AFRICA HERBAL ANTIMALARIAL MEETING
ORGANISED BY THE WORLD AGROFORESTRY CENTRE
(ICRAF) AND THE ASSOCIATION FOR THE PROMOTION
OF TRADITIONAL MEDICINE (PROMETRA)
MARCH, 20th TO 22nd 2006
ICRAF HOUSE NAIROBI, KENYA
NEW EUROPEAN LEGISLATION FOR HERBAL MEDICINAL PRODUCTS
(HMPs) - NEW OPPORTUNITIES FOR AFRICAN PHARMACEUTICAL
INDUSTRIES?
PROF. A.J. VLIETINCK
UNIVERSITY OF ANTWERP (UA)
B-2610 ANTWERP, BELGIUM
• CHAIRMAN OF THE GROUP OF EXPERTS 13A OF THE EUROPEAN
PHARMACOPOEIA (EP)
• MEMBER OF THE COMMITTEE ON HERBAL MEDICINAL PRODUCTS
(HMPC) OF THE EUROPEAN MEDICINES AGENCY (EMEA)
CONTENTS
1. INTRODUCTION
2. LEGAL FRAMEWORK FOR HMPs IN THE EU
2.1. MARKETING AUTHORISATION (MA) PROCEDURES
2.2. MA OF WELL-ESTABLISHED HMPs
2.3. REGISTRATION OF TRADITIONAL HMPs
3. EUROPEAN PHARMACOPOEIA MONOGRAPHS OF HERBAL DRUGS AND HERBAL
PREPARATIONS
4. NOTE FOR GUIDANCE ON SPECIFICATIONS:
TEST PROCEDURES AND ACCEPTANCE CRITERIA
5. MA OR REGISTRATION OF ANTIMALARIALS FROM ARTEMISIA ANNUA
6. CONCLUSION
LEGAL STATUS OF HERBAL PRODUCTS WORLDWIDE
FOOD
DIETARY
SUPPLEMENT
DIETARY SUPPLEMENTS
DRUG
NUTRACEUTICALS
HERBAL PRODUCTS
HERBAL MEDICINAL PRODUCTS
FUNCTIONAL FOODS
•
•
•
•
•
•
•
DESIGNER FOODS
FITNESS FOODS
FOODACEUTICALS
LONGEVITY FOODS
MEDICINAL FOODS
NUTRITIONAL FOODS
THERAPEUTIC FOODS
•
•
•
•
•
•
PHARMACEUTICAL FOODS
PHARMACOFOODS
PHARMAFOODS
PHARMAFOODICALS
PRESCRIPTION FOODS
.
SUPER
FOODS
HERBAL MEDICINAL PRODUCTS
PRESCRIBED BY MEDICAL DOCTORS
PRESCRIPTION SHARES BY COUNTRY IN %
CURRENT LEGAL FRAMEWORK FOR HMPs IN THE EU
DIRECTIVE 2001/83/EC, AS AMENDED (12.06.2003)
• ART. 1 : DEFINITION OF MEDICINAL PRODUCTS
(a) ANY SUBSTANCE OR COMBINATION OF SUBSTANCES PRESENTED AS HAVING PROPERTIES
FOR TREATING OR PREVENTING DISEASE IN HUMAN BEINGS
(b) ANY SUBSTANCE OR COMBINATION OF SUBSTANCES WHICH MAY BE USED IN OR
ADMINISTERED TO HUMAN BEINGS WITH A VIEW TO MAKING A MEDICAL DIAGNOSIS OR TO
RESTORING, CORRECTING OR MODIFYING PHYSIOLOGICAL FUNCTIONS BY EXERTING A
PHARMACOLOGICAL, IMMUNOLOGICAL OR METABOLIC ACTION
• WHEREBY
“SUBSTANCE …. ANY MATTER E.G. VEGETABLE: PLANTS, PARTS OF PLANTS, VEGETABLE
SECRETIONS, EXTRACTS …”
• ESTABLISHES THAT PROOF OF QUALITY, SAFETY AND EFFICACY IS A PRECONDITION FOR
DELIVERING A MARKETING AUTHORIZATION FOR A MEDICINAL PRODUCT.
CURRENT LEGAL FRAMEWORK FOR HERBAL MEDICINAL PRODUCTS
MA PROCEDURES
London
Brussels
National
Mutual recognition
Centralised (?)
Marketing authorisation :
“A medicinal product may only be placed on the market in the
European Union when a marketing authorisation has been issued
by the competent authority of a Member State for its own territory
(national authorisation) or when an authorisation has been
granted in accordance with Regulation (EEC) No. 2309/93 for the
entire Community (a Community authorisation).”
FRIAS, 2004
HMPC – HERBAL COMMITTEE
Composition
Chair : K. Keller
+
Vice-Chair : H. Pittner
1 member/MS + 1 alternate/MS
+
max. 5 co-opted members
+
accompanied by experts
+ 5 CO-OPTED MEMBERS
1
HERBAL MEDICINAL PRODUCTS (HMPs) IN THE EU
•
REGULATORY GUIDANCE ON SOLID GROUNDS
REGULATION No 726/2004 (EC) OF 31.03.2004
TITLE IV, THE EUROPEAN MEDICINES AGENCY (EMEA)
RESPONSIBILITIES AND ADMINISTRATIVE STRUCTURE
ARTICLE 56
1. (d) HMPs
•
DIRECTIVE 2001/83/EC
AS AMENDED BY
DIRECTIVE 2004/24.EC
AND
DIRECTIVE 2004/27/EC
OF 31.03.2004
HMPs IN THE EU : ACCESS TO THE MARKET
 MARKETING AUTHORIZATION (MA)
1. FULL DOCUMENTATION WITH NEW TESTS AND TRIALS
2. FULL BIBLIOGRAPHIC DOCUMENTATION (WELL-ESTABLISHED USE)
3. MIXED APPLICATIONS
 REGISTRATION
4. SIMPLIFIED DOSSIER FOR TRADITIONAL HERBAL MEDICINAL PRODUCTS
CURRENT LEGAL FRAMEWORK FOR HMPs IN THE EU
* DIRECTIVE 2003/63/EC (UPDATED ANNEX I TO THE DIR. 2001/83/EC)
DOSSIER REQUIREMENTS
• SPECIFIC REQUIREMENTS FOR THE DOCUMENTATION AND EXPERT REPORTS ON QUALITY,
SAFETY AND EFFICACY
• SPECIFIC PART ON APPLICATIONS FOR HMPs
• SPECIFIC PART ON BIBLIOGRAPHIC APPLICATIONS
• PRESENTATION AND FORMAT OF AN APPLICATION
- OLD NOTICE TO APLLICANTS (NTA) 1998 EDITION (PARTS I- IV)
- NEW COMMON TECHNICAL DOCUMENT (CTD) 2001 EDITION (MODULES 1 - 5)
• TRANSITION FOR “OLD” HMPs APPLICATIONS UNTIL 30.04. 2005
• MANDATORY FOR “NEW” HMPs APPLICATIONS SINCE 01.07.2003
Part I
PRESENTATION AND CONTENT
OF THE DOSSIER
Part II
Module 1
Pharmaceutical
Regional
Information
1.0
Part III
CTD Table of Contents
2.1
Toxicological
CTD Introduction
2.2
Part IV
Quality
Overall
Summary
2.3
Clinical
1998 EDITION- NTA
Non-clinical
Overview
2.4
Non-clinical
Summaries
2.6
Clinical
Overview
2.5
Clinical
Summary
2.7
Module 3
Module 4
Module 5
Quality
3.0
Nonclinical
Study Reports
4.0
Clinical
Study Reports
5.0
FRIAS, 2004
2001 EDITION- CTD
1
LEGAL BASIS FOR SUBMISSION OF HMPs IN THE EU
* COMPLETE AND INDEPENDENT APPLICATION / STAND ALONE APPLICATION
• ART. 8. 3 (i) OF DIR. 2001/83/EC
“COMPLETE DOSSIER APPLICATION” BASED ON THE MANUFACTURER’S OWN
QUALITY, PRECLINICAL AND CLINICAL RESEARCH DATA
* BIBLIOGRAPHIC APPLICATION
• ART. 10.1 (a) (ii) OF DIR. 2001/83/EC
1. IN DEROGATION OF ART. 8.3.(i), AND …..
(a) THE APPLICANT SHALL NOT BE REQUIRED TO PROVIDE THE RESULTS OF
PHARMACOLOGICAL AND TOXICOLOGICAL TESTS OR THE RESULTS OF CLINICAL
TRIALS IF HE CAN DEMONSTRATE :
ii) …. BY DETAILED REFERENCE TO PUBLISHED SCIENTIFIC LITERATURE THAT THE
CONSTITUENT OR CONSTITUENTS OF THE PROPRIETARY MEDICINAL PRODUCT
HAVE A WELL ESTABLISHED MEDICINAL USE, WITH RECOGNIZED EFFICACY AND
AN ACCEPTABLE LEVEL OF SAFETY
• CAN BE A “MIXED DOSSIER” APPLICATION INCLUDING BOTH EXISTING BIBLIOGRAPHIC EVIDENCE
SUPPLEMENTED WITH THE APPLICANT’S OWN RESEARCH DATA.
* ALTHOUGH THE FULL AND BIBLIOGRAPHIC LEGAL BASES HAVE BEEN TRANSPOSED INTO THE
NATIONAL LEGISLATION, THERE ARE MAJOR DISCREPANCIES BETWEEN THE MS IN THE
CLASSIFICATION AS WELL AS IN THE DOSSIER REQUIREMENTS FOR OBTAINING A MARKETING
AUTHORIZATION.
“ WELL-ESTABLISHED USE” DEMONSTRATION (WEU) (1)
ANNEX 1 TO CD 2001/83 EC AMENDED BY CD 2003/63 (25.06.2003)
CTD 3.2 (a) :
• THE TIME OVER WHICH A SUBSTANCE HAS BEEN USED, NOT LESS THAN
10 YEARS FROM FIRST AND SYSTEMATIC USE AS A MEDICINAL PRODUCT;
• QUANTITATIVE ASPECTS OF THE USE OF THE SUBSTANCE;
• THE DEGREE OF SCIENTIFIC INTEREST IN THE USE OF THE SUBSTANCE, AND
• THE COHERENCE OF SCIENTIFIC ASSESSMENTS.
CTD 3.2 (b) :
BIBLIOGRAPHY “SHOULD COVER ALL ASPECTS OF THE SAFETY AND/OR EFFICACY
ASSESSMENT AND MUST INCLUDE OR REFER TO A REVIEW OF THE RELEVANT
LITERATURE, TAKING INTO ACCOUNT PRE-AND POST-MARKETING STUDIES AND
PUBLISHED SCIENTIFIC LITERATURE CONCERNING EXPERIENCE IN THE FORM
OF EPIDEMIOLOGICAL STUDIES AND IN PARTICULAR OF COMPARATIVE
EPIDEMIOLOGICAL STUDIES”.
“ WELL-ESTABLISHED USE” DEMONSTRATION (WEU) (2)
ANNEX 1 TO CD 2001/83 EC AMENDED BY CD 2003/63 (25.06.2003)
CTD 3.2 (c) : MISSING INFORMATION : JUSTIFICATION MUST BE GIVEN
CTD 3.2 (d) :
NON-CLINICAL AND /OR CLINICAL OVERVIEWS MUST EXPLAIN RELEVANCE OF ANY
DATA SUBMITTED WHICH CONCERN A PRODUCT DIFFERENT FROM THE PRODUCT
INTENDED FROM MARKETING.
CTD 3.2 (e) :
POST-MARKETING EXPERIENCE WITH OTHER PRODUCTS CONTAINING THE SAME
CONSTITUENTS IS OF PARTICULAR IMPORTANCE AND APPLICANTS SHOULD PUT
A SPECIAL EMPHASIS ON THIS ISSUE.
DIRECTIVE 2004 / 24 / EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (2)
* NEW LEGAL BASIS AND PROCEDURE
• SIMPLIFIED REGISTRATION OF TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs)
UNDER ARTICLE 16A
DOES NOT APPLY IN CASE THE “TRADITIONAL” HERBAL PRODUCT FULFILS THE
CRITERIA FOR A FULL MARKETING AUTHORISATION
• APPLICATION TO THE COMPETENT AUTHORITY OF THE MEMBER STATE (MS)
• TIMEFRAME FOR IMPLEMENTATION
- 210 DAYS REVIEW
- MEMBER STATES : MAX. 18 MONTHS
- EMEA : MAX. 18 MONTHS (STARTING ON 22.09.2004)
- THMPs ALREADY ON THE MARKET IN THE MS :
COMPLIANCE WITHIN 7 YEARS (04.2011).
DIRECTIVE 2004 / 24 / EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (3)
* SCOPE
• INDICATION (S) EXCLUSIVELY APPROPRIATE TO THMPs AND DESIGNED FOR USE
WITHOUT SUPERVISION OF A MEDICAL PRACTITIONER FOR DIAGNOSIS, PRESCRIPTION
OR MONITORING OF TREATMENT
• SPECIFIED STRENGTH AND POSOLOGY
• ONLY ORAL OR EXTERNAL USE AND INHALATION
• PERIOD OF TRADITIONAL USE : 30 YEARS (15 YEARS IN AND 15 YEARS OUTSIDE THE EU),
UNLESS OTHERWISE DECIDED BY THE HMPC
• VITAMINS AND MINERALS MAY BE ADDED IF THEIR ACTION IS ANCILLARY TO THE
HERBAL CONSTITUENT(S)
DIRECTIVE 2004 / 24 / EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (4)
* DOSSIER REQUIREMENTS
• ADMINISTRATIVE DOSSIER : APPLICATION FORM, EXPERT REPORTS, SPC
• PHARMACEUTICAL DOSSIER : IDENTICAL TO A “ FULL” MARKETING AUTHORISATION
• BIBLIOGRAPHIC OR EXPERT EVIDENCE THAT THE PRODUCT OR A CORRESPONDING
MEDICINAL PRODUCT HAS BEEN IN MEDICINAL USE FOR AT LEAST 30 YEARS ( NOT
NECESSARY IF LISTED OR MONOGRAPH)
• BIBLIOGRAPHIC REVIEW OF SAFETY DATA TOGETHER WITH AN EXPERT REPORT
(NOT NECESSARY IF LISTED OR MONOGRAPH)
• MS MAY REQUEST FURTHER SAFETY DATA, IF NECESSARY
DIRECTIVE 2004 / 24 / EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (6)
* TASKS OF THE HERBAL COMMITTEE (HMPC)
• ESTABLISH A LIST OF HERBAL SUBSTANCES, PREPARATIONS AND COMBINATIONS
THEREOF FOR USE IN THMPs
• ESTABLISH COMMUNITY HERBAL MONOGRAPHS FOR WELL-ESTABLISHED MARKETING
AUTHORISATIONS OR TRADITIONAL REGISTRATIONS OF HMPs.
MONOGRAPHS SHALL BE USED AS THE BASIS FOR ANY APPLICATION
• AT THE REQUEST OF A MS DRAW UP AN OPINION ON THE ADEQUACY OF THE EVIDENCE OF
THE LONG-STANDING USE
• BE RESPONSIBLE FOR ARBITRATION / REFERRAL PROCEDURES ON THMPs
• GIVE AN OPINION ON OTHER MEDICINAL PRODUCTS CONTAINING HERBAL SUBSTANCES
REFERRED TO THE EMEA/CHMP
DIRECTIVE 2004/24/EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (7)
* POST- AUTHORISATION ACTIVITIES

PHARMACOVIGILANCE REQUIREMENTS

MANUFACTURING AND IMPORT PROVISIONS
 VARIATIONS - TAKING INTO TECHNICAL PROGRESS
 INSPECTION ACTIVITIES

GMP

COMPLIANCE WITH EU PHARMACOPOEIA MONOGRAPHS

PHARMACOVIGILANCE
DIRECTIVE 2004/24/EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (8)
*
LABELLING AND USER PACKAGE LEAFLET
SHALL CONTAIN A STATEMENT
“THE PRODUCT IS A TRADITIONAL HERBAL MEDICINAL PRODUCT FOR USE IN SPECIFIED
INDICATION(S) EXCLUSIVELY BASED UPON LONG STANDING USE”
“THE USER SHOULD CONSULT A DOCTOR OR QUALIFIED HEALTH CARE PRACTIONER IF THE
SYMPTOMS PERSIST DURING THE USE OF THE PRODUCT OR IF ADVERSE EFFECTS NOT
MENTIONED IN THE PACKAGE LEAFLET OCCUR
- A MS MAY REQUIRE TO MENTION THE NATURE OF THE TRADITION IN QUESTION
* ADVERTISEMENT
SHALL CONTAIN THE STATEMENT
“TRADITIONAL HERBAL MEDICINAL PRODUCT FOR USE IN SPECIFIED INDICATION(S) EXCLUSIVELY
BASED UPON “LONG STANDING USE”
OVERVIEW
LEGAL FRAMEWORK FOR HERBAL MPS IN THE EU
LEVEL OF EVIDENCE
Legal basis
Medicinal use
Conditions
New product
Art. 8.3(i)
2001/83/EC
“Complete
application”
Art. 10.1(a)(ii)
2001/83/EC
”Bibliographi
cal
application”
< 10
years
Major claim
 10
years
+ demonstration of
“well established
use”
Minor claim
Minor
Art. 16.a of the
conditions
proposed
SelfDirective on
 30
medication
Traditional
years
Herbal
+ demonstration of
Medicinal
“traditional use”
Products
Fraudulent or misleading
claims
A
B
C
T
X
Labelling
Serious and
minor diseases
Herbal medicinal
Possible
intervention of product for...
(treatment,
medical
prevention
...)
practitioner
No restrictions
regarding
strength,
posology, route
of administration
Limited route of
administration.,
strength &
posology
Traditionally
used for…
(no or limited
scientific
evidence)
FRIAS, 2004
DIRECTIVE 2004/24/EC ON
TRADITIONAL HERBAL MEDICINAL PRODUCTS (THMPs) (9)
*
PERSPECTIVES

PURPOSE
TO ESTABLISH A HARMONISED LEGISLATION FRAMEWORK FOR TRADITIONAL HERBAL
MEDICINAL PRODUCTS IN EUROPE

IMPLEMENTATION
IN ORDER TO PROMOTE THIS HARMONISATION MS SHOULD RECOGNISE NATIONAL
REGISTRATIONS OF THMPs GRANTED BY ANOTHER MS BASED ON COMMUNITY HERBAL
MONOGRAPHS

LIMITATIONS
BORDERLINE MEDICINE-FOOD PRODUCTS
-
THE DIRECTIVE ALLOWS NON-MEDICINAL HERBAL PRODUCTS TO BE REGULATED
UNDER FOOD LEGISLATION IN THE COMMUNITY
-
HERBAL PRODUCTS THAT ARE USED FOR HEALTH ENHANCEMENT/MAINTENANCE,
REDUCTION OF RISK FACTOR FOR A DISEASE/ DISORDER/CONDITION OR GENERAL
PROMOTION OF WELL-BEING/ FUNCTION OF THE HEALTHY BODY/ORGAN WILL
PROBABLY BE REGULATED WITHIN THE AREA OF FOOD SUPPLEMENTS
EUROPEAN DIRECTORATE FOR THE
QUALITY OF MEDICINE (EDQM)
www.edqm.org
EUROPEAN PHARMACOPOEIA
* GROUPS OF EXPERTS 13A AND 13B : PHYTOCHEMISTRY
• SETTING STANDARDS FOR
*
*
*
*
*
PRODUCTION OF HERBAL DRUGS
PHARMACEUTICAL INDUSTRY
QUALITY CONTROL LABORATORIES
REGULATORY AUTHORITIES
COMMUNITY PHARMACISTS
• MONOGRAPHS (TILL 2003)
* HERBAL DRUGS : PUBLISHED :
106
UNDER STUDY :
40
* HERBAL DRUG PREPARATIONS : PUBLISHED :
58
UNDER STUDY : 48
* CERTIFICATION OF SUITABILITY TO THE MONOGRAPHS OF THE EP
PUBLIC COMMITTEE RESOLUTION AP-CSP (99) 4
• EXTENSION OF THE EDQM CERTIFICATION PROCEDURE TO HERBAL DRUG PREPARATIONS
(MARCH, 2003).
OVERVIEW OF HERBAL SUBSTANCES/PREPARATIONS
CPMP/QWP/2819/00, CORR.
EMEA/CVMP/814/00, CORR.
EUR. PH. SUPPL. 2002
HERBAL DRUGS
HERBAL SUBSTANCES
(PLANTAE MEDICINALES)
HERBAL DRUG PREPARATIONS
HERBAL PREPARATIONS
(PLANTAE MEDICINALES PRAEPARATORE)
COMMINUTED OR
POWDERED DRUGS
EXTRACTS
(EXTRACTA)
ESSENTIAL OILS
(AETHEROLEA)
HERBAL
MEDICINAL
PRODUCTS
HERBAL TEAS
(PLANTAE AD PTISANAM)
EXPRESSED JUICES
PROCESSED
EXUDATES
TRADITIONAL
HERBAL
MEDICINAL
PRODUCTS
DIFFERENT TYPES OF HERBAL EXTRACTS
* EUR. PH. 2002, SUPPL. 4.3
HERBAL PREPARATIONS (HP)
HERBAL EXTRACTS (HE)
• LIQUID
• SOFT: SEMI-SOLID
NOT NATIVE HPs
• NATIVE (GENUINE) EXTRACTS
CONSIST SOLELY OF GENUINE
HERBAL EXTRACTABLE MATTER
• NOT NATIVE EXTRACTS
CONTAIN ALSO TECHNICAL
EXCIPIENTS, EXCIPIENTS NEEDED
FOR STANDARDISATION AND/OR
EXTRACTION SOLVENTS.
DRY
NATIVE
HPs
NOT NATIVE
HPs
TYPE A :
STANDARDIZED (ADJUSTED)
EXTRACTS
TYPE B1 :
QUANTIFIED EXTRACTS
TYPE B2 :
OTHER EXTRACTS
REFINED “EXTRACTS (“PURIFIED”,
“ENRICHED” EXTRACTS)
• DER = THE RATIO OF THE STARTING
MATERIAL TO THE GENUINE EXTRACT (20:1 = 5% OF EXTRACTABLE MATTER)
CLASSIFICATION OF PLANT CONSTITUENTS
1. THERAPEUTICALLY
ACTIVE CONSTITUENTS
CHEMICALLY DEFINED SUBSTANCES OR
GROUPS OF SUBSTANCES WHICH, IN AN
ISOLATED STATE, EXERT THE SAME OR
SIMILAR THERAPEUTIC EFFECT AS THE
TOTAL EXTRACT.
2. ACTIVE CONSTITUENTS
(PHARMACAEUTICALLY
RELEVANT CONSTITUENTS)
CHEMICALLY DEFINED SUBSTANCES OR
GROUPS OF SUBSTANCES WHICH, IN AN
ISOLATED STATE, DO NOT EXERT THE
SAME THERAPEUTIC EFFECT AS THE
TOTAL EXTRACT, BUT WHICH ARE
ACCEPTED TO CONTRIBUTE TO THE
THERAPEUTIC ACTIVITY OF THE HERBAL
DRUG PREPARATION.
3. MARKERS
CHEMICALLY DEFINED SUBSTANCES OR
GROUPS OF SUBSTANCES WHICH ONLY
SERVE ANALYTICAL PURPOSES.
EXAMPLES:
SILYMARIN, AESCIN,
ANTRAQUINONES, ALKALOIDS,
CARDIAC GLYCOSIDES, ...
EXAMPLES:
HYPERICINS, PROCYANIDINES,
FLAVONOIDS.
3.1. CHARACTERISTIC
MARKERS
CHARACTERISTIC FOR THE RESPECTIVE
GENUS OR FAMILY OF THE PLANT,
SUITABLE FOR IDENTIFICATION, TESTS AND
ASSAY (E.G. BATCH-TO-BATCH CONTROL).
EXAMPLES:
VALERENIC ACIDS,
ECHINACOSIDE,
ELEUTHEROSIDES B AND E.
3.2. UBIQUITOUS
MARKERS
OCCUR UBIQUITOUSLY IN PLANTS, SUITABLE
FOR ASSAY (E.G. BATCH-TO-BATCH CONTROL).
EXAMPLES:
CHLOROGENIC ACID,
RUTIN.
NOTE FOR GUIDANCE ON SPECIFICATIONS :
TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR HERBAL SUBSTANCES,
HERBAL PREPARATIONS AND HERBAL MEDICINAL PRODUCTS
(CPMP/QWP/2820/00/EMEA/CVMP/815/00)

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

1.
2.
3.
GENERAL CONCEPTS
CHARACTERISATION
DESIGN AND DEVELOPMENT CONSIDERATIONS
PHARMACOPOEIAL TESTS AND ACCEPTANCE CRITERIA
PERIODIC/SKIP TESTING
RELEASE VERSUS SHELF-LIFE ACCEPTANCE CRITERIA
IN-PROCESS TESTS
ALTERNATIVE PROCEDURES
EVOLVING TECHNOLOGIES
REFERENCE STANDARD
STATISTICAL CONCEPTS
GUIDELINES
SPECIFICATIONS : DEFINITION AND JUSTIFICATION
UNIVERSAL TESTS/CRITERIA
 HERBAL SUBSTANCES
 HERBAL PREPARATIONS
 HERBAL MEDICINAL PRODUCTS
SPECIFIC TESTS/CRITERIA
 HERBAL SUBSTANCES
 HERBAL PREPARATIONS
 HERBAL MEDICINAL PRODUCTS
SPECIFICATIONS OF HERBAL SUBSTANCES
NOTE FOR GUIDANCE ON SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE
CRITERIA FOR HERBAL SUBSTANCES (CPMP/QWP/2820/00/EMEA/CVMP/815/00)
BOTANICAL CHARACTERISTICS
BIOLOGICAL/GEOGRAPHICAL VARIATION
- DEFINITION
- CHARACTERS
- IDENTIFICATION
MACROSCOPY
MICROSCOPY
HERBAL SUBSTANCES
PHYTOCHEMICAL CHARACTERS
STABILITY OF
CONSTITUENTS
- KNOWN THERAPEUTIC CONSTITUENTS
- TOXIC CONSTITUENTS
IDENTIFICATION
- TLC
- CHEMICAL
REACTIONS
TESTS
ASSAY
- TOTAL ASH
- IN HCL INSOLUBLE ASH
- FOREIGN MATTER
- EXTRACTABLE MATTER
- PARTICLE SIZE
- WATER CONTENT
CULTIVATION/HARVESTING
DRYING CONDITIONS
PRE/POST HARVEST
TREATMENTS
- PESTICIDES
- FUMIGANTS
- MICROBIAL LEVELS
- AFLATOXINS
- HEAVY METALS ETC..
SPECIFICATIONS OF HERBAL DRUG PREPARATIONS
NOTE FOR GUIDANCE ON SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE
CRITERIA FOR HERBAL PREPARATIONS (CPMP/QWP/2820/00/EMEA/CVMP/815/00)
PHYTOCHEMICAL CHARACTERISTICS
IDENTIFICATION
QUALITY OF HERBALSUBTANCES
STABILITY OF
CONSTITUENTS
ASSAY
HERBAL PREPARATIONS
CHROMATOGRAPHIC PROFILE
. HPLC/UV-DIODE-ARRAY
. HPLC/MS
. GC/MS
. TLC-DENSITOMETRY
METHOD OF PREPARATION
FROM HERBAL DRUG
DEFINITION
- STATE : SOLID, LIQUID ETC.
- RATIO HERBAL DRUG TO HERBAL
PREPARATION OR RATIO HERBAL
SUBSTANCES TO EXTRACTION
SOLVENT
CHARACTERS
SAFETY AND EFFICACY
CONSIDERATIONS
BATCHES USED IN
PRECLINICAL/CLINICAL
TESTING
MICROBIAL STABILITY
DRYING
CONDITIONS
- MICROBIAL LEVELS
- RESIDUAL SOLVENTS
IN EXTRACTS
- WATER CONTENT
- AFLATOXINS
- HEAVY METALS
- PESTICIDES
- FUMIGANTS ETC.
SPECIFICATIONS OF FINISHED HERBAL MEDICINAL PRODUCTS
NOTE FOR GUIDANCE ON SPECIFICATIONS:TEST PROCEDURES AND ACCEPTANCE
CRITERIA FOR HERBAL MEDICINAL PRODUCTS (CPMP/QWP/2820/00/EMEA/CVMP/815/00)
DESCRIPTION OF
DOSAGE FORMS
IDENTIFICATION
. CHROMATOGRAPHIC PROFILE
ASSAY
SPECIFIC TESTS
TABLETS AND HARD
CAPSULES
- DISSOLUTION/DESINTEGRATION
- HARDNESS/FRIABILITY
- UNIFORMITY OF DOSAGE UNITS
- WATER CONTENT
- MICROBIAL LIMITS
QUALITY OF HERBAL
PREPARATIONS
HERBAL MEDICINAL PRODUCTS
MANUFACTURING PROCESS
. TEMPERATURE EFFECTS
. RESIDUAL SOLVENTS
. ORGANIC AND INORGANIC
IMPURITIES
. MICROBIAL LIMITS
ORAL LIQUIDS
- UNIFORMITY OF DOSAGE
STABILITY OF THE
ACTIVE CONSTITUENTS
FORMULATION/PACKAGING
SAFETY AND EFFICACY
CONSIDERATIONS
BACTHES USED IN PRECLINICAL/CLINICAL TESTING
- pH.; WATER CONTENT; SPECIFIC GRAVITY
- MICROBIAL LIMITS : ANTIMICROBIAL, AND ANTIOXIDATIVE
PRESERVATIVE CONTENT
- EXTRACTABLES : ALCOHOL CONTENT
- DISSOLUTION : PARTICLE SIZE DISTRIBUTION
- REDISPERSIBILITY : RECONSTITUTION TIME
ANALYTICAL DEVELOPMENT OF HERBAL PREPARATIONS AND
HERBAL MEDICINAL PRODUCTS
IDENTITY
PURITY
DURING DEVELOPMENT
ANALYSIS METHODS
ASSAY
ACTIVE INGREDIENT
SPECIFICATION AT
REGISTRATION TIME
TEST PROCEDURE
(detailled description)
ANALYTICAL VALIDATION
VALIDATION OF
EACH TEST PROCEDURE
PRECISION
ACCURACY
DETAILLED DESCRIPTION
INCLUDING DOCUMENTS
e.g. : . chromatograms
. spectra
. linearity
VALIDATION MUST PROVE THE
. recovery rates from spiked
ACCURACY OF TEST RESULTS
samples
VALIDATION OF ANALYTICAL METHODS
1. WHICH VALIDATION CHARACTERISTICS HAVE TO BE VALIDATED?
ACCORDING TO ICH (INTERNATIONAL CONFERENCE OF HARMONISATION)
TYPES OF ANALYTICAL
PROCEDURE
IDENTIFICATION
TESTING FOR
IMPURITIES
QUANTITATIVE
ASSAY
DISSOLUTION
(MEASUREMENT ONLY)
CONTENT/POTENCY
LIMIT
CHARACTERISTICS
ACCURACY
PRECISION :
REPEATIBILITY
INTERMEDIATE PRECISON
SPECIFICITY (2)
DETECTION LIMIT
QUANTITATION LIMIT
LINEARITY
RANGE
-
+
-
+
+
-
+
+ (1)
+
- (3)
+
+
+
-
+
+ (1)
+
*
*
-
+
+
-
+
+
- : SIGNIFIES THAT THIS CHARACTERISTIC IS NORMALLY NOT EVALUATED
+ : SIGNIFIES THAT THIS CHARACTERISTIC IS NORMALLY EVALUATED
(1) IN CASES WHERE REPRODUCIBILITY HAS BEEN PERFORMED, INTERMEDIATE PRECISION IS NOT NEED
(2) LACK OF SPECIFICITY OF ONE ANALYTICAL PROCEDURE COULD BE COMPENSATED BY OTHER SUPPORTING
ANALYTICAL PROCEDURE(S)
(3) MAY BE NEEDED IN SOME CASES
PRIMARY REFERENCE STANDARDS
PLANT PREPARATION
ISOLATION
FULL DESCRIPTION INCLUDING
PURIFICATION STEPS
TO PROVE THE STRUCTURES
CHARACTERIZATION
IDENTITY
TEST RESULTS OF ALL SPECIFIED QUALITY
CHARACTERISTICS
AND, IF RELEVANT, FOR PHYSICOCHEMICAL
CHARACTERISTICS
PURITY
TEST RESULTS OF ALL POSSIBLE IMPURITIES
ORGANIC IMPURITIES
WATER CONTENT
INORGANIC IMPURITIES
ASSAY
FULL DESCRIPTION INCLUDING TEST RESULTS
E.G.
100% MINUS H2O AND INORGANIC
IIMPURITIES
SUM OF PEAKS =100% AREA MINUS AREA
OF ALL IMPURITIES
“AS IS”- ASSAY (VALUE)
REFERENCE VALUE FOR WORKING
STANDARD (SECONDARY)
CHROMATOGRAPHIC
PURITY
- DIFFERENTIAL SCANNING
CALORIMETRY
- PHASE SOLUBILITY
ANALYSIS
MOLECULAR PURITY
MARKETING AUTHORIZATION OR REGISTRATION OF HMPs
MARKETING AUTHORIZATION
REGISTRATION
PHARMACOVIGILANCE
APPLIES TO REGISTERED
AND TO AUTHORIZED HMPs
CONSUMER INFORMATION; LABELLING; ADVERTISING
EFFICACY
NEW TRIALS
BIBLIOGRAHIC
SAFETY
NEW TESTS
TRADITIONAL USE
EXPERT REPORT
BIBLIOGRAPHIC
BIBLIOGRAPHIC NEW TESTS
QUALITY CONTROL
GOOD MANUFACTURING PRACTICES
GOOD AGRICULTURE AND
COLLECTION PRACTICES
NEW
N
WEU
TRADITIONAL
MAY BE REPLACED BY A
MONOGRAPH OR THE LIST
FROM THE HMPC IN
REGISTRATIONS
IDENTICAL FOR MARKETING
AUTHORIZATIONS AND
REGISTRATIONS
MARKETING AUTHORIZATION OR REGISTRATION OF
ANTIMALARIALS FROM ARTEMISIA ANNUA L.
NEW
WEU
TRADITIONAL
ARTEMISININ
• DIHYDROARTEMISININ
• ARTHEMETHER
• ARTHEETHER
• ARTELINATE
• ARTESUNATE ...
ARTHEMETHER ...
AND
LUMIFANTRINE
OR
MEFLOQUINE ...
ARTESUNATE ...
AND
SULFAMETHOXYPYRAZINE/
PYRIMETHAMINE ...
ARTEMISIA
ANNUA EXTRACT
AND
OTHER
ANTIMALARIALS
ARTEMISIA
ANNUA
EXTRACT
SUMMARY
• THE HMPC IS FULLY OPERATIONAL SINCE NOVEMBER 2004.
• FIRST DECISIONS ON PROCEDURAL ASPECTS ALREADY PUBLISHED IN
JANUARY 2005.
• POSITIVE ATTITUDE AND COMMITMENT OF ALL EXPERTS.
• THE HMPC IS COMMITTED TO DELIVER SCIENTIFICALLY VALID RESULTS,
AS FAST AS POSSIBLE AND IN FULLY TRANSPARENT WAY.
• BOTH, TRADITIONAL AND WELL-ESTABLISHED HERBAL MEDICINAL PRODUCTS
WILL BENEFIT FROM THESE ACTIVITIES.
• NEW LEGAL AND SCIENTIFIC AREAS ARE TO BE EXPLORED
• SIGNIFICANT WORKLOAD IN PREPARING THE GROUNDS FOR ROBUST RESULTS.
• RESOURCES FROM EMEA AND FROM MEMBER STATES NEED TO BE CLEARLY
ALLOCATED.
K. KELLER, 2006