Phytopharmaceuticals/

Herbal medicines
MIP-C05
Drug Regulatory Affairs

Norfatihah Abdullah
Mahtab Uddin Mojumder
Shabnam Rashidpour

hhu.de
 Table of contents

1) General Information

2) Important definitions

3) Requirements for a HMP to enter the EU market

4) Regulatory pathway

5) HMPC and its functions

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 Phytopharmaceuticals/ Herbal medicines

 Plant-derived compounds with pharmacological activities

 Conventional medicines (single chemical entities) ↔ herbal medicines

(complex mixtures/several constituents)

 Complete composition → very difficult to unravel

 Constituents: a function of environmental conditions/ agricultural practices

 In use from historical times → present

3 References: [1], [2] hhu.de

 Important Definitions

any medicinal product, exclusively

containing as active ingredients one
Herbal Medicinal Products or more herbal substances, one or
more herbal preparations, or a
combination of the two

all mainly whole, fragmented or cut

Herbal Substances plants, or parts of plants in an
unprocessed state, usually in dried
form but sometimes fresh

preparations obtained by subjecting

herbal substances to treatments such
Herbal Preparations as extraction, distillation, expression,
fractionation, purification,
concentration, or fermentation

4 References: [3], [4] hhu.de

 General prerequisites for a HMP to enter EU market

• Same requirements as other MPs [7]

• According to GMP, GACP, and Ph. Eur. standards [7]
Quality

• Although plant-based→ risk of adverse effects [6], [8]

• Long-standing use → simplified safety requirements → no need
Safety for pre-clinical tests and clinical trials [3]

• Long-standing use → plausible efficacy→ no need for pre-clinical

tests and clinical trials [3]
Efficacy

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 Regulatory Pathway

Regulatory pathway for herbal

medicinal products

Well-established use
Traditional use marketing Stand-alone or
registration authorisation mixed application

• Article 16a(1) of • Article 10a of • Article 8(3) of

Directive 2001/83/EC Directive 2001/83/EC Directive 2001/83/EC

6 References: [12] hhu.de

 Traditional Use Registration

Criteria: Main Safety & Efficacy requirements:

 no medical supervision • No clinical tests & trials
• Bibliographic data assessment
 with a specified strength & • EU monographs and list entries -
posology
reference material in application
 an oral, external and/or
inhalation preparation Where to apply:
 used as medication: at least 30 • national competent authority
years (at least 15 in the EU)
 sufficient safety data +
plausible efficacy data Pic. source: https://www.ema.europa.eu/en/partners-networks/eu-
partners/eu-member-states/national-competent-authorities-human

Traditional Herbal
Medicinal Product
THMP

7 References: [3], [12], [13], [14], [15] hhu.de

 Well-established Use Marketing Authorisation

Criteria: Where to apply:

• national competent authority
 Well-established use at least 10
years in the EU
 Recognised efficacy +
acceptable level of safety Pic. source: https://www.ema.europa.eu/en/partners-networks/eu-
partners/eu-member-states/national-competent-authorities-human

Or
• EMA
Main Safety & Efficacy requirements:
• No clinical tests & trials Pic. source: https://www.ema.europa.eu/en
• Bibliographic data assessment
• Scientific literature - well-established
use of active substance
• EU monographs - reference material
in application

8 References: [3], [12], [16] hhu.de

 Stand-alone or Mixed Application

Main Safety & Efficacy Where to apply:

• national competent authority
requirements:
• Data from company’s own
development – “stand-alone”
Or Pic. source: https://www.ema.europa.eu/en/partners-networks/eu-
partners/eu-member-states/national-competent-authorities-human
• Combination of own studies +
bibliographic data – “mixed”
Or

• EMA
New active
Pic. source: https://www.ema.europa.eu/en
substance

9 References: [3], [12], [17] hhu.de

 Examples of one HMP with MA & Registration

HMP with registration

(THMP)

Pic. source: https://w ww.inishpharmacy.com/p/pharma-

nord-ginkgo-biloba-60-tablets/pnginkgo60

Ginkgo leaf (Ginkgo biloba L.)

Pic. source: https://w ww.pharmanord.ie/products/ginkgo-biloba

HMP with MA

Pic. Source: https://w ww.stada.de/produkte/ginkgo-stada-240-mg-filmtabletten

10 References: [19], [20] hhu.de
 Examples of HMP with MA & Registration
Ginkgo STADA®/ Germany Ginkgo-Biloba Pharma Nord®/ Denmark
Pharmaceutical form
Film-coated tablets
Active ingredients
Refined dry extract from Ginkgo biloba L., folium (Ginkgo leaf)
Therapeutic indications
HMP for the improvement of (age-associated) THMP for the relief of heaviness of legs and the
cognitive impairment and of quality of life in sensation of cold hands and feet associated with minor
mild dementia circulatory disorders
Posology and route of administration
- Single dose: 120 mg and oral administration - Single dose: 100 mg and oral administration
Pre-clinical safety data
- Test for Chronic toxicity in dogs, showed only Not required as per Article 16c(1)(a)(iii) of Directive
a low toxicity in the highest dosage group. 2001/83/EC.
- Tests on genotoxicity and carcinogenicity are
not available.

11 References: [18], [19], [20] hhu.de

 Examples of HMP with MA & Registration

 Conclusion from HMPC on ginkgo leaf medicines:

12 Reference: [21] hhu.de

 HMPC

 Committee on Herbal Medicinal Products

 established in accordance with Regulation (EC) No 726/2004

 Responsible for compiling and assessing scientific data

 Support harmonization in European market

 Composed of scientific experts in herbal medicines field

13 References: [22] hhu.de

 Role of HMPC

two main tasks

establishing EU monographs covering the drafting an EU list of herbal substances,

therapeutic uses and safe conditions of preparations and combinations thereof
well-established and/or traditional use for for use in traditional herbal medicinal
herbal substances and preparations products.

14 References: [22] hhu.de

 Role of HMPC

 Prepare scientific guidelines and regulatory guidance

 Help companies prepare MA and registration applications

 cooperate with the EDQM on PH. Eur. standards and EMA guidance on the
quality of herbal medicines

 Cooperate with international bodies on harmonization of regulatory

requirements

15 References: [22] hhu.de

 EU Herbal Monograph

 containing scientific opinion on safety & efficacy data from HMPC

 two sections; the well-established use and traditional use

 Based on:
 nonclinical and clinical data

 documented longstanding use & experience in the EU and outside EU

 basis for the required individual medicinal product information such as the
summary of product characteristics (SmPC) and the package leaflet

16 References: [3], [7], [9], [10] hhu.de

 EU Herbal Monograph

 Example of EU herbal monograph

17 References: [18] hhu.de

 HMPC Aiding Pharmaceuticals

 Providing scientific advice and support

 Providing regulatory support

 Providing template for submission of a request

18 References: [24] hhu.de

 References / Literatures
1. Egbuna, C., Mishra, A. P., Goyal M. R. (2020). Preparation of Phytopharmaceuticals for the Management of
Disorders: The Development of Nutraceuticals and Traditional Medicine (1st Edition). Elsevier, 25-38.
2. Calixto JB. (2000). Efficacy, safety, quality control, marketing, and regulatory guidelines for herbal medicines
(phytotherapeutic agents). Braz J Med Biol Res, 33(2):179-89.
3. European Parliament and Council (2021). Directive 2001/83/EC. Accessed on 2022, November 10 st from https://eur-
lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0083-20210526&from=EN
4. Council of Europe (2021). European Pharmacopoeia: Herbal drugs, monograph 1433 (10th Edition). Supplement
10.5. Strasbourg: Council of Europe.
5. European Medicines Agency (n.d.). Herbal medicinal products: scientific guidelines. Accessed on 2022, November
10st from https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-
guidelines/multidisciplinary/herbal-medicinal-products-scientific-guidelines
6. Calapai G. (2008). European legislation on herbal medicines: a look into the future. Drug Saf, 31(5):428-31.
7. Qu L, et al. (2018). European regulation model for herbal medicine: The assessment of the EU monograph and the
safety and efficacy evaluation in marketing authorization or registration in member states. Phytomedicine, 42:219-
225.
8. Barnes J. (2012). Adverse drug reactions and pharmacovigilance of herbal medicines. In Stephens’ detection and
evaluation of adverse drug reactions (6th Edition). Wiley Blackwell, 645-683.

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 References / Literatures
9. European Medicines Agency (n.d.). European Union monographs and list entries. Accessed on 2022, November 10 st
from https://www.ema.europa.eu/en/human-regulatory/herbal-products/european-union-monographs-list-entries
10. Bilia AR, Costa MDC. (2021). Medicinal plants and their preparations in the European market: Why has the
harmonization failed? The cases of St. John's wort, valerian, ginkgo, ginseng, and green tea. Phytomedicine,
81:153421.
11. Shaw D, et al. (2012). Pharmacovigilance of herbal medicine. J Ethnopharmacol, 140(3):513-518.
12. European Medicines Agency (n.d.). Herbal medicinal products. Accessed on 2022, November 10 st from
https://www.ema.europa.eu/en/human-regulatory/herbal-medicinal-products
13. Pulok, K.M. (Ed.) (2015). Evidence-Based Validation of Herbal Medicine Chapter 9 - Harmonization of Regulatory
Requirements in Europe to Ensure Quality, Safety and Efficacy of Herbal Medicinal Products. Elsevier, 201-216.
14. BASG - Federal Office for Safety in Health Care (2019). Herbal Medicinal Products. Accessed on 2022, November
12th from https://www.basg.gv.at/en/companies/marketing-authorisation-life-cycle/faq-marketing-authorisation-life-
cycle/herbal-medicinal-products#c3121
15. European Medicines Agency (n.d.). European Union monographs and list entries. Accessed on 2022, November 12th
from https://www.ema.europa.eu/en/human-regulatory/herbal-products/european-union-monographs-list-entries
16. Federal Institute for Drugs and Medical Devices (n.d.). Bibliographical Application. Accessed on 2022, November
12th from https://www.bfarm.de/EN/Medicinal-products/Licensing/Types-of-marketing-authorisation/Bibliographical-
application/_node.html

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 References / Literatures
17. European Medicines Agency (2014). Questions & Answers on the EU framework for (traditional) herbal medicinal
products, including those from a ‘non-European’ tradition. Accessed on 2022, November 12th from
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/questions-answers-european-union-
framework-traditional-herbal-medicinal-products-including-those-non_en.pdf
18. European Medicines Agency (2015). Final European Union herbal monograph on Ginkgo biloba L., folium. Accessed
on 2022, November 12th from https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-
herbal-monograph-ginkgo-biloba-l-folium_en.pdf
19. STADA (2020). Gebrauchanweisung Ginkgo STADA® 240 mg Filmtabletten. Accessed on 2022, November 12th from
https://www.stada.de/produkte/ginkgo-stada-240-mg-filmtabletten
20. Health Products Regulatory Authority (2022). Ginkgo-Biloba Pharma Nord film-coated tablets. Accessed on 2022,
November 12th from https://www.hpra.ie/img/uploaded/swedocuments/242db281-e9ea-491d-b886-284cbe0cc0c1.pdf
21. European Medicines Agency (n.d.). Ginkgo folium. Accessed on 2022, November 12th from
https://www.ema.europa.eu/en/medicines/herbal/ginkgo-folium
22. European Medicines Agency (n.d.). Committee on Herbal Medicinal Products (HMPC). Accessed on 2022,
November 7th from https://www.ema.europa.eu/en/committees/committee-herbal-medicinal-products-hmpc
23. European Medicines Agency (n.d.). HMPC members. Accessed on 2022, November 10 st from
https://www.ema.europa.eu/en/committees/hmpc/members
24. European Medicines Agency (n.d.). Herbal medicines: regulatory and scientific support. Accessed on 2022,
November 13th from https://www.ema.europa.eu/en/human-regulatory/herbal-products/herbal-medicines-regulatory-
scientific-support
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 Thank you for your
attention!

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