federal agency for medicines and health products

FAMHP GUIDANCE ON MODULE 3 OF THE HOMEOPATHIC

MEDICINAL PRODUCT DOSSIER:

Mother tincture (homeopathic stock of herbal origin) and specific

data related to dilutions of the stock lower than the No-
Assay-Threshold (NAT)

Version: 19/09/2013
Reference of the document: FAMHP/Homeo/M3/MT
5 Division: Unit Homeo/Phyto
Total number of pages: 10

Disclaimer:
1. This guidance is based on HMPWG guidance on module 3. It is completed with
10 some examples or clarifications in order to facilitate the compilation of the module
3 for a homeopathic stock of herbal origin. All possible cases are not presented.
2. The words “dilution” and “trituration” have to be understood according to the
definition of “potentisation” retaken in the Ph. Eur. monograph “Homoeopathic
preparations (1038)”: Dilutions and triturations are obtained from stocks by a
15 process of potentisation in accordance with a homoeopathic manufacturing
procedure: this means successive dilutions and succussions, or successive
appropriate triturations, or a combination of the 2 processes.

3.2.S.1 General information

3.2.S.1.1 Nomenclature
20 “A definition of the homeopathic stock of herbal origin and the homeopathic name (s)
should be provided.

 Binominal scientific name of plant (genus, species, variety and author) and
chemotype (where applicable)
25  State (fresh or dried) and part(s) of the plant
 Other names (synonyms)/ homeopathic names /Latin names
 Reference of the homeopathic manufacturing procedure
 Description of vehicles used”

30 A monograph of an official Pharmacopoeia of a Member State exists:

this information is included in the monograph.

A monograph of an official Pharmacopoeia of a Member State does not exist:

this information including some references has to be provided
35
Federal agency for medicines and health products
Eurostation II – place Victor Horta 40/40 – 1060 Brussels
Phone +32 2 5248000 fax +32 2 5248001
E-mail [email protected] website www.afmps.be

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 3.2.S.1.2 Structure
Not applicable

3.2.S.1.1 General properties

5 This information is included in the monograph or otherwise has to be provided.

3.2.S.2 Manufacture

10 Intermediate and final dilutions: see the document “dilution”.

Mother tincture:

3.2.S.2.1 Manufacturer
“The name, address, and responsibility of each supplier of the raw material, each
15 manufacturer of the mother tincture, and each proposed production site or facility
involved in manufacturing/collection and testing should be provided”.

Concerning each supplier of the raw material: a document that the supplier respects the
good agricultural and collection practice (GACP) should be provided.
20
If the exhaustive list of the raw material suppliers cannot be mentioned, justification is
needed and a Risk Management/Risk Assessment plan should be provided:

Concerning the quality of the raw material, the applicant should always
25 ensure that:
 the raw material complies with the Ph.Eur monograph 2045 (Herbal
drugs for homoeopathic preparations).
 the risk of possible contaminants is assessed and that this risk is
appropriately managed (and eventually adapted in function of the
30 individual suppliers) = RA/RM
On which level are the tests done? Why?
Which tests are done? Why?
What is the testing frequency? Why?
Depending on the case, e.g. when the origin of the raw material is not well
35 known or e.g. if the cultivation/collection/storage/… are insufficiently
documented, this risk assessment and risk management have to be done
based on other criteria.
All these variable factors should be covered in the data provided to the
FAMHP within the framework of this dossier.
40
If, taking into account the variability in availability of the herbal drug, the
Applicant needs to have several suppliers thereof and he wishes to get a
supplier authorized - within the framework of a medicinal product dossier for
authorization or registration - for which not all information is readily
45 available, all RA/RM data – as described above - have to be submitted for
evaluation. The Applicant should, when providing these data, take into
account the quality guidelines relating to herbal drugs as published on the
EMA-website:
http://www.ema.europa.eu/htms/human/humanguidelines/quality.htm#herbal
50

Concerning each manufacturer of the mother tincture: GMP certificate(s) should be

provided.

55 3.2.S.2.2 Description of manufacturing process and process controls

In this section information should be provided to adequately describe the manufacturing
process and process controls.

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 “The description of the homeopathic stock represents the applicant's commitment for the
manufacture of the homeopathic stock. Information should be provided to adequately
describe the manufacturing process and process controls. For example:
5 A sequential procedural narrative of the manufacturing process should be submitted. The
narrative should include, for example, quantities of raw materials, solvents/vehicles,
reagents (if applicable), critical steps and the controls that are intended to result in the
routine and consistent production of the mother tincture. A flow chart of the
manufacturing process should be included. Reference should be made to the appropriate
10 section of a European Pharmacopoeia, or in absence thereof, to a homeopathic
manufacturing procedure described in an official Pharmacopoeia of a Member State of the
European Union.
The different stages of the preparation of the mother tincture must be sufficiently
described to allow the assessment of the consistency of the quality. The material,
15 processes and specific precautions (light, moisture, miscellaneous contamination, and
temperatures) must be described”.

Reference to a monograph is not enough. Manufacturing procedure has to be provided.

20 Maceration time:
The applicant has to follow the prescriptions of the Ph. Eur. monographs but
also has to detail the different stages of the preparation of the homoeopathic
stocks. In order to guarantee the reproducibility of the quality as asked by
the Ph Eur, the applicant is asked to specify the maceration time taking into
25 account the specific nature of the raw material/ the stock or if not possible a
larger range has to be justified mentioning the factors on which the
maceration time depends and as reflected by appropriate IPC (e.g. when
maceration of 10 days is carried out, when maceration of 20 days is carried
out and when maceration of 30 days is carried out).
30 The applicant is remembered that the Ph. Eur. monograph “Methods of
preparation of homoeopathic stocks and potentisation” mentions that
“Maceration may be replaced by long maceration (maximum 60 days) or
very long maceration (maximum 180 days), provided it is demonstrated by
appropriate data that the quality of the resulting mother tincture is the same
35 as that of the mother tincture prepared by maceration”.

3.2.S.2.3 Control of materials

“The information on the raw material and the solvents/reagents or vehicles used for the
homeopathic stock and final dilutions preparation should be presented”.
40
Solvents/reagents:
The certificates of analysis of ethanol and purified water used for the preparation of the
mother tincture should be provided in this section.

45 Raw materials:
“The state (e.g. fresh, dried) of the material used and, where applicable, information on
pharmacological active, toxic constituents or marker compound(s) 1, if applicable, should
be provided. Additionally a macroscopic and microscopic description2 of the raw material
should be presented”.
50
1
“information on pharmacological active, toxic constituents or marker compound(s)”:
this information should be provided when the raw material is not described in a
monograph or when the raw material contents toxic constituents.
2
55 “a macroscopic and microscopic description”: this information should be provided
when the raw material is not described in a monograph or when the monograph is not
enough to detect a falsification of the supplied raw material.

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 Supportive data should be provided:
“Name and address of the supplier and supplier commitment and/or manufacturer
and manufacturer's commitment , if different from the applicant
5 Data on the origin/source of the material
Synthetic or manufacturing route
Production:
- Natural state of plant (wild or cultivated)
- Harvesting location, time of harvesting and, if possible, stage of vegetation
10 - Conditions of cultivation
- Information on pre or post harvest treatment
- Processing, where applicable
- Duration and conditions of storage”

15 3.2.S.2.4 Control of critical steps and intermediates

The applicant is asked to provide the acceptance criteria of all manufacturing parameters
with a range of numerical values, when applicable.
Manufacturing parameters concerning the maceration process: size of cut raw material,
manufacturing formula, mixing conditions, maceration time, filter size…
20
3.2.S.2.5 Process validation and/or evaluation
To be completed if any reference to an official monograph cannot be made.

3.2.S.2.6 Manufacturing process development

25 To be completed if any reference to an official monograph cannot be made.

3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of structure and other characteristics
30 To be completed with relevant information.

3.2.S.3.2 Impurities
To be completed.

35

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 3.2.S.4 Control of drug substance
3.2.S.4.1 Specifications

1) Raw material:
5
If a monograph exists:

Specifications Acceptance criteria

IDENTIFICATION
Macroscopic descriptions See individual monograph

Microscopic descriptions See individual monograph

Further tests can be required See individual monograph

(ex: thin-layer chromatography)
TESTS
Foreign matter (2.8.2) See individual monograph

Loss on drying (2.2.32) See individual monograph

Adulteration See individual monograph

Pesticides (2.8.13) compliance with the requirements for pesticide

residues

Heavy metals (2.4.27) — cadmium: maximum 1.0 ppm;

— lead: maximum 5.0 ppm;
— mercury: maximum 0.1 ppm
(unless otherwise indicated in the monograph)

Aflatoxins (2.8.18) not more than 2 µg/kg of aflatoxin B1

4 µg/kg for the sum of aflatoxins B1, B2, G1
and G2 (unless otherwise indicated in the
monograph)

Radioactive contamination compliance with the requirements for

radioactive contamination

Microbiological quality TAMC: ≤ 107 CFU/g

TYMC: ≤ 105 CFU/g
Escherichia coli:: ≤ 103 CFU/g
Salmonella: absence (25g)
ASSAY See individual monograph

This table is an example. According to the monograph of the raw material, all these
10 specifications are not retaken or other specifications can be required (water (2.2.13),
total ash (2.4.16), bitterness value (2.8.15), ochratoxin A(2.8.22),…)

Foreign matter: The maximum content of foreign matter is indicated in the

15 individual monograph.

Loss on drying: This test is carried out on dried herbal drugs.

If a fresh plant is processed more than 24 h after
harvesting, a test for loss on drying should be carried out.
20 The minimum limit is indicated in the individual monograph.

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 Pesticides and heavy metals: Where justified**, these tests may be performed on the
mother tincture according to the requirements of the
general monograph “Mother tinctures for homoeopathic
5 preparations (2029)”.

Radioactive contamination: In some specific circumstances, the risk of radioactive

contamination is to be considered. Where justified**, this
test may be performed on the mother tincture
10
Microbiological quality, Aflatoxins: these tests can be required in some cases (dried raw
material,..)

Assay: Where applicable, herbal drugs for homoeopathic

15 preparations are assayed by an appropriate method.
An assay is required for all raw materials containing a toxic
substance, and in this case a maximal limit should be fixed
(link with module 4).

20 **for example: fresh raw material having to be processed less than 24 h after
harvesting.

Pesticides, heavy metals and radioactive contamination:

it is acceptable not to perform tests if raw material from biological
25 agriculture (organic certification has to be provided).
Without the precise information concerning the place of origin of the
raw material, it is impossible to know if the soil is not contaminated
by (persistent) pesticides, heavy metals or radioactivity. Therefore if
the needed information cannot be provided, pesticides, heavy metals
30 and radioactivity tests should be retaken in the specifications of the
raw material and should be carried out in routine (see risk
assessment/risk management plan).

If a monograph does not exist:

35 To be completed on the basis of bibliographic references and laboratory data, and taking
into account Ph. Eur. requirements (see monograph Herbal drugs for homoeopathic
preparations, 2045).

40

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 2) Mother tincture:

If a monograph exists:

Specifications Acceptance criteria

IDENTIFICATION
Where applicable, at least 1 chromatographic See individual monograph
identification test is carried out.
TESTS
Relative density (2.2.5) See individual monograph

Ethanol (2.9.10) See individual monograph

Methanol and 2-propanol (2.9.11) See individual monograph

Dry residue (2.8.16) See individual monograph

Pesticides* (2.8.13) and Heavy metals* Limits will be set, taking into
(2.4.27) consideration the nature and the
origin of the herbal drug. The
dilution factor of the mother
tincture and the limit of detection
of the method are also taken into
account when fixing these limits.

Radioactive contamination* compliance with the requirements

for radioactive contamination

Microbiological quality (5.1.4/5.1.8) compliance with the requirements

for microbiological quality
ASSAY See individual monograph
5
This table is an example.
*when not performed on the raw material

Methanol and 2-propanol: tests have to be performed because maceration process can
10 be responsible for the formation thereof.

Relative density and ethanol: If the test for relative density is carried out, the test for
ethanol need not be carried out, and vice versa.

15 Assay: Where applicable, an assay with quantitative limits is

performed.
An assay should be required for all mother tinctures
containing a toxic substance, and in this case a maximal
limit should be fixed (link with module 4).
20

Microbiological quality:
The no routine testing for microbiological quality has to be justified by use
the suitable decision tree of the note for guidance specifications: test
25 procedures and acceptance criteria for new drug substances and new drug
products: chemical substances (CHMP/ICH/367/96).

Ethanol is scientifically accepted to be bactericidal in aqueous mixtures

at concentrations between 60-95% v/v and the optimum concentration

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 is generally considered to be 70 % v/v. Ethanol is however ineffective
against bacterial spores and has a poor penetration of organic matter
(see Ref. EMEA/531300/2008 and EMA/HMPC/41500/2010) no
routine test is justified.
5 For mother tincture with ethanol content between > 20 % (v/v) and <
60 % (v/v): perform the test for efficacy of antimicrobial preservation
and use the suitable decision tree in order to justify a skip testing.

If a monograph does not exist:

10 To be completed on the basis of bibliographic references and laboratory data, and taking
into account Ph. Eur. requirements (see monograph Mother tinctures for homoeopathic
preparations, 2029).

3) Dilutions:
15 Dilutions below the NAT:
See the section 3.2.S.7 Stability

Dilutions above the NAT:

See the generic dossier “dilution”.
20
3.2.S.4.2 Analytical procedures
To be completed if any reference to an official monograph cannot be made.

3.2.S.4.3 Validation of analytical procedures

25 To be completed if any reference to an official monograph cannot be made.

3.2.S.4.4 Batch analysis

Description of batches and results of batch analysis should be provided for raw material
and mother tincture.
30
If the exhaustive list of suppliers cannot be provided (see 3.2.S.2.1), the applicant is
asked to annex to each certificate of analysis of the raw material, the supportive data
concerning the supplier, the geographical origin and the risk analysis/risk management
plan.
35
3.2.S.4.5 Justification of specification
To be completed if any reference to an official monograph cannot be made.

40 3.2.S.5 Reference standards or materials

Information (supplier and supplier reference) on the reference standards or materials
used for example the TLC and the assay of the raw material and the mother tincture
should be provided.

45
3.2.S.6 Container closure system
Description of container closure system(s) used for storage of the raw material and the
mother tincture should be provided. The combination of the container closure
specifications and the raw material/mother tincture stability data may be sufficient to
50 demonstrate suitability of the container closure system for storage of the raw
material/mother tincture.

Certificate of analysis should be provided. The container closure system should comply
with Ph. Eur. monographs concerning materials and containers.
55
The relation between the provided data and the bottles used for storage and stability
studies has to be established.

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 3.2.S.7 Stability
For each batch used for the stability study, the batch size and the type of container
5 closure system including its size have to be mentioned.

1) Raw material:
Stability data or re-testing may also be required for the raw material that is not
processed immediately after testing. This is the case for dried raw material that is stored
10 before use.

2) Mother tincture:
Stability data of the mother tincture and the final dilution should be provided. For the
final dilution, see the document “dilution”.
15
General requirements:
According to the guideline on stability testing: stability testing of existing active
substances and related finished products (CPMP/QWP/122/02), the stability
studies should be conducted on the active substance packaged in a container
20 closure system that is the same as or simulates the packaging proposed for
storage and distribution.
According to the note for guidance on bracketing and matrixing designs for
stability testing of drug substances and drug products (CPMP/ICH/4104/00), the
various characteristics of the container closure system may affect product
25 stability. These characteristics include especially surface area to volume ratio and
headspace to volume ratio.

Usually if different sizes of bottles are used for the storage, the note for guidance on
bracketing and matrixing designs for stability testing of drug substances and drug
30 products (CPMP/ICH/4104/00) should be followed.
According to this note: “Bracketing can be applied to studies of the same container
closure system where either container size or fill varies while the other remains constant.
However, if a bracketing design is considered where both container size and fill vary, it
should not be assumed that the largest and smallest containers represent the extremes
35 of all packaging configurations. Care should be taken to select the extremes by
comparing the various characteristics of the container closure system that may affect
product stability. These characteristics include container wall thickness, closure
geometry, surface area to volume ratio, headspace to volume ratio, water vapour
permeation rate or oxygen permeation rate per dosage unit or unit fill volume, as
40 appropriate”.

Concerning glass bottles and screw caps of the same supplier, the same type, the same
colour, the same range but of different volume:
According to the previous documents, a long term stability study (and an accelerated
45 stability study) should be performed on the smallest and the biggest bottles in order to
accept as storage container closure system all documented glass bottles of this range
with a volume included in the studied volume range.

Nevertheless a stability study concerning only the worst-case scenario (usually the
50 smallest bottle used for storage of the mother tincture including, if applicable, the bottle
used for storage of the mother tincture in the dilution library) could be accepted if
characteristics of each container closure systems used in the stability study are provided.
Concerning the mother tincture stored in glass bottles, two characteristics have to be
taken into account: the surface area to volume ratio and the headspace to volume ratio.
55 These two characteristics are also the ones to take into account and to be compared if it
is envisaged to change the bottle brand.

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 Concerning stainless steel container:
Use of additional stripes of stainless steel in glass bottles cannot be accepted as such as
a method to simulate the storage in stainless steel containers but can be performed to
demonstrate the compatibility of stainless steel with the mother tincture.
5
After it has been demonstrated that glass and stainless steel could be considered both as
inert materials for the storage of a particular MT, these stainless steel containers could be
accepted if their characteristics (surface area to volume ratio and headspace to volume
ratio) are provided and if the worst-case scenario for glass bottle is also applicable to the
10 stainless steel containers.

Results of the retests performed on different batches of different mother tinctures stored
in stainless steel containers can also be considered as suitable data proving the stability
of the mother tincture in these containers.
15
3) Dilutions:
Dilutions below the NAT:
Stability data or a relevant rationale should be provided:
Stability data from homeopathic stocks can be transferable to dilutions / triturations
20 obtained thereof as far as it was demonstrated/justified that the stock is stable in its new
dilution/trituration medium (e.g. when alcohol % is similar to alcohol % of the mother
tincture, when there is absence of interaction with lactose of trituration) and in their
container closure system during the shelf-life fixed for the stock. That is why:
a table containing the stored intermediate dilutions with their solvents of dilution
25 and their container closure system should be provided,
a rationale with the stability relevant parameters concerning the stock should be
provided.

Dilutions above the NAT:

30 See the generic dossier “dilution”.
the dilutions/triturations higher than the No-Assay-Threshold cannot have an expiry date
that exceeds the expiry date of the stock.

35 References and related documents

HMPWG - GUIDANCE ON MODULE 3 OF THE HOMEOPATHIC MEDICINAL PRODUCT

DOSSIER
(HMA-website http://www.hma.eu/uploads/media/HMPWG_dossier_guidance_mod3.pdf)
40

History

Version Date of application Reason for change

1 4/12/2012 Initial version

2 18/02/2013 Correction of editing error (tables)

3 19/09/2013 Disclaimer, clarification, correction

reference guideline
EMEA/531300/2008

45

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