European Medicines Agency

Post-authorisation Evaluation of Medicines for Human Use

London, 26 July 2007

Doc. Ref. EMEA/HMPC/CHMP/CVMP/214869/2006

COMMITTEE ON HERBAL MEDICINAL PRODUCTS

(HMPC)

DRAFT

GUIDELINE ON QUALITY OF COMBINATION HERBAL

MEDICINAL PRODUCTS 1 / TRADITIONAL HERBAL MEDICINAL
PRODUCTS

DRAFT AGREED BY HMPC DRAFTING GROUP ON February 2007

QUALITY

ADOPTION BY HMPC FOR RELEASE FOR PUBLIC 8 March 2007

CONSULTATION

DRAFT AGREED BY CHMP/CVMP QUALITY WORKING 7 June 2007

PARTY

ADOPTION BY CHMP FOR RELEASE FOR PUBLIC 18 June 2007

CONSULTATION

ADOPTION BY CVMP FOR RELEASE FOR PUBLIC 12 July 2007

CONSULTATION

END OF CONSULTATION (DEADLINE FOR COMMENTS) 31 October 2007

Comments should be provided using this template to hmpc.secretariat@emea.europa.eu

Fax +44 20 7418 7051

KEYWORDS Herbal medicinal products; traditional herbal medicinal products; herbal

substances; herbal preparations; combination herbal medicinal products;
HMPC; quality

1
Throughout the guideline and unless otherwise specified, the term “herbal medicinal product” includes “traditional herbal medicinal
product”.

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©EMEA 2007 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
 GUIDELINE ON QUALITY OF COMBINATION HERBAL MEDICINAL PRODUCTS /
TRADITIONAL HERBAL MEDICINAL PRODUCTS

TABLE OF CONTENTS

EXECUTIVE SUMMARY................................................................................................................... 3

1. INTRODUCTION (BACKGROUND) ........................................................................................ 3

2. SCOPE............................................................................................................................................ 4

3. LEGAL BASIS .............................................................................................................................. 4

4. MAIN GUIDELINE TEXT .......................................................................................................... 4

DEFINITIONS ...................................................................................................................................... 8

REFERENCES ...................................................................................................................................... 8

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 1 EXECUTIVE SUMMARY

2 This guideline applies to herbal medicinal products containing combinations of herbal substances
3 and/or herbal preparations 2 . The quality of a combination herbal medicinal product should be
4 guaranteed and demonstrated in accordance with the existing requirements as set out in: Annex I to
5 Directive 2001/83/EC as amended, Annex I to Directive 2001/82/EC as amended and with current
6 EU/ICH guidelines on quality.

7 For some combination products, identification and assay of individual herbal substances / herbal
8 preparations in the herbal medicinal product is difficult to perform and sometimes impossible. In those
9 situations, the specific provisions set out by the existing legislation and guidelines need to be
10 considered further.

11 This guideline addresses in more detail the approaches for identification and quantitative
12 determination of herbal substances and/or herbal preparations in combination herbal medicinal
13 products taking into account their complex composition and the potential for interference in analysis
14 by other herbal substances/preparations present in the herbal medicinal product. In principle, the
15 identity and the quantity of the active substances in the finished product should be demonstrated.
16 Where a comprehensive analysis of each active substance is not possible even when the specific
17 provisions foreseen in existing guidelines are used, specific emphasis may be placed on the validation
18 and design of the manufacturing process and detailed documentation of each critical step in addition to
19 more global tests of identity and of quantity in the finished product. For these products batch-to-batch
20 consistency in quality has to be reached through appropriate manufacture of the herbal medicinal
21 product and in particular in the choice of the in process controls [IPC] and appropriate testing of the
22 finished product. A comprehensive justification should be provided by the applicant for the approach
23 taken.

24 In these situations it is recommended that applicants consult the relevant Competent Authority for
25 further guidance.

26 1. INTRODUCTION (background)
27 Herbal medicinal products can be combinations of herbal substances and/or herbal preparations. In
28 most cases herbal substances are extracted separately and then mixed in the finished product. However
29 in some instances herbal substances are mixed before extraction.
30 In most authorised combination herbal medicinal products only a limited number of active substances
31 are combined. However, following full implementation of the simplified registration procedure for
32 traditional herbal medicinal products for human use, established by Directive 2004/24/EC, it is
33 expected that the number of applications for combination products will increase.
34 It should be noted that the quality of a medicinal product is independent of its use and therefore all
35 general principles of quality and quality guidance are applicable to all herbal medicinal products.
36 Furthermore, the specific herbal quality guidelines are applicable to all herbal medicinal products.
37 However, the complexity of combination products may have an important impact on the quality
38 control measures to be put in place in order to ensure and demonstrate batch-to-batch consistency in
39 quality. Clarification on how the existing requirements should be interpreted in order to demonstrate
40 quality of combination herbal medicinal products is needed.
41 This guideline takes into account the European Pharmacopoeia monographs on herbal substances and
42 herbal preparations.
43

2
The term “herbal substance” should be considered as equivalent to the term “herbal drug” as defined in the
European Pharmacopoeia and the term “herbal preparation” should be considered as equivalent to the term
“herbal drug preparation” as defined in the European Pharmacopoeia.

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44 2. SCOPE
45 This guideline applies to herbal medicinal products containing combinations of herbal substances
46 and/or herbal preparations. The quality, including stability, of a combination herbal medicinal product
47 should in general be guaranteed and demonstrated in accordance with the existing quality guidance.
48 This guideline addresses the approaches for identification and quantitative determination of herbal
49 substances/preparations in combination herbal medicinal products, taking into account the complex
50 composition of the herbal medicinal product. Most combination herbal medicinal products with
51 marketing authorisation have only a limited number of active substances. The specifications are based
52 on the clinical data presented to support the application and full testing is expected in accordance with
53 the current quality guidance. However, in most EU countries the majority of multi-ingredient products
54 are traditional herbal medicinal products. The specifications of a traditional herbal medicinal product
55 are not required to be based on a clinically tested product but are based on a product with a long-
56 standing use. Due to the complexity of multi-ingredient products, compliance with the existing EU
57 guidelines on quality can be difficult to demonstrate. Although this is addressed by specific provisions
58 in existing guidance, additional clarification and practical guidance on interpretation need to be
59 provided.
60 This guideline should be read in conjunction with the “Guideline on quality of herbal medicinal
61 products/traditional herbal medicinal products” (1), “Guideline on specifications: test procedures and
62 acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional
63 herbal medicinal products” (2), Annex 7 “Manufacture of herbal medicinal products” of Good
64 Manufacturing Practices (GMP) for medicinal products, Volume 4, Rules governing medicinal
65 products in the European Union (3), the “Guideline on declaration of herbal substances and herbal
66 preparations in herbal medicinal products/traditional herbal medicinal products in the SPC (4), the
67 “Guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin
68 (5) and the “Concept paper on quality of combination herbal medicinal products / traditional herbal
69 medicinal products” (6).
70 The additional presence of vitamins and/or minerals in traditional herbal medicinal products is not
71 addressed in this guideline. Reference is made in this regard to the general quality guidance for active
72 substances and finished products. It is however clear that the presence of vitamins and/or minerals in
73 traditional herbal medicinal products does not exclude such products from the scope of this guideline.

74 3. LEGAL BASIS
75 This guideline supports applications for marketing authorisations according to Directive 2001/82/EC,
76 as amended and Directive 2001/83/EC, as amended.
77 A simplified registration procedure was established for traditional herbal medicinal products under
78 Directive 2001/83/EC, as amended by Directive 2004/24/EC. This guideline applies equally to
79 traditional herbal medicinal products for human use.

80 4. MAIN GUIDELINE TEXT

81 Herbal medicinal products contain herbal substances/preparations each consisting of a large number of
82 chemical constituents of which only a few may be characterized. Furthermore, herbal substances are
83 natural in origin and consequently their chemical composition varies. In addition, in most cases the
84 constituents responsible for the therapeutic activity are unknown or only partly explained and often
85 markers are used to characterize these products.
86 In herbal medicinal products containing combinations of herbal substances and/or herbal preparations,
87 quality control may be more problematic because, in addition to the above-mentioned difficulties,
88 other herbal substances and/or preparations may interfere with the analysis, e.g. extraction or detection
89 of a marker may be affected by other herbal substances present (co-elution) in the finished product.

90 The quality of a combination herbal medicinal product should in general be guaranteed and
91 demonstrated in accordance with the existing guidance. All relevant parameters should be tested in
92 the finished product and identification and assay of each herbal substance/herbal preparation included
93 in the product are required. The stability of the finished product must be guaranteed. For some

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 94 combination herbal medicinal products, identification and quantification of individual herbal
95 substances/herbal preparations in the product are difficult to perform and sometimes impossible.
96 Clarification on how the requirements on identification and assay should be interpreted is provided
97 below. It should be stressed that notwithstanding the guidance given, all usual analytical methods for
98 identification and assay should be investigated first, e.g. the methods described in the Ph. Eur. General
99 Chapter 2 “Methods of analysis”. Furthermore, each approach taken should be justified by the
100 applicant, and should take into account the combination herbal medicinal product that is subject of the
101 application.

102 If individual active substance testing for identity, assay or to demonstrate stability cannot be
103 performed in the finished product, alternative strategies may be considered. The simple omission of
104 (a) test(s) is not acceptable as the quality of combination herbal medicinal products should be fully
105 comparable to the quality of other (herbal) medicinal products. In this regard, reducing the number of
106 active substances in the herbal medicinal product could increase the possibilities to perform all tests
107 (e.g. identification, assay etc.) in the finished product. As required for all medicinal products, GMP,
108 process validation and batch records documenting each step in the manufacturing process of the
109 finished product and including results of IPC testing should ensure that, in combination with suitable
110 testing criteria, a product of good and consisting quality is obtained. The manufacturing process
111 should, as required for all medicinal products, be designed in such a way that the manufacture and
112 composition of the finished product is well-controlled and conforms with the declared composition.
113 The manufacturing process design should be supported by strict and well-documented process
114 validation. An appropriate IPC testing programme (e.g. testing at various points during the stepwise
115 addition of the herbal substances/preparations) and an identification test of the herbal substance/herbal
116 preparation immediately before the introduction in the manufacturing process of the finished product
117 are measures to ensure the consistent quality and declared composition of the finished product. Each
118 step of the manufacturing process should be regarded as critical and appropriate procedures to ensure
119 correct addition of ingredients should be in place as routine control. Documentation on GMP should
120 be available to the Competent Authorities upon inspection, and manufacturing and process validation
121 data should be submitted in the marketing authorisation/registration dossier.

122 Where a joint assay is performed, the active substance specification should include a (additional, if
123 different from the pharmacopoeial marker) limit for the common marker.

124 Where applicable, the same principles apply to control tests carried out at an intermediate stage of the
125 manufacturing process of the finished product.

126 The following requirements apply for identification and quantitative determination of each active
127 substance in the combination herbal medicinal product:

128 IDENTIFICATION TEST OF EACH ACTIVE SUBSTANCE (read in conjunction with Decision tree
129 # 1: Identification test of each active substance in combination herbal medicinal products)

130 o where constituents with known therapeutic activity or active markers of the herbal substance /
131 preparation are known, the idenfication of the active constituents should be performed in the
132 finished product in accordance with the Guideline on specifications (2).

133 o where constituents with known therapeutic activity or active markers of the herbal
134 substance/preparation are not known:

135 o Each herbal substance/preparation that can be identified should be identified in the
136 finished product in accordance with the Guideline on specifications (2).

137 o Where the herbal substance/preparation cannot be identified in the finished product,
138 appropriate justification and documentation that all usual analytical methods, e.g. the
139 methods described in the Ph. Eur. General Chapter 2 “Methods of analysis”, have
140 been investigated should be provided. Furthermore:

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141 ƒ The identification test of the herbal substance/preparation should be
142 performed as an in process control at the latest point in the manufacturing
143 process of the finished product where analysis is still possible. The approach
144 taken should be fully justified by the applicant. The identification test should
145 be supported by documented evidence on the manufacture of the finished
146 product batch and process validation.

147 In addition, the release specifications of the finished product should include
148 suitable identification methods for the combination, e.g. characteristic
149 fingerprints, in line with the Guideline on specifications (2). The sum of the
150 identification methods should allow appropriate characterisation of the
151 combination.

152 ƒ If IPC testing of the herbal substance/preparation is not possible, it is required

153 that the herbal substance/preparation is identified according to the active
154 substance specifications immediately before the introduction of the active
155 substance in the manufacture of the finished product. The approach taken
156 should be fully justified by the applicant. The identification test should be
157 supported by documented evidence on the manufacture of the finished
158 product batch and process validation.

159 In addition, the release specifications of the finished product should also
160 include suitable identification methods, e.g. characteristic fingerprints in line
161 with the Guideline on specifications (2). The sum of the identification
162 methods should allow appropriate characterisation of the combination.

163 ASSAY OF EACH ACTIVE SUBSTANCE (read in conjunction with Decision tree # 2: Assay of
164 each active substance in combination herbal medicinal products)

165 o where constituents with known therapeutic activity or active markers of the herbal
166 substance/preparation are known,

167 o an individual assay of the active substance should be performed in the finished
168 product in accordance with the Guideline on specifications (2).

169 o If an individual assay of the herbal substance/preparation is not possible, the

170 quantitative determination can be carried out jointly for two or more herbal
171 substances/preparations (e.g. joint determination of group of anthraquinone-
172 derivatives) in accordance with the Guideline on specifications (2).

173 o where constituents with known therapeutic activity or active markers of the herbal
174 substance/preparation are not known:

175 o Each herbal substance/preparation that can be assayed, should be quantified in the
176 herbal medicinal product in accordance with the Guideline on specifications (2).

177 o If an individual assay of the herbal substance/preparation is not possible, the

178 quantitative determination can be carried out jointly for two or more herbal
179 substances/preparations in accordance with the Guideline on specifications (2).

180 An assay of a common marker gives limited information on the relative composition
181 of the concerned herbal substances/preparations in the herbal medicinal product. As
182 such, markers for joint analysis should be carefully selected and justified. If a joint
183 analysis is considered acceptable, the specifications of the concerned herbal
184 substances/preparations should include a (additional, if different from the
185 pharmacopoeial marker) limit for the common marker. The approach taken should be
186 fully justified by the applicant. Each approach should be supported by careful process
187 validation and documentary evidence should be available.

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188 o Where the herbal substance/preparation cannot be quantified in the finished product,
189 appropriate justification and documentation that all usual analytical methods, e.g. the
190 methods described in the Ph. Eur. General Chapter 2 “Methods of analysis”, have
191 been investigated should be provided.

192 Furthermore, an appropriate manufacturing process design, supported by strict and

193 well-documented process validation, should ensure that the manufacture and quality
194 of the finished product is well-controlled and that the composition of the finished
195 product conforms with the declared composition. The manufacturing process
196 development studies (e.g. analytical profiles during the stepwise addition of the herbal
197 substances/preparations, degradation studies during the manufacture of the finished
198 product) and other studies [e.g. stability studies of the active substance(s)] are pivotal
199 in this regard and should underpin the proposed approach to ensure the quality and
200 composition of the finished product e.g. assay of the active substance as IPC. The
201 approach taken should be fully justified by the applicant. Tests should be supported
202 by documented evidence on the manufacture of the finished product batch.

203 In addition, the release and shelf life specification of the combination should include
204 suitable assay methods for the combination in line with the Guideline on
205 specifications (2), including e.g. semi-quantitative fingerprints, allowing a
206 characteristic quantitative determination of the combination.

207 The requirements above apply to the identification and quantification of each herbal
208 substance/preparation in a combination herbal medicinal product. The overall release and shelf life
209 specifications of a combination herbal product will therefore in general be a mixture of tests that
210 individually identify and quantify the herbal substance(s)/preparation(s) in the finished product and/or
211 tests that jointly quantify herbal substances/preparations in the finished product, and all other suitable
212 identification tests and assays that allow an appropriate characterisation and a characteristic
213 quantitative determination of the combination.

214 Stability of the finished product

215 The stability of the combination herbal medicinal product should be determined in accordance with
216 existing guidance on stability and the specific herbal guidelines (1, 2).

217 For a finished product containing herbal substances/preparations where constituents with known
218 therapeutic activity or active markers are known, the appropriate stability of these active constituents
219 must be demonstrated (see also Decision Tree #2).

220 In accordance with the Guideline on the quality of the herbal medicinal product, if a herbal medicinal
221 product contains combinations of several herbal substances and/or herbal preparations, and if it is not
222 possible to determine the stability of each active substance, the stability of the combination has to be
223 demonstrated by appropriate fingerprint chromatograms, appropriate overall methods of assay and
224 physical or other appropriate tests. The appropriateness of the tests shall be justified by the applicant
225 (1).

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226 DEFINITIONS
227 Constituents with known therapeutic activity: are chemically defined substances or groups of
228 substances which are generally accepted to contribute substantially to the therapeutic activity of a
229 herbal substance, a herbal preparation or a herbal medicinal product.
230 Herbal medicinal products: any medicinal product, exclusively containing as active substances one
231 or more herbal substances or one or more herbal preparations, or one or more such herbal substances
232 in combination with one or more such herbal preparations.
233 Herbal preparations: are obtained by subjecting herbal substances to treatments such as extraction,
234 distillation, expression, fractionation, purification, concentration or fermentation. These include
235 comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and
236 processed exudates.
237 Herbal substances: all mainly whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an
238 unprocessed, usually dried form but sometimes fresh. Certain exudates that have not been subjected to
239 a specific treatment are also considered to be herbal substances. Herbal substances are precisely
240 defined by the plant part used and the botanical name according to the binomial system (genus,
241 species, variety and author).
242 In Process Control (IPC): controls performed during manufacture of the finished product in order to
243 monitor and if necessary to adjust the process to ensure that the finished product conforms to its
244 specifications. The control of the environment or equipment may also be regarded as a part of an in
245 process control.
246 Example : testing at various points during the stepwise addition of the herbal substances/preparations
247 Markers: are chemically defined constituents or groups of constituents of a herbal substance, a herbal
248 preparation or a herbal medicinal product which are of interest for control purposes independent of
249 whether they have any therapeutic activity. Markers serve to calculate the quantity of herbal
250 substance(s) or herbal preparation(s) in the Herbal Medicinal product if that marker has been
251 quantitatively determined in the herbal substance(s) or herbal preparation(s) themselves.
252 There are two categories of markers:
253 Active marker: are constituents or groups of constituents which are generally accepted to
254 contribute to the therapeutic activity.
255 Analytical marker: are constituents or groups of constituents that serve for analytical
256 purposes.
257 Specifications: A list of tests, references to analytical procedures, and appropriate acceptance criteria
258 which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of
259 criteria to which a herbal preparation / herbal substance or herbal medicinal product should conform to
260 be considered acceptable for its intended use. "Conformance to specifications" means that the herbal
261 preparation / herbal substance and / or herbal medicinal product, when tested according to the listed
262 analytical procedures, will meet the listed acceptance criteria. Specifications are binding quality
263 standards that are agreed to between the appropriate governmental regulatory agency and the
264 applicant.
265 Traditional herbal medicinal products: are medicinal products for human use that fulfil the
266 conditions laid down in article 16a (1) of Directive 2001/83/EC, as amended.

267 REFERENCES
268 1. ‘Guideline on quality of herbal medicinal products/traditional herbal medicinal products’
269 (CPMP/QWP/2819/00, EMEA/CVMP/814/00, current version).
270 2. ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal
271 preparations and herbal medicinal products/traditional herbal medicinal products’
272 (CPMP/QWP/2820/00, EMEA/CVMP/815/00, current version).

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273 3. Annex 7 “Manufacture of herbal medicinal products” of Good Manufacturing Practices (GMP) for
274 medicinal products, Volume 4, Rules governing medicinal products in the European Union, current
275 version.
276 4. ‘Guideline on declaration of herbal substances and herbal preparations in herbal medicinal
277 products/traditional herbal medicinal products in the SPC’
278 (EMEA/HMPC/CHMP/CVMP/287539/2005, current version)
279 5. ‘Guideline on good agricultural and collection practice (GACP) for starting materials of herbal
280 origin’ (EMEA/HMPC/246816/2005, current version)
281 6. ‘Concept paper on quality of combination herbal medicinal products traditional herbal medicinal
282 products’ (EMEA/HMPC/CHMP/CVMP/58222/2006)

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 Decision tree # 1
Identification test of each active substance in combination herbal medicinal products

Active substance for which

YES constituents with known NO
therapeutic activity or
active markers are
known.
Identification test in
accordance with the
Guideline on
specifications (2).

YES The active

substance can be identified
in the finished product

NO
Identification test
in accordance
with the
Guideline on The active NO
specifications (2). substance can be identified
as in process control

YES
Documented identification Documented identification test of the active
test of the substance by the manufacturer of the finished
active substance as product immediately before introduction
in process control. of the active substance in the
manufacturing process.
AND
AND
Specification of the finished
product also includes
identification tests Specification of the finished product also
suitable to characterise includes identification tests suitable to
the combination. characterise the combination.

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 Decision tree # 2
Assay of each active substance in combination herbal medicinal products

Active substance for

YES which constituents with NO
known
therapeutic activity or
active markers are
known.
An individual
The active
assay can be
substance can be
performed for the
assayed in the
active substance
finished product

YES NO YES NO

Individual assay in Individual assay in

accordance Joint assay of
active substances accordance with
with the the Guideline
Guideline on in accordance
with the on specifications (2)
specifications(2)
Guideline on
specifications(2)

Joint assay of active Joint assay

substances in accordance YES possible of active NO
with the Guideline substances in accordance
on specifications (2) with the Guideline
on specifications (2)
Appropriate manufacturing
process design & validation
to ensure the declared
composition e.g.
documented assay of the
active substance as in
process control

Specifications of the finished product include tests allowing a

characteristic quantitative determination of the combination. AND

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