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

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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

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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


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


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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…)


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)


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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.


8

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


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


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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%


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


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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)


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


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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.


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


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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.


18


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 für DAC-Alternativverfahren, Pharm. Zeitung online 49

U. Lipke et al. (2008): Internationale Einheiten oder Milligramm, DAZ.online 50


22Dr. Bernhard Wolf, Merckle GmbH

04/09/2012

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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)

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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)

| 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

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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

Routine use (release testing, stability, investigations …)

Primary Standard

Reference Material

Identity, SST

Working Standard

Content & Identity

Structural ElucidationCompendial Standard

OfficialStandard

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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

● 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

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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 KleinHead of RSL Frankfurt

THANK YOU FOR YOUR ATTENTION

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04/09/2012

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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

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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.)

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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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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

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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

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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.)

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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.)

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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???

5

Thank you for your kind attention!

JPRS LabJapanese Pharmacopoeia

Reference Standards Laboratory

2012-09-04

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Establishment and Management of KFDA Reference Standards

In-Kyu Kim Ph.D.

Contents

Ⅱ The Korean Pharmacopoeia

Ⅰ Organization

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Reference StandardsⅢ

IV Future and International Cooperation

2012-09-04

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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 >

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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

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I-4 Mission & Vision

safety

cosmetics and

,

, cosmetics and medical devices

6/33

2012-09-04

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II-1 The Korean Pharmacopoeia(KP)

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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


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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


III Reference Standards (RS)

Chemical Reference Standards- Chemical RSs- Narcotic RSs

Herbal Reference Standards

Biological Reference Standards

Ⅱ

Ⅲ

Ⅰ

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2012-09-04

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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

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54 narcotic reference standards have been established through the collaborative studies with academia since 2003.


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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


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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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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

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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

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· 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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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


Assessment of need and preparation of the proposal

(KFDA)

Collaborative study for validation


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Establishment


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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


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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Distribution


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


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8 Freezer(-80°C)

9 Freezer(-40 °C)

2 Refrigerator(4°C)

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Temperature monitoring system

UPSThermo-hygrostat

Emergency alarm system

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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


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

Documents

Transcript of Regulatory Guide on Reference Standard