etc.
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Types of RS: Primary Standard (PS)
Declared Content (as is):

Calculation
LC Purity (%)
100 water solvents other imp. 100
Confirmation: comparison to absolute method (e.g. titration, N-determination, NMR)
Storage conditions: < -15 C (non-routine use) or as WS Retest date: twice of API (storage < -15 C) or as WS
Types of RS: Working Standard (WS)

Source: routine production batches
API (purity > 98%) intermediate, starting material (purity > 95%)
Identification: vs. PS or OS (or compendial monograph tests) Use: Identity and content determinations Characterisation: at least routine release tests Declared content:
Calculation (if purity > 98%): see PS Confirmation: assay vs. PS / OS or absolute method Assay vs. PS / OS (if purity < 98% or lyophilisates)
Storage conditions: as API or stricter Retest date: as API or as covered by stability/retest data
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04/09/2012
Types of RS: Reference Material (RM)

Source: isolated or synth. impurity, intermediate or starting material (purity > 90%), API batch containing or spiked with impurities Identification: vs. OS or verification of structure (IR, MS, NMR)
Impurity-containing API: vs. impurity RS
Use: Identity, system suitability tests Characterisation: chromatographic purity Declared Content: none (beyond use)
Purity or calculated content (if additional determinations were performed) may be given for information purpose
Storage conditions: as related API or stricter Retest date: as related API or as covered by stability/retest data
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Challenges: Multi-dedicated Use

Application for both API and drug product testing Characterisation is usually performed by API-LC-method Use: LC-methods for drug product may differ (although similar) Risk minimisation for content determination:
High purity of WS: less risk of potential impurity interference
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Challenges: Spiked RS

Material spiked with / containing impurities Variation of retention time possible due to
Method (API vs. DP) Column (also relevant for compendial RS with unique method)
Potential uncertainty of impurity assignment Risk minimisation: different amount (peak area) of impurities
i.e. second dimension
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Challenges: Additional Use

Beyond routine application Example: impurity RM, content is needed for validation (recovery) Content or purity is given on the RSDS as Additional Information Clear indication of lower level of characterisation to avoid misunderstandings in routine application User has to evaluate whether additional information is sufficiently reliable for the respective non-routine use Larger uncertainty should be considered in validation acceptance criteria
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Challenges: Hygroscopic Substances
Definition: uptake of water > 0.2 % at 80% relative humidity [Pharm. Eur. 5.11]
Determination by dynamic vapor sorption (DVS)
Very hygroscopic WS:

single ready-to-use units (e.g. ampoules) with assigned content
Other hygroscopic WS
Multiple-use units (as normal RS) Declared content: on anhydrous or dried basis At time of use: determination of water or loss on drying and recalculation of content as is
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Challenges: Use of Compendial RS

Sometimes lack of clarity for use of compendial standards Standards used for quantitation not always have an assigned content Should also reflect the higher level of characterisation required for quantitative RS
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ACKNOWLEDGEMENTS
Thomas Klein Head of RSL Frankfurt
THANK YOU FOR YOUR ATTENTION
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Establishment of Reference Standards Chinas Point of View

Li Bo, Ph.D.
National Institutes for Food and Drug Control, China 3 September 2012
Outline
Reference standards related laws and
regulations in China
Management system of reference standards NIFDC reference standards overview
04/09/2012
Laws and regulations
1. Drug Administration Law of P.R China

Chapter V : Drug administration
Article 32: The drug testing institution affiliated to the drug regulatory agency under the state council is responsible for establishing national reference standards.
Laws and regulations (Cont.)

2. Drug Registration Regulation
Article 140: National Institutes for Food and Drug Control (NIFDC) is responsible for the characterization of national reference standards. NIFDC could organize local drug testing institutes, drug research institutions and/or drug manufacturers to undertake collaborating study on reference standards.
National Institute of Food and Drug Control
Http://www.nifdc.org.cn
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Article 141: NIFDC is responsible for the overall evaluation of the data package of reference standards regarding with candidates sourcing, characterizing methods, value assignment, traceability, production procedure, stability, filling and packaging conditions etc, and is responsible for making final conclusion on the suitability of using as national reference standards.
National Institute of Food and Drug Control
Http://www.nifdc.org.cn
3. Medical Devices Regulation

NIFDC is responsible for the characterizing, preparation,
and providing the national reference standards of in-vitro diagnostic reagents.
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Ministry of Health (MoH) State Food and Drug Administration Office of the Commissioner Chinese Pharmacopeia Commission National Institutes for Food and Drug Control (NIFDC)
Center for Drug Evaluation (CDE)
National Center for Adverse Drug Reaction Monitoring
Center for Drug Certification (CCD)
Center for Medical Device Evaluation (CMDE)
Center for Health Food Evaluation
Center for Pharmaceutical International Exchange
RS management system
Major responsibilities of NIFDC:
Test pharmaceutical and biological products, medical devices, food and cosmetics, pharmaceutical excipient, and packaging materials Prepare national reference standards Compendial methods development and validation
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National Institutes for Food and Drug Control (NIFDC) Office of the Directors
Institute for Food and Cosmetics
Institute for Chinese Traditional Medicine and Ethnic Medicine
Institute for Chemical Drug Institute for Medical Devices
Institute for Biological Product
Institute for Packaging Material and Pharmaceutical Excipient
Institute of Reference Standards and Standardization (IRSS)

Institute for Food and Drug Safety Evaluation
Institute for Laboratory Animal Resources Institute for Food and Drug Technical Surveillance
Institute for Medical Device Standardization Administration
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RS management system (Cont.)

Major responsibilities of IRSS: Responsible for all activities related to the establishment and management of RS. These activities mainly include: - RS candidate sourcing, - RS characterizing, collaborating studies, production and distribution, - RS storage and stability monitoring & evaluation.
RS management system (Cont.)

There are three scientific divisions under IRSS: Division of RS preparation Division of RS Supply Division of RS Research and Development In addition to these three divisions, NIFDC also has specified teams in each lab in terms of the products they analyze to conduct RS characterizing and collaborating studies.
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NIFDC RS overview
NIFDC currently provides more than 3400 reference Standards nationwide, which Include chemical RS, biological RS, biological RM, referential herbal drugs, medical devices RS , and in-vitro diagnostic reagents RS.
NIFDC RS overview (Cont.)

Year 2005 2006 2007 2008 2009 2010 2011 Chemical RS 906 931 1013 1053 1116 1580 1880 Chemical RS from TCM 337 391 403 435 440 565 590 Referential herbal drugs 572 623 641 652 654 690 720 Biological RS 109 126 153 164 175 190 210 Total 1924 2071 2210 2304 2385 3025 3400
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NIFDC RS overview (Cont.)

2010 Chp Volume I Chemical RS from TCM463 Herbal drugs RS Referential extract 2010 Chp Volume II Reference standards: 36 Reference substances: 870 906 369 16 1754 848
Question?
ESTABLISHMENT OF REFERENCE STANDARDS: POINT OF VIEWS OF INTERNATIONAL AUTHORITIES

Shigeki TSUDA, Senior Managing Director, PMRJ (Japan) 11th IRSS, at EDQM, Strasbourg 3rd September, 2012
Disclaimer
Views expressed in these PowerPoint slides are my own and do not represent the official positions of the Japanese Pharmacopoeia (JP).
Contents

Globalising and Changing World Basic Policy of Japanese Pharmacopoeia (JP) Meaning and Significance of Establishing its own Standards Reality and Future
Globalising and Changing World
US imports 80% of drug substances and 40% of preparations from foreign countries/ areas. Japan is said to import more than 50% of drug substances from overseas. How about the member countries of European Union or Council of Europe?
Policy of JP in standard setting
JP concentrated in developing the standards reflecting the whole picture of drug substances approved and used in Japan Therefore, the experts and the secretariat have hardly paid attention to the standards of other pharmacopoeias. There may be many cases where the monographs of the same drug substance differ slightly (not significantly different) among leading pharmacopoeias. Who is the beneficiary?
Meaning and Significance of Setting Up Its Own Standards
Sovereignty: Key word for not referring to major pharmacopoeias where most new monographs appear for the first time Is there New and another approach ? API producers in newly industrialising countries are said to respect the monograph of the pharmacopoeia in originating country/ region of the drug.
Reality and Future -1
Large and representative pharmacopoeias in the world: Ph. Eur. and USP (number of monographs, quality, new ideas etc.) JP, a medium-sized pharmacopoeia but with limited resources JPs challenges include introduction of impurity RSs, harmonisation of chromatography (in PDG) and information disclosure of impurities, column brand
Reality and Future -2
Use of generics is (rapidly) increasing in many countries including Japan. A nave idea may be that the standard of the pharmacopoeia of the country or region where the new drug was developed is respected by other pharmacopoeias. We see Global meetings on pharmacopoeia have suddenly increased. Some union of medium and small pharmacopoeias???
Thank you for your kind attention!
JPRS Lab
Japanese Pharmacopoeia Reference Standards Laboratory
2012-09-04
Establishment and Management of KFDA Reference Standards
In-Kyu Kim Ph.D.
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Contents
IV Organization The Korean Pharmacopoeia
Reference Standards
Future and International Cooperation
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I-1 History of KFDA

2009
- Reorganized in 2009 1 officer, 5 bureaus (1 officer and 4 departments), 48 divisions, - Criminal Investigations Office, and Foreign Inspection Division were established < 1413 staff members > KFDA-636 NIFDS-238 Reg.KFDA-539
2005 1998 1996
- Restructured in 6 Headquarters, 4 departments - Team-based system was introduced <1200 staff members>
- Founded in Feb, 1998 (KFDA) - 2 divisions, 6 departments, and 5 chief officers, 8 departments, 23 sections < 776 staff members >
- Established in April, 1996 - Food and Drug Safety Headquarter
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I-2 Organization of KFDA

Commissioner
National Institute of Food and Drug Safety Evaluation (NIFDS) Criminal Investigations Office Spokesperson Deputy Commissioner Audit and Inspection Officer
1,500 personnel
General Service Division
Panning & Coordination Bureau
Risk Prevention Policy Bureau
Food Safety Bureau
Pharmaceutical Safety Bureau
Biopharmaceutical and Herbal Medicine Bureau
Medical Device Safety Bureau
Planning and Budget Officer Administrative Management Officer Regulatory Reform and Legal Affairs Officer International Trade and Statistics Officer Information Management Officer Customer Support Officer
Risk Prevention Policy Division Risk Information Division Laboratory Audit & Policy Division Clinical Trials Management Division
Food Safety Policy Division Food Management Division Foodborn Diseases Prevention and Surveillance
Pharmaceutical Safety Policy Division Pharmaceutical Management Division Pharmaceutical Safety Information Team Pharmaceutical Quality Division Narcotics Control Division
Biopharmaceutical Policy Division Herbal Medicine Policy Division Cosmetics Policy Division
Medical Device Policy Division Medical Device Management Division Medical Device Quality Division
KFDA Regional offices (6)
Director General For Nutrition Policy
Food Standardization Department
Drug Evaluation Department

Drug Approval and Review Management Division Pharmaceutical Standardization Division Cardiovascular and Neuropharmacological Drugs Division Oncology and Antibiotics Division Gastroenterology and Metabolism Products Division Bioequivalence Evaluation Division
Biopharmaceutical and Herbal Medicine Department
Medical Device Evaluation Department
Seoul Busan Gyeonin Daegu Gwangju Daejeon

Nutrition Policy Division Dietary Life Safety Division Medical Device Novel Food Division
Food Standardization Division Health/Functional Food Standardization Division Food Additivies Standardization Division
Biologics Division Advanced Therapy Products Division Herbal Medicinal Products Division Cosmetics Evaluation Division
Diagnostic Medical Devices Division Therapeutic Medical Devices Division Medical Materials and Supplies Division
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I-3 Organization of NIFDS

Director General
General Service Division
3 Depts, 2 Centers 18 Divisions, 8 Teams 250 personnel
Research Planning & Management Division
Food Safety Evaluation Department

Food Chemical Residues Division Food Contaminants Division Food Microbiology Division Food Additives and Packages Division Nutrition and Functional Food Research Team Scientific Food Investigation Team Risk Analysis & Research Division Health Effects Analysis Team
Pharmaceuticals and Medical Devices Research Department
Toxicological Evaluation and Research Department

Toxicological Research Division Toxicological Screening and Testing Division Pharmacological Research Division Clinical Research Division Advanced Analysis Team Laboratory Animal Resources Division
Center for Drug Development Assistance
National Center for Lot Release
Pharmaceutical Standardization Research and Testing Division New Drug Research Team Biologics Research Division Advanced Therapy Products Research Division Herbal Medicine Research Division Cosmetics Research Team Medical Devices Research Division Fusion Technology Medical Devices Team Radiation Safety Division
Blood Products Team
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I-4 Mission & Vision
, cosmetics and medical devices
safety cosmetics and
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II-1 The Korean Pharmacopoeia(KP)
The statute for pharmaceuticals

the Korean Pharmaceutical Affairs Act established by KFDA first established on October 10, 1958
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Publication
No. of monographs
Published Year
No. of Reference Standard
KP 1 KP 2 KP 3 KP 4
635 1182 1013 1212 2.4 times increase
1958 1967 1976 1982 revised every 5 years
KP 9 KP 10
1511
2007 2012
1163
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No. of RS listed in KP
No. of RS distributed from KFDA-NIFDS
Chemical RS Herbal RS Biological RS Total
1010 114 39 1163
58 50 2 110
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III Reference Standards (RS)
Chemical Reference Standards - Chemical RSs - Narcotic RSs Herbal Reference Standards
Biological Reference Standards
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III-1 Chemical Reference Standards

Introduction
Chemical Medicines Narcotics
KFDANIFDS
Establishment Distributio n
Cooperation
EDQM USP JP WHO (IS)
Academia Research Institutes
National Agencies Pharmaceutical Companies Research Institutes Universities
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List of Reference Standards
57 chemical reference standards have been established through the collaborative studies with academia since 2006.
YEAR 2006 NUMBER 17 NAME
Aceclofenac, Acetyl-L-Carnitine HCl, Ambroxol HCl, Asprin, Caffeine anhydrous, Carvedilol, Chlorpheniramine maleate, Cilostazol, Cimetidine, DL-Carnitine HCl, Famotidine, Gabapentin, Glimepiride, Loratadine, Pyridoxine HCl, Terazosin HCl, Triamcinolone Acyclovir, Bambuterol HCl, Ciprofloxacin, Clobetasol propionate, Domperidone, Domperidone maleate, Enalapril maleate, Finasteride, Fluoxetine HCl, Gliclazide, Hydrochlorothiazide, Hyoscine butylbromide, Itraconazole, Lansoprozole, Lovastatin, Metformin HCl, Nibumetone, Nifedipine, Nimesuline, Triflusal Amitriptyine HCl, Atenolol, Capteolol HCl, Cetipizine HCl, Diclofenac sodium, Felodipine, Gemcitabine hydrochloride, Ketorolac tromethamine, Medroxyprogesterone acetate, Methocarbamol, Norfloxacin, Ofloxacin, Ondansetron HCl, Oxaprozin, Phenylephrine HCl, Pravastatin sodium, Prednisolone, Ranitidine HCl, Risperidone, Sulfasalazine 12/33
2007
20
2008
20
TOTAL
57
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54 narcotic reference standards have been established through the collaborative studies with academia since 2003.
YEAR 2003 2005 2006 2007 2008 NUMBER 5 5 8 9 10 NAME Carisoprodol, Dextromethorphan HBr, Fenfluramin HCl, MDMA HCl, Methamphetamine HCl Alfentanil HCl , Chlordiazepoxide HCl, Clonazepam, Fentanyl Citrate, Sufentanil Citrate Alprazolam, Codeine phosphate, Diazepam, Hydrocodone Bitartrate, Morphine HCl, Morphine Sulfate, Oxycodone HCl, Pethidine HCl Diazepam, Dihydrocodeine Bitartrate, Hexobarbital, Hydrocodone Bitartrate, Hydromorphone HCl, Ketamine HCl, Lorazepam, Oxycodone HCl, Phenobarbital Clobazam, Diethylproprion HCl, Ephedrine HCl, 5-MeO-Dipt HCl, Methylphenidate HCl, Midazolam, Pentazocine, Phendimetrazine tartrate, Pseudoephedrine HCl, 2-Cl HCl Benzylpiperazine 2HCl, Bromazepam, Clonazepam, Dihydrocodeine Bitartrate, Estazolam, Fentanyl Citrate, Flunitrazepam, GHB, Hydromorphone HCl, MDBP HCl, Methaqualone, Temazepam, Zolpidem tartrate Amphetamine, Amphetamine Sulfate, Codeine phosphate, Flurazepam HCl, Hydrocodone Bitartrate, m-Hydroxybenzylpiperazine, P-Hydroxybenzylpiperazine, MeOPP, Methamphetamine HCl, Morphine HCl, Morphine Sulfate, Norfenfluramine HCl, Oxycodone HCl, Pethidine HCl, Triazolam, (-)-Delta-tetrahydrocannabinol
2009
13
2010
16
TOTAL
54*
* Total number is not sum of the each years established product, because overlapping products exist.
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2012 New Narcotic reference standards
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Name Codeine phosphate hydrate Hydrocodone bitartrate Morphine hydrochloride hydrate Morphine sulfate hydrate Oxycodone hydrochloride hydrate Pethidine hydrochloride 1-(4-methoxyphenyl)piperazine(MeOPP) Amphetamine Flurazepam hydrochloride Methamphetamine hydrochloride m-Hydroxybenzylpiperazine HCl Norfenfluramine HCl Pentobarbital Phentermine hydrochloride p-Hydroxybenzylpiperazine HCl Triazolam (-)-Delta-tetrahydrocannabinol(THC)
Guideline for the distribution of narcotics

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Procedure of Establishment
Procurement of the candidate
Synthesis Synthesis
Analytical testing of the Candidates
Quality verification
Packaging & Certificate
Distribution / Monitoring
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Example : Codeine Phosphate Hydrate
Identification UV, FT-IR, FT-NMR, - Qualitative Tests for phosphate Specific Optical Rotation pH Purity Chloride Sulfate Related substances Water Quantitative Assay
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Packaging & Certificate
Bulk
Vial (100mg)
Vial (200mg)
Vial (20mg)
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Distribution of Narcotic RS(2009~2011 )
Distribution by the products Distribution by the institution
National Agency(ex cluded KFDANIFDS) 7%
Starting materials of narcotics 26%
Cannabis 2%
Narcotics 23%
National Agency(K FDANIFDS) 25%
Antipsych otic 49%
Research institute and University 13%
Pharmace utical Company 55%
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Stability Test The KFDA has conducted the stability test on all products biannually - in order to make sure if the national chemical RSs maintains the consistent quality. The stability test is performed by KFDA with academia In 2012, the stability monitoring was carried out for total 49 standards
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III-2 Herbal Reference Standards

List of Control Reference Standards
In 2001, KFDA/NIFDS initiated the program of establishing herbal reference standards in order to strengthen the quality of herbal medicines. So far, 68 herbal control reference standards have been established through the collaborative studies with researchers. YEAR 2001 2002 2003 2004 2005 2006 2008 2009 TOTAL NUMBER 9 10 10 8 3 4 15 9 68
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NAME
Aconitine, Nodakenin, Mesaconitine, Hypaconitine, Benzoylaconine, Neoline, Sogarine, Decursin, Decursinol angelate Hesperidin, Ephedrine hydrochloride, Amygdalin, Berberine Cl, Baicalin, Puerarin, Magnolol, Loganin, Schizandrin, Paeoniflorin Geniposide, Gentiopicrin, Ginsenoside Rb1, Ginsenoside Rg1, Icariin, Paeonol, Poncirin, Sennoside A, Sennoside B, Betaine Catechin, Eleutheroside B, Eugenol, 6-Gingerol, Glycyrrhizin, Saikosaponin A, Saikosaponin D, Tanshinone IIA Acanthoside D, Naringin, Psolaren Esculetin, 6,7-Dimethylesculetin, Arecoline, Harpagoside Paeoniflorin, Albiflorin, Paeonol, Glycyrrhizic acid, Liguiritin, Evodiamine, Rutaecrapine, Baicalein, (+)-matrine, (+)-Oxymatrine, Gomisin A, Gomisin N, Schizandrin, Decursin, Nodakenin Nodakenin, Baicalin, Liquiritigenin, (+)-Oxymatrine, Morroniside, Bisdemethoxycurcumin, Albiflorin, Salvianolic acid B, Decurinol
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List of Reference Medicine Plant Materials(RMPM)
So far, 90 RMPM have been established through the collaborative studies with researchers.
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Example of Certificate
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III-3 Biological Reference Standards

KFDA has promoted a project to establish and provide national reference standards from 1998
YEAR 1998 2001 2002 2003 2004 2006 2007 2008 NUMBER 1 4 4 5 1 1 6 6 NAME Somatropin Tetanus Toxin, JE Vaccine, Interferon alpha-2a, Coagulation Factor V Erythropoietin, Bordetella pertussis Vaccine, Live Varicella Vaccine, Antithrombin HBsAg, Hepatitis C Virus RNA, Prekallikrein Activator, Diphtheria Toxoid, Interferon alpha-2a Snake Venom Pertussis Vaccine Diphtheria Toxoid, Diphthera antitoxin, anti-FHA(filamentous hemagglutinin), anti-PT(pertussis toxoid), anti-pertussis, JE Vaccine Hepatitis B surface antigen working standard, Hepatitis B surface antigen mixed titer panel, Anti-Hepatitis B Immunoglobulin, Live Varicella Vaccine, Hepatitis B Surface antigen low titer panel, Blood Grouping RBC Reagents Anti-HIV 1/2 Mixed titer Performance Panel, Anti-HIV 1 Working Standards, Anti-HCV Mixed titer Performance Panel, Botulinum toxin Type A anti-toxin(Rabbit), Purified Vi Polysaccharide Typhoid Vaccine, Coagulation Factor Tetanus Anti-toxin Coagulation Factor : Concentrate
2009 2010 2011 TOTAL
6 1 1 36
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Establishment
Assessment of need and preparation of the proposal
(KFDA)
Consulting and making contract

(KFDA, manufacturers, research institutes etc)
Manufacturing the candidate reference standard

Collaborative study for validation

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V. Establishment III-3 Biological Reference Standards Establishment

Statistic analysis and report
(KFDA, statistic experts)
Assign code numbers and determine prices

(KFDA)
Package inserts preparation

(KFDA)
Listing in the KFDA website and catalogue

(KFDA)
Completed 25/35

Distribution
By year 2011, Production: 83,620 vials External distribution: 15.8% Internal distribution: 8.5% In year 2011 External distribution: 2,333 vials Internal distribution: 819 vials
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13
2012-09-04

Distribution
27/35

Storing and Management
Separate storage room Yearly validation of freezers by outsourcing Daily monitoring of temperature and humidity UPS, emergency alarming system SOPs of procedure for manufacturing, distribution and equipments Annual stability testing and statistic analysis
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14
2012-09-04

8 Freezer(-80C) 9 Freezer(-40 C) 2 Refrigerator(4C)
29/35

Temperature monitoring system Emergency alarm system
Thermo-hygrostat
UPS
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15
2012-09-04

Stability Test The KFDA has conducted the stability test on all products annually in order to make sure if the national biological reference standards maintains the consistent potency
- first year : 0, 3, 6, 9, 12 months - after one year : once a year (except. HPV L1 DNA)
The stability test is performed by the KFDA or entrusted to another agency In 2011, the stability monitoring was carried out for total 30 standards
- in-house : 3 standards (anti-pertussis and etc. - outsourcing : 18 standards (Diphtheria toxin and etc.) - in-house & outsourcing : 9 standards (Live Varicella Vaccine and etc.)
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IV Future and International Cooperation

Increasing the RS items - Covering all the reference standards that are needed Augmentation of organization - Reference Standard Center Quality upgrade - Introduction of ISO Guide 34 Cooperation for the better system of RSs - EDQM, USP, JP, WHO, etc.,
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Regulatory Guide On Reference Standard

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Regulatory Guide On Reference Standard

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PHARMACEUTICAL REFERENCE STANDARDS

3-4 September 2012, Strasbourg, France

Session 1 Presentations (Part 2) Regulatory Aspects

Suitable for the intended use!

SYMPOSIUM PHARMACEUTICAL REFERENCE STANDARDS 03-04 September 2012, STRASBOURG, France

Management of Reference Standards within Sanofi: Experiences and Challenges

Sanofi Structure of RS Management

Sanofi Structure of RS Management

Decentralised testing by expert laboratories (40)

Reference Standards Processes

Need of RS (replacement, new) Monitoring (stocks retest dates)

Generation of certificate valid RS inclusion in data base R&D, PD new products

Processing of orders, invoice, up-date of data base

IntraNet RSL Homepage

Online ordering system via IntraNet

Assurance of availability of sufficient quantities

Types and Traceability of RS

Official Standard Reference Material Working Standard

Routine use (release testing, stability, investigations )

Content & Identity

Types of RS: Official Standard (OS)

Regular verification of validity of the respective compendial standard

Types of RS: Primary Standard (PS)

Identification: structural elucidation (NMR, MS, etc.) Use:

Characterisation: thorough purity investigations

Types of RS: Primary Standard (PS)

Declared Content (as is):

100 water solvents other imp. 100

Confirmation: comparison to absolute method (e.g. titration, N-determination, NMR)

Types of RS: Working Standard (WS)

Types of RS: Reference Material (RM)

Challenges: Multi-dedicated Use

Challenges: Additional Use

Challenges: Hygroscopic Substances

Very hygroscopic WS:

Challenges: Use of Compendial RS

Thomas Klein Head of RSL Frankfurt

THANK YOU FOR YOUR ATTENTION

Establishment of Reference Standards Chinas Point of View

Management system of reference standards NIFDC reference standards overview

Laws and regulations

1. Drug Administration Law of P.R China

Laws and regulations (Cont.)

National Institute of Food and Drug Control

Laws and regulations (Cont.)

National Institute of Food and Drug Control

Laws and regulations (Cont.)

3. Medical Devices Regulation

Center for Drug Evaluation (CDE)

National Center for Adverse Drug Reaction Monitoring

Center for Drug Certification (CCD)

Center for Medical Device Evaluation (CMDE)

Center for Health Food Evaluation

Center for Pharmaceutical International Exchange

Institute for Chemical Drug Institute for Medical Devices

Institute for Biological Product

Institute for Packaging Material and Pharmaceutical Excipient

Institute of Reference Standards and Standardization (IRSS)

Institute for Medical Device Standardization Administration

RS management system (Cont.)

RS management system (Cont.)

NIFDC RS overview (Cont.)

NIFDC RS overview (Cont.)