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regulatory guide
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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 1 – Presentations (Part 2) Regulatory Aspects
04/09/2012
1
USE OF REFERENCE STANDARDS AND QUALITY CONTROL:EXPERIENCES AND UNMET NEEDS
Strassburg
3.Sep.2012
2
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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
2
3
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
Dr. Bernhard Wolf, Merckle GmbH
4
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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
3
5
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, Sigma-Aldrich, VWR…)
Dr. Bernhard Wolf, Merckle GmbH
6
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)
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
4
7
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.
Dr. Bernhard Wolf, Merckle GmbH
8
Intended Use of Reference Substances
Identity
Assay
Chemical purity
System suitability test
Suitable for the intended use!
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
5
9
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
Dr. Bernhard Wolf, Merckle GmbH
10
Shelf life of Reference Substances
Pharmacopeial reference standards
- Ph.Eur.: batch validity statement (BVS) www.edqm.eu
- BP : current batch no. System www.bpclab.co.uk
- USP : 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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
6
11
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%
Dr. Bernhard Wolf, Merckle GmbH
12
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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
7
13
Storage of Reference Substances
Primary pharmacopoeial standards
- original unopend container
- refrigerator (2 -8°C, 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)
Dr. Bernhard Wolf, Merckle GmbH
14
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 (> - 15°C)
EX – exsiccator
Storage place
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
8
15
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.
Dr. Bernhard Wolf, Merckle GmbH
16
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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
9
17
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.
Dr. Bernhard Wolf, Merckle GmbH
18
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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
10
19
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
Dr. Bernhard Wolf, Merckle GmbH
20
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
Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
11
21
Helpful links and publications (continued)
K. Albrecht (2007): Referenzsubstanzen für DAC-Alternativverfahren, Pharm. Zeitung online 49
U. Lipke et al. (2008): Internationale Einheiten oder Milligramm, DAZ.online 50
Dr. Bernhard Wolf, Merckle GmbH
22Dr. Bernhard Wolf, Merckle GmbH
04/09/2012
1
| 1
SYMPOSIUM PHARMACEUTICAL REFERENCE STANDARDS03-04 September 2012, STRASBOURG, France
Management of Reference Standards within Sanofi: Experiences and Challenges
Joachim Ermer, Sanofi
03 September, 2012
| 2
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: 25°C, 4-8°C, -20°C, -80°C (~120 m2)
● ~ 2000 substances (~ 350 kg)
● ~ 400 retests / characterisations per year
● ~ 2500 orders (~ 22 000 units)
● ~ 500 „customers“ (internal & external)
04/09/2012
2
| 3
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)
| 4
Reference Standards Processes
Need of RS(replacement,
new)
Requestinternal
testing sites
Monitoring(stocks
retest dates)
R&D, PDnew
products
valid RS• inclusion in
data base
IntraNet RSL Homepage
Processing of orders, invoice, up-date
of data base
Online order
Generationof certificate
Retest
Identification of source
Industrial production site,Process development (PD)
External source
Expert LabsPD (special tests)IQC (routine tests)Coordination
of charac-terisation
04/09/2012
3
| 5
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
| 6
Types and Traceability of RS
Routine use (release testing, stability, investigations …)
Primary Standard
Reference Material
Identity, SST
Working Standard
Content & Identity
Structural ElucidationCompendial Standard
OfficialStandard
04/09/2012
4
| 7
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
| 8
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.
04/09/2012
5
| 9
Types of RS: Primary Standard (PS)
● Declared Content (as is):
● Calculation
● 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
100
.100(%)
impothersolventswaterPurityLC
| 10
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
04/09/2012
6
| 11
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
| 12
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
04/09/2012
7
| 13
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“
| 14
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
04/09/2012
8
| 15
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
| 16
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
04/09/2012
9
| 17
ACKNOWLEDGEMENTS
Thomas KleinHead of RSL Frankfurt
THANK YOU FOR YOUR ATTENTION
| 18
04/09/2012
1
Establishment of Reference Standards
China’s Point of View
Li Bo, Ph.D.
National Institutes for Food and Drug Control, China
3 September 2012
Reference standards related laws and
regulations in China
Management system of reference standards
NIFDC reference standards overview
Outline
04/09/2012
2
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.
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
Laws and regulations (Cont.)
04/09/2012
3
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
Laws and regulations (Cont.)
3. Medical Devices Regulation
“NIFDC is responsible for the characterizing, preparation,
and providing the national reference standards of in-vitro
diagnostic reagents”.
Laws and regulations (Cont.)
04/09/2012
4
State Food and Drug Administration
Office of the Commissioner
Chinese Pharmacopeia Commission
Center for Drug Evaluation (CDE)
Center for Drug Certification(CCD)
National Institutes for Food and Drug Control (NIFDC)
National Center for Adverse Drug Reaction Monitoring
Center for Medical Device Evaluation (CMDE)
Center for Health Food Evaluation
Center for Pharmaceutical International Exchange
Ministry of Health (MoH)
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
……
RS management system
04/09/2012
5
Office of the Directors
Institute for Chemical Drug
Institute for Medical Devices
Institute of Reference Standards and Standardization (IRSS)
Institute for Chinese Traditional Medicine and Ethnic Medicine
Institute for Biological Product
Institute for Packaging Material and Pharmaceutical Excipient
Institute for Laboratory Animal Resources
National Institutes for Food and Drug Control (NIFDC)
Institute for Food and Drug Safety Evaluation
Institute for Food and Drug Technical Surveillance
Institute for Food and Cosmetics
Institute for Medical Device Standardization Administration
04/09/2012
6
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.
RS management system (Cont.)
04/09/2012
7
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
Year Chemical RS
Chemical RS from TCM
Referential herbal drugs
Biological RS
Total
2005 906 337 572 109 1924
2006 931 391 623 126 2071
2007 1013 403 641 153 2210
2008 1053 435 652 164 2304
2009 1116 440 654 175 2385
2010 1580 565 690 190 3025
2011 1880 590 720 210 3400
NIFDC RS overview (Cont.)
04/09/2012
8
2010 Chp Volume I:
Chemical RS from TCM:463
Herbal drugs RS: 369
Referential extract: 16
2010 Chp Volume II : 1754
Reference standards: 36
Reference substances: 870
NIFDC RS overview (Cont.)
906
848
Question?
1
Shigeki TSUDA, Senior Managing Director, PMRJ (Japan)
11th IRSS, at EDQM, Strasbourg3rd September, 2012
ESTABLISHMENT OF REFERENCE STANDARDS:
POINT OF VIEWS OF INTERNATIONAL AUTHORITIES
Disclaimer
Views expressed in these PowerPoint slides are my own and do not represent the official positions of the Japanese Pharmacopoeia (JP).
2
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?
3
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.
4
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
JP’s 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 naïve 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???
2012-09-04
1
1/33
Establishment and Management of KFDA Reference Standards
In-Kyu Kim Ph.D.
Contents
Ⅱ The Korean Pharmacopoeia
Ⅰ Organization
2/33
Reference StandardsⅢ
IV Future and International Cooperation
2012-09-04
2
I-1 History of KFDA
- 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
2009
1996
1998
2005
- Established in April, 1996- Food and Drug Safety Headquarter
- 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 >
3/33
I-2 Organization of KFDACommissioner
Spokesperson
DeputyCommissioner
Criminal Investigations Office Audit and Inspection Officer
GeneralServiceDivision
Panning & Coordination Bureau
Risk Prevention Policy Bureau
Food SafetyBureau
PharmaceuticalSafety Bureau
Biopharmaceuticaland Herbal
Medicine Bureau
Medical DeviceSafety Bureau
• Planning and Budget Officer• Administrative Management
Officer• Regulatory Reform and Leg-
al 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 Surv-eillance
• Pharmaceutical Safety Policy Division
• Pharmaceutical Management Division
• Pharmaceutical SafetyInformation Team
• Pharmaceutical Quality Division
• Narcotics ControlDivision
• Biopharmaceutical Policy Division
• Herbal Medicine Policy Division
• Cosmetics Policy Division
• Medical Device Policy Division
• Medical Device Management Division
• Medical Device QualityDivision
Director GeneralFor Nutrition Policy
Food Standardiz-ation Department
Drug EvaluationDepartment
Biopharmaceutical and Herbal Medicine
Department
Medical DeviceEvaluation
Department
• Food StandardizationDivision
• Health/FunctionalFood StandardizationDivision
• Food AdditiviesStandardizationDivision
• Drug Approval and Review Management Division
• Pharmaceutical Standar-dization Division
• Cardiovascular and NeuropharmacologicalDrugs Division
• Oncology and Antibiotics Division
• Gastroenterology and Metabolism Products Division
• Bioequivalence EvaluationDivision
• Biologics Division• Advanced Therapy
Products Division• Herbal Medicinal
Products Division• Cosmetics Evaluation
Division
• Diagnostic Medical Devices Division
• Therapeutic Medical Devices Division
• Medical Materialsand Supplies Division
• Nutrition Policy Division• Dietary Life Safety
Division Medical Device• Novel Food Division
KFDA Regional offices (6)
Seoul
Busan
Gyeonin
Daegu
Gwangju
Daejeon
National Institute of Food and Drug Safety
Evaluation (NIFDS)
4/33
1,500 personnel
2012-09-04
3
• 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
의료제품연구부
Cen
ter for D
rug
Develo
pm
ent
Assistan
ce
Pharmaceuticals and Medical Devices
Research Department
Food Safety Evaluation
Department
Toxicological Evaluation and Research Department
• Pharmaceutical StandardizationResearch 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
• Toxicological Research Division
• Toxicological Screeningand Testing Division
• Pharmacological Research Division
• Clinical Research Division
• Advanced Analysis Team
• Laboratory Animal Resources Division
General Service Division
Research Planning & Management Division
Director General
3 Depts, 2 Centers 18 Divisions, 8 Teams
250 personnelN
ation
al Cen
ter for Lo
t R
elease
Blood
Prod
ucts Team
I-3 Organization of NIFDS
5/33
I-4 Mission & Vision
safety
cosmetics and
,
, cosmetics and medical devices
6/33
2012-09-04
4
II-1 The Korean Pharmacopoeia(KP)
7/33
The statute for pharmaceuticals
the Korean Pharmaceutical Affairs Act
established by KFDA
first established on October 10, 1958
8/33
Publication No. of monographs Published Year No. of ReferenceStandard
KP 1 635 1958KP 2 1182 1967KP 3 1013 1976KP 4 1212 1982
2.4 timesincrease
revisedevery 5 years
KP 9 1511 2007 1163KP 10 2012
II-1 The Korean Pharmacopoeia(KP)
2012-09-04
5
9/33
No. of RS listed in KP No. of RS distributed from KFDA-NIFDS
Chemical RS 1010 58
Herbal RS 114 50
Biological RS 39 2
Total 1163 110
II-1 The Korean Pharmacopoeia(KP)
III Reference Standards (RS)
Chemical Reference Standards- Chemical RSs- Narcotic RSs
Herbal Reference Standards
Biological Reference Standards
Ⅱ
Ⅲ
Ⅰ
10/33
2012-09-04
6
Establishment Distribution
Cooperation
EDQMUSPJP
WHO (IS)
KFDA-NIFDS
Chemical Medicines Narcotics
AcademiaResearch Institutes
III-1 Chemical Reference Standards Introduction
National AgenciesPharmaceutical Companies
Research Institutes Universities
11/33
57 chemical reference standards have been established through the collaborative studies with academia since 2006.
III-1 Chemical Reference Standards List of Reference Standards
12/33
YEAR NUMBER NAME
2006 17
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
2007 20
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
2008 20
Amitriptyine HCl, Atenolol, Capteolol HCl, Cetipizine HCl, Diclofenacsodium, Felodipine, Gemcitabine hydrochloride, Ketorolac tromethamine,
Medroxyprogesterone acetate, Methocarbamol, Norfloxacin, Ofloxacin, Ondansetron HCl, Oxaprozin, Phenylephrine HCl, Pravastatin sodium,
Prednisolone, Ranitidine HCl, Risperidone, Sulfasalazine
TOTAL 57
2012-09-04
7
54 narcotic reference standards have been established through the collaborative studies with academia since 2003.
III-1 Chemical Reference Standards List of Reference Standards
13/33
YEAR NUMBER NAME
2003 5 Carisoprodol, Dextromethorphan HBr, Fenfluramin HCl, MDMA HCl, Methamphetamine HCl
2005 5 Alfentanil HCl , Chlordiazepoxide HCl, Clonazepam, Fentanyl Citrate, Sufentanil Citrate
2006 8Alprazolam, Codeine phosphate, Diazepam, Hydrocodone Bitartrate, Morphine HCl, Morphine
Sulfate, Oxycodone HCl, Pethidine HCl
2007 9Diazepam, Dihydrocodeine Bitartrate, Hexobarbital, Hydrocodone Bitartrate, Hydromorphone
HCl, Ketamine HCl, Lorazepam, Oxycodone HCl, Phenobarbital
2008 10Clobazam, Diethylproprion HCl, Ephedrine HCl, 5-MeO-Dipt HCl, Methylphenidate HCl,
Midazolam, Pentazocine, Phendimetrazine tartrate, Pseudoephedrine HCl, 2-Cl HCl
2009 13Benzylpiperazine 2HCl, Bromazepam, Clonazepam, Dihydrocodeine Bitartrate, Estazolam,
Fentanyl Citrate, Flunitrazepam, GHB, Hydromorphone HCl, MDBP HCl, Methaqualone, Temazepam, Zolpidem tartrate
2010 16
Amphetamine, Amphetamine Sulfate, Codeine phosphate, Flurazepam HCl, HydrocodoneBitartrate, m-Hydroxybenzylpiperazine, P-Hydroxybenzylpiperazine, MeOPP, Methamphetamine
HCl, Morphine HCl, Morphine Sulfate, Norfenfluramine HCl, Oxycodone HCl, Pethidine HCl, Triazolam, (-)-Delta-tetrahydrocannabinol
TOTAL 54*
* Total number is not sum of the each year’s established product, because overlapping products exist.
2012 New Narcotic reference standards
No. Name
1 Codeine phosphate hydrate
2 Hydrocodone bitartrate
3 Morphine hydrochloride hydrate
4 Morphine sulfate hydrate
5 Oxycodone hydrochloride hydrate
6 Pethidine hydrochloride
7 1-(4-methoxyphenyl)piperazine(MeOPP)
8 Amphetamine
9 Flurazepam hydrochloride
10 Methamphetamine hydrochloride
11 m-Hydroxybenzylpiperazine HCl
12 Norfenfluramine HCl
13 Pentobarbital
14 Phentermine hydrochloride
15 p-Hydroxybenzylpiperazine HCl
16 Triazolam
17 (-)-Delta-tetrahydrocannabinol(THC)
Guideline for the distributionof narcotics
III-1 Chemical Reference Standards List of Reference Standards
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2012-09-04
8
Analytical testing of the Candidates
SynthesisProcurement of the candidate
Quality verification
Packaging & Certificate
Distribution / Monitoring
Synthesis
III-1 Chemical Reference Standards Procedure of Establishment
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Identification – UV, FT-IR, FT-NMR, - Qualitative Tests for phosphate– Specific Optical Rotation– pH
Purity – Chloride– Sulfate– Related substances
Water Quantitative Assay
III-1 Chemical Reference Standards Example : Codeine Phosphate Hydrate
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2012-09-04
9
Bulk
Vial(100mg)
Vial(200mg)
Vial(20mg)
III-1 Chemical Reference Standards Packaging & Certificate
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III-1 Chemical Reference Standards Distribution of Narcotic RS(2009~2011 )
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Narcotics23%
Antipsychotic49%
Starting materials
of narcotics
26%
Cannabis2%
Pharmaceutical
Company55%
Research institute
and University
13%
National Agency(K
FDA-NIFDS)
25%
National Agency(ex
cluded KFDA-NIFDS)
7%
Distribution by the products Distribution by the institution
2012-09-04
10
III-1 Chemical Reference Standards Stability Test
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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
· 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.
III-2 Herbal Reference Standards
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YEAR NUMBER NAME
2001 9 Aconitine, Nodakenin, Mesaconitine, Hypaconitine, Benzoylaconine, Neoline, Sogarine, Decursin, Decursinol angelate
2002 10 Hesperidin, Ephedrine hydrochloride, Amygdalin, Berberine Cl, Baicalin, Puerarin, Magnolol, Loganin, Schizandrin, Paeoniflorin
2003 10 Geniposide, Gentiopicrin, Ginsenoside Rb1, Ginsenoside Rg1, Icariin, Paeonol, Poncirin, Sennoside A, Sennoside B, Betaine
2004 8 Catechin, Eleutheroside B, Eugenol, 6-Gingerol, Glycyrrhizin, Saikosaponin A, Saikosaponin D, Tanshinone IIA
2005 3 Acanthoside D, Naringin, Psolaren
2006 4 Esculetin, 6,7-Dimethylesculetin, Arecoline, Harpagoside
2008 15Paeoniflorin, Albiflorin, Paeonol, Glycyrrhizic acid, Liguiritin, Evodiamine, Rutaecrapine, Baicalein, (+)-matrine, (+)-Oxymatrine, Gomisin A, Gomisin N, Schizandrin, Decursin, Nodakenin
2009 9 Nodakenin, Baicalin, Liquiritigenin, (+)-Oxymatrine, Morroniside, Bisdemethoxycurcumin, Albiflorin, Salvianolic acid B, Decurinol
TOTAL 68
List of Control Reference Standards
2012-09-04
11
· So far, 90 RMPM have been established through the collaborative studies with researchers.
III-2 Herbal Reference Standards
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List of Reference Medicine Plant Materials(RMPM)
III-2 Herbal Reference Standards Example of Certificate
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2012-09-04
12
KFDA has promoted a project to establish and provide national reference standards from 1998
III-3 Biological Reference Standards
YEAR NUMBER NAME
1998 1 Somatropin
2001 4 Tetanus Toxin, JE Vaccine, Interferon alpha-2a, Coagulation Factor VⅢ
2002 4Erythropoietin, Bordetella pertussis Vaccine, Live Varicella
Vaccine, Antithrombin
2003 5 HBsAg, Hepatitis C Virus RNA, Prekallikrein Activator, Diphtheria Toxoid, Interferon alpha-2a
2004 1 Snake Venom
2006 1 Pertussis Vaccine
2007 6Diphtheria Toxoid, Diphthera antitoxin, anti-FHA(filamentous hemagglutinin), anti-PT(pertussis
toxoid), anti-pertussis, JE Vaccine
2008 6Hepatitis 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
2009 6Anti-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 FactorⅧ
2010 1 Tetanus Anti-toxin
2011 1 Coagulation Factor Ⅸ: Concentrate
TOTAL 36
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Manufacturing the candidate reference standard
(KFDA, manufacturers, research institutes etc)
Consulting and making contract
(KFDA, manufacturers, research institutes etc)
Assessment of need and preparation of the proposal
(KFDA)
Collaborative study for validation
(KFDA, manufacturers, research institutes etc)
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Establishment
III-3 Biological Reference Standards
2012-09-04
13
Statistic analysis and report
(KFDA, statistic experts)
Listing in the KFDA website and catalogue
(KFDA)
Package inserts preparation
(KFDA)
Assign code numbers and determine prices
(KFDA)
Completed
V. Establishment
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Establishment
III-3 Biological Reference Standards
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
Distribution
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III-3 Biological Reference Standards
2012-09-04
14
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Distribution
III-3 Biological Reference Standards
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
Separate storage room
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Storing and Management
III-3 Biological Reference Standards
2012-09-04
15
8 Freezer(-80°C)
9 Freezer(-40 °C)
2 Refrigerator(4°C)
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Storing and Management
III-3 Biological Reference Standards
Temperature monitoring system
UPSThermo-hygrostat
Emergency alarm system
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Storing and Management
III-3 Biological Reference Standards
2012-09-04
16
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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Stability Test
III-3 Biological Reference Standards
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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