HOMEOPATHIC MEDICINAL PRODUCT WORKING GROUP

(HMPWG)

POINTS TO CONSIDER ON NON-CLINICAL SAFETY OF HOMEOPATHIC

MEDICINAL PRODUCTS OF BOTANICAL, MINERAL AND CHEMICAL
ORIGIN

DISCUSSION IN THE HMPWG April 2002 - November 2005

FIRST COMMENTS OF THE INDUSTRY October 2005
DISCUSSION IN THE WG HMPWG December 2005
RELEASE FOR CONSULTATION January 2006
DEADLINE FOR COMMENTS 31 March 2006
DISCUSSION IN THE HMPWG June 2006
ADOPTION FOR TRANSMISSION TO HMA June 2006
DEADLINE FOR COMMENTS 15 January 2007
ADOPTION FOR TRANSMISSION TO HMA March 2007
ADOPTION BY HMA July 2007

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1 Introduction
Homeopathic medicinal products of botanical, mineral and chemical origin must be regulated
according to the same non-clinical principles that are applied to other medicinal products.
Specifically homeopathic medicinal products must demonstrate adequate safety.

A non-clinical assessment strategy should take the different origins of homeopathic medicinal
products into account and refer to the relevant European guidelines.

This point to consider applies to homeopathic medicinal products as stated in the Directive
2001/83/EC as amended.

2 Scope

This point to consider describes a general framework and practical approach on how to deal with
the non-clinical assessment of homeopathic medicinal products of botanical, mineral and chemical
origin.
Firstly, the criteria for establishing a first safe dilution of a given homeopathic medicinal product of
botanical, mineral and chemical origin are presented.

Secondly, recommendations on the requirements for non-clinical assessment (Module 4) for

homeopathic medicinal products of botanical, mineral and chemical origin are formulated.

3 Criteria for establishment of first safe dilution

3.1 General remarks

The criteria for the establishment of a first safe dilution are defined in a decision-tree (see Annex 1).
These are subject to updating according to the state-of-the-art of scientific knowledge. This
approach enables the establishment of a first safe dilution for a homeopathic medicinal product of
botanical, mineral and chemical origin. Ultimately, a validated list of first safe dilutions of
homeopathic medicinal products of botanical, mineral and chemical origin can be compiled.
Homeopathic stocks are different in their degree of analytical qualification. While chemical stocks
are analytically qualified, the degree of analytical qualification of botanical preparations is
dependent upon the type of preparation, as is described in the Guideline on Quality of Herbal
Medicinal Products/Traditional Herbal Medicinal Products (CPMP/QWP/2819/00), in the European
Pharmacopoeia or, in the absence thereof, by the pharmacopoeias currently used officially in the
Member States. Furthermore, for botanical, mineral or chemical substances that are also used in
food, the assessment of the safety should consider the fact that they are allowed as food or as a
constituent of food and should refer to the existing data of the food and food supplements area1.

The establishment of a first safe dilution for homeopathic medicinal products of botanical, mineral
and chemical origin marks the threshold for the submission of a detailed non-clinical safety
assessment (Module 4).

1
Regulation 178/2002/EC modified by 1642/2003/EC and all related directives Food supplements 2002/46/EC

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For homeopathic medicinal products for which neither analytical (chemical or phytochemical) nor
toxicological data are available, a justification for a given dilution will be provided within a module
4 on the basis of existing data.

3.2 Background information on TTC principle

For genotoxic homeopathic medicinal products of botanical, mineral and chemical origin and under
the conditions as defined in Annex 1, the recommendations formulated in the Guideline on the
Limits of Genotoxic impurities (CPMP/SWP/5199/02) are chiefly followed. However, the
recommendations by Kroes et al. (20042) with respect to the level of the Threshold of Toxicological
Concern (TTC) are applied and therefore a TTC of 0.15.10-3 mg/day is defined.
According to the recommendations by Kroes et al. (2004) the following structural groups were
excluded from the TTC approach: aflatoxins, nitroso- and azoxy-compounds, heavy metals,
polyhalogenated dibenzodioxin, -dibenzofuran or –biphenyl. Additionally, Aristolochia species are
excluded from the TTC approach for homeopathic medicinal products of botanical origin in
compliance with the Position Paper on the Risks Associated with the Use of Herbal Products
containing Aristolochia species (EMEA/HMPWP/23/00). The TTC approach is not applicable for
these substances and consequently the non-clinical risk assessment should be performed on a case-
by-case basis and should involve the submission of a module 4.

3.3 Background on PDE

For well-described non-genotoxic carcinogenic or teratogenic homeopathic medicinal products of

botanical, mineral and chemical origin, an estimate of daily human exposure at and below which
there is a negligible risk to human health can be identified (Permitted Daily Exposure or PDE).
Procedures for the derivation of PDE are considered in the Appendix 3 of the Note for Guidance on
Impurities: Residual Solvents (CPMP/ICH/283/95). This approach requires the availability of
adequate non-clinical data, which can be found in Peer-Reviewed Monographs (e.g. WHO, ECB).

3.4 Calculation of the first safe dilution

For the conversion of the PDE (mg/day), TTC (mg/day) or LHRD/1003 (mg/day, see Annex 1) to a
first safe dilution, the worst case scenario should be adopted. This implies that the proposed dose
of stock is present in 10 ml of oral solution or in 10 g of trituration. This concentration, expressed
as a decimal dilution (DH = -log(PDE/TTC/LHRD:100) is taken as the reference for further
calculations. The DH can be converted to other dilution types, including centesimal Hahnemannian
(CH), Korsakovian (K) or fifty millesimal (LM) by taking into account the specific conversion
factor for dilution (CFdilution) as detailed in Table 1.
The PDE, TTC or LHRD/100, as referred to in Table 1, should be interpreted as a dose of stock.
When considering a stock of botanical origin, the manufacturing method of the mother tincture and
of 1DH (D1) should be taken into account by applying the specific conversion factor for the
manufacturing method (CFmanufacturing method) as detailed in Table 2. CFmanufacturing method is
related to the equivalent quantity of dried plant in the mother tincture and/or in 1DH (D1)
manufactured by the methods described in the European Pharmacopoeia.

2
Kroes et al. 2004 “Structure-based thresholds of toxicological concern (TTC): guidance for application to
substances present at low levels in the diet” Food and chemical toxicology 42, 65-83.
3
For herbal medicinal products the LHRD as recommended in recognised EU monographs should be applied.

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 Table 1. Calculation of the First Safe Dilution and the Conversion Factor for Dilution (CFdilution) taking into
account the pharmaceutical form and the type of dilution

FIRST SAFE
CFdilution for pharmaceutical
DILUTION CFdilution for 1% impregnated
forms containing 10% or less
nDH pharmaceutical forms by a
CFdilution for trituration or than 10% of a dilution or
n=-log (concentration dilution quantitatively
solution trituration quantitatively
of PDE, LHRD/100 or equivalent to the first safe
equivalent to the first safe
TTC in 10ml solution dilution (nDH)
dilution (nDH)
or 10g trituration)*
nDH xDH xCH/K xLM xDH xCH/K xLM xDH xCH/K xLM

n = even x=n x=n/2 x=(n-6)/5* x=n-2 x=(n-2)/2 x=(n-8)/5* x=n-1 x=n/2 x= (n-7)/5*
n = uneven x=n x=(n+1)/2 x=(n-6)/5* x=n-2 x=(n-1)/2 x=(n-8)/5* x=n-1 x=(n-1)/2 x=(n-7)/5*
In case of application of valid for valid for valid for
the TTC criteria, n=9
• oral preparations- liquid • impregnated oral preparations • cutaneous and transcutaneous
forms & solids forms preparations
• oral preparations - solid • ear preparations
forms (triturations) • eye preparations
• vaginal preparations
• rectal preparations
* round up to the higher whole number
DH: Decimal Hahnemannian (D, X); CH (C): Centesimal Hahnemannian; K: Korsakovian

Table 2. Calculation of Conversion Factor for Different Manufacturing Methods

(CFmanufacturing method)

Manufacturing CFmanufacturing method of mother tincture (MT) and D1 (1DH) (European pharmacopoeia)4
method calculated with reference to the dried plant material

Ratio raw material (stated in dried plant)/MT Ratio raw material (stated in dried plant)/D1
Eur. Ph.method 4c . 1 part dried plant + 9 parts ethanol, 1 part MT + 9 parts ethanol= 1/10MT,
(1/10 ) equivalent to 1/10 part dried plant/part MT equivalent to 1/100 part dried plant/part D1
Eur. Ph method. 4d . 1 part dried plant+ 19 parts ethanol, 1 part MT + 9 parts ethanol = 1/10 MT,
(1/20) equivalent to 1/20 part dried plant/ part MT equivalent to 1/200 part dried plant/part D1
Eur. Ph. , method 1
1a 1 part expressed juice + 1 part ethanol = 1/2 part 2 parts MT + 8 parts ethanol = 2/10 MT,
juice/part MT, equivalent to 2/10*((100-T)/2T) part dried plant/ part D1
equivalent to ((100-T)/2T) part dried plant/part MT
1b 1 part fresh plant latex + 2 parts ethanol = 1/3 part 3 parts MT + 7 parts ethanol=3/10 part MT/part D1,
juice/part MT, equivalent to 3/10*((100-T)/3T) part dried plant/part D1
equivalent to ((100-T)/3T) part dried plant/part MT
Eur. Ph. , method. 2a,2b 1 part of fresh plant + (1*T/100) parts ethanol = 2 parts of MT + 8 parts ethanol = 2/10 MT,
(100/100+T) part fresh plant part /MT, equivalent to 2/10 * [(100-T)/(100+T)] part dried
equivalent to [(100-T)/(100+T)] part dried plant/part plant/part D1
MT
Eur. Ph. , method 3a,3b 1 part of fresh plant + (2*1*T/100) parts ethanol = 3 parts of MT + 7 parts ethanol = 3/10 MT,
[100/(100+2T] part fresh plant / part MT, equivalent to 3/10 * [(100-T)/(100+2T)] part dried
equivalent to [(100-T)/(100+2T)] part dried plant/part plant/part D1
MT
Eur. Ph. , method 4a,4b 1 part of dried plant+ 10 parts ethanol = 1/11 part dried D1 equivalent to MT
plant/part MT mentioned as D1
T: loss on drying (%); D1: first decimal dilution (1DH)
Working hypothesis for Eur. Ph., methods 1: the % of juice/latex is equivalent to T
Note: CFmanufacturing method is only valid if the same part(s) of the plant and similar alcohol strength are used for the manufacturing of MT.

4
Methods of preparation of homeopathic stocks and potentisation Eur. Ph. 2371

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4 Requirements for Non-Clinical Data Submission (Module 4)

For compounds at a final dilution equal to or higher than the one mentioned in the list of first safe
dilutions, a reference to the list of first safe dilutions in Module 4 will suffice. However, the
relevant guidelines should still apply for the excipient(s) used and the impurities or degradation
products detected (e.g. CPMP/ICH/2737/99, CPMP/ICH/2738/99, CPMP/ICH/283/95).

For compounds at a final dilution lower than the one mentioned in the list of first safe dilutions and
for compounds not included in the list of first safe dilutions, a detailed Module 4 should be
compiled. This should be based upon the specificity of the raw material and taking into account the
requirements detailed in the Annex 1 of the Directive 2001/83/EC as amended . Any missing data
should be justified; e.g. justification must be given why demonstration of an acceptable level of
safety can be supported although some studies are lacking.

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 ANNEX 1. Decision Tree on the Criteria for the establishment of a First Safe Dilution

Yes Regulation 178/2002/EC modified by

Allowed as food or constituent of food 1642/2003/EC and all related directives
Food supplements 2002/46/EC
No

Maximum amount of raw Authorised allopathic Lowest Human Recommended Dose

material is medicinal productsNote 2 Yes (LHRD)/100
≤ 0.15.10- 3 mg/day (TTC) Non-genotoxic LHRD as mentioned in the Summary
AND phytochemical or Non-carcinogenic of Product Characteristics
chemical characterisation Non-teratogenic
available Note 1 No
Yes Identification as a genotoxicant
Toxicity data available Yes
Evidence from in vivo and/or in
OK (e.g. Monograph) Note 1
vitro studies

No Yes

Other toxicity studies Sufficient evidence for

threshold-related mechanism?

PDE based on lowest Yes No

NOEL or LOELNote 3
PDENote 3 Max. amount of raw
material
≤0.15.10-3 mg/day
No

Yes Sufficient phytochemical

Toxicity data unavailable or chemical
characterization provided

Yes No

Maximum amount of raw First safe dilution

material equivalent to CH12 Note 4

≤0.15.10-3 mg/day
(TTCNote 1)

Note 1
Excl. aflatoxins, nitroso- and azoxy-compounds, heavy metals, polyhalogenated dibenzodioxin, -
dibenzofuran or –biphenyl. For herbal products, Aristolochia species are excluded.

Note 2
Including authorised and registered herbal medicinal products (2004/24/EC).

Note 3
PDE calculation according CPMP/ICH/283/95

Note 4
Or justify in a module 4 for lower dilutions

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Abbreviations
C: Centesimal Hahnemannian dilution
CH: Centesimal Hahnemannian dilution
Cfdilution: conversion factor for dilution
CFmanufacturing method: conversion factor for manufacturing method
D: Decimal Hahnemannian dilution
DH: Decimal Hahnemannian dilution
D1: First decimal dilution (1DH)
ECB: European chemicals bureau
Eur. Ph.: European pharmacopoeia
HMA : Heads of medicines agencies
HMPWG : Homeopathic medicinal products working group
K: Korsakovian dilution
LHRD: Lowest Human Recommended Dose
LM: fifty millesimal dilution
LOEL: Lowest Observable Effect Level
log: logarithm
MT: mother tincture
NOEL: No observable effect level
PDE :Permitted Daily Exposure
T: : loss on drying (%);
TTC : Threshold of Toxicological Concern
WHO: World Health Organisation
X: Decimal Hahnemannian dilution

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